tap vol 5 issue 17

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

ESMO Congress

Recent discoveries in biology, therapy, and (most importantly) the interplay between

these two have led to groundbreaking advances in chronic lymphocytic leukemia (CLL). These ad-vances underline the impact of the “translational” approach to cancer management in general.

Standard of Care ReconsideredOver the past few decades, CLL therapy has

relied on the use of chemotherapy, more recently combined with antibodies (“chemoimmuno-therapy”). These treatments have become the standard of care in the first-line treatment set-ting, with FCR (fludarabine, cyclophosphamide,

Linking Biology and Therapy in

Chronic Lymphocytic Leukemia

By Stephan Stilgenbauer, MD

Oncology Meetings CoverageBreast Cancer Symposium ��3–10ESMO Congress ��12–25, 32–33Best of ASCO �� 48–54NCCN Hematologic Malignancies Congress ��57–58, 61

Cediranib in Recurrent Cervical Cancer ��14BRAF/MEK Inhibitor Combinations in Melanoma ��16FDA Update �� 26–30Direct From ASCO �� 43–47Lawrence H. Einhorn, MD, on Testicular Cancer ��73Lung Cancer Trials �� 80

MORE IN THIS ISSUE

continued on page 57

NCCN Annual Congress on Hematologic Malignancies

CLEOPATRA: Survival With Dual HER2 Blockade ‘Unprecedented’By Caroline Helwick

In the final overall survival analysis of the phase III CLEOPATRA trial, HER2-positive metastatic breast

cancer patients lived 15.7 months longer if they re-ceived pertuzumab (Perjeta) in addition to trastuzumab (Herceptin) and docetaxel, investigators reported at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1

“The 56.5 months of median overall survival is un-precedented in this indication and confirms the per-tuzumab regimen as the first-line standard of care in HER2-positive metastatic disease,” said Sandra M. Swain, MD, FACP, Medical Director of the Washing-ton Cancer Institute at MedStar Washington Hospital Center in Washington, DC, who reported the find-ings at a press briefing and at the ESMO Presidential Symposium.

“Many of us work our whole career to have this kind of data,” said Dr. Swain. “I’ve been doing this for about 30 years, and I have to say, this is very excit-

ing for me and the patients I treat.”

Luca Gianni, MD, Head of the Department of Medi-cal Oncology at the San Raffaele Scientific Institute in Milan, Italy, who formally discussed the study at the Presidential Symposium, shared Dr. Swain’s enthusi-asm. “These are outstand-ing results,” he said. He added that the study has many strengths, and as for weaknesses, “Frankly, I couldn’t find any.”

“The combination of docetaxel/trastuzumab/pertuzumab is the new standard—not an option—for first-line treatment of HER2-positive metastatic breast cancer,” according to Dr. Gianni.

Sandra M. Swain, MD, FACP

Melanoma Treatment 16, 20 | Beyond R-CHOP for Lymphoma 61 | Head and Neck Carcinoma 70 VOLUME 5, ISSUE 17NOVEMBER 1, 2014



Dr. Stilgenbauer is Associate Professor and Deputy Chairman of the Department of Internal Medicine III, Ulm University, Germany.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

A Harborside Press® PublicationSend your comments to [email protected]

Until the results of randomized trials come out, high-dose melphalan consolidation should be considered the standard of care for all transplant-eligible patients with myeloma.

—Sergio A. Giralt, MD

Experts Debate the Need for Upfront vs Late Stem Cell Transplant in Multiple MyelomaBy Alice Goodman

W ith powerful new drugs capable of achieving sustained and deep remissions in multiple

myeloma, the role of upfront stem cell transplanta-tion is being questioned by experts, who debated the pros and cons at the National Comprehen-sive Cancer Network (NCCN) 9th Annual Con-gress on Hematologic Malignancies, held recently in New York.1

In Defense of Upfront TransplantTaking the pro position, Sergio A. Giralt, MD,

Chief of the Adult Bone Marrow Transplant Service and Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center in New York, maintained, “The preponderance of evidence supports the use of high-dose melphalan and autolo-gous stem cell transplant as upfront consolidation

therapy for myeloma. Until the results of randomized trials come out, high-dose melphalan consolidation should be considered the standard of care for all transplant-eligible patients with myeloma.”

It is agreed that com-plete remission is an im-portant surrogate for

The ASCO Post | NOVEMBER 1, 2014

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropri-ate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices.

Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at [email protected]. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email [email protected] or fax (631) 692-0805.

Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

hibited. For permission inquiries, contact [email protected].

Editorial Mission: The ASCO Post communicates timely in-formation to a broad audience of oncology specialists, help-ing to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Circulation: The ASCO Post is sent free of charge to ap-proximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and he-matologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com.

Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $271;

Canada: $397; Individual International: $523; Institutional Domestic: $335; Canada: $461; Institutional International: $587. Single Copy Domestic: $52; Canada: $59; Interna-tional: $65. Contact [email protected].

Correspondence: Address general inquiries to Harbor-side Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Edi-tor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: [email protected].

Advertising: For information on advertising rates, re-prints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: [email protected].

Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language ap-pears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.”

Advertiser and advertising agency accept and assume li-ability for all content (including text, representations, il-lustrations, opinions, and facts) of advertisements print-ed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards.

The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, in-surrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation inter-ruption of any kind, work slow-down, or any condition be-yond the control of the publisher affecting production or delivery in any manner.

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJame Abraham, MD Cleveland Clinic

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Joseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Health System

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Wisconsin School of Medicine

Harold J. Burstein, MD Dana-Farber Cancer Institute

Robert W. Carlson, MD National Comprehensive Cancer Network

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

Jay S. Cooper, MD Maimonides Medical Center

John Cox, DO Texas Oncology

E. David Crawford, MD University of Colorado

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Bishoy Morris Faltas, MD Weill Cornell Medical College

John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Moffitt Cancer Center

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Michael P. Link, MD Stanford University Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Mary S. McCabe, RN, MA Memorial Sloan Kettering Cancer Center

William T. McGivney, PhD Philadelphia, Pennsylvania

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Lee S. Schwartzberg, MD University of Tennessee Health Science Center

Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Jamie Von Roenn, MD American Society of Clinical Oncology

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

William C. Wood, MD Winship Cancer Institute, Emory University

International EditorsClement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Nagi El-Saghir, MD American University of Beirut, Lebanon

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John F. Smyth, MD University of Edinburgh Edinburgh, Scotland

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff Conor Lynch, Executive Editor [email protected]

Cara H. Glynn, Director of Editorial [email protected]

Andrew Nash, Associate Director of Editorial [email protected]

Jo Cavallo, Senior Editor and Correspondent [email protected]

Susan Reckling, Senior Editor [email protected]

Sarah McGullam, Web Editor [email protected]

Michael Buckley, Art Director [email protected]

Terri Caivano Layout Artist [email protected]

Gail Van Koot, Editorial Coordinator [email protected]

Norman Virtue, Production Manager [email protected]

Shannon Meserve, Circulation Manager [email protected]

Frank Buchner, Chief Technology Officer [email protected]

Leslie Dubin, Vice-President, Director of Sales [email protected]

Anthony Cutrone, President [email protected]

John A. Gentile, Jr, Chairman [email protected]

Contributing Writers:Charlotte Bath, Margot Fromer, Alice Goodman, Caroline Helwick, Susan London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations.

Disclosure information available at ASCOPost.com.

Editorial Board

ASCOPost.com | NOVEMBER 1, 2014 PAGE 3

Breast Cancer Symposium

Novel Agents May Address Endocrine Therapy ResistanceBy Caroline Helwick

P rogress has recently been swift in the development of new drugs to

improve the response to hormone ther-apy in breast cancer, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the Univer-sity of California, San Francisco, Helen Diller Family Comprehensive Can-cer Center. At the 2014 Breast Cancer Symposium in San Francisco, Dr. Rugo described these promising agents and their effect on acquired resistance.

Resistance to endocrine therapy is an impediment in the treatment of breast cancer patients with hormone receptor–positive tumors. This is caused by mul-tiple heterogeneous alterations in the tu-

mor and tumor environment, including “loss” of estrogen receptor–alpha and upregulation of alternative signal trans-duction pathways. The first of these ob-stacles might be tackled through histone deacetylase (HDAC) inhibition, where-as the second might be ameliorated by antagonizing the PI3K/AKT/mTOR pathway (which is altered in up to 50% of estrogen receptor–positive tumors) and blocking cyclin-dependent kinases (CDKs) and growth factor receptors, Dr. Rugo suggested.

The most promising agents for these strategies are inhibitors of the PI3K pathway, CDK 4/6 inhibitors, and HDAC inhibitors, according to Dr. Rugo. She noted, “We still have a des-perate need for biomarkers to identify tumors that are most likely to benefit from these novel approaches.”

Everolimus Plus ExemestaneThe demonstration of a 50% re-

duction in progression when the mTOR inhibitor everolimus (Afinitor) was combined with exemestane in BOLERO-2 led to the U.S. Food and Drug Administration (FDA) approval of this combination in women who had disease progression on nonsteroi-dal aromatase inhibitors.1 Since toxic-

ity can be an issue with everolimus, ef-forts to identify a predictive biomarker have been robust, but futile.2

“But we are making progress,” she emphasized. “We found that we can improve outcome by adding targeted agents. Now, we move to the next steps.”

HDAC Inhibitor Plus Exemestane

The phase II ENCORE 301 trial evaluated exemestane with and without the HDAC inhibitor entinostat in wom-en progressing after treatment with a nonsteroidal aromatase inhibitor.3 The addition of entinostat led to a 10-month improvement in overall survival, from 19.8 months with exemestane alone

to 28.1 months with the combination (hazard ratio [HR] = 0.59, P = .04).

Because of these impressive find-ings, the FDA granted entinostat a Breakthrough Therapy designation. The phase III E2112 trial will further evalu-ate entinostat plus exemestane in 600 metastatic patients. Importantly, prior treatment with everolimus is allowed in this study.

With HDAC inhibition, epigenetic changes may lead to the loss of estrogen receptor–alpha and make it more dif-ficult to inhibit this receptor. Histone deacetylation could boost the reappear-ance of estrogen receptor–alpha tran-scription; it also “opens up” the struc-ture of DNA to turn the relevant genes on, she explained.

PI3K InhibitorsThere is more than one way to tar-

get the PI3K/mTOR pathway, includ-ing the pan-PI3K inhibitor buparlisib (BKM120) and the alpha-specific PI3K inhibitor alpelisib (BYL719), she said.

In a study led by investigators from Vanderbilt University in Nashville, buparlisib shrank tumors in 2 of 20 advanced breast cancer patients and stabilized disease in 6, producing a met-abolic partial response in 18FDG-PET

scans in 9 patients.4 “This is a reasonably well tolerated

and interesting agent, and these excit-ing data have led to a number of trials,” she said. The drug will be evaluated for its differential benefits based on PI3K mutation status.

BELLE-2 has enrolled 1,060 estro-gen receptor–positive, aromatase inhibi-tor–resistant, mTOR inhibitor-naive pa-tients to receive fulvestrant (Faslodex) plus buparlisib or placebo. BELLE-3 will evaluate this combination after pri-or treatment with an mTOR inhibitor. NEOBELLE will evaluate both buparl-isib and alpelisib (alone and in combina-tion), plus letrozole. A phase Ib study of alpelisib alone and in combination with fulvestrant had been completed by the time of the Breast Cancer Symposium, and results of first data were presented at the ESMO Congress in Madrid.

The phase II FERGI trial is evaluat-ing the pan-PI3K inhibitor pictilisib (GDC-0941) in combination with ful-vestrant in women with prior aromatase inhibitor exposure; the arm evaluating GDC-0980, a dual PI3K/mTOR inhib-itor, was closed due to toxicity. The al-pha-specific PI3K inhibitor GDC-0032 is in phase I development.

Cyclin-Dependent KinasesCyclin-dependent kinases, which in-

hibit the tumor suppressor Rb protein, are a very active area of research and drug development. Rb plays a pivotal role in the negative control of the cell cycle. Hyperphosphorylation of Rb is mediated in the G1 phase by CDK4 and CDK6 interacting with cyclin D1, and this results in tumor progression.

Palbociclib, a CDK4/6 inhibitor, induces cell-cycle arrest and allows Rb to bounce back. In breast cancer cell lines, single-agent palbociclib was most inhibitory in luminal and HER2-ampli-fied tumors, a preclinical finding that could help tailor therapy.

In the recent PALOMA-1 trial, the addition of palbociclib to letrozole led to a significant improvement in pro-

gression-free survival, from 10.2 to 20.2 months (HR = .488; P = .0004).5 Based on these results, palbociclib earned a Breakthrough Therapy designation.

Additional trials of palbociclib are underway, including an international registration study of 480 patients in the first-line setting (in combination with letrozole), a phase III trial (in combi-nation with fulvestrant), a postneoad-juvant study (in combination with an aromatase inhibitor), an adjuvant pilot trial in high-risk patients, a study in pa-tients with prior PI3K inhibitor therapy (in combination with fulvestrant or tamoxifen), and others.

Other CDK inhibitors in develop-ment include LEE011, which is being studied in combination with letrozole, with exemestane, with exemestane plus everolimus, and with alpelisib. “Pre-clinical data suggest there is marked synergy for a CDK inhibitor combined with an alpha-specific PI3K inhibitor, so these studies are very interesting,” Dr. Rugo indicated.

Abemaciclib (LY2835219) has also demonstrated single-agent efficacy and a different toxicity profile than palbo-ciclib: less neutropenia but more di-arrhea.6 It is being studied as a single agent in a phase II trial of heavily pre-treated patients, and in combination with fulvestrant in a phase III trial, with an eye toward registration, she said.

FGFR InhibitorsFibroblast growth factor receptor

(FGFR) inhibitors may also prove valu-able in treating resistant tumors. Cur-rently, there are two drugs to watch: dovitinib is being evaluated in a phase II study in combination with fulvestrant in patients with FGFR-amplified and non-amplified tumors, while lucitanib will be studied in a phase II monotherapy trial of patients with FGFR-amplified tumors.

Concluding her talk, Dr. Rugo said, “We have exemestane and everolimus approved in the second and third line for patients with previous exposure to

These studies of novel agents represent a new paradigm in the treatment of metastatic estrogen receptor–positive breast cancer, with more to come.

—Hope S. Rugo, MD

Future Approaches in Endocrine-Positive Disease

■ The development of resistance to endocrine therapy is an obstacle in treating advanced breast cancer patients with hormone receptor–positive disease.

■ Novel agents in development may overcome resistance.

■ The most promising agents for this task are HDAC inhibitors, pan-PI3K inhibitors, alpha-specific PI3K inhibitors, and possibly FGFR inhibitors.

continued on page 4

Breast Cancer



aromatase inhibitors, and we are look-ing forward to the next step. These studies of novel agents represent a new paradigm in the treatment of metastatic estrogen receptor–positive breast can-cer, with more to come.” n

Disclosure: Dr. Rugo receives research funding to UCSF from Novartis, Pfizer, and Lily.

References1. Baselga J, Campone M, Piccart M, et

al: Everolimus in postmenopausal hormone-

receptor–positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

2. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alter-ations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Presented June 3, 2013.

3. Yardley DA, Ismail-Khan RR, Meli-char B, et al: Randomized phase II, dou-ble-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recur-

rent or metastatic estrogen receptor-posi-tive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol 31:2128-2135, 2013.

4. Mayer IA, Abramson VG, Isakoff SJ, et al: Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparl-isib with letrozole in estrogen receptor-posi-tive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin On-col 32:1202-1209, 2014.

5. Finn RS, Crown JP, Lang I, et al: Fi-nal results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase

(CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1; TRIO-18). American Association for Cancer Research Annual Meeting. Abstract CT101. Presented April 6, 2014.

6. Patnaik A, Rosen LS, Tolaney SM, et al: LY2835219, a novel cell cycle inhibitor selec-tive for CDK4/6, in combination with fulves-trant for patients with hormone receptor posi-tive (HR+) metastatic breast cancer. ASCO Annual Meeting. Abstract 534. Presented June 1, 2014.

Endocrine Therapy Resistancecontinued from page 3

What Is the Real Risk of Breast Cancer Associated With Atypical Hyperplasia?By Caroline Helwick

Women with atypical hyperplasia have an absolute risk of about

1% per year for developing breast can-cer—a level of risk that has been un-derappreciated. Not enough is being done to protect these women, accord-ing to Lynn C. Hartmann, MD, Pro-fessor of Oncology at the Mayo Clinic in Rochester, Minnesota.

At the 2014 Breast Cancer Sym-posium, Dr. Hartmann noted that approximately 10% of the 1.3 million benign breast biopsies performed an-nually in the United States are found to have atypical hyperplasia, mak-ing this benign lesion about twice as common as ductal carcinoma in situ. This points to a large population that deserves better risk management, she said.

Fairly Common ConditionAtypical hyperplasia comprises

ductal and lobular subtypes, which occur with similar frequency in the population and carry similar risks for subsequent breast cancer.

In an effort to better understand atypical hyperplasia and to define its associated risks, Dr. Hartmann led a study of 698 women biopsied at the Mayo Clinic between 1967 and 2001 and followed over time.1 At a mean follow-up of 12.5 years, 143 developed breast cancer, translating into an approximate fourfold relative risk for both subtypes, vs the general population.

For both atypical ductal and lobu-lar hyperplasia, ipsilateral cancer was twice as common as contralateral tu-mors, and most (80%) were invasive ductal cancers. The ipsilateral breast is at especially high risk for breast cancer within 5 years of diagnosis, and long-term risk is elevated in both breasts.1

Conventional Risk Stratification Difficult

Conventional risk determination is not very helpful in the atypia popu-lation, including family history, she indicated. In the Mayo Clinic cohort, patients with a positive family history (weak or strong) were no more likely to develop cancer than those with no fam-ily history (P = .23). According to Dr. Hartmann, this makes biologic sense.

“In displaying the phenotype of atypia, the breast tissue has already in-tegrated various exogenous and endog-enous risk exposures, including family history,” she pointed out.

The Gail model and the Tyrer-Cuzick model are also not useful in predicting in-dividual risk. “We compared Gail model

scores for our patients with atypia who developed breast cancer and those who did not and found the scores to be com-pletely superimposable,” she reported.

Within the Mayo Clinic cohort, the number of women with atypia who developed breast cancer was 1.7 times more than the Gail model predicted (P < .001), indicating that the Gail model significantly underestimates breast can-cer risk in this population.2 The Tyrer-Cuzick model, on the other hand, sig-nificantly overestimated the risk and did not accurately distinguish, on an

individual level, between women who developed invasive breast cancer and those who did not.3

“These models are based on epide-miologic risk factors, such as family history. Such risks have driven the de-velopment of atypical hyperplasia and don’t serve to further stratify risk when

the phenotype of atypia is present. I would not suggest using these models in this population,” she said.

Risk Stratification Is PossibleIt is possible, however, to stratify risk

according to the number of atypical foci in the pathology specimen. In the Mayo Clinic cohort, the number of atypical foci was linearly associated with pro-gressive relative risk. Relative risks were 3.19 for women with one focus of dis-ease, 5.53 for those with two foci, and 7.61 for those with three or more.

“It’s like staging cancer: the more there is, the higher the aggressiveness factor. It’s similar with atypical hyper-plasia,” she said.

Putting this information together with other published risk information can be more helpful clinically, as it is not focused on relative risk, which can be confusing to women, but rather, on absolute risk.

Dr. Hartmann described a risk model that incorporates time since biopsy and the number of foci of disease, resulting in a cumulative incidence of breast cancer out to 25 years. At 15 years, for example, the model predicts the risk of breast can-cer at 14% for women with one focus of atypia, 23% for those with two foci, and 34% for those with three or more.

Dr. Hartmann and her colleagues will soon be publishing the full set of these data, the model, and their recom-mendations.

“The most important message is that the cumulative risk of breast cancer [in women with atypical hyperplasia] is about 1% per year, and this is higher than most people have previously appreci-ated,” she said. “If you have information on the number of foci, you can further stratify women into significantly differ-ent risk levels. In our model, in women with multiple foci, we are seeing quite a high cumulative risk of breast cancer.”

The most important message is that the cumulative risk of breast cancer [in women with atypical hyperplasia] is about 1% per year, and this is higher than most people have previously appreciated.

—Lynn C. Hartmann, MD

Atypical Hyperplasia and Breast Cancer Risk

■ Women with atypical hyperplasia—ductal or lobular—have an absolute risk of about 1% per year for developing a later breast cancer.

■ Family history does not enhance this risk, but presence of multiple foci of disease does.

■ Current guidelines may be insufficient in terms of monitoring for and preventing breast cancer in these populations.

■ These patients might be candidates for chemoprevention.

continued on page 5

Breast Cancer



Not Enough Being Done“We are not doing enough for the

more than 100,000 women diagnosed with atypical hyperplasia a year,” Dr. Hartmann maintained.

She pointed out that women with atypical hyperplasia currently do not qualify under several sets of guidelines for screening by magnetic resonance imaging, largely because accurate risk data are lacking. Guidelines by the American Cancer Society, National Comprehensive Cancer Network, and American College of Radiology focus on hereditary risk.

“Most of the published guidelines state only relative risk data for atypi-cal hyperplasia or a lower lifetime risk, such as 15%, which does not qualify

them for screening magnetic resonance imaging. Their high cumulative risk is not yet recognized,” she pointed out.

Chemoprevention is an effective means of reducing risk, based on four pharmacologic intervention trials that also included women with atypia. Women with atypia actually achieved higher relative risk reductions than the high-risk population in general—41% to 70% vs 38%. This makes sense, she added, because the large majority of atypical hyperplasias are positive for the estrogen receptor, and 90% of breast cancers that develop after prior atypia are also estrogen receptor–positive.

In 2013, the ASCO guidelines for breast cancer risk reduction were up-dated to recommend that chemopre-vention be discussed as an option, and the U.S. Preventive Services Task Force

acknowledged a moderate net benefit with tamoxifen/raloxifene in reducing breast cancer risk in high-risk women. The problem is that chemoprevention is used very infrequently in all high-risk subsets, Dr. Hartmann noted.

“Many women are reluctant to use these drugs because of a fear of side ef-fects, but physicians are also reluctant to prescribe them, especially family physi-cians, who report being unfamiliar with the agents and their side-effect profiles,” she offered.

“Chemoprevention in this particular high-risk population should be encour-aged,” she said. For optimal decision-making, patients and physicians need information about the absolute risk of developing breast cancer, the absolute gain from chemoprevention, and the absolute risk of serious side effects.

“Relative risk information does not help us care for these women,” she added. n

Disclosure: Dr. Hartmann reported no potential conflicts of interest.

References1. Hartmann LC, Radisky DC, Frost

MH, et al: Understanding the premalignant potential of atypical hyperplasia through its natural history: A longitudinal cohort study. Cancer Prev Res 7:211-217, 2014.

2. Pankratz VS, Hartmann LC, Degnim AC, et al: Assessment of the accuracy of the Gail model in women with atypical hyper-plasia. J Clin Oncol 26:5374-5379, 2008.

3. Boughey JC, Hartmann LC, Ander-son SS, et al: Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk predic-tion in women with atypical hyperplasia. J Clin Oncol 28:3591-3596, 2010.

Atypical Hyperplasiacontinued from page 4

High-Risk Benign Breast Lesions: Some Patients Can Avoid Surgery By Caroline Helwick

High-risk atypical benign breast lesions are upgraded to cancer in

more than 15% of patients, but the rou-tine excision of such lesions is prob-ably unnecessary. At the 2014 Breast Cancer Symposium in San Francisco, researchers presented information that could guide the selection of patients who might safely avoid surgery.1

Alvaro Peña, MD, and colleagues from the Mayo Clinic, Rochester, Min-nesota, evaluated clinical, imaging, and histologic features associated with can-cer upgrade in cases with atypical ductal hyperplasia in a core needle biopsy and developed a multivariate model to predict this risk. The model was based on a ret-rospective review of patients undergoing surgical excision of atypical ductal hyper-

plasia diagnosed by core biopsy between 2005 and 2013 at the Mayo Clinic.

Of 399 biopsies, 55 were found to be ductal carcinoma in situ and 9 were in-vasive cancers. These 64 lesions yielded an upgrade rate of 16%.

In the multivariate analysis, three fac-

tors related to core biopsy were strongly associated with upgrade: the estimated percentage of lesion removed by imag-ing, presence of individual cell necrosis, and number of foci of atypical ductal hyperplasia. Their prediction model showed an average C-statistic (ie, the area under the receiver operating charac-teristic curve) of 0.77, and was based on the following odds ratios (ORs): • Percentage of lesion removed: with

the reference being > 90% removed, risk was highest among patients with < 50% removed (OR = 3.8) and was moderate (OR = 1.4) for those with 50% to 90% removed (P < .001).

• Presence of individual cell necrosis: compared to patients without necro-sis, upgrade was more likely when biopsies showed individual cell ne-crosis (OR = 4.3, P < .001).

• Number of foci of atypical ductal hyperplasia: compared to patients with just one focus, upgrade was more likely among patients with two or three foci (OR = 2.1) and more than three foci (OR = 3.6, P = .009).

The predictive model showed a sub-group with low risk for upgrade at ex-cision: women with (1) no individual cell necrosis, and (2) either one focus with ≥ 50% removal, or two to three foci with 90% removal. Approximately 32% of the sample met these criteria and 4.9% were upgraded to cancer. In contrast, those not meeting this had an upgrade rate of 21.4%.

“If these findings are validated, wom-en whose biopsies meet low-risk crite-ria might be considered for prevention therapy and surveillance rather than surgical excision,” Dr. Peña suggested.

Lobular Neoplasia: Can Some Patients Avoid Surgery?

Investigators from Virginia Piper Cancer Institute in Minneapolis, Min-nesota, evaluated the need for reexcision among patients with lobular neoplasia diagnosed on core biopsy. Their study aimed to determine the “upgrade” rates in these patients and to identify subsets of those who do not require subsequent surgical excision. The study was present-ed by Barbara Susnik, MD.2

The analysis was based on 13,772 breast core biopsies, of which 373 cases (2.7%) were lobular neoplasia. A final cohort of 302 patients underwent 316 biopsies that revealed classic lobular neoplasia (n = 228), lobular neoplasia with ductal atypia (n = 53), and variant lobular neoplasia (n = 15), including lobular carcinoma in situ with necrosis and pleomorphic lobular carcinoma in situ.

Women whose biopsies meet low-risk criteria might be considered for prevention therapy and surveillance rather than surgical excision.

—Alvaro Peña, MD

continued on page 9

Surgery for High-Risk Benign Breast Lesions

■ A review from the Mayo Clinic found that 16% of patients with high-risk atypical ductal hyperplasia on biopsy were upgraded to cancer.

■ The risk for upgrade was lowest for women whose biopsies did not demonstrate individual cell necrosis, and who had either one focus of disease plus ≥ 50% of lesion removed or at least two foci with 90% of lesions removed.

■ This low-risk profile was characteristic of 32% of patients, of whom 4.9% were upgraded to cancer—a group who might be considered for surveillance and chemoprevention.

■ In another single-institution series, investigators concluded that patients with classic lobular neoplasia have a low rate of upgrade to cancer (3.5%), where the upgrade rate was 27% for the variant lobular neoplasia subset and 28% for patients with ductal atypia.

■ The researchers suggest that patients with classic lobular neoplasia diagnosed on concordant core biopsy targeting calcifications may be able to avoid reexcision.

Breast Cancer

NOW IN THE FIRST LINE FORPATIENTS WITH WT KRAS mCRC

mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fi ssures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of infl ammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening infl ammatory or infectious complications. Dose modifi cations for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated profi ciency in the specifi c technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package

insert for instructions on the identifi cation of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix®

administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fi brosis have been observed in patients treated with Vectibix®. Pulmonary fi brosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confi rmed.

• In patients with a history of interstitial pneumonitis or pulmonary fi brosis, or evidence of interstitial pneumonitis or pulmonary fi brosis, the benefi ts of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the fi rst-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix®

(6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal infl ammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4

• The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone

• Prespecifi ed major effi cacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02)

• Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC• Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm

(n = 331) (HR = 0.83; 95% CI: 0.70, 0.98)• There were no OS or PFS benefi ts in Vectibix®-treated patients with mutant KRAS mCRC

IndicationVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

• As fi rst-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fl uoropyrimidine-, oxaliplatin-, and irinotecan-containing

chemotherapy

Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-afl ibercept) prescribing information, sanofi -aventis.

Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page.

©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1 Visit www.vectibix.com

VECT14CDNY4157_B_NowApproved_KingSz_r15.indd All Pages 6/3/14 6:51 PM

NOW IN THE FIRST LINE FORPATIENTS WITH WT KRAS mCRC

mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fi ssures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of infl ammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening infl ammatory or infectious complications. Dose modifi cations for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated profi ciency in the specifi c technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package

insert for instructions on the identifi cation of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix®

administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fi brosis have been observed in patients treated with Vectibix®. Pulmonary fi brosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confi rmed.

• In patients with a history of interstitial pneumonitis or pulmonary fi brosis, or evidence of interstitial pneumonitis or pulmonary fi brosis, the benefi ts of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In an interim analysis of an open-label, multicenter, randomized clinical trial in the fi rst-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

• NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix®

(6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal infl ammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4

• The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone

• Prespecifi ed major effi cacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02)

• Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC• Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm

(n = 331) (HR = 0.83; 95% CI: 0.70, 0.98)• There were no OS or PFS benefi ts in Vectibix®-treated patients with mutant KRAS mCRC

IndicationVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

• As fi rst-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fl uoropyrimidine-, oxaliplatin-, and irinotecan-containing

chemotherapy

Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-afl ibercept) prescribing information, sanofi -aventis.

Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on adjacent page.

©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1 Visit www.vectibix.com

VECT14CDNY4157_B_NowApproved_KingSz_r15.indd All Pages 6/3/14 6:51 PM

http://www.vectibix.com

Vectibix® (panitumumab) Brief Summary of full PreScriBing information

Warning: Dermatologic toXicityDermatologic toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (nci-ctc grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

inDicationS anD uSagemetastatic colorectal cancerVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing

Information].• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-,

and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information].limitation of useVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information].DoSage anD aDminiStrationPatient SelectionPrior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.recommended DoseThe recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].Dose modificationsDose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion

reaction for the duration of that infusion.• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the

severity and/or persistence of the reaction, permanently discontinue Vectibix®.Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose.• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1

to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.Preparation and administrationDo not administer Vectibix® as an intravenous push or bolus.contrainDicationSNone.WarningS anD PrecautionSDermatologic and Soft tissue toxicityIn Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].increased tumor Progression, increased mortality, or lack of Benefit in Patients with KRAS-mutant mcrcDetermination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®.electrolyte Depletion/monitoringProgressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.infusion reactionsIn Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].acute renal failure in combination with chemotherapySevere diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.Pulmonary fibrosis/interstitial lung Disease (ilD)Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.PhotosensitivityExposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.ocular toxicitiesKeratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapyIn an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.aDVerSe reactionSThe following adverse reactions are discussed in greater detail in other sections of the label:• Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and

Warnings and Precautions (5.1)]• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see

Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]• Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)]• Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)]• Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)]• Photosensitivity [see Warnings and Precautions (5.7)]• Ocular Toxicities [see Warnings and Precautions (5.8)]• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and

Chemotherapy [see Warnings and Precautions (5.9)]clinical trials experienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC.Vectibix® MonotherapyIn Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).table 1: adverse reactions (≥ 5% Difference) observed in Patients treated with Vectibix® monotherapy and Best Supportive care compared to Best Supportive care alone (Study 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.table 2: adverse reactions (≥ 5% Difference) observed in Patients with Wild-type (Wt) KRAS tumors treated with Vectibix® and folfoX chemotherapy compared to folfoX chemotherapy alone (Study 3)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).Infusion ReactionsInfusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].immunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing experienceThe following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.• Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis,

skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]

• Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)]Drug interactionSNo formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.uSe in SPecific PoPulationSPregnancyPregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.nursing mothersIt is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Pediatric useThe safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.geriatric useOf the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.oVerDoSageDoses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.Patient counseling informationAdvise patients to contact a healthcare professional for any of the following:• Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings

and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)]• Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage

and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)]• Diarrhea and dehydration [see Warnings and Precautions (5.5)]• Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings

and Precautions (5.6) and Adverse Reactions (6.1)]• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]Advise patients of the need for:• Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)]• Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for

2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)]• Adequate contraception in both males and females while receiving Vectibix® and for 6 months

after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

Study 1Vectibix® Plus

Best Supportive care(n = 229)


SyStem organ claSS Preferred Term

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

eye DiSorDerSGrowth of eyelashes 13 (6)

gaStrointeStinal DiSorDerSNausea 52 (23) 2 (< 1) 37 (16) 1 (< 1)Diarrhea 49 (21) 4 (2) 26 (11)Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1)Stomatitis 15 (7) 2 (< 1)

general DiSorDerS anD aDminiStration Site conDitionS

Fatigue 60 (26) 10 (4) 34 (15) 7 (3)Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1)

infectionS anD infeStationS Paronychia 57 (25) 4 (2)

reSPiratory, tHoracic, anD meDiaStinal DiSorDerS

Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7)

SKin anD SuBcutaneouS tiSSue DiSorDerS

Erythema 150 (66) 13 (6) 2 (< 1)Pruritus 132 (58) 6 (3) 4 (2) Acneiform dermatitis 131 (57) 17 (7) 2 (< 1) Rash 51 (22) 3 (1) 2 (< 1) Skin fissures 45 (20) 3 (1) 1 (< 1) Exfoliative rash 41 (18) 4 (2) Acne 31 (14) 3 (1) Dry skin 23 (10) Nail disorder 22 (10) Skin exfoliation 21 (9) 2 (< 1)Skin ulcer 13 (6) 1 (< 1)

Vectibix® Plus folfoX(n = 322)

folfoX alone(n = 327)


Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

eye DiSorDerSConjunctivitis 58 (18) 5 (2) 10 (3)

gaStrointeStinal DiSorDerSDiarrhea 201 (62) 59 (18) 169 (52) 29 (9)

Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1)


Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1)Asthenia 79 (25) 16 (5) 62 (19) 11 (3)


inVeStigationS

Weight decreased 58 (18) 3 (< 1) 22 (7)

metaBoliSm anD nutrition DiSorDerS

Anorexia 116 (36) 14 (4) 85 (26) 6 (2)Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1)Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5)

Dehydration 26 (8) 8 (2) 10 (3) 5 (2)


Epistaxis 46 (14) 30 (9)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)


Rash 179 (56) 55 (17) 24 (7) 1 (< 1)Acneiform dermatitis 104 (32) 33 (10)Pruritus 75 (23) 3 (< 1) 14 (4)Dry skin 68 (21) 5 (2) 13 (4)Erythema 50 (16) 7 (2) 14 (4)Skin fissures 50 (16) 1 (< 1) 1 (< 1)Alopecia 47 (15) 30 (9)Acne 44 (14) 10 (3) 1 (< 1)Nail disorder 32 (10) 4 (1) 4 (1)Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14.Vectibix® (panitumumab)Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 USAPatent: http://pat.amgen.com/vectibix/© 2006-2014 Amgen Inc. All rights reserved.v20 05/14

VECT14CDNY4157_B_NowApproved_KingSz_BS_r15.indd 1 6/3/14 6:51 PM



In patients with pure lobular neo-plasia, 20 patients had a synchronous ipsilateral core biopsy containing can-cer. Of these, biopsy sites closely ap-proximated the same quadrant in five patients, and two biopsy sites were in different quadrants in 15 patients. Dis-cordance between imaging and patho-logic assessments was observed in six cases (2.6%).

In the classic lobular neoplasia group, eight patients (3.5%) were upgraded to carcinoma (ductal carci-noma in situ in five and invasive can-cer in three). Seven of these patients were biopsied for calcification. The researchers found no association be-

tween upgrade and high risk (ie, family or personal history), type of pure lobu-lar neoplasia in the core biopsy, calcifi-cations in the core biopsy, and size of targeted calcifications.

In contrast, in the variant group, four (27%) were upgraded, and in the sub-set with lobular neoplasia with ductal atypia, 15 (28%) were upgraded.

“While lobular neoplasia with non-classic morphology or with associated ductal atypia requires surgical excision, this can be avoided in classic lobular neoplasia diagnosed on core biopsy,” Dr. Susnik suggested.

She advised that pathologists as well as radiologists should correlate imaging findings with pathology, and radiolo-gists must critically evaluate the target-

ed calcifications to assure the lesion has been adequately sampled.

These findings led the researchers to recommend surgical excision for pa-tients with:• lobular neoplasia on core biopsy

with discordant findings• lobular neoplasia variants (lobular

carcinoma in situ with necrosis, pleo-morphic lobular carcinoma in situ)

• lobular neoplasia associated with another risk lesion (such as atypical ductal hyperplasia and flat epithelial atypia)

• lobular neoplasia when the imaging target is mass/density/asymmetry on magnetic resonance imaging Based on difficulties in assessing

upgrade, excision should also be con-

sidered for patients having synchro-nous biopsy with carcinoma in the same breast. n

Disclosure: Drs. Peña and Susnik reported no potential conflicts of interest.

References1. Peña A, Fazzio RT, Shah S, et al: A

multivariate model to predict cancer up-grade from atypical ductal hyperplasia by core needle biopsy. Breast Cancer Sympo-sium. Abstract 3. Presented September 5, 2014.

2. Susnik B, Day D, Krueger J, et al: Surgical outcome of lobular neoplasia diagnosed in core biopsy: Prospective study of 316 cases. Breast Cancer Sym-posium. Abstract 4. Presented Septem-ber 5, 2014.

Benign Breast Lesionscontinued from page 5

BRCA Mutations Found in Many Breast Tumors Called ‘ER-Positive’By Caroline Helwick

BRCA mutations may occur in nearly one-third of breast cancer patients

who would have been described as hav-ing triple-negative cancer except that their tumors express low levels of estrogen receptor, so the tumors are described as ER–low positive, according to researchers

from The University of Texas MD Ander-son Cancer Center, Houston, who pre-sented their findings at the 2014 Breast Cancer Symposium in San Francisco.1

“The rate of deleterious BRCA1/2 germline mutations in ER-negative vs ER–low positive (1%–9%) breast can-cer is similar,” reported Rachel Ann Sanford, MD, a medical oncology fel-low at MD Anderson. The reported in-cidence of deleterious germline BRCA mutations in patients with triple-nega-tive tumors is 11% to 24%.

The investigators are recommend-ing, therefore, that BRCA testing be of-fered not just to women under age 60 with tumors that are ER/progesterone receptor–negative and HER2-negative, but also to those with tumors that are ER–low positive.

The 2011 guidelines from ASCO and the College of American Patholo-

gists recommend that breast cancers with estrogen receptor staining as low as 1% on immunohistochemistry be considered ER-positive. This means that guidelines for referring patients to genetic counseling and possible BRCA testing—ie, those under the age of 60

with triple-negative breast cancer—ex-clude patients with ER–low positive tu-mors (those staining at 1% to 9%).

“This may lead to the undertesting of appropriate patients,” Banu Arun, MD, the senior investigator, said in an inter-view with The ASCO Post. Dr. Arun is Professor of Breast Medical Oncology and Co-Director of the Clinical Cancer Genetics program at MD Anderson.

“We still need to test these pa-tients. In our study, 1% to 9% of ER-positive patients had BRCA mutation rates similar to triple-negative patients. And it is thought that biologically these tumors act more like triple-negative tumors,” she said.

Study DetailsTheir study was a review of a pro-

spectively maintained research database of all breast cancer patients seen at MD Anderson between 2004 and 2014. Of these, 1,608 had tumors with estrogen receptor staining < 10% and negative progesterone receptor and HER2 sta-tus. BRCA testing results were obtained for 144 of these patients. Most had been referred for genetic counseling because of family history, Dr. Sanford noted.

There were 22 patients with ER staining of 1% to 9%, and of these, 7 (31.8%) tested positive for a deleteri-ous BRCA germline mutation. This was BRCA1 in 22.7% and BRCA2 in 9.1%. Of the 122 patients with ER < 1% (ie, labeled as ER-negative), 33 patients (27%) had BRCA mutations.

“The incidence of deleterious germ-line BRCA mutations in patients with ER–low positive vs ER-negative breast cancers is not significantly different,” Dr. Sanford reported. “Therefore, we strongly recommend that BRCA test-ing be offered to women under age 60 with tumors that are ER–low positive, in addition to those that are proges-terone receptor–negative and HER2-negative.”

The researchers acknowledged that this study was based on a small popu-lation of patients who may not be rep-resentative of typical breast cancer pa-tients. They would like to validate the findings in larger, more diverse popu-lations to produce “more robust data” that might facilitate a change in the cur-rent guideline, Dr. Arun said.

Interest From the AudienceStuart J. Schnitt, MD, Professor of

Pathology at Harvard Medical School, Boston, found the research provoca-tive and said it clearly has clinical ramifications.

“The issue of what constitutes an ER-positive tumor is a huge clinical problem. I can’t tell you how many

We strongly recommend that BRCA testing continue to be offered to women under age 60 with tumors that are ER–low positive, progesterone receptor–negative, and HER2-negative.

—Rachel Ann Sanford, MD, and colleagues


Banu Arun, MD Stuart J. Schnitt, MD

Breast Tumors With ER ‘Low Positivity’

■ BRCA mutations were identified in 32% of tumors with estrogen receptor staining of 1%–9%, ie, “ER–low positive” tumors.

■ This was a higher rate than that found in ER-negative (ER < 1%) tumors, in a study at The University of Texas MD Anderson Cancer Center.

■ Currently, these women would not be referred for genetic counseling.

■ The investigators recommend genetic counseling and consideration of BRCA testing for women ≤ 60 years old with ER–low positive/progesterone receptor–negative/HER2-negative tumors.

Breast Cancer

Vectibix® (panitumumab) Brief Summary of full PreScriBing information

Warning: Dermatologic toXicityDermatologic toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (nci-ctc grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

inDicationS anD uSagemetastatic colorectal cancerVectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:• As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing

Information].• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-,

and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information].limitation of useVectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information].DoSage anD aDminiStrationPatient SelectionPrior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.recommended DoseThe recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].Dose modificationsDose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion

reaction for the duration of that infusion.• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the

severity and/or persistence of the reaction, permanently discontinue Vectibix®.Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2

doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at the original dose.• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1

to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.Preparation and administrationDo not administer Vectibix® as an intravenous push or bolus.contrainDicationSNone.WarningS anD PrecautionSDermatologic and Soft tissue toxicityIn Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)].increased tumor Progression, increased mortality, or lack of Benefit in Patients with KRAS-mutant mcrcDetermination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®.electrolyte Depletion/monitoringProgressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.infusion reactionsIn Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].acute renal failure in combination with chemotherapySevere diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.Pulmonary fibrosis/interstitial lung Disease (ilD)Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.PhotosensitivityExposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.ocular toxicitiesKeratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapyIn an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.aDVerSe reactionSThe following adverse reactions are discussed in greater detail in other sections of the label:• Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and

Warnings and Precautions (5.1)]• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see

Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]• Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)]• Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)]• Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)]• Photosensitivity [see Warnings and Precautions (5.7)]• Ocular Toxicities [see Warnings and Precautions (5.8)]• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and

Chemotherapy [see Warnings and Precautions (5.9)]clinical trials experienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC.Vectibix® MonotherapyIn Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).table 1: adverse reactions (≥ 5% Difference) observed in Patients treated with Vectibix® monotherapy and Best Supportive care compared to Best Supportive care alone (Study 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®.table 2: adverse reactions (≥ 5% Difference) observed in Patients with Wild-type (Wt) KRAS tumors treated with Vectibix® and folfoX chemotherapy compared to folfoX chemotherapy alone (Study 3)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).Infusion ReactionsInfusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].immunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing experienceThe following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.• Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis,

skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]

• Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)]Drug interactionSNo formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine.uSe in SPecific PoPulationSPregnancyPregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.nursing mothersIt is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Pediatric useThe safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.geriatric useOf the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.oVerDoSageDoses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.Patient counseling informationAdvise patients to contact a healthcare professional for any of the following:• Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings

and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)]• Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage

and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)]• Diarrhea and dehydration [see Warnings and Precautions (5.5)]• Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings

and Precautions (5.6) and Adverse Reactions (6.1)]• Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)]Advise patients of the need for:• Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)]• Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for

2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)]• Adequate contraception in both males and females while receiving Vectibix® and for 6 months

after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

Study 1Vectibix® Plus




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

eye DiSorDerSGrowth of eyelashes 13 (6)

gaStrointeStinal DiSorDerSNausea 52 (23) 2 (< 1) 37 (16) 1 (< 1)Diarrhea 49 (21) 4 (2) 26 (11)Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1)Stomatitis 15 (7) 2 (< 1)


Fatigue 60 (26) 10 (4) 34 (15) 7 (3)Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1)



Dyspnea 41 (18) 12 (5) 30 (13) 8 (3) Cough 34 (15) 1 (< 1) 17 (7)


Erythema 150 (66) 13 (6) 2 (< 1)Pruritus 132 (58) 6 (3) 4 (2) Acneiform dermatitis 131 (57) 17 (7) 2 (< 1) Rash 51 (22) 3 (1) 2 (< 1) Skin fissures 45 (20) 3 (1) 1 (< 1) Exfoliative rash 41 (18) 4 (2) Acne 31 (14) 3 (1) Dry skin 23 (10) Nail disorder 22 (10) Skin exfoliation 21 (9) 2 (< 1)Skin ulcer 13 (6) 1 (< 1)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

eye DiSorDerSConjunctivitis 58 (18) 5 (2) 10 (3)

gaStrointeStinal DiSorDerSDiarrhea 201 (62) 59 (18) 169 (52) 29 (9)

Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1)


Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1)Asthenia 79 (25) 16 (5) 62 (19) 11 (3)


inVeStigationS

Weight decreased 58 (18) 3 (< 1) 22 (7)

metaBoliSm anD nutrition DiSorDerS

Anorexia 116 (36) 14 (4) 85 (26) 6 (2)Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1)Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5)

Dehydration 26 (8) 8 (2) 10 (3) 5 (2)


Epistaxis 46 (14) 30 (9)




Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)


Rash 179 (56) 55 (17) 24 (7) 1 (< 1)Acneiform dermatitis 104 (32) 33 (10)Pruritus 75 (23) 3 (< 1) 14 (4)Dry skin 68 (21) 5 (2) 13 (4)Erythema 50 (16) 7 (2) 14 (4)Skin fissures 50 (16) 1 (< 1) 1 (< 1)Alopecia 47 (15) 30 (9)Acne 44 (14) 10 (3) 1 (< 1)Nail disorder 32 (10) 4 (1) 4 (1)Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14.Vectibix® (panitumumab)Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799 USAPatent: http://pat.amgen.com/vectibix/© 2006-2014 Amgen Inc. All rights reserved.v20 05/14

VECT14CDNY4157_B_NowApproved_KingSz_BS_r15.indd 1 6/3/14 6:51 PM



cases I have seen that under the mi-croscope look basal-like, and when I pick up the ER stain, I am hoping I don’t find ER positivity in the 1% range. I don’t think we are doing these patients a favor by calling them ER-positive,” Dr. Schnitt offered during the discussion.

He said that molecular studies have shown that some of these tumors clus-

ter in basal-like groups and have char-acteristics that are not compatible with ER-positive tumors. “It’s almost like these are the ER equivalent to HER2 2+ tumors,” he suggested. “I almost wonder if we need to find out if they are functionally ER-positive or really triple-negative. The good thing is, they constitute a relatively small proportion of patients.”

Hope S. Rugo, MD, Professor of Medicine and Director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Com-prehensive Cancer Center, also com-mented. “This is a small study, but it’s quite an interesting set of data. If this were a clinical trial, we would say the

findings are ‘hypothesis-generating’ and warrant further study,” she said. “In the setting of something that can have such a huge impact as finding a BRCA mutation, it’s worth consider-ing screening patients with tumors that look triple-negative but have very low ER positivity.” n

Disclosure: Dr. Arun reported no potential

conflicts of interest. Dr. Rugo receives research funding to UCSF from Novartis, Pfizer, and Lily.

Reference1. Sanford RA, Song J, Guiterrez-Bar-

rera AM, et al: High incidence of germline BRCA mutation in patients with ER low positive/PR negative/HER2-neu negative tumors. Breast Cancer Symposium. Ab-stract 2. Presented September 4, 2014.

BRCA and ER Positivitycontinued from page 9

Hope S. Rugo, MD

Important coverage from the upcoming San Antonio Breast Cancer Symposium,

December 9-13, 2014

Coming Soon in

The ASCO Post

For more information, visit www.sabcs.org

COBI-54978_M2_UnbrJrnlAd_Isl.indd10-3-2014 10:54 AM Patricia Lopez / John Sysak

Client CodeClient

LiveOverall TrimBleed

# of Colors

COB/092414/0002Genentech/Cobimetinib

6.925” x 9.25”7.3” x 10”8.2” x 10.75”

4C

Colors Cyan, Magenta, Yellow, Black

FontsTrade Gothic LT Std (Bold No. 2, Regular, Oblique, Bold Condensed No. 20)

Job info Fonts & ColorsImages

Saved at

0.29%

from hsplopez5577 by

Printed At

53858_Thumb_Spring_HR.tif (CMYK; 333 ppi; 90%), BioOnc_WM_R_4C.ai (69%), Gene_Logo_KO_T.ai (73.68%)

Notes None

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.

http://www.gene.com


News

UCSF Study Finds $18 Billion Tobacco Toll in California, 2009

Smoking took an $18.1 billion toll in California in 2009—$487 for each

resident—and was responsible for more than one in seven deaths in the state, more than from AIDS, influenza, diabe-tes, or many other causes, according to the first comprehensive analysis in more

than a decade on the financial and health impacts of tobacco.

While the number of smokers in Cali-fornia declined from a decade ago, and fewer cigarettes were smoked on a daily basis, nearly 4 million people still smoked, including an estimated 146,000 adoles-

cents, reported the new University of Cali-fornia San Francisco (UCSF) study.1

Snapshot of State’s Tobacco UseThe study, a snapshot of tobacco use

throughout the state, was based on data from 2009, the most recent available when

the study began. Similar statewide studies were conducted by the same investigators in 1999 and 1989.

“Studying the economic impact of smoking helps us to better understand how tobacco use affects the entire state and allows us to track changes that have occurred over time,” said Principal Inves-tigator Wendy Max, PhD, Professor of Health Economics at the UCSF School of Nursing and Director of the UCSF Insti-tute for Health & Aging.

“We found that while the California Tobacco Control Program has led to re-ductions in tobacco use in the state over the last decade, smoking is still far too prev-alent and results in far too many deaths and high health-care costs,” she said.

Cigarette smoking is a leading cause of preventable death in the United States, triggering substantial health-care costs and lost productivity from illness and prema-ture death. The toll extends to nonsmok-ers exposed to secondhand smoke who also are known to suffer ill health effects and increased mortality.

In the new report, the UCSF research-ers profiled the state’s 58 counties with to-tal costs, costs per resident and per smok-er, expenditures for each type of health care, smoking prevalence, and mortality measures.

Tobacco Control Policies“County-level estimates of the costs

of smoking help to identify geographic disparities in the economic burden of to-bacco use. These data are useful for local governments and policymakers to devel-op more effective tobacco control policies at the local level,” said coauthor Hai-Yen Sung, PhD, Professor of Health Econom-ics at the UCSF School of Nursing and the UCSF Institute for Health & Aging.

The report found that the state’s tobacco control efforts are resulting in fewer smoking-attributable deaths, reduced real costs of smoking, and low-er smoking prevalence rates compared to a decade ago. Nonetheless, costs remain high and the wide variation in smoking costs across the counties sug-gests that many geographic areas would benefit from targeted efforts to reduce smoking. n

Disclosure: The project was supported by a grant from the Tobacco-Related Disease Research Program of the University of California’s Office of the President.

Reference1. Max W, Sung HY, Shi Y, et al: The Cost

of Smoking in California, 2009. Institute for Health & Aging, School of Nursing University of California, San Francisco. October 2014.

COBI-54978_M2_UnbrJrnlAd_Isl.indd10-3-2014 10:54 AM Patricia Lopez / John Sysak

Client CodeClient


# of Colors

COB/092414/0002Genentech/Cobimetinib

6.925” x 9.25”7.3” x 10”8.2” x 10.75”

4C

Colors Cyan, Magenta, Yellow, Black

FontsTrade Gothic LT Std (Bold No. 2, Regular, Oblique, Bold Condensed No. 20)


Saved at

0.29%

from hsplopez5577 by

Printed At

53858_Thumb_Spring_HR.tif (CMYK; 333 ppi; 90%), BioOnc_WM_R_4C.ai (69%), Gene_Logo_KO_T.ai (73.68%)

Notes None

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.

http://www.biooncology.com


ESMO CongressBreast Cancer

CLEOPATRA DetailsThe CLEOPATRA trial, which en-

rolled 808 patients from 204 centers in 25 countries, evaluated the benefit of dual HER2-blockade in metastatic breast can-cer. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor.

Patients were randomly assigned to trastuzumab and docetaxel plus either pertuzumab or placebo. They received pertuzumab at an 840-mg loading dose, then 420 mg intravenously or placebo ev-ery 3 weeks plus trastuzumab at an 8-mg/kg loading dose, then 6 mg/kg intrave-nously every 3 weeks and docetaxel at 75 mg/m2 intravenously every 3 weeks for at least six cycles (median of eight), with the anti-HER2 agents continued until disease progression.

A previous analysis performed in May 2012 showed that the addition of pertuzumab increased progression-free

survival significantly, to 18.5 months, from 12.4 months with placebo. While a strong trend toward an overall survival benefit was observed, median overall sur-vival had not been reached in the experi-mental arm.

The final survival analysis reported at ESMO, performed after 385 deaths and at a median follow-up of 50 months, showed median overall survival to be 56.5 months in the pertuzumab arm vs 40.8 months in the placebo arm (hazard ratio [HR] = 0.68, P = .0002).

Results Called ‘Phenomenal’“I think these results are phenom-

enal,” remarked Dr. Swain, who is a Past President of ASCO. She noted that median survival with trastuzumab is already good, at nearly 41 months, but adding pertuzumab offers another 16 months of life to these patients. “I’ve

never seen that in any other trial of met-astatic breast cancer,” she said.

In the analysis, the previously dem-onstrated increase in progression-free survival was also sustained, which had formed the basis for the 2012 approval by the U.S. Food and Drug Administra-tion of pertuzumab in combination with trastuzumab and docetaxel in this setting.

Median progression-free survival was 18.7 months vs 12.4 months—an increase of 6.3 months (HR = 0.68, P < .0001).

Dr. Swain commented at an ESMO press briefing that the similarity between the hazard ratios for progression-free and overall survival suggests that, at least for this placebo-controlled trial, “progres-sion-free survival is a good surrogate for overall survival.”

No Increased Cardiac ConcernsSafety, including a lack of cardiac tox-

icity, was also confirmed in the updated

analysis. “There were no new safety con-cerns or cumulative toxicity noted,” she indicated. “The majority of events oc-curred during the docetaxel portion of treatment. The safety data holds up at further follow-up.”

Grade ≥ 3 neutropenia occurred in 46.2% of the placebo arm and 49.0% of the experimental arm. Other grade ≥ 3 adverse events included leukopenia (14.9% vs 12.3%), febrile neutropenia (7.6% vs 13.7%), and diarrhea (5.1% vs 9.3%). Importantly, she said that symp-tomatic left-ventricular dysfunction as well as declines in left-ventricular ejec-tion fraction were rare and were similar

between the arms. Symptomatic declines occurred in

1.8% of the placebo arm and 1.5% of the experimental arm, whereas left-ven-tricular ejection fraction declines to < 50% and by ≥ 10% from baseline were

observed in 7.4% and 6.1%, respectively. One new symptomatic left-ventricular dysfunction event occurred in the per-tuzumab group after 40 months, and re-solved. Left-ventricular ejection fraction declines were reversed in 88% of patients.

“There was a concern that we would see more cardiac events with two mono-clonal antibodies, but we actually saw less,” she reported.

Dual HER2 Blockade for All Patients

Dr. Swain maintained that, based on a consistent benefit across subgroups, virtually all women with HER2-positive metastatic breast cancer should be con-sidered candidates for the pertuzumab/trastuzumab/docetaxel regimen at this point. Future studies are expected to con-firm this, she indicated.

Co-investigator Javier Cortes, MD,

of Vall D’Hebron Institute of Oncology in Barcelona, agreed. “I can see no reason to justify the use of trastuzumab without pertuzumab,” he said.

Dr. Gianni, in his discussion, empha-sized that CLEOPATRA sets a new para-digm for the treatment of HER2-positive metastatic breast cancer “because of the almost 5 years of median overall survival and because patients gain a dramatic im-provement of more than 1 year over the best possible treatment so far.”

The results are in line with the “dramatic improvement” also seen in NeoSphere, the trial he led in the neo-adjuvant setting, where the triplet was associated with a 46% pathologic com-plete response rate. “That was with ex-

actly the same treatment that is a win-ner in CLEOPATRA,” he noted.

“But no matter how big the success, ‘What comes next?’” he asked. “What can we do to improve the therapy of HER2-positive metastatic breast cancer beyond CLEOPATRA’s results?”

Since HER2-positive breast cancer is not a molecularly homogeneous disease, he suggested that improvements can be expected by addressing key features of this subtype linked to different sensitivi-ties: hormone receptor status, PIK3CA status, and immune environment.

For hormone receptor–positive pa-tients, whose outcome to this triplet is less robust than for hormone receptor–negative patients, he suggested testing pertuzumab/trastuzumab plus tamoxi-fen. For patients with PIK3CA-activating mutations, whose prognosis was worse than patients with wild-type disease in CLEOPATRA, the addition of a PIK3CA inhibitor, or the use of ado-trastuzumab emtansine (Kadcyla, formerly known as T-DM1), might be beneficial. Future re-search may also show that the use of the new immunomodulating agents could be of value in addressing resistance to this combination.

Meanwhile, he said, clinicians have a new treatment paradigm to apply to their patients. “CLEOPATRA is an un-questionable therapeutic success,” he stated, “with unquestionable clinical implications.” n

Disclosure: Drs Gianni and Cortes reported no potential conflicts of interest. Dr. Swain has received research funding (via her institution) from Genentech/Roche, is a steering committee member (uncompensated) of Genentech/Roche, received travel expenses from Genentech/Roche, and honorarium from Roche.

Reference1. Swain S, Kim S, Cortes J, et al: Final over-

all survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. ESMO 2014 Con-gress. Abstract 3500. Presented September 28, 2014.

Dual HER2 Blockadecontinued from page 1

The combination of docetaxel/trastuzumab/pertuzumab is the new standard—not an option—for first-line treatment of HER2-positive metastatic breast cancer.

—Luca Gianni, MD

Many of us work our whole career to have this kind of data. I’ve been doing this for about 30 years, and I have to say, this is very exciting for me and the patients I treat.

—Sandra M. Swain, MD, FACP

Javier Cortes, MD

CLEOPATRA Trial Details

■ In the final overall survival analysis of the international phase III CLEOPATRA trial, median overall survival was improved by almost 16 months with dual HER2 blockade.

■ The trial evaluated the addition of pertuzumab to trastuzumab plus docetaxel in 808 HER2-positive metastatic breast cancer patients.

■ Median overall survival was 56.5 months with the combination vs 40.8 months with placebo (HR = 0.68, P = .0002).

■ The combination did not increase the risk for cardiac events.

■ Pertuzumab/trastuzumab/docetaxel might become the standard of care for HER2-positive metastatic breast cancer.

78589-R1-V2_AmgAssist_CKingSize_ASCOPost_July_V2.indd 1 5/27/14 5:45 PM

http://www.amgenassist.com


ESMO Congress

Encouraging Early Signals for Cediranib in Recurrent Cervical Cancer By Alice Goodman

Cediranib (a potent tyrosine ki-nase inhibitor of vascular endo-

thelial growth factor receptor (VEG-FR)-1, -2, and -3) produced a modest improvement in progression-free survival and a robust improvement in response rates compared with placebo when added to chemotherapy in pa-tients with recurrent cervical cancer, according to results of the Cediranib in Recurrent Cervical Cancer (CIRCCa) trial reported at the European Society for Medical Oncology (ESMO) 2014

Congress in Madrid.1

The news from this trial was greeted with cautious optimism, and correla-tive biomarker studies are ongoing in several long-term survivors to deter-mine which patients have the best chance of benefit.

“Cediranib improved progression-free survival and significantly in-creased responses, with a manageable increase in diarrhea, hypertension, and neutropenia. This study has opened up a new avenue of investigation for this difficult-to-treat cancer. I think we have the basis for a phase III trial in the future,” stated Paul Symonds, MD, FRCP, FRCR, Professor in Clinical Oncology, University of Leicester, and consultant oncologist to the Univer-sity Hospitals of Leicester NHS Trust, United Kingdom.

Study DetailsThe majority of patients with cervi-

cal cancer are cured, but those who ex-perience recurrence have a dismal prog-nosis and typically die within 1 year, Dr. Symonds explained. “We know that pa-tients with high levels of tumor angio-genesis are more likely to have a recur-rence after treatment, so it was logical to

study cediranib,” he noted. The study included 69 patients

with histologically proven, relapsed or metastatic cervical cancer unsuit-able for radiation or surgery. Patients were randomly assigned 1:1 to receive carboplatin/paclitaxel with or without oral cediranib. About 70% had some component of pelvic tumor, 30% had extrapelvic disease only, 13% had local disease only, and 57% had both pelvic and local disease.

The primary endpoint was pro-

gression-free survival. Secondary endpoints included change in plasma VEGFR-2 from baseline to 28 days after response to chemotherapy. Six cycles of chemotherapy were delivered in 79% of patients.

The study met the primary endpoint, with a modest increase in progression-free survival, from 30 weeks on placebo to 35 weeks with cediranib. No differ-ence was observed in overall survival, but the study was not powered to detect such a difference, Dr. Symonds noted. Median overall survival was 59 weeks on placebo and 63 weeks on cediranib.

Overall response rate was 66% in the cediranib arm vs 42% in the con-trol arm. “This is a good response rate, and we haven’t seen this in pre-

vious trials,” Dr. Symonds said.Additionally, a marked increase

from baseline in log10 VEGFR expres-sion was observed in the placebo arm, whereas a drop in VEGFR expression was found in the cediranib arm, show-ing that the drug was working as ex-pected.

Long-Term SurvivalDr. Symonds pointed out that al-

though the survival curve for both arms falls precipitously at the begin-ning of the trial, after 1 year, there is a tail in the curve for long-term survivals with no evidence of progression. He noted that there were nine patients in

each arm who were 2-year survivors.“These patients are living without

tumor. It will be important to see what correlative biomarker analysis shows in this group, and this will provide clues for our next group of studies. We hope to have those data early next year,” he noted.

The toxicity was manageable. Diar-rhea was controlled with loperamide, and hypertension was treated with cal-cium channel blockers. Although neu-tropenia was increased in the cediranib arm, no febrile neutropenia or sepsis occurred. No treatment-related deaths were reported in the trial. n

Disclosure: Dr. Symonds reported no potential conflicts of interest. For full disclosures of all study authors, visit www.esmo.org.

Reference1. Symonds P, Gourley C, Davidson S,

et al: CIRCCa: A randomised double blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cer-vical cancer. ESMO 2014 Congress. Ab-stract LBA25_PR. Presented September 28, 2014.

Gynecologic Oncology

EXPERT POINT OF VIEW

Andrés Poveda, MD, Fundación Instituto Valenciano de Oncologia, Valencia, Spain,

who was not involved in the Cediranib in Recur-rent Cervical Cancer (CIRCCa) trial, said that the study provides supportive evidence that adding an antiangiogenic drug is beneficial in recurrent cer-vical cancer. Dr. Poveda moderated the European Society for Medical Oncology (ESMO) session where these data were presented.

“Bevacizumab [Avastin] was recently approved by the [U.S. Food and Drug Administration] for cervical cancer, and that changed clinical practice…. The impact on [progression-free survival] is im-portant, and other trial objectives were reached, such as response rate,” Dr. Poveda said in an ESMO statement.

The hope is that a phase III trial of cediranib will be favorable and that this will be another new treatment for cervical cancer, he said. n

Disclosure: Dr. Poveda reported no potential conflicts of interest.

Cediranib in Cervical Cancer

■ Cediranib added to chemotherapy improved progression-free survival and tumor shrinkage over chemotherapy alone in recurrent cervical cancer, a disease for which there are few good treatment options.

■ Cervical tumors with high levels of angiogenesis have a worse prognosis. Cediranib is a potent angiogenesis inhibitor.

■ In designing phase III trials of cediranib, it will be especially important to identify biomarkers for response in a small group of long-term survivors who remain tumor free.

Andrés Poveda, MD

This study has opened up a new avenue of investigation for this difficult-to-treat cancer. I think we have the basis

for a phase III trial in the future. —Paul Symonds, MD, FRCP, FRCR

Visit The ASCO Post website at ASCOPost.com


ESMO Congress

Rolf A. Stahel, MD

Professor Johann de Bono

Practice-Changing Results at ESMO 2014

A record number of 19,859 attendees at the European Society for Medical

Oncology (ESMO) 2014 Congress dis-cussed changes to oncology that will soon have a positive impact on the care of pa-tients around the world.

“We are particularly pleased to see participants from 131 countries at the congress this year,” said ESMO President Rolf A. Stahel, MD. “The European

Society for Medical Oncology is truly a global congress with growing participa-tion from countries outside Europe, es-pecially the far east.”

Precision Medicine in Cancer Care

A theme of the congress was “pre-cision medicine in cancer care”, said Professor Johann de Bono, from Royal Marsden Hospital and the Institute of Cancer Research, United Kingdom, and Chair of the ESMO 2014 Scientific Com-mittee. “We are increasingly able to target

cancer treatments to the important mo-lecular mechanisms that underpin the malignancy. This is what we mean by pre-cision medicine.”

Scientific highlights of ESMO 2014 in-cluded trials that will change clinical prac-tice very soon, noted Professor de Bono. “We were excited to hear the results of a number of very important studies that will have a direct impact on the way we treat patients in the clinic, in a range of tumor types including lung cancer, breast cancer, and melanoma,” he said. “An improvement in treatment for cancer anorexia and ca-chexia, as reported at this Congress, is also a much-needed advance.”

ESMO has an important role to play in driving further improvements in diagno-

sis, treatment, and care of patients by sup-porting scientific research, said Dr. Stahel. New initiatives include the development of courses on clinical trials to help oncologists who wish to take part in research, and the development of the ESMO Magnitude of Clinical Benefit Scale, which will provide a

means of assessing approved therapies by using important clinical measures.

As part of this goal of facilitating re-search, ESMO will also continue to strengthen its collaborations and connec-tions with other disciplines that are impor-tant in developing new therapies, he said.

“Through these and other initiatives, I am committed to ensuring ESMO uses its power and strength to promote and facilitate clinical and translational re-search in Europe and ultimately to help improve outcomes for our patients,” said Dr. Stahel. n

SAFETY:7”

SAFETY:10”

TRIM:7.875”

TRIM:10.5”

BLEED:8.375”

BLEED:11.125”

Patients (N=286)• Advanced, recurrent, or metastatic ALK-positive NSCLC

Alectinib1

CrizotinibRan

dom

ize

1:1

THIS ADVERTISEMENT PREPARED BY AREA23 Sig Date Time Time Spent Spell Check

Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GenentechProduct: Alectinib Job#: 100173873Colors: 4C Sizes: Bleed: 8.375"” W x 11.125" H

Sm Trim: 7.875" W x 10.5" H Live: 7" W x 10" H Gutter: N/A

Publications:Journal of Thoracic Oncology:

Oncology Times:

The ASCO Post:

Journal of Clinical Oncology:

HEM/ONC Today:

The New England Journal of Medicine:

A Size

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Now enrolling for alectinib

NCT02075840BO28984

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail [email protected].

Primary Endpoint: • Progression-free survival (PFS), investigator-assessed,

by RECIST 1.1

Key Inclusion Criteria2: • Advanced, recurrent, or metastatic ALK-positive NSCLC

• Life expectancy ≥12 weeks

• ECOG performance status of 0-2

• No prior systemic therapy for advanced, recurrent, or metastatic disease

• Measurable disease by RECIST 1.1

Secondary Endpoints: • Objective response rate, investigator-assessed,

using RECIST 1.1

• Time to CNS progression, IRC-assessed, using RECIST 1.1

• PFS, IRC-assessed, using RECIST 1.1

• Duration of response

• Overall survival

• Safety: incidence of adverse events

• AUC of alectinib

• Patient-reported outcomes

Key Exclusion Criteria2: • Prior malignancy in past 3 years

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from a prior therapy

• Baseline QTc >470 ms or symptomatic bradycardia <45 beats per minute

• Concomitant strong cytochrome P4503A inhibitors/inducers or QT-prolonging medications

© 2014 Genentech USA, Inc. All rights reserved. BIO0002445101 Printed in USA.

100173873_GEN_Phase3_JRN_ad_FR.indd 1 8/5/14 11:48 AM



ESMO Congress

BRAF/MEK Inhibitor Combinations Impressive in Melanoma TrialsBy Caroline Helwick

For advanced/metastatic melanoma patients with BRAF mutations, two

pathway inhibitors are better than one, according to studies presented at the European Society for Medical Oncol-ogy (ESMO) 2014 Congress that dem-onstrated improved progression-free and overall survival for regimens com-bining a BRAF inhibitor with an inhibi-tor of the MEK protein.

“The two combination trials presented here today are compelling. We have at least two combination therapies that look bene-ficial,” commented Jeffrey S. Weber, MD, PhD, Senior Member of the Moffitt Can-

cer Center and Director of the Donald A. Adam Comprehensive Melanoma Center in Tampa, Florida, at an ESMO press brief-ing. Dr. Weber presented a separate study of nivolumab vs chemotherapy in previ-ously treated patients, showing that 95% of responders to the immunotherapy were still in remission at 24 weeks.1

The combination of a BRAF inhibi-tor and a MEK inhibitor appears to mitigate the emergence of disease resis-tance that occurs with BRAF inhibition alone and ameliorate cutaneous toxic-ity. The COMBI-v and coBRIM stud-ies, both in previously untreated BRAF

mutation–positive patients and both presented at the ESMO Presidential Symposium, supported these concepts.

“Studies show the combination should be used instead of a BRAF in-hibitor as a single agent. The data are very convincing,” concluded Caroline Robert, MD, PhD, Head of the Derma-tology Unit at the Institut Gustave-Rous-sy, Villejuif, France, at a press briefing.

Dabrafenib Plus TrametinibThe COMBI-v trial compared the

combination of the BRAF inhibi-tor dabrafenib (Tafinlar) at 150 mg

twice daily plus the MEK inhibitor trametinib (Mekinist) at 2 mg/d with vemurafenib (Zelboraf ) monotherapy (960 mg twice daily) in 704 treatment-naive patients with the BRAF V600 mutation.2 Overall survival was the primary endpoint of the study.

“The Independent Data Monitoring Committee recommended stopping the study based on an interim analysis that demonstrated an overall survival benefit that crossed the prespecified ef-ficacy stopping boundary for the com-bination,” announced Dr. Robert at the


Oncologists are now “in the luxury position of having two highly

potent agents to treat BRAF V600–mutated melanoma,” noted Christian Blank, MD, PhD, Group Leader of Immunology at The Netherlands Can-cer Institute, Amsterdam, who dis-

cussed the two papers at the ESMO 2014 Presidential Symposium. How-ever, he added, targeting BRAF alone no longer seems good enough. The initial enthusiasm for BRAF inhibitors was dampened when progression-free survival proved short-lived and relapses occurred rapidly and robustly.

There is strong rationale for dual targeting of the MAP kinase pathway to prevent early tumor “escape” observed

during single BRAF inhibition, which is often associated with reactivation of downstream MEK and ERK and ulti-mately tumor proliferation. Additional blockade of this downstream pathway with MEK inhibitors has now been shown to prolong progression-free sur-

vival. In the two trials presented at the ESMO meeting, the addition of tra-metinib (Mekinist) or cobimetinib to a BRAF inhibitor almost doubled pro-gression-free survival over vemurafenib (Zelboraf) alone, Dr. Blank noted.

Nevertheless, he cautioned, the dif-ferences between the arms in these studies were more striking than what was observed in the phase III COMBI-d trial presented at the 2014 ASCO Annu-

al Meeting. In that study, the dabrafenib (Tafinlar)/trametinib combination improved progression-free survival by only 2 weeks over dabrafenib alone (9.3 vs 8.8 months), although the hazard ra-tio was strong (HR = 0.75; P = .035).1

In the ESMO trials, response rates were almost identical, and progression-free survival was shorter in coBRIM. The hazard ratios were similar, as were the hazard ratios for overall survival.

Adverse event rates and treatment-related discontinuations were similar as well, but the “quality” of the side effects was different. In both studies, adverse events were mainly driven by those observed with the drugs as single com-pounds. With both combinations, a reduction in skin toxicity was observed over vemurafenib alone, Dr. Blank noted.

“The only difference was the fre-quency of serous retinopathy [< 1% in COMBI-v vs 20% in coBRIM], but by trial design, coBRIM mandated more frequent ophthalmologic examina-tions,” he pointed out, adding that this side effect was transient.

New Standard of Care Emerging

“These trials both confirm the idea of combining BRAF and MEK inhibi-tion to improve progression-free surviv-al and response rates, and what we saw is indicative of an overall survival ben-efit. I think that, as we have now seen three phase III trials showing benefit from dual MAP kinase pathway target-ing, this is becoming the new standard therapy for BRAF-mutated melanoma,” Dr. Blank concluded.

He did suggest that the overall sur-

vival benefit from these combinations may ultimately prove less impressive than might be presaged by the progres-sion-free survival differences. If so, there could be several possibilities, including crossover from placebo to the combina-tion, the inclusion of poor-prognosis pa-tients, and rapid deterioration of patients upon progression. It will be “crucial,” he said, to analyze the effect of subsequent treatments in these populations.

At the press briefing, Jeffrey S. Weber, MD, of the Moffitt Cancer Center in Tampa, Florida, agreed with the new emerging paradigm and sug-gested the two BRAF/MEK inhibitor combinations are similar in efficacy.

“The data are more mature from the COMBI-v trial, and dabrafenib plus trametinib is already approved in the United States. This is a terrific combination, but at the end of the day, these are probably relatively similar regimens,” he maintained. “We now have a wealth of options for our pa-tients. It’s great.” n

Disclosure: Dr. Blank has served as an advisor and received honoraria from both Roche and GlaxoSmithKline. Dr. Weber disclosed receiving honoraria from Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, and Abbvie; clinical research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Macrogenics (to Moffitt Cancer Center); serving as an advisor to Ichor Therapeutics, Lion Biotechnologies, and Pieris, and owning stock in Celidex Therapeutics, Altor BioScience, and cCAM Biotherapeutics.

Reference1. Long GV, Stroyakovsky DL, Gogas

H, et al: COMBI-d. ASCO Annual Meet-ing. Abstract 9011. Presented June 1, 2014.

Melanoma

I think that, as we have now seen three phase III trials showing benefit from dual MAP kinase pathway targeting, this is becoming the new standard therapy for BRAF-mutated melanoma.

—Christian Blank, MD, PhD

At the end of the day, these are probably relatively similar regimens. We now have a wealth of options for our patients.

—Jeffrey S. Weber, MD


0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n Su

rviv

ing

Months

Avastin plus chemotherapy (n=227)Chemotherapy alone (n=225)

6 120 18 36 4224 30

3.9-month increasein median OS

(HR=0.74 [95% CI, 0.58–0.94],P=0.0132)

Now Approved in Cervical Cancer for women with persistent, recurrent, or metastatic disease

Avastin plus chemotherapy demonstrated a statistically signi� cant increase in median OS vs chemotherapy alone in the GOG 240 study (16.8 vs 12.9 months)1

IndicationAvastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence

in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 3.2% across

clinical studies — Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious

and fatal complications, is increased in Avastin-treated patients— Do not initiate Avastin for at least 28 days after surgery and until the surgical

wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined

— Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention

Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis,

central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9%

— Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)

— Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included— GI � stulae (up to 2%)— Non-GI � stulae (≤1.8%) — Arterial thromboembolic events (grade ≥3, 2.6%)— Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — GI-vaginal � stulae occurred in 8.2% of patients in a cervical cancer trial — Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent,

recurrent, or metastatic cervical cancer treated with Avastin— Hypertension (grade 3–4, 5%–18%)— Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the � rst dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-speci� c adverse events In CC, grade 3 or 4 adverse reactions in study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal � stula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.CC=persistent, recurrent, or metastatic cervical cancer.Reference: 1. Avastin Prescribing Information. Genentech, Inc. August 2014.

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel.OS=overall survival; HR=hazard ratio; CI=con� dence interval.

©2014 Genentech USA, Inc. All rights reserved. AVA0002613100 Printed in USA. (08/14) www.avastin-hcp.com

77905ha_b.indd 1 9/4/14 10:27 PM

http://www.avastin-hcp.com/#

AVAPTTP-54815A_M2_BS_KgSz.indd8-27-2014 2:23 PM Arthur George / John Sysak

Client CodeClient


# of Colors

AVA0000764007 Genentech/AVASTIN

9.5" x 12.5"10.25" x 13"None

100% K

Colors Black

FontsFrutiger LT Std (67 Bold Condensed, 66 Bold Italic, 57 Condensed, 56 Italic), Frutiger LT Pro (58 Condensed Italic), Universal Std (Greek with Math Pi), Myriad Pro (Regular), Symbol Std (Medium), Optima LT Std (Medium)


Saved at

None

from hsageorge5575 by

Printed At

None

Notes None

Solution for intravenous infusionInitial U.S. Approval: 2004This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.1.3 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]1.4 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.1.5 Persistent, Recurrent, or Metastatic Carcinoma of the CervixAvastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).]

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal Perforations and FistulaeSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients.The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer but were also reported less commonly in patients with other types of cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.2% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).]5.2 Non‑Gastrointestinal FistulaeSerious and sometimes fatal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑marketing experience. Most events occurred within the first 6 months of Avastin therapy.From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae.Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]5.3 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.4 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Venous Thromboembolic EventsPatients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).]

5.7 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.8 Posterior Reversible Encephalopathy Syndrome (PRES)PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).]

5.9 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).]

5.10 Infusion ReactionsInfusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.11 Ovarian FailureThe incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:• Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage

and Administration (2.4), Warnings and Precautions (5.1).]• Non-Gastrointestinal Fistulae [See Dosage and Administration (2.4),

Warnings and Precautions (5.2).]• Surgery and Wound Healing Complications [See Boxed Warning, Dosage

and Administration (2.4), Warnings and Precautions (5.3).]• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4),

Warnings and Precautions (5.4).]• Arterial Thromboembolic Events [See Dosage and Administration (2.4),

Warnings and Precautions (5.5).]• Venous Thromboembolic Events [See Dosage and Administration (2.4),

Warnings and Precautions (5.6).]• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and

Precautions (5.7).]• Posterior Reversible Encephalopathy Syndrome [See Dosage and

Administration (2.4), Warnings and Precautions (5.8).]• Proteinuria [See Dosage and Administration (2.4), Warnings and

Precautions (5.9).]• Infusion Reactions [See Dosage and Administration (2.4), Warnings and

Precautions (5.10)]• Ovarian Failure [See Warnings and Precautions (5.11), Use in Specific

Populations (8.6).]The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data below reflect exposure to Avastin in 4817 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 59 years), 44% male and 85% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of

Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.Surgery and Wound Healing ComplicationsThe incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).]Venous Thromboembolic EventsThe overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.ProteinuriaGrade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

Congestive Heart Failure (CHF)The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.Ovarian FailureThe incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).]Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with

chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

Arm 1 Arm 2 IFL+ Placebo IFL+ Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC:No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis,

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

S:9.5"

S:12.5"

T:10.25"

T:13"

77905ha_b.indd 2 9/4/14 10:27 PM AVAPTTP-54815A_M2_BS_KgSz.indd8-27-2014 2:23 PM Arthur George / John Sysak

Client CodeClient


# of Colors


9.5" x 12.5"10.25" x 13"None

100% K

Colors Black



Saved at

None


Printed At

Gene_Logo_K_T.ai (52.39%)

Notes None

small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8

(Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).Persistent, Recurrent, or Metastatic Carcinoma of the CervixAll grade adverse reactions were collected in Study 9.Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4.

Table 4NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9(Incidence Difference of ≥ 5% Between Treatment Arms in

Chemo + Avastin vs. Chemo Alone)Grade 1‑4 reactions

Grade 3‑4 reactions

Chemo Alone

(n=222)

Chemo+ Avastin(n=218)

Chemo Alone

(n=222)


Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16%General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15%Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16%Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10%Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3%Nervous System Disorders Headache 13% 22% Dysarthria 1% 8%Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6%Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12%Psychiatric Disorders Anxiety 10% 17%Reproductive System and Breast Disorders Pelvic Pain 8% 14%Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17%Renal and Urinary Disorders Proteinuria 3% 10%

Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%).There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone.6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusionEye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: PancytopeniaHepatobiliary disorders: Gallbladder perforationInfections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formationMusculoskeletal: Osteonecrosis of the jawRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphoniaSystemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive PotentialAvastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.11), Adverse Reactions (6.1).]

10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

17 PATIENT COUNSELING INFORMATIONAdvise patients:• To undergo routine blood pressure monitoring and to contact their health

care provider if blood pressure is elevated.• To immediately contact their health care provider for unusual bleeding, high

fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

• Of increased risk of wound healing complications during and following Avastin.

• Of increased risk of an arterial thromboembolic event.• Of the potential risk to the fetus during and following Avastin and the need

to continue adequate contraception for at least 6 months following last dose of Avastin.

• Of the increased risk for ovarian failure following Avastin treatment.

08/14 AVA0000764008 Initial U.S. Approval: February 2004

Code Revision Date: August 2014Avastin® is a registered trademark

of Genentech, Inc. ©2014 Genentech, Inc.

Avastin® (bevacizumab)

Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

S:9.5"

S:12.5"

T:10.25"

T:13"

77905ha_b.indd 3 9/4/14 10:27 PM


press briefing. “We saw a significant im-provement in all endpoints.”

The preplanned interim analysis found a 31% reduction in mortality among patients on the combination, and a 44% reduction in the risk of pro-gression or death, compared to vemu-

rafenib monotherapy. After a median follow-up of 11 months, median over-all survival was 17.2 months with ve-murafenib alone and was not reached in the dabrafenib/trametinib arm (HR = 0.69; P = .005).

“The curves separated early, at 3 months. The P value was clearly below the prespecified boundary (P < .0214),” Dr. Robert noted.

Overall response rates were 64% for the combination (with 13% complete responses) vs 51% for vemurafenib (with 8% complete responses).

Median progression-free survival was 11.4 months for dabrafenib/trametinib recipients and 7.3 months for the vemu-rafenib group (hazard ratio [HR] = 0.56; P < .001); response rates were 64% and 51% (P < .001), and duration of response was 13.8 vs 7.5 months, respectively.

Patients tolerated the combination well, and the rates of adverse events and serious adverse events were gen-erally similar in the two arms. “In fact, grade 3 toxicities were actually lower with the combination (48%) than with single-agent vemurafenib (57%),” Dr. Robert noted.

Cutaneous malignancies occurred in 1% of the experimental arm vs 18% of the vemurafenib arm, and hyperprolif-erative events and photosensitivity were also less frequent with the two drugs.

Vemurafenib Plus CobimetinibVemurafenib (960 mg twice daily)

plus the MEK inhibitor cobimetinib (60 mg/d) was compared to vemu-rafenib alone, in 28-day cycles, in the coBRIM study of 495 treatment-naive patients.3 The data were presented at the meeting by Grant McArthur, MD, Head of the Cancer Therapeutics Pro-

gram at the Peter MacCallum Cancer Centre in Melbourne.

The study’s primary endpoint was met when the combination arm achieved a median progression-free survival of 9.9 months, compared to 6.2 months with vemurafenib alone (HR = 0.51, P < .0001)—a 49% reduction in the risk of progression, according to investigator-assessed review. The in-dependent review analysis was similar (HR = 0.60, P = .0003). Response rates were 68% vs 45% (P < .0001), with complete responses achieved by 10% vs 4%, respectively—differences deemed “striking” by Dr. McArthur.

The interim analysis of overall survival found a 35% reduction in deaths (HR = 0.65; P < .046). Median overall survival was not reached in ei-ther arm, but 9-month survival rates were 81.1% and 72.5%, Dr. McArthur reported.

The toxicity profile was consistent with previous trials. Gastrointestinal side effects were more common with the combination, but were primarily grade 1. Photosensitivity reaction was also more common, but cutaneous squamous cell carcinoma and kera-toacanthomas were significantly less frequent with the two drugs. Serous retinopathy occurred in 51 patients

BRAF/MEK Inhibitorscontinued from page 16

We saw a significant improvement in all endpoints.

—Caroline Robert, MD, PhD

We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma.

—Grant McArthur, MD


ESMO Congress

AVAPTTP-54815A_M2_BS_KgSz.indd8-27-2014 2:23 PM Arthur George / John Sysak

Client CodeClient


# of Colors


9.5" x 12.5"10.25" x 13"None

100% K

Colors Black



Saved at

None


Printed At

None

Notes None

Solution for intravenous infusionInitial U.S. Approval: 2004This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.1.3 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]1.4 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.1.5 Persistent, Recurrent, or Metastatic Carcinoma of the CervixAvastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).]

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal Perforations and FistulaeSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients.The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer but were also reported less commonly in patients with other types of cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.2% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).]5.2 Non‑Gastrointestinal FistulaeSerious and sometimes fatal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑marketing experience. Most events occurred within the first 6 months of Avastin therapy.From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae.Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]5.3 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.4 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Venous Thromboembolic EventsPatients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).]

5.7 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.8 Posterior Reversible Encephalopathy Syndrome (PRES)PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).]

5.9 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).]

5.10 Infusion ReactionsInfusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.11 Ovarian FailureThe incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:• Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage

and Administration (2.4), Warnings and Precautions (5.1).]• Non-Gastrointestinal Fistulae [See Dosage and Administration (2.4),

Warnings and Precautions (5.2).]• Surgery and Wound Healing Complications [See Boxed Warning, Dosage

and Administration (2.4), Warnings and Precautions (5.3).]• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4),

Warnings and Precautions (5.4).]• Arterial Thromboembolic Events [See Dosage and Administration (2.4),

Warnings and Precautions (5.5).]• Venous Thromboembolic Events [See Dosage and Administration (2.4),

Warnings and Precautions (5.6).]• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and

Precautions (5.7).]• Posterior Reversible Encephalopathy Syndrome [See Dosage and

Administration (2.4), Warnings and Precautions (5.8).]• Proteinuria [See Dosage and Administration (2.4), Warnings and

Precautions (5.9).]• Infusion Reactions [See Dosage and Administration (2.4), Warnings and

Precautions (5.10)]• Ovarian Failure [See Warnings and Precautions (5.11), Use in Specific

Populations (8.6).]The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data below reflect exposure to Avastin in 4817 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 59 years), 44% male and 85% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of

Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.Surgery and Wound Healing ComplicationsThe incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).]Venous Thromboembolic EventsThe overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.ProteinuriaGrade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

Congestive Heart Failure (CHF)The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.Ovarian FailureThe incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).]Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with

chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

Arm 1 Arm 2 IFL+ Placebo IFL+ Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC:No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis,

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

S:9.5"

S:12.5"

T:10.25"

T:13"

77905ha_b.indd 2 9/4/14 10:27 PM AVAPTTP-54815A_M2_BS_KgSz.indd8-27-2014 2:23 PM Arthur George / John Sysak

Client CodeClient


# of Colors


9.5" x 12.5"10.25" x 13"None

100% K

Colors Black



Saved at

None


Printed At

Gene_Logo_K_T.ai (52.39%)

Notes None

small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8

(Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).Persistent, Recurrent, or Metastatic Carcinoma of the CervixAll grade adverse reactions were collected in Study 9.Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4.

Table 4NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9(Incidence Difference of ≥ 5% Between Treatment Arms in

Chemo + Avastin vs. Chemo Alone)Grade 1‑4 reactions

Grade 3‑4 reactions

Chemo Alone

(n=222)


Chemo Alone

(n=222)


Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16%General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15%Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16%Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10%Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3%Nervous System Disorders Headache 13% 22% Dysarthria 1% 8%Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6%Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12%Psychiatric Disorders Anxiety 10% 17%Reproductive System and Breast Disorders Pelvic Pain 8% 14%Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17%Renal and Urinary Disorders Proteinuria 3% 10%

Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%).There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone.6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusionEye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: PancytopeniaHepatobiliary disorders: Gallbladder perforationInfections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formationMusculoskeletal: Osteonecrosis of the jawRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphoniaSystemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive PotentialAvastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.11), Adverse Reactions (6.1).]

10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

17 PATIENT COUNSELING INFORMATIONAdvise patients:• To undergo routine blood pressure monitoring and to contact their health

care provider if blood pressure is elevated.• To immediately contact their health care provider for unusual bleeding, high

fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

• Of increased risk of wound healing complications during and following Avastin.

• Of increased risk of an arterial thromboembolic event.• Of the potential risk to the fetus during and following Avastin and the need

to continue adequate contraception for at least 6 months following last dose of Avastin.

• Of the increased risk for ovarian failure following Avastin treatment.

08/14 AVA0000764008 Initial U.S. Approval: February 2004

Code Revision Date: August 2014Avastin® is a registered trademark

of Genentech, Inc. ©2014 Genentech, Inc.

Avastin® (bevacizumab)

Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

S:9.5"

S:12.5"

T:10.25"

T:13"

77905ha_b.indd 3 9/4/14 10:27 PM


ESMO Congress

receiving the combination (20%) vs one patient on vemurafenib mono-therapy.

Toxicities of at least grade 3 were observed in 65% of the combination arm and 59% of the monotherapy arm, and discontinuations due to treatment were similar (approximate-ly 12%).

“This study provides clear and

definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and objective response rates, and our preliminary overall survival analysis is promising,” Dr. McArthur noted at a press briefing. “We are adding a second agent to a very active drug, vemurafenib, and we still get striking results.”

“We anticipate that the combina-tion of a BRAF and MEK inhibitor

will become a new standard treat-ment for advanced BRAF-mutant melanoma,” he said. “The data lay the foundation for the addition of treat-ments, either in sequence or in fur-ther combination, to obtain even bet-ter results.” n

Disclosure: Dr. Weber disclosed receiving honoraria from Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, and AbbVie; clinical research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Macrogenics (to Moffitt Cancer Center); serving as an advisor to Ichor Therapeutics, Lion Biotechnologies, and Pieris, and owning stock in Celldex Therapeutics, Altor BioScience, and cCAM Biotherapeutics. Dr. Robert has received fees for advisory board participation from Bristol-Meyers Squibb, Roche, Merck, GlaxoSmithKline, Novartis, and Amgen. Dr. McArthur has received research support from Roche, Novartis, Pfizer, Millennium, and Celgene and is a consultant for Provectus.

References1. Weber JS, Minor DR, D’Angelo SP,

et al: A phase 3 randomized, open-label study of nivolumab versus investigator’s

choice chemotherapy in previously treat-ed advanced melanoma. ESMO 2014 Congress. Abstract LBA3_PR. Presented September 29, 2014.

2. Robert C, Karaszewska B, Schachter J, et al: COMBI-v: A ran-domized, open-label, phase III study comparing the combination of dab-rafenib and trametinib with vemu-rafenib as first-line therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. ESMO 2014 Congress. Ab-stract LBA4_PR . Presented September 29, 2014.

3. McArthur GA, Ascierto PA, Lar-kin J, et al: Phase 3, double-blind, pla-cebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAF V600 mutation-positive patients with unre-sectable locally advanced or metastatic melanoma. ESMO 2014 Congress. Ab-stract LBA5_PR . Presented September 29, 2014.

BRAF/MEK Inhibitorscontinued from page 19

Dual Targeting in Melanoma Therapy

■ Two phase III trials of metastatic melanoma patients harboring BRAF mutations confirmed the benefit of dual BRAF and MEK pathway blockade.

■ In the phase III COMBI-v trial, dabrafenib plus tremetinib improved survival by 31%, compared with vemurafenib monotherapy, and reduced the risk of progression by 44%.

■ In the coBRIM study, cobimetinib plus vemurafenib reduced the risk of progression by 49%, compared to vemurafenib alone.

■ The combinations were very well tolerated, with a low rate of serious adverse events, and less skin toxicity than was seen with vemurafenib alone.

Nivolumab Yields ‘Impressive’ Duration of Response as Late-Line Melanoma TreatmentBy Caroline Helwick

N ivolumab yielded an “impressive” duration of response when used

as second- or third-line treatment for patients with advanced melanoma, ac-cording to Jeffrey S. Weber, MD, of the Moffitt Cancer Center in Tampa, Florida, who presented preliminary re-sults of a phase III trial at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1

“Here we present a definitive phase III trial of nivolumab in patients who failed prior treatment,” he said at an

ESMO press briefing. “Of 38 patients who responded, 36, or 95%, are ongo-ing at week 24. The vast majority of responders to nivolumab are still in remission. The median duration of re-sponse has not been reached and will certainly be very long.”

Nivolumab is a monoclonal anti-body targeting the programmed death receptor-1 (PD-1) immune checkpoint protein. Based on the findings from this study, nivolumab received a Priority Review designation from the U.S. Food and Drug Administration as a treat-ment for pretreated patients. The drug is already approved for use in Japan.

CA209-037 DetailsThe phase III CA209-037 trial com-

pared nivolumab with dacarbazine or

carboplatin/paclitaxel in previously treated patients with unresectable or metastatic melanoma. Patients in this study had all received the CTLA-4 blocker ipilimumab (Yervoy) and 18% had received the BRAF inhibitor ve-murafenib (Zelboraf). Baseline char-

acteristics were similar except for the fact that the nivolumab arm contained slightly more patients with brain metas-tasis and more with elevated lactate de-hydrogenase (LDH) levels, which have been associated with worse outcomes in melanoma.

The 405 patients were randomly as-signed 2:1 to single-agent nivolumab at 3 mg/kg intravenously every 2 weeks (n = 272) or investigator’s choice of che-motherapy (n = 133). The coprimary endpoints were objective response rates in the first 120 patients after at least 6 months of follow-up (ie, at the planned interim analysis) and overall survival.

High Response Rates, Long Response Duration

At the time of the analysis, the nivolumab arm had a median time on treatment of 5.3 months, compared to

2.0 months in the chemotherapy arm. The percentages discontinuing treat-ment were 52% and 82%, respectively, which was due to progression in 43% and 61%, respectively.

Responses, which were assessed “rigorously” by central review using RECIST 1.1 criteria, Dr. Weber said, were demonstrated by 32% of patients in the nivolumab arm compared to 11% receiving chemotherapy, with complete responses observed in 3% and 0%, re-spectively.

Among responders, 95% had on-going responses after a minimum fol-low-up of 24 weeks; median duration of response was not reached in the nivolumab arm and 3.5 months with chemotherapy. “The vast majority of responders continue in remission,” Dr. Weber noted.

Melanoma

I hope that, at least for second- or third-line therapy, this study is the death knell for chemotherapy in melanoma … and puts to rest the idea that it should be a comparator arm in trials. We now have better drugs.

—Jeffrey S. Weber, MD

Nivolumab in Ipilimumab-Refractory Melanoma

■ As treatment of advanced melanoma patients previously treated with ipilimumab and, in some, a BRAF inhibitor, nivolumab as a single agent produced responses in 32% of patients, compared to 11% of the chemotherapy arm.

■ Among responders, 95% were still in remission after at least 24 weeks of follow-up.

■ Overall survival data are not yet mature.


Fonts: Helvetica Neue LT StdImages: CSP_Background_Journal_AD.psd (CMYK; 236 ppi; Users:elehmann:Desktop:CPS1363...inks:CSP_Background_Journal_AD.psd), Christine Kosel_1876_4c_transp.psd (CMYK; 513 ppi; Users:elehmann:Desktop:CPS1363...Christine Kosel_1876_4c_transp.psd), CPS_Logo_CMYK.eps (Users:elehmann:Desktop:CPS1363...Ad_King_DR:Links:CPS_Logo_CMYK.eps), Celgene_logo_CMYK.eps (Users:elehmann:Desktop:CPS1363...ing_DR:Links:Celgene_logo_CMYK.eps), Icons Phase 2 for dev_300dpi.psd (CMYK; 375 ppi; Users:elehmann:Desktop:CPS1363...s:Icons Phase 2 for dev_300dpi.psd), Top_Shadow_Blue.psd (CMYK; 295 ppi, 194 ppi; Users:elehmann:Desktop:CPS1363..._King_DR:Links:Top_Shadow_Blue.psd)

CPS13632_JournalAd_King_DR.indd Eric Lehmann

app

rova

ls

9-9-2014 2:22 PM _______________

______________

_______________

_______________

_______________

_______________

_______________

Print Scale: NoneInk Density: 300%

Bleed: 11.125" x 14.25"Trim: 10.5" x 13.875"Safety: 9.5" x 13"

Folded Size: NoneGutter: NoneScale: 1" = 1"

Colors: Cyan Magenta Yellow Black

GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE

Job Description: Journal Ad -

King

Job #: CPS13632

Stage: DISK RELEASE

Round: 1

C M Y K

Cosmos Communications 1

1ja

28830a 09.10.14 133

Q1 Q2

Celgene Patient Support® offers you and your patients fi nancial assistance and insurance-related services from a single Specialist assigned to your area. Co-pays for Celgene medications are reduced to $25 or less for eligible patients.

Celgene Patient Support® is a registered trademark of Celgene Corporation.

© 2014 Celgene Corporation 08/14 US-CELG140179a

a Subject to eligibility requirements.

ChristineCelgene Patient Support® Specialist

for personal supportYour single source

Celgene Commercial Co-pay Programa

Financial assistance through third-party organizations

Celgene Free Medication Programa

Help with locating transportation assistance

Call Celgene Patient Support® at 1-800-931-8691Monday – Friday, 8 AM – 7 PM ET

Online enrollment now available at www.celgenepatientsupport.comOr e-mail us: [email protected]

S:9.5”

S:13”T:10.5”

T:13.875”B:11.125”

B:14.25”

https://www.celgene.com/patients/celgene-patient-support/

https://www.celgene.com


ESMO Congress

Responses were observed regard-less of pretreatment PD-L1 [ligand] expression status, BRAF mutation sta-tus, or prior ipilimumab benefit. While response rates were higher (44%) among patients with PD-L1 expres-sion, PD-L1 was not a predictive mark-er, since 20% of PD-L1-negative pa-tients also responded, he pointed out.

In addition, a number of patients continued nivolumab beyond the RECIST-defined progression, and 8% overall experienced at least a 30% re-duction in target lesion tumor burden. Dr. Weber pointed out that RECIST 1.1 does not encompass this delayed benefit accruing with immunotherapy.

Data on overall survival are still pending. Dr. Weber predicted that the long duration of response will ulti-mately translate into prolonged overall survival.

Tolerability Demonstrated “In terms of side effects and toxic-

ity, there was a clear edge for nivolum-ab,” Dr. Weber added.

Grade 3/4 adverse events were much less frequent in the nivolumab arm (9% vs 31%), and there were no nivolumab-related grade 3/4 toxici-ties that were reported by more than 2% of patients. Adverse events of any grade were observed in 68% and 79%, respectively.

“The majority of nivolumab treat-ment–related adverse events were low-grade and manageable using recommend-ed treatment algorithms,” he added.

No More ChemotherapyWhile chemotherapy as a treatment

for melanoma had long been unsatis-

factory to clinicians and patients, Dr. Weber said at the press briefing that CA209-037 will spell the end of che-motherapy in advanced melanoma.

“I haven’t used single-agent dacar-bazine in years or carboplatin/pacli-taxel in many months,” he said. “I hope that, at least for second- or third-line therapy, this study is the death knell for chemotherapy in melanoma … and puts to rest the idea that it should be a

comparator arm in trials. We now have better drugs.” n

Disclosure: Dr. Weber disclosed receiving honoraria from Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, and AbbVie; clinical research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Macrogenics (to Moffitt Cancer Center); serving as an advisor to Ichor Therapeutics, Lion Biotechnologies, and Pieris, and owning stock in Celldex Therapeutics, Altor

BioScience, and cCAM Biotherapeutics.

Reference1. Weber J, Minor D, D’Angelo SP, et al:

A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy in patients with advanced melanoma with prior anti-CTLA-4 therapy. 2014 ESMO Congress. Abstract LBA3_PR. Presented September 29, 2014.


As discussant of the nivolumab paper presented by Weber et al

at the ESMO Presidential Sympo-sium, Ignacio Melero, MD, PhD, of the Universidad de Navarra in Spain, said “We are presented today with

very exciting clinical data. The only disappointment is that the survival data are not mature.”

Dr. Weber reported “a very im-pressive objective response rate of 32%, not including cases that look to me like pseudoprogression,” he said. The adverse event profile of the drug “looks favorable,” he add-ed, and he was particularly encour-

aged by the lack of pneumonitis. The study population, the response

rate and the safety profile are similar to that recently described for the anti–PD-1 agent pembrolizumab (Keytru-da) in ipilimumab (Yervoy)-refractory

patients,1 he noted. In that phase I study, the response rate was 26% and the overall survival was “impressive,” he said, “not reaching the median over-all survival at 14 months.”

Tip of the IcebergShowing a Kaplan-Meier curve of

progression-free survival, he com-mented, “We have now to focus on

the area over the curve, because it is made of death, pain, and suffering. It is likely that at least part of that area will be addressable by immuno-therapy…. I believe that melanoma treatment with anti–PD-1 is only the tip of the iceberg…. The trend one can foresee is that we will be mov-ing PD-1 blockade up front in treat-ment…. The best is yet to come, particularly with combinations in immunotherapy.”

Dr. Melero remarked in closing, “From this exciting ESMO Congress, it is clear that the main conclusion is this: immunotherapy of cancer is no longer a quixotic task.” n

Disclosure: Dr. Melero has served as an advisor to Bristol-Myers Squibb, Roche/Genentech, and AstraZeneca.

Reference1. Robert C, Ribas A, Wolchok JD, et

al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipili-mumab-refractory advanced melanoma: A randomized dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014.

From this exciting ESMO Congress, it is clear that the main conclusion is this: immunotherapy of cancer is no longer a quixotic task.

—Ignacio Melero, MD, PhD

Nivolumab in Melanomacontinued from page 20

Don’t Miss These Important Reports in This Issue of The ASCO Post

Jamie Ostroff, PhD, on e-cigarettes among patients with cancer see page 37

Avraham Eisbruch, MD, on cetuximab and chemoradiation for advanced head and neck cancer see page 71

Peter Paul Yu, MD, FACP, FASCO on transforming data into learning see page 44

Andrew D. Zelenetz, MD, PhD, on diffuse large B-cell lymphoma see page 62

Lawrence H. Einhorn, MD, on treating testicular cancer in 2014 see page 73

Priyanka Sharma, MD, on advancements in treating breast cancer see page 48

Visit The ASCO Post online at ASCOPost.com


ESMO Congress

Women Underrepresented in Oncology Leadership Positions, Greek Survey Shows

A growing number of oncologists in Greece are female, but wom-

en continue to be underrepresented in leadership positions, according to a survey reported at the ESMO 2014 Congress.

“In Greece, and across Europe, women oncologists still find it hard to access leadership or academic positions,” said Helena Linardou, MD, Associate Director of the First Department of Oncology at the Met-ropolitan Hospital, Athens, Greece, who presented the survey results.

‘This Needs to Change’“Women are indeed increasingly

choosing oncology specialties in Greece, however, most decision-making posts are still dominated by men across the profession, in pri-vate practice, academia, and national health environments. This needs to change,” she said.

The survey of 80 female members of the Hellenic Societies of Medical, Radiation, and Surgical Oncology showed that while women were wide-ly represented in workplaces, team leaders were men in 82% of cases.

“The survey also showed that women oncologists are hugely un-derrepresented in international sci-entific meetings and scientific soci-ety boards and still have difficulties travelling abroad and accessing edu-cation opportunities at the interna-tional level,” Dr. Linardou said.

Forum of WomenThe study was conducted as part

of a European initiative of and for fe-male oncology professionals, known as “Women for Oncology” (W4O),1 launched by the European Society for Medical Oncology in 2013.

The Greek national equivalent, called ‘W4O-Hellas,’ aims to create a support network for female oncolo-gists, but also to provide a platform of direct communication and essen-tial contribution from women doc-tors to women cancer patients, Dr. Linardou said.

“This forum of women will pro-mote the interaction and exchange of ideas among women oncologists in Greece and across Europe and will embrace and assist them through-out their career in oncology. The novelty, however, is that at the same

time, this forum will offer advice, awareness, and support directly from women oncologists to women suffer-ing from cancer and their families in Greece.” n

Disclosure: Dr. Linardou reported no potential conflicts of interest.

Reference1. Linardou H, Christopoulou A,

Agelaki S, et al: Women 4 Oncology in

Greece: Exploring common challenges. Survey of the Hellenic Society of Medi-cal Oncology Among Women Oncol-ogy Professionals. ESMO 2014. Abstract 1082O. Presented September 28, 2014.

Oncology Worldwide

Primary Endpoint: • Objective survival

Secondary Endpoints: • Safety: incidence of adverse events

• Overall response rate

• Progression-free survival

• Duration of response

Key Inclusion Criteria2: • Locally advanced or metastatic NSCLC

(stage IIIB, stage IV, or recurrent)

• Representative FFPE tumor specimens

• Disease progression during or following platinum-containing treatment regimen

• Measurable disease, defined by RECIST v1.1


Key Exclusion Criteria2: • History of autoimmune disease

• Active hepatitis B or hepatitis C

• Prior treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

Patients with locally advanced ormetastatic NSCLC who have failed platinum-containing chemotherapy

Now Enrolling

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.


A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)OAK

MPDL3280A1

(an engineered anti-PDL1 antibody)

Docetaxel

N=850Randomized 1:1

Visit: clinicaltrials.gov or

antiPDL1ClinicalTrials.com/hcp

For more information



Call: Genentech Trial Information

Support Line: 1-888-662-6728 (US only)

E-mail: [email protected]

77659ha_h.indd 1 7/29/14 11:19 PM



ESMO Congress

Novel Oral Agent Treats Cachexia in Patients With Non–Small Cell Lung CancerBy Alice Goodman

For the first time, studies show that a drug is effective in treating several

domains of cancer-related cachexia. Oral anamorelin increased lean body mass, achieved weight gain, and improved qual-ity of life in patients with cancer-related cachexia in two pivotal phase III studies presented together at the European Soci-ety for Medical Oncology (ESMO) 2014 Congress in Madrid. These studies did not show an effect on hand-grip strength, one of the two coprimary endpoints.

“[These are] the largest random-ized controlled [trials] ever conducted in cachexia. Although anamorelin did not improve hand-grip strength, it did improve anorexia/cachexia symptoms and was incredibly well tolerated. Over-all survival results are pending and will be presented over time,” said lead au-thor Jennifer S. Temel, MD, Clinical Director of Thoracic Oncology at Mas-sachusetts General Hospital, Associate Director of the Dana-Farber/Partners Cancer Care Hematology/Oncology Fellowship, and Associate Professor at Harvard Medical School, Boston.

“Cachexia is one of the most trou-

bling symptoms of cancer for patients and their families. It can be a limiting factor for treatment of cancer,” said study coauthor David C. Currow, BMed, MPH, PhD, FRACP, Professor of Palliative and Supportive Services at Flinders University, Adelaide, Australia. Dr. Currow spoke about study results at an ESMO press conference.

“For the first time, a drug is effective in treating cachexia. This will signifi-cantly change how we think about can-cer-related cachexia and how we treat patients with cancer,” he said.

Anamorelin is an investigational agent under development by Helsinn. It is a first-in-class oral ghrelin receptor agonist. Release of ghrelin stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism.

Patients with cancer-related cachex-ia keep losing weight and often have poor appetite. They are often too sick to get the cancer treatment that they need. A drug such as anamorelin may allow patients to be well enough to continue with their cancer treatment.

Identically Designed TrialsROMANA 1 (N = 484) and

ROMANA 2 (N = 495) were identi-cally designed phase III studies that ran-domly assigned patients with inoperable stage III and IV non–small lung cancer (NSCLC) and cachexia in a 2:1 ratio to receive either anamorelin at 100 mg/d or placebo for 12 weeks. Eligible patients were to have a life expectancy of greater than 4 months. The majority of patients were receiving chemotherapy, and ap-proximately 12% were getting radio-therapy. Cachexia was defined as ≥ 5% weight loss within the past 6 months or body mass index < 20 kg/m2.

After 12 weeks, patients had the option of blinded continuation on the same arm to which they were originally random-ized, continuing anamorelin or placebo, and results of this study ( ROMANA 3) will be presented in the future.

Both studies found that patients randomly assigned to placebo contin-ued to lose weight and lean body mass over the 12-week study period, while those assigned to anamorelin gained lean body mass. The differences be-tween the two groups for weight were highly significant at weeks 3, 6, 9, and

12. (P < .0001 for all comparisons).In ROMANA 1, median increase in

lean body mass was 1.10 kg with anamo-relin vs a loss of 0.44 kg in the placebo group. In ROMANA 2, median increase was 0.75 kg compared with a loss of 0.96 kg on placebo (P < .0001 for both stud-ies). The net effect of difference was more than 1.5 kg in both studies at 12 weeks.

In ROMANA 1, body weight in-creased by an average of 2.2 kg on anamorelin vs 0.14 kg on placebo. In ROMANA 2, body weight increased by an average of 0.95 kg vs a loss of 0.57 kg on placebo (P < .0001 for both studies).

Both groups declined in hand-grip strength over the course of the study.

Quality-of-Life FindingsFurther, quality of life as assessed by

the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) Anorexia-Cachexia Domain, also showed a signifi-cant difference between the two treatment arms at all time points favoring anamore-lin treatment over placebo, especially for ROMANA 1. This instrument included questions about appetite and appearance.

“These were clinically meaningful


“The study was well performed and was a good representative sample of patients with cachexia,” said formal discussant Florian Scotté,

MD, PhD, a medical oncologist in the Department of Oncology at the Georges Pompidou European Hospital, Paris, regarding the study presented by Temel et al at the ESMO 2014 Congress. “More than 65% of patients will have muscle wasting and lose muscle function,” he noted.

He said the effect of the drug on lean body mass was important, but he was not convinced that hand-grip strength is a good way to evaluate physical function and daily living, because it only evaluates upper-body strength and not lower-extremity strength.

He noted that another pair of studies of a different investigational agent for cachexia called enobosarm showed an effect on lean body mass but failed to show a significant effect of this agent on stair-climb power.

“There are many reasons patients have malnutrition. We need to attend to this topic and prevent, cure, and work using a multidisciplinary approach,” he commented. n

Disclosure: Dr. Scotté reported no potential conflicts of interest.

Palliative Care

These were clinically meaningful changes in quality of life.

—Jennifer S. Temel, MD

These are incredibly exciting results. The benefits are consistent…. This therapy has the potential to affect cancer therapy across all treatment centers.

—David C. Currow, BMed, MPH, PhD, FRACP

Treating Cachexia

■ Up until now, no drug has been successful in treating cancer-related cachexia, a debilitating sequela of advanced cancer marked by involuntary extreme weight loss and lack of appetite.

■ The novel oral agent anamorelin appears to be effective in treating cachexia, resulting in weight gain, increased lean body mass, and improved quality of life.

There are many reasons patients have malnutrition. We need to attend to this topic and prevent, cure, and work using a multidisciplinary approach.

—Florian Scotté, MD, PhD



ESMO Congress

Treatment of Cachexiacontinued from page 24

Local Treatments Fail to Improve Survival in MesotheliomaBy Alice Goodman

The prognosis for malignant pleu-ral mesothelioma remains dim,

despite attempts to intensify treat-ment in the phase II SAKK 17/04 trial and other studies. The results of SAKK 17/04, presented at the 2014 European Society for Medical Oncol-ogy (ESMO) Congress in Madrid, showed that the addition of hemitho-racic radiation to chemotherapy and surgery failed to improve local control and overall survival.

Disappointing Results“We wanted to see if the combina-

tion of chemotherapy, surgery, and hemithoracic radiation would prevent or delay relapse in patients with malig-nant pleural mesothelioma. This is the

largest prospective trial of multimo-dality therapy in malignant pleural me-sothelioma. To our disappointment, it did not,” said lead author Rolf A. Stahel, MD, Professor in the Oncol-ogy Clinic at University Hospital, Zu-rich, and current President of ESMO.

“Mesothelioma is a dreadful dis-ease. The survival time with combi-nation chemotherapy approaches 20 months, and radiation did not im-

prove outcomes. These patients have a heavy treatment burden. They un-dergo chemotherapy and a radical sur-gery with pneumonectomy, taking out the lining of the chest wall and part of the diaphragm, and still they relapse in the same area. They did no better with radiation,” Dr. Stahel said.

The SAKK 17/04 study enrolled 151 patients and treated them with three cycles of cisplatin/pemetrexed (Alimta) chemotherapy. Of these, 125 underwent surgery and 96 (63.5%) had a complete macroscopic resec-tion; 54 patients gave consent and were randomly assigned in a 1:1 ra-tio to receive radiation or no further treatment.

Relapse-free survival was 11 months with surgery alone vs 12.2 months with radiation therapy. Me-dian overall survival was 20.8 months for surgery alone and 19.3 months for radiation. The study did not meet its primary endpoint, which was defined as a 1-year increase in locoregional relapse-free survival.

“Hemithoracic radiation after sur-gery has no benefit,” Dr. Stahel con-cluded. “With maximizing therapy, we have not done better.”

The next logical step is to investi-gate whether targeted therapy can im-prove relapse-free survival, he contin-ued. “We have some good signals that immunotherapy with checkpoint in-hibitors will be the next step,” he said.

Clues to Immune TargetIn fact, a separate study presented

at the ESMO meeting hints at a new

direction. The study analyzed tissue samples from 119 patients with malig-nant pleural mesothelioma and found that 20.7% of patients’ tumors ex-pressed a protein called programmed cell death ligand 1 (PD-L1) that is as-sociated with poor outcomes.

This protein is active in several tumor types; it “puts the brakes” on the immune system’s ability to fight the cancer. Treatments that block PD-L1 have shown promise in mela-noma and lung cancer, and the hope is that drugs that block this pathway may be worth pursuing in meso-thelioma, said study author Susana Cedres, MD, a medical oncologist at Vall d’Hebron Institute of Oncology in Barcelona.

“The results of our study could offer a new treatment for a subset of patients with pleural mesothelioma who expressed PD-L1. These patients

could be treated with targeted im-mune checkpoint inhibitors,” Dr. Ce-dres said in a statement released by ESMO. n

Disclosure: The study authors reported no potential conflicts of interest.

References1. Stahel R, Riesterer O, Alexandros X,

et al: Neoadjuvant chemotherapy and ex-trapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy: Final results of the randomized multicenter phase II trial SAKK 17/04. ESMO 2014 Congress. Abstract LBA37_PR. Presented Septem-ber 29, 2014.

2. Cedres S, Ponce Aix S, Zugazagoi-tia J, et al: Analysis of expression of pro-grammed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma. 2014 ESMO Congress. Abstract 1556O_PR. Presented September 29, 2014.

Thoracic Oncology

Treating Mesothelioma

■ A randomized phase II study found that adding radiation to chemotherapy plus radical surgery did not improve local relapse rate or overall survival in malignant pleural mesothelioma.

■ Better treatments are urgently needed, but it appears that local treatments will not be the way forward; investigators are pursuing immunotherapy with anti–PD-1/PD-L1 inhibitors in this challenging disease.


“M esothelioma has been the focus of a graveyard of negative trials,” said Stefan

Zimmermann, MD, Senior Oncologist at the He-matology/Oncology Clinic, HFR Fribourg– Can-tonal Hospital, Fribourg, Switzerland, during the ESMO 2014 Congress.

“The epidemiology of mesothelioma is compli-cated, with a long latency period of about 20 to 30 years from asbestos exposure and the emergence of cancer. Oncologists have been looking for a very long time for effective local therapies, including surgery, intrapleural che-motherapy, and various types of radiation. Intravenous chemotherapy had limited effectiveness, but so far it is the only treatment modality with any evidence-based benefit,” Dr. Zimmermann continued.

“None of the local treatment modalities has been able to provide clini-cally meaningful benefit to patients,” he added. “Local therapy won’t save the day, and this study is another signal that we need to improve the systemic approach.”

More recently there is interest in immunotherapy, and immune check-point inhibitors are actively being studied in Europe. “Perhaps immunother-apy can make a difference,” he said. n

Disclosure: Dr. Zimmermann reported no potential conflicts of interest.

Stefan Zimmermann, MD

Rolf A. Stahel, MD

changes in quality of life,” Dr. Temel noted.Low rates of toxicity were seen. The

most common adverse events were nausea and hyperglycemia. A few pa-tients had diabetes, she said.

Hyperglycemia is expected as part of the mechanism of action, and events

were well managed using standard clinical protocols. “These effects were specifically sought given the effect of ghrelin (and therefore ghrelin agonists) on glucose metabolism,” Dr. Currow ex-plained to The ASCO Post.

“These are incredibly exciting re-sults. The benefits are consistent. Up until now you couldn’t change lean

body mass in patients with cancer-related cachexia. This therapy has the potential to affect cancer therapy across all treatment centers,” Dr. Currow said.

Patients will be followed for survival for 1 year from trial entry. n

Disclosure: Drs. Temel and Currow reported no potential conflicts of interest. For full disclosures of the study authors, visit www.esmo.org/

Conferences/ESMO-2014-Congress/Abstracts.

Reference1. Temel J, Currow D, Fearon K, et

al: Anamorelin for the treatment of can-cer anorexia-cachexia in NSCLC: Results from the phase 3 studies ROMANA 1 and 2. ESMO 2014 Congress. Abstract 1483O-PR. Presented September 27, 2014.


FDA Update

FDA Approves Bortezomib Injection for Previously Untreated Patients With Mantle Cell Lymphoma

The U.S. Food and Drug Admin-istration (FDA) has approved

bortezomib (Velcade) injection for previously untreated patients with mantle cell lymphoma. This is the first treatment in the United States to be ap-proved for use in previously untreated patients with mantle cell lymphoma. Bortezomib was previously approved for the treatment of relapsed or refrac-tory mantle cell lymphoma in 2006.

Phase III StudyThis approval is based on the re-

sults of an international, random-ized, head-to-head phase III study that showed that previously untreat-ed patients receiving a bortezomib-containing combination (VR-CAP; bortezomib, rituximab [Rituxan], cyclophosphamide, doxorubicin, and prednisone) experienced a 59% rela-tive improvement in the study’s pri-mary endpoint of progression-free

survival compared to those who were administered the standard R-CHOP (rituximab, cyclophosphamide, doxo-rubicin, vincristine, and prednisone) regimen (median, 25 vs 14 months; hazard ratio [HR] = 0.63; P < .001) at a median follow-up of 40 months. The complete response rate for pa-tients receiving VR-CAP vs R-CHOP was 44% vs 34%.

The open-label, multicenter, pro-spective study evaluated the efficacy and safety of VR-CAP vs R-CHOP in 487 patients with previously untreated mantle cell lymphoma who were ineli-gible or not considered for a bone mar-row transplant. Bortezomib (1.3 mg/m2) was administered intravenously in combination with intravenous ritux-imab, cyclophosphamide, doxorubi-cin, and oral prednisone for six 3-week treatment cycles. For patients with a response first documented at cycle 6, two additional VR-CAP cycles were recommended.

Adverse ReactionsThe most common adverse reac-

tions occurring in ≥ 20% of patients receiving the VR-CAP regimen were

neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, pe-ripheral neuropathy, pyrexia, nausea, and diarrhea. Infections were reported for 31% of patients in the VR-CAP

arm and 23% of the patients in the R-CHOP arm including pneumonia (8% vs 5%). Adverse reactions leading to discontinuation occurred in 8% of pa-tients in the VR-CAP arm and 6% of

patients in the R-CHOP arm. In the VR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sen-sory neuropathy (1%). n

When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH

• CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA

• Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration

• Monitor electrolytes periodically

• Avoid drugs known to prolong the QT interval

• Only prescribers and pharmacies certifi ed with the restricted distribution program are able to prescribe and dispense CAPRELSA

To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certifi cation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

FDA-approved in April 2011 as the fi rst medication for advanced MTC.1

CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA

Lead the way

with

Lead / Forward


FDA Update

FDA Approves Netupitant and Palonosetron Combination Capsule for Chemotherapy-Induced Nausea and Vomiting

The U.S. Food and Drug Administra-tion (FDA) has approved a combi-

nation of netupitant and palonosetron (Akynzeo) to treat nausea and vomiting in patients undergoing cancer chemotherapy.

The new drug, also known as NEPA, is a fixed-combination capsule comprised of two agents: oral palonosetron, which prevents nausea and vomiting during the acute phase (within the first 24 hours) af-

ter the start of chemotherapy, and netupi-tant, which prevents nausea and vomiting during both the acute phase and the de-layed phase (from 25 to 120 hours) after the start of cancer chemotherapy.

“Supportive care products, such as [NEPA], help ease the nausea and vom-iting patients may experience as a side effect of cancer chemotherapy,” said


When you and your patient face the challenge of advanced medullary thyroid cancer (MTC),


• CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA

• Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration

• Monitor electrolytes periodically

• Avoid drugs known to prolong the QT interval

• Only prescribers and pharmacies certifi ed with the restricted distribution program are able to prescribe and dispense CAPRELSA

To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certifi cation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

FDA-approved in April 2011 as the fi rst medication for advanced MTC.1

CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA

Lead the way

with

Lead / Forward

http://www.caprelsa.com/hcp/index.aspx


FDA Update

Julie Beitz, MD, Director of the Office of Drug Evaluation III in the FDA’s Cen-ter for Drug Evaluation and Research.

Clinical Trial ResultsNEPA’s effectiveness was estab-

lished in two clinical trials of 1,720

participants receiving cancer che-motherapy. Participants were ran-domly assigned to receive NEPA or oral palonosetron. The trials were designed to measure whether the study drugs prevented any vomiting episodes in the acute, delayed, and overall phases after the start of cancer chemotherapy.

Results of the first trial showed that 98.5%, 90.4%, and 89.6% of NE-PA-treated participants did not expe-rience any vomiting or require rescue medication for nausea during the acute, delayed, and overall phases, re-spectively. In contrast, 89.7%, 80.1%, and 76.5% of participants treated with oral palonosetron did not expe-

rience any vomiting or require res-cue medication for nausea during the acute, delayed, and overall phases, respectively. The second trial showed similar results.

Common side effects of NEPA in the clinical trials were headache, asthenia, fatigue, dyspepsia, and con-stipation. n

Netupitant/Palonosetroncontinued from page 27

HR=0.35 (95% CI: 0.24, 0.53) P<.0001

Median PFS not reached

(95% CI: 22.6 months,

non-estimable)

16.4 months median PFS

(95% CI: 8.3, 19.7)

CAPRELSA 300 mg

59/231Events/Patients

Placebo

41/100

2

Risk of Progression Overall Survival (OS)

Subgroup analysis showed similar PFS results for2:

• Symptomatic patientsHR=0.31 (95% Cl: 0.19, 0.53)

• Patients who had progressed within 6 months prior to ZETA study enrollmentHR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2

• Further OS analysis will take place when ≥50% of patients have died3

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signifi cantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2

Results from a phase 3,

international, randomized,

double-blind, placebo-

controlled trial in adult

patients (N=331) with

unresectable locally

advanced or metastatic

MTC. At disease progression,

patients had the option

to receive open-label

CAPRELSA.2,3

65% Relative Reduction in Risk of Progression2

Additional Important Safety Information for CAPRELSA (contd)

• Do not use in patients with congenital long QT syndrome

• CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA

• Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction

• Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA canthen be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above

• Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions

• Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

0.0

0.25

0.50

0.75

Pro

gre

ssio

n-f

ree

su

rviv

al

60 12 2418 30 36

1.0

Months

173231 145 33118 1 0

CAPRELSA300 mg

Number at Risk

47100 30 624 0 0Placebo

www.LeadWithCAPRELSA.com

Additional Important Safety Information for CAPRELSA

• Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed

• Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event

• Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage

• Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA

• Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose

• Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly

• Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS

• Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval

• Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis

• CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established

• CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA

• The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%)

• CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

* PFS is defi ned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.2

CAPRELSA is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 2977331 4/14

References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information,

including Boxed WARNING, on adjacent pages.

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS)

For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com


FDA Update

Blinatumomab Receives FDA Priority Review Designation in Acute Lymphoblastic Leukemia

The U.S. Food and Drug Administra-tion (FDA) has accepted for review

Amgen’s Biologics License Application for blinatumomab for the treatment of adults with Philadelphia chromo-

some–negative relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). As part of the acceptance, the FDA granted blinatumomab priority re-view with a Prescription Drug User Fee

Act action date of May 19, 2015. Blinatu-momab is an investigational bispecific T-cell engager (BiTE) antibody construct designed to direct the body’s T cells


HR=0.35 (95% CI: 0.24, 0.53) P<.0001

Median PFS not reached

(95% CI: 22.6 months,

non-estimable)

16.4 months median PFS

(95% CI: 8.3, 19.7)

CAPRELSA 300 mg

59/231Events/Patients

Placebo

41/100

2

Risk of Progression Overall Survival (OS)

Subgroup analysis showed similar PFS results for2:

• Symptomatic patientsHR=0.31 (95% Cl: 0.19, 0.53)

• Patients who had progressed within 6 months prior to ZETA study enrollmentHR=0.41 (95% Cl: 0.25, 0.66)

• First OS analysis: at the time of the primary analysis of PFS, 15% of patients had died. There was no significant difference in OS between the 2 treatment groups2

• Further OS analysis will take place when ≥50% of patients have died3

In the treatment of advanced medullary thyroid cancer (MTC),

CAPRELSA Signifi cantly Prolonged Progression-Free Survival (PFS)* vs Placebo in the ZETA Study2

Results from a phase 3,

international, randomized,

double-blind, placebo-

controlled trial in adult

patients (N=331) with

unresectable locally

advanced or metastatic

MTC. At disease progression,

patients had the option

to receive open-label

CAPRELSA.2,3

65% Relative Reduction in Risk of Progression2

Additional Important Safety Information for CAPRELSA (contd)

• Do not use in patients with congenital long QT syndrome

• CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA

• Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction

• Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA canthen be resumed at a reduced dose

• Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above

• Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions

• Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation

0.0

0.25

0.50

0.75

Pro

gre

ssio

n-f

ree

su

rviv

al

60 12 2418 30 36

1.0

Months

173231 145 33118 1 0

CAPRELSA300 mg

Number at Risk

47100 30 624 0 0Placebo

www.LeadWithCAPRELSA.com

Additional Important Safety Information for CAPRELSA

• Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed

• Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event

• Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage

• Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA

• Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose

• Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA treated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly

• Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA

• Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS

• Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval

• Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis

• CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established

• CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA

• The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%)

• CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

* PFS is defi ned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.3 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.2

CAPRELSA is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca. All rights reserved. 2977331 4/14

References: 1. FDA Web site. US Department of Health and Human Services, Food and Drug Administration. Notable FY 2011 approvals. http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276413.htm. Accessed March 27, 2014. 2. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information,

including Boxed WARNING, on adjacent pages.

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS)

For more information, contact the CPAS Program at 1-800-367-4999 or visit www.CAPRELSACPAS.com


FDA Update

against CD19-expressing target cells.The application includes data from

a phase II trial in adult patients with Philadelphia chromosome–negative relapsed/refractory B-precursor ALL treated with blinatumomab, which met its primary endpoint.

BiTE antibody constructs are a type of immunotherapy being investi-gated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified an-tibodies are designed to engage two dif-ferent targets simultaneously, thereby juxtaposing T cells to cancer cells and inducing apoptosis. n

Blinatumomabcontinued from page 29

We Want to Hear From You

Send your news to The ASCO Post by contacting [email protected].

Visit The ASCO Post online at www.ASCOPost.com

CAPRELSA®

(vandetanib) Tablets for Oral Use

BRIEF SUMMARY. Before prescribing, please see full Prescribing Information.


CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients

receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagne-

semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to

CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT

interval. Only prescribers and pharmacies certified with the restricted distribution program are able to

prescribe and dispense CAPRELSA [see Warnings and Precautions].

INDICATIONS AND USAGECAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with

unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or

slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

DOSAGE AND ADMINISTRATIONThe recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable

toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the

next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for

approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immedi-

ately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can

also be administered through nasogastric or gastrostomy tubes.

Dosage AdjustmentFor adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg

for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities.

Interrupt CAPRELSA for the following:

• Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns

to less than 450 ms.

• CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.

For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade

1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a

prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions].

For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine

clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings

and Precautions and Use in Specific Populations].

For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe

hepatic impairment [see Use in Specific Populations].

CONTRAINDICATIONSDo not use in patients with congenital long QT syndrome [see Boxed Warning].

WARNINGS AND PRECAUTIONSQT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) in

full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in

patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than

450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT

syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with

ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired

renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and

monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline,

2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor

electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT

prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain

serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium

levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to

prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients

already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more

frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than

450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration].

Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients

treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage

and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after

treatment discontinuation.

Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with

CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the

randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently

with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy

after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who

experience a severe ischemic cerebrovascular event.

Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer

CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA

in patients with severe hemorrhage.

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of

heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be

reversible upon stopping CAPRELSA.

DiarrheaDiarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC

study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early

detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for

severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration].

Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of

thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-

treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after

starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur,

examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients

for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be

controlled, do not resume CAPRELSA [see Dosage and Administration].

Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema

diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any

patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical

studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue

CAPRELSA treatment in patients with RPLS.

Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone,

disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but

not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and

pimozide) [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in

patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information

available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and

Administration, Use in Specific Populations and Clinical Pharmacology (12.3) in full Prescribing Information ].

Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and

efficacy have not been established [see Dosage and Administration].

Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In

nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or

lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female

fertility, embryofetal development, and postnatal development of pups. If this drug is used during pregnancy, or if

the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a

fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they

must use effective contraception during CAPRELSA treatment and for at least four months following the last dose

of CAPRELSA [see Use in Specific Populations].

CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only

through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies

certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS require-

ments and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the label:

• QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions]

• Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions]

• Interstitial Lung Disease [see Warnings and Precautions]

• Ischemic Cerebrovascular Events [see Warnings and Precautions]

• Hemorrhage [see Warnings and Precautions]

• Heart Failure [see Warnings and Precautions]

• Diarrhea [see Warnings and Precautions]

• Hypothyroidism [see Warnings and Precautions]

• Hypertension [see Warnings and Precautions]

• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions]

• Embryofetal Toxicity [see Warnings and Precautions]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect

the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer

were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58%

male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to

CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of

CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency:

diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection,

decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109

(47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of

231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions

leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia

(1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation

(0.9%), and hypertension (0.9%).

Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence inCAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1]

System Organ Class CAPRELSA 300 mg PlaceboPreferred Term N=231 N=99

All Grades Grade 3-4 All Grades Grade 3-4 (%) (%) (%) (%)

Gastrointestinal Disorders

Diarrhea/Colitis 57 11 27 2

Nausea 33 1 16 0

Abdominal Pain2 21 3 11 0

Vomiting 15 1 7 0

Dyspepsia 11 0 4 0

Dry Mouth 9 0 3 0

Skin and Cutaneous Disorders

Rash3 53 5 12 0

Dermatitis Acneiform/Acne 35 1 7 0

Dry Skin 15 0 5 0

Photosensitivity Reaction 13 2 0 0

Pruritus 11 1 4 0

Nail abnormalities4 9 0 0 0

Alopecia 8 N/A 0 N/A

Vascular Disorders

Hypertension/Hypertensive

Crisis/Accelerated Hypertension 33 9 5 1

Nervous System Disorders

Headache 26 1 9 0

Dysgeusia 8 0 3 0

General Disorders

Fatigue5 24 6 23 1

Infections

Upper Respiratory Tract Infections6 23 0 16 0

Metabolic and Nutritional Disorders

Decreased Appetite 21 4 12 0

Hypocalcemia 11 2 3 0

Investigations

ECG QT Prolonged7 14 8 1 1

Eye Disorders

Corneal Abnormalities8 13 0 1 0

Blurred Vision 9 0 1 0

Renal Disorders

Proteinuria 10 0 2 0

Psychiatric Disorders

Depression 10 2 3 0

Endocrine Disorders

Hypothyroidism 6 0 0 0

Musculoskeletal Disorders

Muscle Spasms 6 0 1 0

1. CTCAE version 3 was used to grade adverse events.2. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort.3. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis,

dermatitis bullous, generalized erythema, and eczema.4. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.5. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.6. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and

tracheitis.7. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction.8. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits,

acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients whoreceived placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was morecommon in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer(9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) intreated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination,including slit lamp examination, in patients who report visual changes.Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibitionof VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSAtreated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% inpatients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroidcancer (MTC) study.

Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at aHigher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1]

Laboratory Abnormalities CAPRELSA 300 mg PlaceboN = 231 N = 99


Chemistries


ALT Increased 51 2 19 0

Hypoglycemia 24 0 7 1

Creatinine Increased 16 0 1 0

Hypomagnesemia 7 <1 2 0

Hematologic

Neutropenia 10 <1 5 2

Thrombocytopenia 9 0 3 01. CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.DRUG INTERACTIONSEffect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use ofknown strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John’s Wort because it candecrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transportertype 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that aretransported by OCT2 [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on DigoxinCAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities whenadministering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) in full Prescribing Information].Drugs that Prolong the QT IntervalAvoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions].USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnantwoman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to thoseexpected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patientbecomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancyat a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax),there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of liveembryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times thehuman exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embry-ofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study.Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax inpatients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of theheart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicatingdelayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity(1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natalpup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactatingrats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of thedrug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk andbecause of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established.Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determinewhether they respond differently compared to younger patients.Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg inpatients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min)renal impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology (12.3) infull Prescribing Information].Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8),moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild(Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment hadcomparable mean AUC and clearance values to those with normal hepatic function. There are limited data inpatients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is notrecommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have notbeen established. [see Dosage and Administration and Warnings and Precautions].Females and Males of Reproductive PotentialContraception Females of reproductive potential should avoid pregnancy. Use effective contraception duringtreatment and up to 4 months after the last dose of CAPRELSA.Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate thatvandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information].OVERDOSAGEIn the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adversereactions may not resolve quickly.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850CAPRELSA is a registered trademark of the AstraZeneca group of companies© AstraZeneca 2014. All Rights Reserved. 3/14 2975903 5/14

CAPRELSA® (vandetanib) Tablets 2


Announcements

Peter Carroll, MD, MPH, Receives Grant for Early Detection of Prostate Cancer

The ZERO Cancer Research Fund has awarded the Jim Lafferty Me-

morial Research Grant in the amount of $45,000 to Peter Carroll, MD, MPH, of the University of California San Francisco, for the purpose of re-searching new and improved methods

for early detection of prostate cancer. The grant is part of the ZERO Cancer Research Fund, which is charged with supporting innovative, high-reward research that offers the best return on investment for patients and families fighting prostate cancer.

Identifying Aggressive vs Nonaggressive Disease

“Dr. Carroll’s research addresses an important challenge in diagnos-ing prostate cancer—the ability to distinguish aggressive from nonag-gressive disease,” said ZERO’s CEO

Jamie Bearse. “This promising re-search will give men and families more options when deciding how best to treat their prostate cancer.”

Dr. Carroll’s research includes devel-oping a low-cost mechanism to ensure men diagnosed with low-risk disease that immediate treatment is not nec-essary. He proposes to do this at sub-stantially lower cost when compared to commercially available genomic clas-sifiers—a technique that can be done in almost all pathology laboratories around the world.

Heart of Early Detection“My research is at the heart of ear-

ly detection and addresses the major criticism of early detection—overde-tection—which in the United States leads to overtreatment,” said Dr. Carroll.

The Jim Lafferty Memorial Research Grant was made through the ZERO Cancer Research Fund and came from a partnership between ZERO—The End of Prostate Cancer and Shining Down, a nonprofit founded by Jennifer Lafferty and Tamara Wyman in memory and honor of their husband and dear friend, Jim Lafferty, who lost his battle with prostate cancer in 2010 at the young age of 40.

Promising Research and Education

“We are absolutely thrilled to grant these funds to Dr. Carroll for early detection research,” said Tamara Gardner. “Jim’s passion was to edu-cate men of all ages and their families about prostate cancer and treatment options. We’re honoring his memory by supporting this promising research that can help men and families.”

The ZERO Cancer Research Fund aims to raise funds and issue grants to focus on early detection and other diag-nostic tools that can determine aggres-sive and nonaggressive prostate cancer. To learn more and support the ZERO Cancer Research Fund, visit www .zerocancer.org/zero-research-fund. n

Peter Carroll, MD, MPH

CAPRELSA®

(vandetanib) Tablets for Oral Use

BRIEF SUMMARY. Before prescribing, please see full Prescribing Information.


CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients

receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagne-

semia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to

CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT

interval. Only prescribers and pharmacies certified with the restricted distribution program are able to

prescribe and dispense CAPRELSA [see Warnings and Precautions].

INDICATIONS AND USAGECAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with

unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or

slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

DOSAGE AND ADMINISTRATIONThe recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable

toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the

next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for

approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immedi-

ately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can

also be administered through nasogastric or gastrostomy tubes.

Dosage AdjustmentFor adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg

for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities.

Interrupt CAPRELSA for the following:

• Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns

to less than 450 ms.

• CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.

For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade

1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a

prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions].

For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine

clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings

and Precautions and Use in Specific Populations].

For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe

hepatic impairment [see Use in Specific Populations].

CONTRAINDICATIONSDo not use in patients with congenital long QT syndrome [see Boxed Warning].

WARNINGS AND PRECAUTIONSQT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2) in

full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in

patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than

450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT

syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with

ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired

renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and

monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline,

2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor

electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT

prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain

serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium

levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to

prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients

already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more

frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than

450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration].

Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients

treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage

and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after

treatment discontinuation.

Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with

CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.

Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.

Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the

randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently

with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy

after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who

experience a severe ischemic cerebrovascular event.

Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer

CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA

in patients with severe hemorrhage.

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of

heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be

reversible upon stopping CAPRELSA.

DiarrheaDiarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC

study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early

detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for

severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration].

Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of

thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-

treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after

starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur,

examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.

Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients

for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be

controlled, do not resume CAPRELSA [see Dosage and Administration].

Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema

diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any

patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical

studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue

CAPRELSA treatment in patients with RPLS.

Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone,

disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but

not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and

pimozide) [see Drug Interactions and Clinical Pharmacology (12.2) in full Prescribing Information].

Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in

patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information

available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and

Administration, Use in Specific Populations and Clinical Pharmacology (12.3) in full Prescribing Information ].

Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and

efficacy have not been established [see Dosage and Administration].

Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In

nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or

lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female

fertility, embryofetal development, and postnatal development of pups. If this drug is used during pregnancy, or if

the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a

fetus. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they

must use effective contraception during CAPRELSA treatment and for at least four months following the last dose

of CAPRELSA [see Use in Specific Populations].

CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only

through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies

certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS require-

ments and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the label:

• QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions]

• Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions]

• Interstitial Lung Disease [see Warnings and Precautions]

• Ischemic Cerebrovascular Events [see Warnings and Precautions]

• Hemorrhage [see Warnings and Precautions]

• Heart Failure [see Warnings and Precautions]

• Diarrhea [see Warnings and Precautions]

• Hypothyroidism [see Warnings and Precautions]

• Hypertension [see Warnings and Precautions]

• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions]

• Embryofetal Toxicity [see Warnings and Precautions]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the

clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect

the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer

were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58%

male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to

CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of

CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency:

diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection,

decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109

(47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of

231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions

leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia

(1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation

(0.9%), and hypertension (0.9%).

Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence inCAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1]

System Organ Class CAPRELSA 300 mg PlaceboPreferred Term N=231 N=99


Gastrointestinal Disorders

Diarrhea/Colitis 57 11 27 2

Nausea 33 1 16 0

Abdominal Pain2 21 3 11 0

Vomiting 15 1 7 0

Dyspepsia 11 0 4 0

Dry Mouth 9 0 3 0

Skin and Cutaneous Disorders

Rash3 53 5 12 0

Dermatitis Acneiform/Acne 35 1 7 0

Dry Skin 15 0 5 0

Photosensitivity Reaction 13 2 0 0

Pruritus 11 1 4 0

Nail abnormalities4 9 0 0 0

Alopecia 8 N/A 0 N/A

Vascular Disorders

Hypertension/Hypertensive

Crisis/Accelerated Hypertension 33 9 5 1

Nervous System Disorders

Headache 26 1 9 0

Dysgeusia 8 0 3 0

General Disorders

Fatigue5 24 6 23 1

Infections

Upper Respiratory Tract Infections6 23 0 16 0

Metabolic and Nutritional Disorders

Decreased Appetite 21 4 12 0


Investigations

ECG QT Prolonged7 14 8 1 1

Eye Disorders

Corneal Abnormalities8 13 0 1 0

Blurred Vision 9 0 1 0

Renal Disorders

Proteinuria 10 0 2 0

Psychiatric Disorders

Depression 10 2 3 0

Endocrine Disorders

Hypothyroidism 6 0 0 0

Musculoskeletal Disorders

Muscle Spasms 6 0 1 0

1. CTCAE version 3 was used to grade adverse events.2. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort.3. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis,

dermatitis bullous, generalized erythema, and eczema.4. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.5. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.6. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and

tracheitis.7. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction.8. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits,

acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients whoreceived placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was morecommon in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer(9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) intreated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination,including slit lamp examination, in patients who report visual changes.Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibitionof VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSAtreated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% inpatients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroidcancer (MTC) study.

Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at aHigher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1]

Laboratory Abnormalities CAPRELSA 300 mg PlaceboN = 231 N = 99


Chemistries


ALT Increased 51 2 19 0

Hypoglycemia 24 0 7 1

Creatinine Increased 16 0 1 0

Hypomagnesemia 7 <1 2 0

Hematologic

Neutropenia 10 <1 5 2

Thrombocytopenia 9 0 3 01. CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.DRUG INTERACTIONSEffect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use ofknown strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John’s Wort because it candecrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transportertype 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that aretransported by OCT2 [see Clinical Pharmacology (12.3) in full Prescribing Information].Effect of CAPRELSA on DigoxinCAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities whenadministering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) in full Prescribing Information].Drugs that Prolong the QT IntervalAvoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions].USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnantwoman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to thoseexpected at the recommended human dose of 300 mg/day. If CAPRELSA is used during pregnancy, or if the patientbecomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancyat a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax),there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of liveembryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times thehuman exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embry-ofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study.Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax inpatients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of theheart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicatingdelayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity(1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natalpup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactatingrats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of thedrug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk andbecause of the potential for serious adverse reactions in nursing infants from CAPRELSA, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established.Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determinewhether they respond differently compared to younger patients.Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg inpatients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min)renal impairment [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology (12.3) infull Prescribing Information].Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8),moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild(Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment hadcomparable mean AUC and clearance values to those with normal hepatic function. There are limited data inpatients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is notrecommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have notbeen established. [see Dosage and Administration and Warnings and Precautions].Females and Males of Reproductive PotentialContraception Females of reproductive potential should avoid pregnancy. Use effective contraception duringtreatment and up to 4 months after the last dose of CAPRELSA.Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate thatvandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information].OVERDOSAGEIn the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adversereactions may not resolve quickly.

Distributed by:AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850CAPRELSA is a registered trademark of the AstraZeneca group of companies© AstraZeneca 2014. All Rights Reserved. 3/14 2975903 5/14

CAPRELSA® (vandetanib) Tablets 2

http://www.zerocancer.org/zero-research-fund

http://www.zerocancer.org/zero-research-fund


ESMO Congress

Long-Term Results of COU-AA-302 Confirm Abiraterone BenefitBy Alice Goodman

Final results of the COU-AA-302 trial continue to support the survival

benefit of abiraterone acetate (Zytiga) in men with chemotherapy-naive metastatic castration-resistant prostate cancer, often referred to as the “predocetaxel space.”

“The study met the overall survival endpoint and all secondary endpoints with statistical as well as clinical signifi-

cance,” stated Charles J. Ryan, MD, Pro-fessor of Clinical Medicine and Urology at the University of California, San Fran-cisco, Helen Diller Family Comprehen-sive Cancer Center. “Despite 44% cross-over from the control arm to treatment with abiraterone, the survival benefit associated with abiraterone was main-tained.” Dr. Ryan presented these results at the 2014 ESMO Congress in Madrid.1

Study DetailsCOU-AA-302 randomly assigned

1,088 patients with metastatic castration-resistant prostate cancer to treatment with abiraterone plus concurrent prednisone at 5 mg or placebo plus the same dose of prednisone. The study was unblinded after an interim analysis by an indepen-dent data monitoring committee found a significant difference in radiographic pro-gression-free survival and a trend toward improved overall survival. At that time, patients in the placebo arm were allowed to cross over to active treatment.

At the third interim analysis, radio-graphic progression-free survival was significantly improved in the abiraterone-treated group: 16.5 vs 8.2 months in the placebo group, representing a 48% risk re-duction of disease progression and death for abiraterone (P < .0001). At that time, it appeared that there would be an overall survival benefit as the data matured, Dr. Ryan said. “A clear-cut benefit for [abi-raterone] was observed for all secondary endpoints,” he noted.

Survival DataIn the final overall survival analysis,

the benefit for abiraterone appeared less

robust than that suggested by progres-sion-free survival at the interim analysis. After a median follow-up of 49.2 months, overall survival was significantly better for patients receiving abiraterone, with a me-dian of 34.7 vs 30.3 months for placebo (P = .0027). The survival treatment effect was consistent across clinical and demo-graphic variables.

After adjusting for crossover of 44% of placebo patients to the abiraterone arm, abiraterone reduced the risk of dis-ease progression or death by 26%, Dr. Ryan continued.

He noted that the survival curves separated gradually, and the curves re-mained separated at the final analysis. “Well over 25% of abiraterone-treated patients have survived 48 months or longer,” he noted.

Before unblinding, subsequent ther-

apy was used by 67% of the abiraterone group and 80% of the control arm. In the final analysis, median time to opiate use was significantly longer in the abi-raterone group: 33.4 vs 23.4 months, respectively (P < .0001).

Regarding prespecified adverse events of special interest, abiraterone recipients had more fluid retention, more cardiac disorders, and more ala-nine transaminase increases compared with the control arm.

“The final data support the contin-ued collection of all data vs early trial termination in clinical trials conduct,” Dr. Ryan said.

“The management of metastatic [castration-resistant prostate cancer] has undergone a sea change with the regulatory approval of five agents for this indication. Most of these agents

were approved after the COU-AA-302 trial enrolled its first patients. It is likely that sequential use of these agents will improve survival overall for men with castration-resistant prostate cancer. Future trials will need to be designed with this in mind, as sequential use of so many therapies can delay separation of survival curves and confound trial data. This is a good problem to have,” Dr. Ryan commented. n

Disclosure: Dr. Ryan has received honoraria from Janssen.

Reference1. Ryan C, Smith M, Fizazi K, et al: Final

overall survival analysis of COU-AA-302, a randomized phase 3 study of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior che-motherapy. ESMO 2014 Congress. Abstract 753O. Presented September 28, 2014.


Regarding this confirmatory anal-ysis presented by Ryan et al at

the ESMO 2014 Congress, formal discussant Bertrand Tombal, MD, PhD, Chairman of the Division of Urology and Associated Professor of Physiology at Université Catholique

de Louvain, Brussels, said, “COU-AA-302 profoundly impacted the way we treat patients. The final anal-ysis is important. In Europe, some of us don’t have [abiraterone], and hopefully these data will speed up reimbursement for [the drug] in the predocetaxel space.”

He noted, “The study showed a disproportionate benefit for progres-sion-free survival [compared with] overall survival. This is a problem for some people, but not for me.”

Regarding the primary endpoint, he pointed out that progression-free

survival is a regulatory requirement. “But when you treat patients, the most important benefit is to improve their outcome. Keep that in mind,” he told the audience.

Significance of CrossoverBecause of the crossover, COU-

AA-302 is really a study of early vs delayed hormone therapy. “To me, the benefit of giving the patient ear-lier is the most important question. Delaying treatment has a major im-pact on time to chemotherapy, and on patient-reported outcomes such as pain and quality of life,” he said.

“By introducing earlier hormone therapy, we influence the time of progression, and change the im-pact on the patient, but we don’t improve overall survival. I believe we should disregard the fact that the benefit for progression-free sur-vival is stronger than that for over-all survival. Abiraterone has many other benefits, and the trial is re-ally about early vs delayed therapy,” he said. n

Disclosure: Dr. Tombal is a paid advisor or investigator for Amgen, Astellas, Bayer, Medivation, Ferring, Janssen, and Sanofi-Aventis.

Genitourinary Oncology

Despite 44% crossover from the control arm to treatment with abiraterone, the survival benefit associated with abiraterone was maintained.

—Charles J. Ryan, MD

Role of Abiraterone in Prostate Cancer

■ Final overall survival analysis of the pivotal phase III COU-AA-302 trial confirms the benefit of abiraterone in the predocetaxel space in men with metastatic castration-resistant prostate cancer.

■ The overall survival benefit at a median of almost 50 months of follow-up was less robust than that expected in light of the magnitude of benefit for progression-free survival at an interim analysis.

■ Nevertheless, abiraterone emerges as a standard of care prior to docetaxel in metastatic castration-resistant prostate cancer.

I believe we should disregard the fact that the benefit for progression-free survival is stronger than that for

overall survival. Abiraterone has many other benefits, and the trial is really about early vs delayed therapy.

—Bertrand Tombal, MD, PhD


ESMO Congress

Radiotherapy Should Be Added to Hormone Therapy in Node-Positive Prostate Cancer By Alice Goodman

Node-positive prostate cancer has typically been excluded from

clinical trials, leaving oncologists with little evidence to guide manage-ment for this group of patients. A study presented at the European So-ciety for Medical Oncology (ESMO) 2014 Congress sheds light on this is-sue, providing the strongest evidence to date that radical radiotherapy (to the pelvis and lymph nodes) added to androgen-deprivation therapy improves survival in node-positive patients.1

The evidence comes from a post hoc analysis of the control arm of the phase III STAMPEDE trial, which showed that the addition of radia-tion to androgen-deprivation therapy

prolonged failure-free survival, an endpoint that included biochemical failure, disease progression, or death, in men with high-risk prostate cancer, including both node-negative and node-positive cancers.

Radiation plus androgen-depri-vation therapy is already considered standard of care for high-risk node-negative patients, and these new data support similar management of node-positive patients.

STAMPEDE Details“The STAMPEDE trial supports

the use of radical radiotherapy in both node-positive and node-nega-tive patients and argues against the use of androgen-deprivation therapy alone for node-positive disease,” stat-ed Chris Parker, MD, Consultant in Clinical Oncology at the Royal Mars-den Hospital, London.

The analysis focused on a cohort of 721 men from the control arm of STAMPEDE. All men initiated treat-ment with androgen-deprivation therapy. Radiotherapy was optional

at study initiation, but after two large trials established the role of radical radiotherapy added to androgen-deprivation therapy in node-negative disease, radiation to the prostate (with or without radiation to the pelvis and lymph nodes) was planned for node-negative patients in the control arm of STAMPEDE. At baseline, median prostate-specific antigen level was 43 ng/mL, 40% (n = 287) were node-positive on imaging (not histology), and median Gleason score was 8 to 10.

Median failure-free survival was 63 months for all 721 patients in the control arm. Radiation was planned in 121 node-negative men and not planned in 59. Among node-negative men who got radiation, the 3-year

failure-free survival rate was 84%, compared with 62% in those who did not. The adjusted risk reduction in fa-vor of radiation was 74%.

“These results coincide precisely with those from the completed ran-domized trials and are encouraging when we move to node-positive pa-tients where we don’t have such data from randomized trials,” Dr. Parker continued.

In node-positive patients, radia-tion was planned for 98 men and not planned for 80 men. The 3-year failure-free survival rate was 71% for men who got radiation vs 47% for those who did not, representing a 49% reduction in risk of progression or death.

“This analysis is based on inten-tion to give radiation when enrolling in STAMPEDE. It is possible that pa-tients slated for radiation did not get it, and it is also possible that some patients for whom radiation was not intended at enrollment, subsequently received it,” he added.

Landmark AnalysisA landmark analysis was conducted

to account for these possibilities and showed even more impressive results than the original analysis; the adjusted hazard ratio in node-positive men was 0.35, representing a 65% reduction in risk of progression or death. In node-negative patients, risk of progression

or death was reduced by 74%. “Results were remarkably simi-

lar for men with node-positive and node-negative disease. Depending on which analysis you go by, the addition of radiation to [androgen-deprivation therapy] reduced the risk of [failure-free survival] by 49% or 65% in node-positive men,” he said.

“One limitation of this analysis is that the groups were small,” Dr. Park-er said. “However, we have no better-quality data on node-positive men anywhere else, so we should use these data to guide clinical management,” he stated. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference1. James N, Spears M, Clarke N, et al:

Impact of node status and radiotherapy on failure free survival in men with newly diagnosed non-metastatic prostate can-cer: Data from >690 patients in the con-trol arm of the STAMPEDE trial. ESMO 2014 Congress. Abstract 754O. Present-ed September 28, 2014.


The formal discussant of the study presented by James et al at the ESMO 2014 Congress was Bertrand Tombal, MD, PhD, Chairman of the Divi-

sion of Urology and Associated Professor of Physiology at Université Catholique de Louvain, Brussels. He praised the STAMPEDE trial as “wonderful, because

it informs current clinical practice and also addressed primary treatment in patients with positive nodes.”

“Too many of these patients are left to fate with [androgen-deprivation therapy] alone. This study gives us a strong signal to rethink how we treat these patients. The question was not addressed in the protocol, but the data suggest we should change the way we treat them. Local control is a crucial question, and maybe it is time to rethink our approach to the high-risk patient as well as the recurrent early [castration-resistant prostate cancer] patient,” he stated. n

Disclosure: Dr. Tombal is a paid advisor or investigator for Amgen, Astellas, Bayer, Medivation, Ferring, Janssen, and Sanofi-Aventis.


We have no better-quality data on node-positive men anywhere else, so we should use these data to guide clinical management.

—Chris Parker, MD

Treating Node-Positive Prostate Cancer

■ Patients with newly diagnosed node-positive prostate cancer are typically excluded from clinical trials; thus, little is known about optimal management for these patients.

■ Analysis of the control arm of a large randomized trial suggests that node-positive prostate cancer should be treated with radical radiotherapy in addition to androgen-deprivation therapy.

Local control is a crucial question, and maybe it is time to rethink our approach to the high-risk patient as well as the recurrent early [castration-resistant prostate cancer] patient.

—Bertrand Tombal, MD, PhD

For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based � rst-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

019517_elalns_PM92674_OT_fa.indd 1 9/26/14 1:28 PM

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

After completion of � rst-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8

You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

Why consider maintenance therapy*?

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4

Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC

Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months.§ Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety InformationCommon Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0)

Adverse Reactions: Grades 3-4In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%).

Adverse Reactions: All GradesIn the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data

See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598. 6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529. 8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.


For patients with advanced nonsquamous† NSCLC

Continue treatment.* Extend survival.1-4

Select Important Safety InformationContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPremedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

* Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA continuation maintenance showed extended overall survival with a safety pro� le consistent with previously reported ALIMTA single-agent trials

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.



Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.


NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

NCCNGuidelines®2.9

months

Median OS

SAFETYP r o f i l e

PARAMOUNT

57%

of patients

After completion of � rst-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8

You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

Why consider maintenance therapy*?

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4

Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC

Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months.§ Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy.b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety InformationCommon Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0)

Adverse Reactions: Grades 3-4In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%).

Adverse Reactions: All GradesIn the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data

See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598. 6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529. 8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.


http://www.alimtahcp.com

Indications for ALIMTAALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small celllung cancer.



Important Safety Information for ALIMTAMyelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ContraindicationALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and PrecautionsPrior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insuf� ciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insuf� ciency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug InteractionsSee Warnings and Precautions for speci� c information regarding NSAID administration in patients with renal insuf� ciency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Speci� c Patient Populations

It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Ef� cacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration GuidelinesComplete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapyThe most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

PM_HCP_ISI_NSCLC1M_17OCT2012

PM92674 09/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.ALIMTA® is a registered trademark of Eli Lilly and Company.


ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5 PRINTER VERSION 1 OF 4

ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.

75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose

75% of previous dose

Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)



Journal Spotlight

E-Cigarettes Unhelpful in Smoking Cessation Among Patients With Cancer

In a new study of patients with cancer who smoke, those using e-cigarettes

in addition to traditional cigarettes were more nicotine-dependent and equally or less likely to have quit smoking tradi-tional cigarettes than nonusers.1

The rising use of e-cigarettes has

raised many questions among pa-tients and their health-care provid-ers including whether e-cigarette use helps or hinders quitting efforts. To examine available clinical data about e-cigarette use and cessation among patients with cancer, Jamie Ostroff,

PhD, of the Memorial Sloan Kettering Cancer Center in New York, and her colleagues studied 1,074 patients with cancer who smoked and were enrolled between 2012 and 2013 in a tobacco treatment program within a compre-hensive cancer center.

Threefold Increase in UseThe researchers observed a threefold

increase in e-cigarette use from 2012 to 2013 (10.6% vs 38.5%). At enrollment, e-cigarette users were more nicotine-dependent than non-users, had more




ALIMTA® (pemetrexed for injection)

BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with CisplatinALIMTA® is indicated in combination with cisplatin therapy for the initial treatment

of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — MaintenanceALIMTA is indicated for the maintenance treatment of patients with locally advanced

or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small

cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural MesotheliomaThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line TherapyThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous

infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent MedicationsVitamin SupplementationInstruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily

beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

CorticosteroidsAdminister dexamethasone 4 mg by mouth twice daily the day before, the day of, and

the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all

patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir

hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.


Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.


a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3,

treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2)

Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose


Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea



Grade 3 or 4 mucositis 50% of previous dose


a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity

CTC GradeDose of ALIMTA

(mg/m2)Dose of Cisplatin

(mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or

nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no

dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow

lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity

reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS

5.1 Requirement for Premedication and Concomitant Medication to Reduce ToxicityVitamin SupplementationPrior to treatment with ALIMTA, initiate supplementation with oral folic acid and

intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

CorticosteroidsAdminister dexamethasone the day before, the day of, and the day after ALIMTA

administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia,

thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment

is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal InsufficiencyCaution should be used when administering NSAIDs concurrently with ALIMTA to

patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringObtain a complete blood count and renal function tests at the beginning of each cycle

and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)



Journal Spotlight

prior quit attempts, and were more likely to be diagnosed with lung or head and neck cancers. At follow-up, e-cigarette users were just as likely as nonusers to be smoking. Seven-day abstinence rates were 44.4% vs 43.1% for e-cigarette us-ers and nonusers, respectively (exclud-

ing patients who were lost to follow-up).“Consistent with recent observations

of increased e-cigarette use in the general population, our findings illustrate that e-cigarette use among tobacco-dependent cancer patients has increased within the past 2 years,” said Dr. Ostroff. She stressed that the study had several limitations, and additional studies are required.

“Controlled research is needed to evaluate the potential harms and ben-efits of e-cigarettes as a potential cessa-tion approach for cancer patients. In the meantime, oncologists should advise all smokers to quit smoking traditional combustible cigarettes, encourage use of FDA-approved cessation medications, refer patients for smoking cessation

counseling, and provide education about the potential risks and lack of known benefits of long-term e-cigarette use.” n

Reference1. Borderud SP, Li Y, Burkhalter JE, et

al: Electronic cigarette use among patients with cancer. Cancer. September 22, 2104 (early release online).

E-Cigarettescontinued from page 37



platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category DBased on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse

reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with CisplatinTable 4 provides the frequency and severity of adverse reactions that have been

reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

ReactionbALIMTA/cisplatin

(N=839)Gemcitabine/cisplatin

(N=830)

All Grades Toxicity (%)

Grade 3-4 Toxicity (%)



All Adverse Reactions 90 37 91 53

Laboratory Hematologic Anemia Neutropenia Leukopenia Thrombocytopenia

33291810

61554

46382127

1027813

Renal Creatinine elevation 10 1 7 1

Clinical Constitutional Symptoms Fatigue 43 7 45 5

Gastrointestinal Nausea Vomiting Anorexia Constipation Stomatitis/Pharyngitis Diarrhea Dyspepsia/Heartburn

5640272114125

7621110

5336242012136

4610020

Neurology Neuropathy-sensory Taste disturbance

98

00c

129

10c

Dermatology/Skin Alopecia Rash/Desquamation

127

0c

0218

1c

1

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported

as Grade 1 or 2.No clinically relevant differences in adverse reactions were seen in patients based

on histology.In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin

arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%Body as a Whole — febrile neutropenia, infection, pyrexiaGeneral Disorders — dehydrationMetabolism and Nutrition — increased AST, increased ALTRenal — creatinine clearance decrease, renal failureSpecial Senses — conjunctivitis

Incidence Less than 1%Cardiovascular — arrhythmiaGeneral Disorders — chest painMetabolism and Nutrition — increased GGTNeurology — motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction TherapyTable 5 provides the frequency and severity of adverse reactions reported in >5% of

the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.

All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy

ReactionbALIMTA (N=438)

Placebo (N=218)






Laboratory Hematologic Anemia Neutropenia Leukopenia

1566

332

601

101

Hepatic Increased ALT Increased AST

108

00

44

00


Gastrointestinal Nausea Anorexia Vomiting Mucositis/stomatitis Diarrhea

1919975

12011

65123

10000

Infection 5 2 2 0

Neurology Neuropathy-sensory 9 1 4 0

Dermatology/Skin Rash/Desquamation 10 0 3 0


b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients

based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.

Incidence 1% to 5%Dermatology/Skin — alopecia, pruritus/itchingGastrointestinal — constipationGeneral Disorders — edema, fever (in the absence of neutropenia)Hematologic — thrombocytopeniaRenal — decreased creatinine clearance, increased creatinine, decreased

glomerular filtration rate



Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%Cardiovascular — supraventricular arrhythmiaDermatology/Skin — erythema multiformeGeneral Disorders — febrile neutropenia, allergic reaction/hypersensitivityNeurology — motor neuropathyRenal — renal failure

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction TherapyTable 6 provides the frequency and severity of adverse reactions reported in >5%

of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.

The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.

Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

Adverse Reaction Organ System and Term

ALIMTA(N=333)

Placebo(N=167)

All Gradesa

Toxicity (%)Grade 3-4a

Toxicity (%)All Gradesa

Toxicity (%)Grades 3-4a

Toxicity (%)

All Adverse Reactions 53 17 34 4.8

Laboratory Hematologic Anemia Neutropenia

159

4.83.9

4.80.6

0.60

Clinical Constitutional Symptoms Fatigue 18 4.5 11 0.6

Gastrointestinal Nausea Vomiting Mucositis/stomatitis

1265

0.30

0.3

2.41.82.4

000

General Disorders Edema 5 0 3.6 0

a Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo

b NCI CTCAE Criteria version 3.0

Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

Incidence 1% to 5%Blood/Bone Marrow — thrombocytopeniaGeneral Disorders — febrile neutropenia

Incidence Less than 1%Cardiovascular — ventricular tachycardia, syncopeGeneral Disorders — painGastrointestinal — gastrointestinal obstructionNeurologic — depressionRenal — renal failureVascular — pulmonary embolism

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Additional Experience Across Clinical TrialsSepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients.

6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of

ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions occurred with ALIMTA when used as a single-agent and in combination therapies.

Blood and Lymphatic System – Immune-mediated hemolytic anemiaGastrointestinal — colitis, pancreatitisGeneral Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitisSkin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal

necrolysis. Some cases were fatal.

7 DRUG INTERACTIONS

7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Although ibuprofen (400 mg four times a day) can decrease the clearance of

pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.

In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic DrugsALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration

and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].Based on its mechanism of action, ALIMTA can cause fetal harm when administered

to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

8.3 Nursing MothersIt is not known whether ALIMTA or its metabolites are excreted in human

milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric UseEfficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was

administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric UseALIMTA is known to be substantially excreted by the kidney, and the risk of adverse

reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients







6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

10278

13




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS





















FDA Update

Lenvatinib Receives Priority Review Designation for Advanced Thyroid Cancer

The U.S. Food and Drug Adminis-tration (FDA) has given Priority

Review designation to the New Drug Ap-plication for lenvatinib mesylate as a treat-ment for progressive radioactive iodine–refractory differentiated thyroid cancer. Lenvatinib is an oral multiple receptor

tyrosine kinase inhibitor with a unique binding mode that selectively inhibits the kinase activities of vascular endothe-lial growth factor receptors, in addition to other proangiogenic and oncogenic path-way-related tyrosine kinases thought to be involved in tumor proliferation.

Priority Review designation is grant-ed when the FDA believes the drug has the potential to provide “a significant improvement in safety or effectiveness of the treatment, prevention, or diagno-sis of a serious condition.”

Lenvatinib was previously granted

Orphan Drug designation for use in various types of thyroid cancer in the United States, Japan, and Europe. It is currently under investigation in thy-roid, hepatocellular, endometrial, non–small cell lung cancer, and other solid tumor types. n






6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

1027813




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS

























6 ADVERSE REACTIONS









(N=830)







33291810

61554

46382127

10278

13




5640272114125

7621110

5336242012136

4610020


98

00c

129

10c


127

0c

0218

1c

1














Placebo (N=218)







1566

332

601

101


108

00

44

00



1919975

12011

65123

10000

Infection 5 2 2 0




















ALIMTA(N=333)

Placebo(N=167)

All Gradesa




Toxicity (%)



159

4.83.9

4.80.6

0.60



1265

0.30

0.3

2.41.82.4

000

















7 DRUG INTERACTIONS





















Partnering With Community Centers to Advance Oncology CareA Conversation With Richard R. Barakat, MD, FACSBy Jo Cavallo

Last fall, Richard R. Barakat, MD, FACS, the Ronald O. Perelman

Chair in Gynecologic Surgery at Me-morial Sloan Kettering Cancer Cen-

ter, was named to the new position of Deputy Physician-in-Chief for the Memorial Sloan Kettering Regional Care Network and Cancer Alliance, a

new initiative meant to foster a strong partnership with community oncolo-gy providers. The Memorial Sloan Ket-tering Cancer Alliance was borne out

of the realization that while the vast majority of oncology care in the Unit-ed States is delivered by community oncologists, it often can take years for cancer advances developed in compre-hensive cancer centers to be adopted in the community setting, according to Dr. Barakat. The Cancer Alliance was created with the aim of speeding up that process.

The Alliance is also meant to create a new model of care that will reduce the barriers to high-quality cancer care for patients and improve their lives. Among the goals of the newly formed Cancer Alliance is the establishment of Memorial Sloan Kettering clinical trial sites at specific Alliance member hospi-tals to increase the number of patients enrolled in clinical trials. Increasing en-rollment into clinical trials is becoming especially important, said Dr. Barakat, as clinical trials become more complex and are designed based on mutation-driven classification rather than on disease type.

A year ago, Hartford HealthCare, a multihospital health-care system in Connecticut, was selected as the charter member of the newly formed Memorial Sloan Kettering Cancer Alliance. Over that time, experts from Memorial Sloan Kettering and Hartford HealthCare es-tablished a single, elevated standard of care among all five of Hartford Health-Care’s cancer programs, now known collectively as the Hartford Health Care Cancer Institute. In September, the Hartford Health Care Cancer Institute became the first certified member of the Memorial Sloan Kettering Cancer Alliance.

In addition to his position as Depu-ty Physician-in-Chief of the Memorial Sloan Kettering Cancer Alliance, Dr. Barakat is also President of the Society of Gynecologic Oncology (SGO) and the Foundation for Gynecologic On-cology. The ASCO Post talked with Dr. Barakat about the goals of the Cancer Alliance and his agenda for his term as President of SGO.

Director’s Corner


ALIMTA® (pemetrexed for injection) PV 8927 AMP

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics

of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function

will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderOf 3,946 patients (Male 70.5% ) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 RaceOf 3,946 patients (Caucasian 78.6%) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included

neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was

clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA- Approved Patient Labeling (PPI)Instruct patients to read the patient package insert before initiating ALIMTA.• Instructpatientsontheneedforfolicacidandvitamin B12 supplementation to

reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them toimmediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instructpatients tocontact theirphysician if persistent vomiting,diarrhea,orsigns of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescriptionor over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013



Director’s Corner

Project RationaleWhy did Memorial Sloan Kettering

create the Cancer Alliance?The idea was mission-driven and

based on a realization presented in the Institute of Medicine report, Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, which maintained that the majority of cancer care in the United States occurs in the community and not at large compre-

hensive cancer centers. We wanted to export, as was recommended in that report, the latest, most effective treat-ments that are often developed in large comprehensive cancer centers and bring them out more rapidly into the community setting.

In addition, we knew that with all the new advances in medical oncol-ogy, we wanted to expand our access to patients so that they could be included in cutting-edge cancer research. For example, Hartford HealthCare Cancer Institute, the first member in the Can-cer Alliance, sees over 6,000 patients a year. Having access to that many more patients will expand our ability to en-roll greater numbers of patients into clinical trials and bring new treatments to more patients. In fact, the Hartford HealthCare Cancer Institute will in-clude our first clinical trials site estab-lished through the Cancer Alliance.

Central to the Alliance is the con-cept of bidirectional learning, in which both institutions share a willingness to collaborate and learn from each other. The Hartford HealthCare sys-tem consists of five hospitals. We met with members of their disease manage-ment teams focusing on the six most common disease sites treated in the Hartford HealthCare system, includ-ing breast, colon, lung, prostate, endo-

metrial, and kidney cancer, to develop standards of care that we all agree on.

The first phase of the collabora-tion was to look at how Hartford HealthCare physicians practice on-cology, what their standards of care are, and how they compared to ours. We then agreed on acceptable stan-dards, so the Hartford HealthCare system could be aligned with the Me-morial Sloan Kettering system, which

will allow their patients to be treated in a similar manner.

Some of the Hartford HealthCare clinicians have also joined our disease management teams, and it has been a very rewarding experience to provide them with training in new procedures. For example, our gynecologic surgeons have developed a sentinel lymph node mapping system for gynecologic can-cers. Some of Hartford HealthCare’s gynecologic surgeons came to our cen-ter and observed how we do the proce-dure, and they are now starting to use it throughout their hospitals.

Conversely, Hartford HealthCare has a Center for Education Simulation and Innovation, which offers a com-prehensive range of robotic and high-technology training capabilities, and several of our fellows have visited the center to further their surgical train-ing. So the collaboration is allowing us

to practice oncology care in a way that we consider to be standard of care in the most advanced way possible.

Other MembersWho are the other members in the

Cancer Alliance?We are in active discussions with

other several regional institutions, but until the official letter of intent is signed, I can’t talk about who the other

members might be. Our goal is to have a small number of high-quality systems included in the Alliance. This is a heav-ily collaborative and interactive model and, therefore, it will probably only in-volve a few (ie, 3–5) excellent partners.

Community IntegrationWill having this partnership strength-

en community oncology practices?Yes, absolutely. It will align them

with our standards of care, provide access to cutting-edge clinical trials, and allow for new technologies to get diffused into the community setting much more quickly.

Society GoalsWhat are your goals for your Presi-

dential term in the Society of Gynecologic Oncology and the Foundation for Gyne-cologic Oncology?

What is of greatest concern to every-one is how medical care reimbursement will occur in the future, so in 2012 we convened a Practice Summit of thought leaders in gynecologic oncology to as-

sess the health-care system and develop and test new payment systems, includ-ing a diagnosis-based episode bundled payment system. We used endometrial cancer as a disease site, and we plan to come up with a payment model that we can present to insurers.

That is one major focus of ours. An-other is the resolution passed in June by the American Medical Association op-posing any limitation on ordering of ge-netic testing based solely on physician specialty. We support the resolution and are planning a Genetics Summit in January with thought leaders in gyneco-logic oncology to assess the landscape of the current practice of genetic testing and counseling and develop a model for future practice. The last thing we want to see happen is a decrease in access to genetic testing.

We also recently published our endpoints for studies of ovarian can-cer to address the unique character-istics of the disease and improve out-comes for patients.1

Patients with ovarian cancer are living longer. Sometimes when the disease recurs, patients can be com-pletely asymptomatic, so overall sur-vival might not be the best endpoint

for trials in ovarian cancer. When pa-tients have a recurrence, there is often a crossover of treatment, so we pre-sented our concerns about develop-ing meaningful clinical trial endpoints to the U.S. Food and Drug Adminis-tration. We then met in person with the agency and had a constructive dialogue about surrogate endpoints for overall survival when considering drug approval, such as response rate, progression-free survival, patient-reported outcomes, and composite

endpoints that include other features of clinical benefit, such as symptom modulation or physical activity.

We discussed our issues concerning the role of molecular profiling in the community setting, whether clinical tri-als involving agents with no track record of efficacy should be allowed for pa-tients with platinum-sensitive disease, and the addition of molecular targets to upfront therapy. It was an open-forum discussion and it produced some posi-tive results, including the possibility of conducting a workshop to bring more experts into the discussion.

We are pleased that our article helped ignite this important conversa-tion, and I’m looking forward to tack-ling the other issues I mentioned con-fronting gynecologic oncologists, so we can make greater progress in these cancers. n

Disclosure: Dr. Barakat reported no potential conflicts of interest.

Reference1. Herzog TJ, Armstrong DK, Brady

MF, et al: Ovarian cancer clinical trial endpoints: Society of Gynecologic On-cology white paper. Gynecol Oncol 132:8-17, 2014.

Richard R. Barakat, MD, FACS

The collaboration is allowing us to practice oncology care in a way that we consider to be standard of care in

the most advanced way possible. —Richard R. Barakat, MD, FACS

We wanted to export … the latest, most effective treatments that are often developed in large

comprehensive cancer centers and bring them out more rapidly into the community setting.

—Richard Barakat, MD, FACS


ALIMTA® (pemetrexed for injection) PV 8927 AMP

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics

of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function

will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderOf 3,946 patients (Male 70.5% ) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 RaceOf 3,946 patients (Caucasian 78.6%) studied across the five registration studies for

ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included

neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was

clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA- Approved Patient Labeling (PPI)Instruct patients to read the patient package insert before initiating ALIMTA.• Instructpatientsontheneedforfolicacidandvitamin B12 supplementation to

reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them toimmediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instructpatients tocontact theirphysician if persistent vomiting,diarrhea,orsigns of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescriptionor over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013


Take a Closer Look at ALL

Visit www.UnderstandingALL.com

Complete Remission May Not Ensure Survival in Adults with B-ALL (B-cell Acute Lymphoblastic Leukemia)

Of the adult patients with B-ALL who achieve a hematologic complete remission,1,2 44% will eventually relapse,1-3 with only 10% still alive 5 years after their first relapse.4

Several risk factors such as a patient’s age, cytogenetics, and the speed and depth at which a minimal residual disease (MRD) response is achieved can predict risk of relapse.1,3,5-9

Testing at the molecular level for MRD can allow a patient’s risk of relapse to be accurately gauged and treatment to be tailored accordingly.3

Is your treatment approach getting to the molecular level?

References: 1. Jain N, Gurbuxani S, Rhee C, Stock W. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders-Elsevier; 2013:960-980. 2. Hoelzer D. Am Soc Clin Oncol Educ Book. 2013:290-293. doi:10.1200/EdBook_AM.2013.33.290. 3. Hoelzer D, Gökbuget N, Ottmann O, et al. Hematology Am Soc Hematol Educ Program. 2002;162-192. 4. Forman SJ, Rowe JM. Blood. 2013;121:1077-1082. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 8, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Leukemia and Lymphoma Society. Acute Lymphoblastic Leukemia. Published February 2014. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/leukemia/pdf/all.pdf. Accessed July 8, 2014. 7. Rowe JM. Br J Haematol. 2009;144:468-483. 8. Moorman AV, Harrison CJ, Buck GA, et al. Blood. 2007;109:3189-3197. 9. Bassan R, Hoelzer D. J Clin Onc. 2011;29:532-543. © 2014 Amgen Inc. All rights reserved. USA-103-100324

How Well Can Risk of Relapse Be

Predicted in

Adult B-ALL?

08-04405_R01_AAUS_Tabl_1pg_JA_ASCO.indd 1 10/2/14 2:31 PM

http://www.amgenoncology.com


Direct From ASCO

Despite Potential to Overwhelm, Surveys Still Essential Research Tool

The age of the Internet and world-wide connectivity has made it

easier than ever to send out surveys to a wide audience quickly and easily. This ease of access can make surveys an affordable and readily available re-search tool for independent investiga-tors, but it can also make surveys an inbox-crowding nuisance.

“With the Internet, people are get-ting bombarded with all sorts of dif-ferent types of surveys, and people are getting a bit ‘surveyed out,’” said Mark Clemons, MD, of the Division of Medical Oncology at The Ottawa Hos-pital Cancer Centre, Ottawa, Ontario. “Surveys are still important though. They are one of the few research tools that can really drive change, improve the standard of care, and have an over-all societal benefit.”

Dr. Clemons and colleagues re-cently published a Perspective piece titled “Surviving Surveys” in the Jour-nal of Oncology Practice discussing why physicians should still pay attention to academic surveys and offering tips to investigators to help their survey get responses.1

Survey ExplosionIn their article, Dr. Clemons and

colleagues grouped surveys into three categories: (1) surveys sent by pharmaceutical companies, (2) surveys sent for input about clinical trials or clinical practice guidelines, and (3) surveys sent by investigators

researching clinical or practice-relat-ed topics.

A search of the Scopus database for publications in oncology based on investigator-initiated surveys

showed a marked increase in the number of manuscripts citing aca-demic survey research published be-tween 2004 and 2013. However, Dr. Clemons and colleagues pointed out that research has shown a substan-tial decline in survey response rates in recent years, ranging from 36%

to 59%, with Internet-based surveys frequently having lower response rates than traditional mail-based surveys.

These decreasing response rates

should be of concern to the oncology community, Dr. Clemons said.

“Without robust response rates, we will not know if survey results are gen-eralizable to a real-world setting,” Dr. Clemons said. “It is possible that with response rates in the 20% level that the types of people who are respond-ing [to the survey] may be practicing differently than the 80% who are not responding.”

Valuable Research ToolAccording to the Perspective piece,

surveys are a key research tool used to gauge how patients are treated in the real world and to gather the opinions of physicians treating them.

The investigators provided several reasons why physicians should actively participate in surveys when able.

First, a response, even a negative response, can affect survey results. At a minimum, replying to a survey indicating that one does not treat a particular disease may help get a physician removed from an irrelevant mailing list.

With the Internet, people are getting bombarded with all sorts of different types of surveys, and people are getting a bit ‘surveyed out.’ Surveys are still important though. They are one of the few research tools that can really drive change, improve the standard of care, and have an overall societal benefit.

—Mark Clemons, MD

Progress Against Cancer: A Snapshot

F ive decades ago, cancer was viewed as a monolithic and

largely untreatable disease, with only a handful of hard-to-tolerate and mostly ineffective therapies avail-able. Since that time, major U.S. in-vestments in cancer research have led to dramatic improvements in our biologic understanding of cancer and important advances in our ability to treat and prevent the disease.

As a result, more people are sur-viving cancer than ever before. To-day, two out of three people live at least 5 years after a cancer diagnosis, up from roughly one out of two in the 1970s. There are nearly 14 million survivors in the United States alone. Fueled by earlier detection and better treatments, the nation’s cancer death rate has dropped 20% since the early 1990s, reversing decades of increases.

Highlights of Cancer Progress• Targeted therapies: Highly tai-

lored, more effective treatments have been developed to target the genetics of many cancers, providing better cancer control and fewer side effects.

• Drug approvals: The number of drugs available to treat cancer grew from just a handful to more than 170 drug indications today, most ap-proved in the last decade.

• Surgical advances: Today’s cancer surgeries are more precise, less dis-figuring, and produce fewer com-plications than in the past, without sacrificing effectiveness.

• Radiation therapy: Advanced tech-nologies allow radiation to be tai-lored to each patient’s tumor type, size and location, improving survival and minimizing the risk of serious

side effects such as lung scarring and heart damage.

• Multidisciplinary treatment: Many patients now receive care-fully-honed combinations of treat-ments—including chemotherapy, surgery, radiation and/or targeted drugs—to extend survival and offer the best chance for cure.

• Side effects management: Better ways of managing nausea, pain, and other side effects are enabling pa-tients to live better, more fulfilling lives.

• Major successes: Revolutionary progress against some cancers shows what is possible. Five-year survival

rates for breast cancer, testicular can-cer, and some childhood cancers are now over 90%.Under the guidance of an editorial

board of 20 of the nation’s leading oncolo-gists, ASCO has developed an interactive Cancer Progress Timeline that highlights some of the most important advances that have contributed to progress against cancer. To explore the timeline, visit CancerProgress.net/timeline. n

Selected portions reprinted from CancerProgress.Net. © American Society of Clinical Oncology. “Progress Against Can-cer: A Snapshot.” www.cancerprogress.net, 2014. All rights reserved.


Gastrointestinal Cancers SymposiumJanuary 15-17, 2015

Moscone West Building

San Francisco, California

Genitourinary Cancers SymposiumFebruary 26-28, 2015

Rosen Shingle Creek

Orlando, Florida

Save the Date


Direct From ASCO

Illumination and Innovation: Transforming Data Into LearningBy Peter Paul Yu, MD, FACP, FASCO

“Illumination” is a provocative word, evoking as it does the ban-

ishment of the darkness of ignorance by the light of new knowledge. Today, we are benefiting from a steady stream of new knowledge about the molecu-lar basis of cancer and the interaction between host and tumor immunology. The concept of patient-centered care is illuminating how we view the role of patients in shared decision-making, the definition of quality of care, and the pro-fessional responsibility of physicians.

At the same time, the challenge of delivering cancer care that incorporates these advances in thinking, both in the United States and globally, are signifi-cant societal hurdles. Innovation—the creative use of illumination to transform how we improve the lives of patients

with cancer in a sustainable and scalable manner—is the necessary companion to illumination.

Rapid Learning Health SystemsAs physician-scientists, we are accus-

tomed to using data to generate and test new models. Propitiously, the arrival of digital health has provided an invaluable source of new data from which to gener-ate knowledge and learning. The blend-ing of big health data and medical infor-matics now gives us a tool with which to accelerate learning, a concept described as “Rapid Learning Health Systems.” These data sets are derived from real-world patient experiences, and conse-

quently, the data they contain reflect how patients with cancer are treated in the daily practice of medicine, the ben-efit and harm patients experience, the efficiency of care delivery, and most in-terestingly, the variation in all of this.

If we are able to match these data sets with data on patient outcomes and con-sumption of medical resources, we will be positioned to contribute new knowl-edge to the health-care reform discus-sion. CancerLinQ™ is ASCO’s version of a Rapid Learning Health System ap-plied to oncology. We anticipate that it will provide insights for the design of new models of cancer care delivery that are sustainable and that address societal objectives, provide supportive mecha-nisms to sustain a thriving community practice base, and allow the voice of the physician to be resonant. By sharing our data, we all receive in return something that is greater than the sum of the parts.

Presidential ThemeMy Presidential theme for ASCO’s

51st year is Illumination and Innovation: Transforming Data Into Learning. With the transformation of data into knowl-edge and thence from knowledge to learning lies an unprecedented oppor-tunity to move our health-care delivery and research systems forward. It begins with a willingness to share our data and involves analysis of that data in ways that will seem foreign and new, along with

agile thinking to accept the knowledge and apply it. The most difficult part will be the recognition that the authority of conventions is often derived more from

the comfort of habit than from reason. Illumination and innovation are

how the most adaptable will survive in a changing environment. As on-cologists, we have always been and always will be at the forefront of cre-ativity and disruptive change; it is the nature of who we are, and why we en-deavor in this most difficult of medi-cal specialties to illuminate the path forward. n

Selected portions reprinted from ASCO Connection. © American Society of Clinical Oncology. “Illumination and Innova-tion: Transforming Data into Learning.” connection.asco.org. June 2, 2014. All rights reserved.

Dr. Yu is the 2014-2015 President of ASCO. He is a medical oncologist and hematologist, Director of Cancer Research at Palo Alto Medical Foundation, and a member of the Alliance for Clinical Trials in Oncology and the Gynecologic Oncology Group (GOG). He is also the Chair of ASCO’s Research, Policy & Practice Subcommittee, an ASCO Liaison to the College of American Patholo-gists Cancer Biomarker Reporting Com-mittee, and Past Chair of the ASCO HIT Working Group.

We anticipate that [CancerLinQ] will provide insights for the design of new models of cancer care delivery that

are sustainable and that address societal objectives, provide supportive mechanisms to sustain a thriving community practice base, and allow the voice of the

physician to be resonant. —Peter Paul Yu, MD, FACP, FASCO

Top 10 most-accessed articles published in 2011 in Journal of Clinical Oncology

Top 5 articles recently published in

Journal of Oncology Practice

What’s Hot in

JOPEnd-of-Life Care for Blood Cancers: A Series of Focus Groups

With Hematologic Oncologists

by Oreofe O. Odejide, et al

Improving the Quality of Care for Patients Diagnosed With

Glioma During the Perioperative Period

by Natalie B.V. Riblet, et al

Are Patients With Thoracic Malignancies at Risk for Uncontrolled

Symptoms

by Manali I. Patel, et al

Clinic Offering Affordable Radiation Therapy to Increase Access

to Care for Patients Enrolled in Hospice

by Jessica M. Schuster, et al

Patients Prefer Chemotherapy on the Same Day As Their Medical

Oncology Outpatient Appointment

by Peter K.H. Lau, et al

JOP.ascopubs.org

Volume 7, Issue 3 May 2011

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al

Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al

Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

Journal of oncology Practice

www.jop.ascopubs.org

http://jop.ascopubs.org/content/early/2014/10/07/JOP.2014.001537.abstract










Our Roots Go DeepTake a deeper look at our reliability and qualityvisit biotechnologybyamgen.comDownload the LAYAR app on your smartphone and scan this page.

At Amgen, we pour commitment, passion, and a drivefor perfection into every biologic medicine we make.

From innovative biotechnology to extensive experience in biologic manufacturing, see how Amgen strives to deliver on its commitment to your patients.

©2014 Amgen Inc. All rights reserved. 80012-R2-V1

our roots go deepFor reliability and quality,

http://www.amgenbiotech.com


Direct From ASCO

Conquering Cancer.

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer

worldwide by funding breakthrough research and sharing

cutting-edge knowledge. We are the go-to organization

in supportingthe world’s preeminent cancer specialists,

so one day we can live in a world free from the fear of

cancer. To get to know us better now and be a part of our

ambitious future, visit ConquerCancerFoundation.org.

Together, anything is possible.

DonATe ToDAY!ConquerCancerFoundation.org

ASCO Recruits Members to Help Improve Access to Colorectal Cancer Screening, Follow-up Care

ASCO is among the medical profes-sional societies supporting the Na-

tional Colorectal Cancer Roundtable (NCCRT) by recruiting physician leaders from within its membership for a pilot pro-gram called Links of Care. The program

was established to promote health equity and to improve access to colorectal can-cer screening and follow-up care among patients at community health centers.

Following a competitive selection process, three Federally Qualified Health

Centers (FQHCs) in New Haven, Con-necticut, Port Royal, South Carolina, and St. Paul, Minnesota, received grant funding to launch the pilot programs. Each pilot community will develop local models that address barriers to colorec-

tal cancer screening tests and follow up care for patients served by community health centers. n

© 2014. American Society of Clinical Oncology. All rights reserved.

CancerLinQ™ Receives Major Commitment From CTCA®The Conquer Cancer Foundation of

ASCO has received a major com-mitment of support for the development of CancerLinQ™ from Cancer Treatment Centers of America, Inc (CTCA), a na-tional network of five cancer hospitals. The donation is the largest received to date in support of CancerLinQ, a cutting-edge health information technology platform that will harness “big data” to revolution-ize how we care for people with cancer.

“We are grateful for Cancer Treat-ment Centers of America’s support of CancerLinQ,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “CancerLinQ will allow us to learn from the experiences of every person living with cancer and, thus, transform the way it is understood and treated.”

“Since our founding 25 years ago, we have been committed to care and treat-ment of patients battling complex or ad-

vanced-stage diagnosis,” said CTCA Pres-ident and CEO Gerard van Grinsven. “We have also been ardent supporters of the need to bring emerging evidence-based therapies directly to the patient bedside, as quickly as possible. We believe the ASCO CancerLinQ program ranks among the most exciting developments in the evolution of cancer care and so, consistent with this commitment, we are delighted to contribute to its further de-

velopment and implementation for the benefit of cancer patients everywhere.”

CancerLinQ is supported by the Conquer Cancer Foundation of ASCO. CancerLinQ is a project of ASCO’s Institute for Quality. For more infor-mation, please visit: www.asco.org/ cancerlinq. n



Direct From ASCO

Latest Patient Booklet From ASCO and Cancer.Net: Palliative Care

ASCO Answer’s new Palliative Care booklet teaches patients

and their families about this special-ized area of medicine, explaining the difference between palliative care and hospice care and how palliative care is more than receiving a drug to ease physical symptoms. The booklet also includes questions to ask your health-care team, as well as a list of organiza-tions that provide more information and support.

Copies can be purchased at www.cancer.net/estore. ASCO mem-bers receive a 20% discount, and ship-ping is free. n


Second, survey-based research can play an important role in patient care and determining funding decisions re-lated to specific problems or diseases. Third, surveys provide physicians with an outlet to get their opinions heard. Finally, a physician’s willingness to participate allows them to contribute to improving patient care.

“Surveys also help the career de-velopment of the new generation of physicians who are going to be looking after us all in the future,” Dr. Clemons said.

Surveys offer a unique opportunity to bring young investigators forward into the research world. By answering surveys, physicians can help enable trainees to get great research training and, ultimately, become independent investigators, he said.

Make Surveys Stand OutDr. Clemons said that even within

his large academic group surveys are great research tools to investigate phy-sician opinions and practices, especial-

ly as peer-reviewed research funding budgets decrease.

He and his colleagues offered sever-al tips to investigators who use surveys to help gain respondents:• Use a total design approach, which

focuses on providing an incentive, designing user-friendly question-naires, employing a follow-up strat-

egy, and providing a return stamped envelope.

• Keep the survey brief and personal-ized to get optimal response rates.

• Implement follow-up, such as with an additional copy of the survey at a later time, or following up via the telephone. “Keep it short and keep it topical,”

Dr. Clemons recommended. n

Reference1. Mazzarello S, Clemons M, Graham

ID, et al: Surviving surveys. J Oncol Pract. August 5, 2014 (early release online).


Surveys as Research Toolcontinued from page 43

Key inclusion criteria• Metastatic or unresectable locally advanced NSCLC • T790M mutation-positive tumor • Progression after only one prior EGFR-targeted therapy • Previous treatment with ≤1 prior chemotherapy • No intervening treatment between prior EGFR-targeted therapy and rociletinib

Primary endpoint• Objective response rate

Rociletinib(CO-1686)

NOW ENROLLING: 2L T790M+ MUTANT EGFR NSCLC

Evaluating the safety and efficacy of rociletinib (CO-1686) in patients withnon–small cell lung cancer (NSCLC) with the T790M EGFR mutation

Call:• 1-855-262-3040 (inside the United States) • +1-303-625-5160 (outside the United States)

Visit:• TIGERtrials.com• clinicaltrials.gov (NCT01526928)

E-mail:• [email protected]

Learn more about all ongoing TIGER clinical trials at TIGERtrials.com.

Rociletinib (CO-1686) is an investigational product and is not approved in any country.

Copyright © 2014 Clovis Oncology. ROCI-201 9/14

For more details about the TIGER 2 trial or to refer a patient

26186_clovco_fa1_ascopst.indd 1 10/9/14 2:06 PM

http://www.clovisoncology.com


Best of ASCO®

For Triple-Negative Breast Cancer, Adding Carboplatin to Anthracycline/Taxane Produces Benefit, but How Much?By Charlotte Bath

Combination chemotherapy for triple-negative breast cancer is

anthracycline- and taxane-based and has not really changed much in the past 10 years, but “we are starting to see emerging data with selective ac-tivity of platinum agents,” Priyanka Sharma, MD, told participants at the Best of ASCO Chicago session she moderated on triple-negative breast cancer.

Dr. Sharma, Associate Professor of Medicine, University of Kansas School of Medicine, Kansas City, reported on four randomized phase II studies showing improvement in pathologic complete response in early-stage tri-ple-negative breast cancer when car-boplatin is added to the anthracycline/taxane treatment backbone. The mag-nitude of long-term benefit from car-boplatin is still not known, Dr. Sharma noted, and the survival data are “eager-ly awaited.”

Dr. Sharma also reviewed bio-marker studies showing that germline BRCA1/2 status does influence sys-temic treatment response in triple-negative breast cancer. Higher patho-logic complete response rates occurred among patients with genetic muta-tions and those with a family history of breast or ovarian cancer.

Greater Risk of Relapse“Women with [triple-negative breast

cancer] are at greater risk of relapse for every stage of breast cancer, so it is clear that we need to improve on systemic therapy,” Dr. Sharma stated. “The re-lationship between BRCA defects and triple-negative breast cancer has been established,” she noted. There are phe-notypic and molecular similarities be-tween BRCA1-associated breast cancer and sporadic triple-negative breast can-cer, and 10% to 20% of triple-negative breast cancers harbor germline BRCA mutations. Moreover, nongermline BRCA1/homologous recombination defects may be present in up to 50% of triple-negative breast cancer cases.

The relationship between BRCA de-fects and triple-negative breast cancer has therapeutic implications. “BRCA1 deficient and basal-like cell lines dem-onstrate unique chemosensitivities,” Dr. Sharma said. They include a greater sensitivity to platinum agents and gem-citabine, a lack of selective sensitivity

to anthracyclines, and a decreased sen-sitivity to taxanes. Platinum agents are being explored for use in women with triple-negative breast cancer, with most of the insights into their use coming from neoadjuvant trials.

Neoadjuvant Carboplatin With Paclitaxel

Women with stage II/IIIa HER2-negative breast cancer treated neoad-juvantly with weekly paclitaxel and carboplatin followed by CEF (cyclo-phosphamide/epirubicin/fluorouracil) had a significantly improved pathologic complete response compared to those who received paclitaxel alone before CEF, in a study by Tamura et al.1 Among the 181 eligible patients, there were 75 with triple-negative breast cancer.

The pathologic complete response rate was 31.8% among 88 patients re-ceiving carboplatin with paclitaxel vs 17.6% for 91 patients receiving pacli-taxel without carboplatin (P = .01). In the triple-negative subgroup, the pathologic complete response rate was 61.2% with carboplatin vs 26.3% with-out carboplatin (P = .003).

Dr. Sharma pointed out the differ-ences in EGFR expression among the tu-mor samples obtained from 46 patients. Overall, 45% of EGFR-positive patients had pathologic complete response, com-pared to 11.5% of EGFR-negative pa-tients (P = .010). Among those receiving carboplatin with paclitaxel, the patho-logic complete response rate was 63.8% for EGFR-positive patients vs 18.2% for EGFR-negative patients (P = .040). However, EGFR was more likely to be a surrogate for triple-negative status rather than a response biomarker.

Neoadjuvant Carboplatin With Docetaxel

Neoadjuvant carboplatin with docetaxel produced encouraging

pathologic complete response rates, which were similar to observed rates for neoadjuvant doxorubicin/cyclo-phosphamide/taxane plus carboplatin combinations, but without the poten-tial cardiac and secondary leukemia toxicities, according to a study led by Dr. Sharma.2 Following neoadjuvant therapy and surgery, 32 out of 49 pa-tients with triple-negative breast can-cer (65%) had achieved pathologic complete response, including 22 out of the 36 patients (61%) with BRCA1/2 wild-type disease vs 10 out of 13 pa-tients (77%) with a BRCA mutation (P = .50).

Rates for near–pathologic complete response were based on a residual cancer burden score of 0 or 1 follow-ing neoadjuvant therapy and surgery.

Overall, 38 patients (78%) achieved near–pathologic complete response, including 27 patients (75%) with BRCA1/2 wild-type disease and 11 patients (85%) with a BRCA mutation (P = .70).

Postneoadjuvant Therapy Residual disease predicts high risk of

relapse, Dr. Sharma observed, but due to lack of data on efficacy of alternative agents in this setting, the current stan-dard is no further therapy. Carefully de-signing and conducting residual disease adjuvant trials is a valuable opportunity for patients and science, she said. Alter-native ways of thinking about residual disease include the possibility that the wrong neoadjuvant chemotherapy agents were chosen and it might be beneficial to investigate something dif-ferent, or perhaps blood markers can be used to identify patients with residual disease who are likely to experience ear-ly relapse.

A study by Turner et al3 concluded that patients with detectable muta-tions in circulating free DNA fol-

lowing treatment for primary breast cancer “are at high risk of relapse and may be suitable candidates for thera-peutic trials of novel agents.” Results of this study discussed by Dr. Sharma showed that among 31 patients with early-stage breast cancer, who received neoadjuvant chemotherapy, muta-tion tracking in blood predicted early relapse in 4 of the 5 patients who re-lapsed (detected on the 6-month post-surgery specimen). Among the five patients who developed recurrence, three were HER2-positive, one was es-trogen receptor–positive, and one had triple-negative breast cancer.

The median follow-up of this study was short at 17 months, so the ability to detect late relapse is still unknown, Dr. Sharma noted. She added, how-ever, that the study is “an important proof-of-concept study with the po-tential to guide patient selection in postneoadjuvant therapy trials.”

Based on preclinical data suggest-ing that the combination of DNA-damaging chemotherapy and inhibi-tion of poly(ADP-ribose)polymerase (PARP) is synergistic in BRCA-defi-cient and triple-negative breast cancer cell lines, Dwadasi et al4 compared postoperative cisplatin with or with-out the investigational PARP inhibitor rucaparib among women with triple-negative breast cancer or known BRCA mutation–associated breast cancer. Eligible patients had residual lymph node involvement or > 2 cm invasive disease after anthracycline- or taxane-based neoadjuvant therapy.

Prior treatment with cisplatin was not allowed, but prior treatment with carboplatin was. Among the 128 pa-tients enrolled, the median tumor size at surgery was 1.9 cm (range, 0–11.5 cm) and the median number of lymph nodes involved was 1 (range, 0–38).

Disease-free survival at 1 year was similar at 82% in the two arms. Dr. Sharma pointed out that the dose of rucaparib used in this trial was much lower than the currently recommend-ed phase II single-agent dose of 600 mg orally twice daily. An “interesting observation,” according to Dr. Sharma, was the underutilization of clinical BRCA testing, with only 30% of BRCA mutations identified as part of rou-tine clinical care. Another interesting observation was that there have been

The key to moving forward [in the treatment of triple-negative breast cancer] is to look at biomarkers of response.

—Priyanka Sharma, MD

Breast Cancer


Best of ASCO®

50 Years of Advancements in Treating Breast Cancer Have Led to Tumor-Centered Treatment AlgorithmBy Charlotte Bath

Transformations in the treatment of early-stage breast cancer have

shifted the therapeutic approach from a “stage-centered treatment algorithm” to a “tumor biology-centered treatment algorithm,” Priyanka Sharma, MD, Associate Professor of Medicine, Uni-versity of Kansas School of Medicine, Kansas City, stated at the recent Best of ASCO meeting in Chicago. Dr. Sharma summarized advances in breast cancer treatment in the past 50 years as a pre-lude to the session she conducted on triple-negative breast cancer.

Key AdvancesAs an example of the more tumor-

centered approach, Dr. Sharma point-ed out that 50 years ago, the standard surgical treatment was radical mastec-tomy, including removal of the breast, pectoralis muscle, and regional lymph nodes. In contrast, the current stan-dard is breast-conservation treatment with sentinel lymph node dissection, even moving toward omitting axillary lymph node dissection for some pa-tients with node-positive disease.

Radiotherapy, used 50 years ago only

for mastectomy in high-risk disease, has now been widely adopted for treating breast cancer, due to improved efficacy, decreased toxicity, and faster, more con-venient treatment. Chemotherapy has evolved from regimens based on cyclo-phosphamide, methotrexate, and fluoro-uracil to those based on an anthracycline and taxane, and tumor biology–driven assays to omit chemotherapy in early-stage hormone-positive breast cancer are

now routinely used in clinical practice. Another major development was

the use of adjuvant chemotherapy with trastuzumab (Herceptin) for HER2-positive breast cancer. In addi-tion, endocrine treatments for wom-en with hormone receptor–positive disease have decreased recurrence and increased survival.

“Large randomized studies done by the cooperative groups have defined ev-ery therapeutic principle in treatment of early-stage breast cancer over the past 50 years,” Dr. Sharma noted.

Remaining ChallengesMany challenges remain, she added.

They include reconciliation of discor-dant stage/biology findings, standard-ization of next-generation pathology,

de-escalation of therapy in patients with good prognosis, staying on the lookout for other major breast cancer–predis-posing genes, organization of clinical tri-als and definition of success keeping in mind intratumor and intertumor hetero-geneity and determination of which ab-errations are critical to target, especially for triple-negative breast cancer. n

no recurrences among eight BRCA mutation carriers treated on the ruca-parib arm.

Another investigational PARP in-hibitor, olaparib, is being tested as ad-juvant therapy in BRCA mutation car-riers in the OlympiA trial, Dr. Sharma reported. That trial includes patients with residual disease following neo-adjuvant therapy with six cycles of anthracycline-based and/or taxane-based therapy.

Biomarkers of Response“The key to moving forward,” Dr.

Sharma said, “is to look at biomark-ers of response,” and two biomarker analyses from the GeparSixto trial did that. Building on previous findings that tumor-infiltrating lymphocytes are linked to response to carboplatin-based chemotherapy and prognosis among patients with triple-negative breast cancer, Denkert et al5 evaluated 12 immunologically relevant genes in 481 core biopsies (83% of GeparSixto samples).

The investigators reported that all

12 of the immune markers “were signif-icantly linked” to increased pathologic complete response rates in univariate analysis, and 11 “were also significant in multivariate analysis, including clinical parameters.” In addition, some markers “showed a significant interac-tion with treatment.”

The 12 immune mRNA markers were measured by quantitative reverse transcription–polymerase chain re-action assay and correlated well with tumor-infiltrating lymphocytes. Dr. Sharma remarked that the visual as-sessment is inexpensive and tissue-efficient. The use of tumor-infiltrating lymphocytes and immune genes as biomarkers of response in triple-nega-tive breast cancer “has potential thera-peutic implications” for other targeted agents like PD-1 and PD-L1 antibod-ies, she stated.

The use of immune marker mRNAs in addition to tumor-infiltrating lym-phocytes to identify patients with increased response to carboplatin requires further validation in other breast cancer trials. Future studies

should seek to correlate tumor-infil-trating lymphocytes/immune genes with other potential predictors of plati-num response, such as germline BRCA mutations and genomic instability, Dr. Sharma added.

Another GeparSixto correlative study by von Minckwitz et al6 found that germline BRCA1/2 and RAD mu-tations as well as a family history of breast and/or ovarian cancer can iden-tify patients most likely to benefit from carboplatin. “This is the first random-ized study to report on germline BRCA status,” Dr. Sharma stated. She antici-pated that 8 to 10 more germline BRCA alterations are likely to be identified by GeparSixto and said that survival data are expected in 2015. (Details of that study were reported in the August 15, 2014, issue of The ASCO Post.)

Clinical RealityDespite the established benefit

of germline BRCA testing in women newly diagnosed with breast cancer, “the reality in clinics,” Dr. Sharma noted, is that only about 44.5% of

women are tested. “Insurance coverage can be denied for up to 20% of triple-negative breast cancer patients meet-ing National Comprehensive Cancer Network (NCCN) criteria for testing,” Dr. Sharma reported. “We capture a complete family history in less than one-third of these cancer patients. So obviously one of the take-home mes-sages is that we need to improve family history–taking and genetic counseling and testing efforts,” she remarked.

“Looking beyond germline BRCA1/2 mutations, there are other factors” that might influence systemic treatment response among patients with triple-negative breast cancer, Dr. Sharma said. They include tumor ge-nomic instability, BRCA 1 epigenetic silencing, and germline and somatic mutations in other homologous re-combination pathway genes.

Ongoing and Upcoming TrialsDr. Sharma is serving as principal

investigator of a correlative study that will evaluate “BRCAness” as a prog-nostic marker in patients with triple-negative breast cancer treated with adjuvant anthracycline-based chemo-therapy. A panel of BRCAness markers will be performed on tumor tissue ge-nomic DNA and RNA taken from tu-mor tissue samples from 443 patients. Each marker will be evaluated indi-vidually and an exploratory analysis performed of interaction between all the markers.

A SWOG phase II study in devel-opment will be investigating whether the addition of a PARP inhibitor to platinum-based therapy improves progression-free survival for patients with germline BRCA mutation–associ-ated breast cancers and sporadic triple-negative breast cancers that express the BRCAness phenotype. Patients with metastatic triple-negative breast cancer and BRCA mutation–associated breast cancer will be randomly assigned be-tween cisplatin/vinorelbine with or without veliparib. All patients will have germline BRCA testing after random-ization and will then be assigned to the BRCA–confirmed negative or BRCA–confirmed positive group.

Two upcoming randomized, phase III trials involve patients with triple-negative breast cancer who have re-sidual disease after treatment with neoadjuvant chemotherapy. One trial will compare postoperative platinum-based chemotherapy to observation. The other trial, which is in develop-ment, will evaluate the efficacy and

Large randomized studies done by the cooperative groups have defined every therapeutic principle in treatment of early-stage breast cancer

over the past 50 years. —Priyanka Sharma, MD


Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3

Learn more at MelanomaAntigens.com

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.

Dendritic cell

©2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568

In melanoma…

T cell

A T CELL IS ONLY AS EFFECTIVE AS THE ANTIGEN THAT ACTIVATES IT1

T:21”

T:14”

B:21.5”

B:14.25”

TVUS14CDNY5955_C_DSE_JA_Spread_KING_SS_r3.indd All Pages 9/23/14 11:23 AM

Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3

Learn more at MelanomaAntigens.com

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.

Dendritic cell

©2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568

In melanoma…

T cell

A T CELL IS ONLY AS EFFECTIVE AS THE ANTIGEN THAT ACTIVATES IT1

T:21”T:14”

B:21.5”B:14.25”

TVUS14CDNY5955_C_DSE_JA_Spread_KING_SS_r3.indd All Pages 9/23/14 11:23 AM

http://www.amgenoncology.com


Best of ASCO®

safety of PD-1 antibody MK-3475 as adjuvant therapy in patients with > 1 cm residual invasive cancer or any positive lymph nodes after neoadju-vant chemotherapy. n

Disclosure: Dr. Sharma reported no potential conflicts of interest.

References1. Tamura K, Hashimoto J, Tsuda H, et

al: Randomized phase II study of weekly paclitaxel with or without carboplatin fol-

lowed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA HER2-negative breast can-cer. ASCO Annual Meeting. Abstract 510. Presented June 2, 2014.

2. Sharma P, Stecklein S, Klemp JR, et al: Efficacy of neoadjuvant carboplatin/docetaxel based chemotherapy in spo-radic and BRCA mutation associated triple-negative breast cancer. ASCO An-nual Meeting. Abstract 1022. Presented June 2, 2104.

3. Turner NC, Garcia-Murillas I, Schi-avon G, et al: Tracking tumor specific mu-

tations in circulating-free DNA to predict early relapse after treatment of primary breast cancer. ASCO Annual Meeting. Abstract 510. Presented May 31, 2014.

4. Dwadasi S, Tong Y, Walsh T, et al: Cisplatin with or without rucaparib after preoperative chemotherapy in pa-tients with triple-negative breast can-cer (TNBC): Hoosier Oncology Group BRE09-146. ASCO Annual Meeting. Ab-stract 1019. Presented June 2, 2104.

5. Denkert C, von Minckwitz, Brase JC, et al: Expression of immunologic genes in triple-negative and HER2-positive breast

cancer in the neoadjuvant GeparSixto trial: Prediction of response to carbopla-tin-based chemotherapy. ASCO Annual Meeting. Abstract 510. Presented May 31, 2014.

6. von Minckwitz G, Hahnen E, Fas-ching PA, et al: Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto. ASCO Annual Meeting. Abstract 1005. Presented June 2, 2104.

Triple-Negative Breast Cancercontinued from page 49

Variety of Adjuvant Strategies Explored in HER2-Positive and Other Breast Cancer TypesBy Charlotte Bath

Adjuvant trastuzumab (Herceptin) was shown to be effective in pa-

tients with breast cancers ≤ 2 cm, re-gardless of estrogen receptor status, in a meta-analysis1 of five chemotherapy trials, but a “pressing question” remain-ing is whether T1a/b, N0 tumors war-rant the use of adjuvant trastuzumab, Andrew D. Seidman, MD, com-mented at the Best of ASCO meeting in Chicago. Dr. Seidman is Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medi-cine at Weill Cornell Medical Center, New York.

Among a total of 12,589 patients with HER2-positive tumors, 4,220 had tumors ≤ 2 cm, with 2,588 receiving trastuzumab and 1,632 not receiving the monoclonal antibody. “Propor-tional benefit was similar for [hormone receptor]–positive and [hormone re-ceptor]–negative cohorts, but the pat-terns and incidence of relapse appeared to differ over follow-up time,” Dr. Seid-man noted.

At 8 years, the cumulative recur-rence rate for patients with hormone receptor–positive disease was 12.7% for those receiving trastuzumab vs 19.4% for those in the observation arm—an 8-year gain of 6.7% (hazard ratio [HR] = 0.64, P = .005)—and the respective cumulative mortality rates were 5.3% vs 7.4%, a gain of 2.1% (HR = 0.68, P = .12). For patients with hormone recep-tor–negative disease, the cumulative re-currence rates at 8 years were 24.0% for those receiving trastuzumab vs 33.4% for patients in the observation arm—an 8-year gain of 9.4% (HR = 0.7, P = .0001)—and the respective cumulative mortality rates were 12.4% vs 21.2%, a gain of 8.8% (HR = 0.6, P =.0001).

The five studies were the Herceptin Adjuvant (HERA) trial, North Central Cancer Treatment Group (NCCTG) N9831 trial, National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, PACS 04 trial, and Finland Herceptin (FinHER) trial. The analy-sis was conducted by researchers at the National Cancer Institute and others in this country and in Europe.

More Pressing QuestionDr. Seidman posed the question

of whether hormone receptor status predicts specific benefit from adjuvant trastuzumab in small tumors. The an-swer, he said, is no.

“We shouldn’t be selecting for the use of trastuzumab based on hormone re-

ceptor status. This is consistent with and reinforces current guidelines. I think the more pressing question that these data don’t really get at, is whether smaller T1 cancers warrant adjuvant trastuzumab. These patients were underrepresented in this analysis,” Dr. Seidman.

Single-center studies have looked at the smaller T1a/b, N0 tumors. Dr. Se-idman cited an MD Anderson Cancer Center series finding worse outcomes for patients with small node-negative

cancers that are HER2-positive com-pared to HER2-negative in the absence of trastuzumab therapy.2 At 5 years, the relapse-free survival rate was 77.1% in HER2-positive patients vs 93.7% in HER2-negative patients. Similarly, the National Comprehensive Cancer Net-work (NCCN) series presented at the 2013 ASCO Annual Meeting showed a worse outcome for HER2-positive patients, with a 5-year disease-free sur-vival rate of 83.3% vs 89.0% for HER2-negative patients.3

Standard of Care for Select Patients

In a nonrandomized registry study, patients with breast cancer that was HER2-positive, estrogen receptor–neg-

ative or –positive, node-negative, and with tumors ≤ 3 cm were treated with paclitaxel plus trastuzumab, followed by continuation of trastuzumab every 3 weeks for a up to a year. There was no randomization, and patients were com-pared to historical controls.

“These results show excellent out-comes for these patients, with very few events, a 3-year disease-free survival rate of 98% for T1c breast cancers, and of 99.5% for T1a/b breast cancers,” Dr.

Seidman stated. “In my institution, this does represent the standard of care for select patients with smaller, node-nega-tive, HER2-positive breast cancers, spe-cifically in scenarios where you might think anthracyclines are to be avoided, even the use of regimens such as TCH [docetaxel, carboplatin, trastuzumab].”

The paclitaxel-plus-trastuzumab reg-imen used in the study described above will be compared to ado-trastuzumab emtansine (Kadcyla, formerly known as T-DMI) for women with stage I, HER2-positive breast cancer in the ATEMPT trial.4 The primary outcome measure is disease-free survival. Secondary out-come measures include overall survival and, within a 2-year time frame, the per-centage of participants with grade 3/4 cardiac dysfunction, grade 2–4 throm-bocytopenia, and amenorrhea at vari-ous time points after start of treatment in premenopausal women. Estimated enrollment is 500 patients, and recruit-ment is still open.

Bevacizumab Not Very Promising in Breast Cancer

Incorporating bevacizumab (Avas-tin) into adjuvant therapy containing an anthracycline and a taxane did not im-prove invasive disease–free survival or overall survival, the primary endpoints of Eastern Cooperative Oncology Group (ECOG) 5103,5 one of several other breast cancer studies reviewed at the Best of ASCO. At a median follow-up of 47.5 months, “there was abso-lutely no signal that survival would be improved [with the addition of bevaci-zumab],” Dr. Seidman said. “This is an-other negative study for bevacizumab.”

He noted that the results “are simi-

Breast Cancer

We shouldn’t be selecting for the use of trastuzumab based on hormone receptor status…. I think the more pressing question … is whether smaller T1 cancers warrant adjuvant trastuzumab.

—Andrew D. Seidman, MD



Best of ASCO®

lar and consistent with two previous adjuvant studies,” the BEATRICE6 and BETH7 trials. “For the moment, it doesn’t look very promising for bevaci-zumab in breast cancer,” he stated.

The rationale for the study was that since tumor growth is dependent on an-giogenesis, and proangiogenic pathways are more numerous and redundant as cancer progresses, giving bevacizumab in the adjuvant setting might provide greater benefit. The drug has been shown to improve progression-free survival, al-though not overall survival, in patients with metastatic breast cancer.

All patients received doxorubicin and cyclophosphamide followed by weekly paclitaxel. In addition, patients were randomly assigned to one of three groups and received either placebo (arm A), bevacizumab during chemotherapy (arm B), or bevacizumab during che-motherapy followed by bevacizumab monotherapy for 10 cycles, adminis-tered concurrently with radiation and hormonal therapy (arm C). Bevacizum-ab exposure “was less than anticipated,” according to the study abstract, with about 24% of patients in arm B and 55% in arm C discontinuing bevacizumab before completing planned therapy.

Higher Rate of Congestive Heart Failure

The median age of patients was 52, and 62% of patients in all treatment arms had estrogen receptor–positive breast cancer. Between 50% and 52% of patients in all arms had tumors in the > 2 to ≤ 5 cm range, and 10% had tumors > 5 cm. Lymph node status was similar for patients in all three arms, with 26% negative, 43% with one to three positive nodes, and 31 with at least three posi-tive nodes.

Local therapy was also similar across arms, with the most common treat-ments being breast-conserving surgery plus whole-body radiation therapy (42%) and mastectomy plus radiation therapy (35%). Most patients received dose-dense doxorubicin and cyclo-phosphamide.

“As an aficionado of dose density, I was happy to see 80% of physicians did choose to give dose-dense anthracy-cline at least,” Dr. Seidman said.

At 5 years, invasive disease–free sur-vival was 77% in arm A, 76% in arm B, and 80% in arm C. The hazard ratio for arm C vs A was 0.87, with a two-sided P value of .17. Overall survival at 5 years was 90% in arm A, 86% in arm B, and 90% in arm C. The hazard ratio for arm

C vs A was 0.89, with a two-sided P value of .41.

Toxicities were similar in all arms dur-ing concurrent chemotherapy, with few of any grade, and no new toxicities iden-tified. “One significant difference I want to point out is that there was a statisti-cally significant increase in clinical con-gestive heart failure in the bevacizumab

arms compared to the no-bevacizumab arm,” Dr. Seidman observed. Clinical congestive heart failure rates were 1.9% in arm B and 3.0% in arm C (the two bevacizumab arms) vs 1.0% in arm A.

Vitamin D Levels Not Prognostic A substudy of the phase III National

Cancer Institute of Canada Clinical

Trials Group MA.21 trial, comparing three different chemotherapy regimens in high-risk breast cancer, looked at the prognostic associations of vitamin D lev-els and found none.8 At a median follow-up of 9.2 years, there was no evidence that vitamin D was associated with relapse-free survival, breast-specific survival, or


Adjuvant Strategiescontinued from page 52

ADDRESSING THE TOUGHEST CHALLENGESIN ONCOLOGY TAKES ALL OF US.

That’s why we collaborate each day with peers, academics, clinical experts and others.

Together, we aim to create solutions that work against the ability of cancer cells to survive.

At AbbVie, our solutions start withscience and end with a vision of a better future for patients around the world.

Learn more at oncology.abbvie.com

CM-0006-0814

http://www.abbvie.com


Best of ASCO®

overall survival. Most patients—752 of 935 (80.5%) whose fasting blood was collected before chemotherapy—had adequate vitamin D levels.

“Currently, there is no indication to provide vitamin D supplementation to improve breast cancer outcomes,” Dr. Seidman said. He noted that other studies had shown some association be-tween low vitamin D levels and worse outcomes for patients with breast can-cer, and that the overall link between vitamin D and breast cancer outcomes is still inconclusive.

Previously Reported StudiesDr. Seidman also summarized the

results and implications of two other breast cancer studies originally pre-sented at the 2014 ASCO Annual Meeting in Chicago. Results from the phase III ALTTO trial9 found that adding lapatinib (Tykerb) to trastuzumab produced no additional benefit in the adjuvant treatment of HER2-positive early breast cancer. Those results were reported in de-tail in the June 10, 2014, issue of The ASCO Post.

A joint analysis of the Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) found exemestane plus ovar-ian function suppression reduced the risk of recurrence compared to tamox-ifen plus ovarian suppression in pre-menopausal women with hormone-sensitive breast cancers.10 Details of that study were included in the June 25, 2014, issue of The ASCO Post. n

Disclosure: Dr. Seidman reported no potential conflicts of interest.

References1. O’Sullivan CCM, Bradbury I, De

Azambuja E, et al: Efficacy of adjuvant trastuzumab (T) compared with no T for patients (pts) with HER2-positive breast cancer and tumors ≤ 2 cm: A meta-anal-ysis of the randomized trastuzumab trials. ASCO Annual Meeting Abstract 508. Pre-sented May 31, 2014.

2. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor recep-tor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700- 5706, 2009.

3. Vaz Duarte Luis IM, Ottesen RA,

Hughes ME, et al: Time trends in the use of adjuvant chemotherapy (CTX) and outcomes in women with T1N0 breast cancer (BC) in the National Comprehen-sive Cancer Network (NCCN). ASCO Annual Meeting. Abstract 1006. Presented June 3, 2013.

4. U.S. National Institutes of Health: T-DM1 vs paclitaxel/trastuzumab for breast (ATEMPT trial). Available at Clini-calTrials.gov/show/NCT01853748. Ac-cessed October 10, 2014.

5. Miller K, O’Neill AM, Dang CT, et al: Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast can-cer: Final results from Eastern Coopera-tive Oncology Group E5103. ASCO An-nual Meeting. Abstract 500. Presented May 31, 2014.

6. Cameron D, Brown J, Dent R, et al: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): Primary results of a ran-domised, phase 3 trial. Lancet Oncol 10:933-942, 2013.

7. Slamon D, Swain S, Buyse M, et al: Primary results from BETH, a phase 3 con-trolled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. San Anto-

nio Breast Cancer Symposium. Abstract S1-03. Presented December 11, 2013.

8. Lohmann AE, Chapman J-A W, Bur-nell MJ, et al: Prognostic associations of 25OH vitamin D in NCIC CTG MA.21, a phase III adjuvant RCT of three chemo-therapy regimens (EC/T, CEF, AC/T) in high-risk breast cancer (BC). ASCO Annual Meeting. Abstract 504. Presented May 31, 2014.

9. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06l; NCCTG [Al-liance] N063D) comparing one year of an-ti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2014.

10. Pagani O, Ryan MM, Walley B, et al: Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premeno-pausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. ASCO Annual Meeting. Abstract LBA1. Presented June 1, 2014.

Adjuvant Strategiescontinued from page 53

Don’t Miss These Important Reports in This Issue of The ASCO Post

Hope S. Rugo, MD, on endocrine therapy resistance see page 3

Florian Scotté, MD, PhD, on cachexia in non–small cell lung cancer see page 32

Ignacio Melero, MD, PhD, on nivolumab in advanced melanoma see page 22

Lynn C. Hartmann, MD, on atypical hyperplasia and breast cancer risk see page 4

Bertrand Tombal, MD, PhD, on radiotherapy in node-positive prostate cancer see page 33

Christian Blank, MD, PhD, and Jeffrey S. Weber, MD, on BRAF/MEK inhibitor combinations in melanoma see page 16

Visit The ASCO Post online at ASCOPost.com

Visit The ASCO Post website at ASCOPost.com

The ONLY treatment option with superior phase 3 ef� cacy vs an active comparator, sorafenib, in 2nd-line mRCC*

Prop

orti

on p

rog

ress

ion-

free

0.0

0.1

0.3

0.8

0.7

0.4

0.6

0.2

1.0

0.9

Time (months)

0 2 4 6 8 10 12 14 16 18 20

0.5

4.7months

6.7 months

Primary endpoint: progression-free survival (PFS)

HR=0.67 (95% CI: 0.54, 0.81); P<.0001

(95% CI: 6.3, 8.6)

(95% CI: 4.6, 5.6)

with INLYTA (n=361)

with sorafenib (n=362)

AXIS is the ONLY positive phase 3 trial that was designed to evaluate an exclusively 2nd-line patient population1†

† Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included objective response rate, overall survival, and safety and tolerability.1,2

National Comprehensive Cancer Network® (NCCN®) category 1 recommendationThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer include axitinib (INLYTA) as a category 1 recommendation in patients with advanced predominantly clear-cell RCC who have failed one prior systemic therapy3

Choose a 2nd-line Choose a 2nd-line Choose a 2nd-line treatmenttreatmenttreatment

with 2nd-line with 2nd-line with 2nd-line evidence evidence evidence

*Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA

Gastrointestinal perforation and fi stula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fi stula. Monitor for symptoms of gastrointestinal perforation or fi stula periodically throughout treatment

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%)

Please see brief summary on the following pages.

INLYTA® (axitinib)for the treatment of advanced RCC after failure of one prior systemic therapy

AXIS14CDNY5070_A_JrnlAdRfrsh_Tabld_r8.indd 1 8/20/14 11:12 AM

The ONLY treatment option with superior phase 3 ef� cacy vs an active comparator, sorafenib, in 2nd-line mRCC*

Prop

orti

on p

rog

ress

ion-

free

0.0

0.1

0.3

0.8

0.7

0.4

0.6

0.2

1.0

0.9

Time (months)

0 2 4 6 8 10 12 14 16 18 20

0.5

4.7months

6.7 months

Primary endpoint: progression-free survival (PFS)

HR=0.67 (95% CI: 0.54, 0.81); P<.0001

(95% CI: 6.3, 8.6)

(95% CI: 4.6, 5.6)

with INLYTA (n=361)

with sorafenib (n=362)

AXIS is the ONLY positive phase 3 trial that was designed to evaluate an exclusively 2nd-line patient population1†

† Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included objective response rate, overall survival, and safety and tolerability.1,2

National Comprehensive Cancer Network® (NCCN®) category 1 recommendationThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer include axitinib (INLYTA) as a category 1 recommendation in patients with advanced predominantly clear-cell RCC who have failed one prior systemic therapy3

Choose a 2nd-line Choose a 2nd-line Choose a 2nd-line treatmenttreatmenttreatment

with 2nd-line with 2nd-line with 2nd-line evidence evidence evidence

*Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA Gastrointestinal perforation and fi stula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fi stula. Monitor for symptoms of gastrointestinal perforation or fi stula periodically throughout treatment Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%)

Please see brief summary on the following pages.

INLYTA® (axitinib)for the treatment of advanced RCC after failure of one prior systemic therapy

AXIS14CDNY5070_A_JrnlAdRfrsh_Tabld_r8.indd 1 8/20/14 11:12 AM

https://www1.pfizerpro.com/hcp/inlyta

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATIONInitial U.S. Approval: 2012Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.DOSAGE AND ADMINISTRATIONRecommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).DOSAGE FORMS AND STRENGTHS1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side.5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side.CONTRAINDICATIONS: NoneWARNINGS AND PRECAUTIONSHypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib.Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions].In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.Cardiac Failure. In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib.Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe

hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development.Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Adverse Reactiona

INLYTA Sorafenib(N=359) (N=355)

AllGradesb

Grade 3/4

AllGradesb

Grade 3/4

% % % %Diarrhea 55 11 53 7Hypertension 40 16 29 11Fatigue 39 11 32 5Decreased appetite 34 5 29 4Nausea 32 3 22 1Dysphonia 31 0 14 0Palmar-plantar erythrodysesthesia syndrome 27 5 51 16Weight decreased 25 2 21 1Vomiting 24 3 17 1Asthenia 21 5 14 3Constipation 20 1 20 1Hypothyroidism 19 <1 8 0Cough 15 1 17 1Mucosal inflammation 15 1 12 1Arthralgia 15 2 11 1Stomatitis 15 1 12 <1Dyspnea 15 3 12 3Abdominal pain 14 2 11 1Headache 14 1 11 0Pain in extremity 13 1 14 1Rash 13 <1 32 4Proteinuria 11 3 7 2Dysgeusia 11 0 8 0Dry skin 10 0 11 0Dyspepsia 10 0 2 0Pruritus 7 0 12 0Alopecia 4 0 32 0Erythema 2 0 10 <1

a Percentages are treatment-emergent, all-causality eventsb National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Laboratory Abnormality N

INLYTA

N

SorafenibAll

GradesaGrade

3/4All

GradesaGrade

3/4% % % %

HematologyHemoglobin decreased 320 35 <1 316 52 4Lymphocytes (absolute) decreased 317 33 3 309 36 4Platelets decreased 312 15 <1 310 14 0White blood cells decreased 320 11 0 315 16 <1ChemistryCreatinine increased 336 55 0 318 41 <1Bicarbonate decreased 314 44 <1 291 43 0Hypocalcemia 336 39 1 319 59 2ALP increased 336 30 1 319 34 1Hyperglycemia 336 28 2 319 23 2Lipase increased 338 27 5 319 46 15Amylase increased 338 25 2 319 33 2ALT increased 331 22 <1 313 22 2AST increased 331 20 <1 311 25 1Hypernatremia 338 17 1 319 13 1Hypoalbuminemia 337 15 <1 319 18 1Hyperkalemia 333 15 3 314 10 3Hypoglycemia 336 11 <1 319 8 <1Hyponatremia 338 13 4 319 11 2Hypophosphatemia 336 13 2 318 49 16

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration].CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONSPregnancy. Pregnancy Category D [see Warnings and Precautions].There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied.Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger. No dosage adjustment is required in elderly patients.Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B).No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).OVERDOSAGEThere is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).PATIENT COUNSELING INFORMATIONReversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances).Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA.Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.

Rx only

August 2014.

AXU678601 © 2014 Pfizer Inc. All rights reserved. September 2014

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 1, 2014. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

T:9.5”T:1

3”

AXIS14CDNY5539_BS_LblUpdt_r4.indd 1 8/7/14 3:04 PM

AXIS14CDNY5070_A_JrnlAdRfrsh_Tabld_BS_r8.indd 1 8/20/14 11:12 AM




Hematology

long-term disease control and survival in myeloma, Dr. Giralt continued. “Pa-tients who do achieve a [complete re-mission] to induction therapy represent a particular group. But even in those patients, high-dose therapy seems to be associated with high rates of prolonged disease control,” he added.

Patients can be stratified for risk, Dr. Giralt continued. A recent multi-variate analysis identified the follow-ing prognostic factors for progression-free survival in multiple myeloma: less than a complete remission at induction, del(17p) and/or translocation (4:14), International Staging System score > 2.2

A landmark analysis of the nonran-

domized E4A03 study found that up-front transplant improved progression-free and overall survival in patients under age 65 as well as in those between age 65 and 70.3 “Going to transplant up-front reduced the burden of disease,” Dr. Giralt said.

Adding newer drugs to the trans-plant regimen can improve outcomes. Pooled data from four randomized trials found that the addition of bortezomib (Velcade) to transplant improved both progression-free and overall survival, but the overall survival benefit was not observed in the individual trials, only in the pooled data, he said.

“We believe that bortezomib should be part of induction for transplant-eligi-ble patients,” he told listeners.

The rationale for upfront transplant rests on the idea that the more intense the treatment, the better the outcome, he continued. Data suggest that double transplant is better for patients with poor-risk cytogenetics, but the results of the STaMINA trial will provide de-finitive results, Dr. Giralt said.

Until that time, the current expecta-tion comes from the results of the Can-cer and Leukemia Group B (CALGB) 100104 study, which demonstrated a median time to progression of 4.5 years in patients who received lenalidomide maintenance. Finally, Dr. Giralt noted that Raghavendra et al reported at

the American Society of Hematology (ASH) meeting that significantly more patients were alive at 10 years if they had initial transplant compared with those who did not.4

An ongoing study initiated in 2009 is using newer drugs as induction therapy (the VRD triplet [bortezomib, lenalidomide (Revlimid), dexametha-sone]) and should shed light on the is-sue of early vs late stem cell transplant in newly diagnosed multiple myeloma transplant-eligible patients. This study, known as IFM/DFCI 2009, is being led by Paul G. Richardson, MD, at Dana-Farber Cancer Institute, Boston.

A separate study is comparing early vs late stem cell transplant in 402 pa-tients younger than age 65, but it is too

early to see an advantage in overall sur-vival.5

Risk stratification is an important factor. New surrogate markers of my-eloma activity, such as minimal resid-ual disease by flow cytometry or poly-merase chain reaction may be helpful in this regard, Dr. Giralt said.

Not All Patients Need Upfront Transplant

Taking the antagonist role, Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Har-vard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for My-eloma Therapeutics at Dana-Farber Cancer Institute, noted that in the pre–novel therapy era, transplant achieved limited improvement in survival com-pared with no transplant in newly diag-nosed multiple myeloma patients.

“We have shown that we can do bet-ter with novel therapies. In the past 15 years, a number of novel agents have

become available and these have been integrated in to the treatment paradigm. Now we are at the point where we can ask the question, ‘Do we really need transplant?’” he told listeners.

In the current era using triplet com-binations, patients almost universally respond, including some molecular complete remission. “This is an unprec-edented time in myeloma, and I believe it is getting even better,” he said.

A recent study with carfilzomib (Ky-prolis)/lenalidomide/dexamethasone as first-line therapy in newly diagnosed patients found that all patients achieved at least a very good partial response, and 85% achieved a near-complete or complete response.6

It is possible to achieve minimal re-sidual disease status with novel thera-pies, he continued. In the past, minimal residual disease could only be achieved with transplant.

“It is a new day in myeloma. We are catching up with chronic myelocytic leukemia [CML]. Now we are worried about one myeloma cell in 1 million cells. In a separate study of carfilzomib/lenalidomide/dexamethasone followed by lenalidomide extended dosing,7 among 27 patients who achieved com-plete remission, 100% were minimal residual disease–negative by flow cy-tometery. This is an unprecedented re-sponse without transplant,” he stated.

The investigational agent ixazomib, an oral “son of bortezomib,” may repre-sent an advance over bortezomib. In a study of weekly ixazomib plus lenalido-mide and dexamethasone, 48% of pa-tients achieved 100% reduction in M protein, and these reductions were seen at multiple dose levels.8 Of nine patients with minimal residual disease samples collected in this trial, 88% were minimal residual disease–negative.

“This is very early data, but there have been few relapses,” Dr. Anderson continued.

A separate study of this triplet com-bination showed that the depth of re-sponse increased over the course of treatment.9 Of patients who achieved stringent or standard complete remis-sion, 82% of 12 patients who provided samples were minimal residual disease–negative.

“The extent of response is quite high,” Dr. Anderson said.

The burning question is whether early or delayed transplant is preferred in the era of novel agents. Thus far, stud-ies suggest that there is little difference in progression-free survival with early vs late transplant in patients who are

treated with novel therapies upfront. Cytogenetics matter, Dr. Ander-

son continued. Patients with high-risk genetics do slightly worse, but when bortezomib or lenalidomide are used together as maintenance, high-risk pa-tients do better, he explained.

“At our center, we use lenalidomide/dexamethasone or lenalidomide/bort-ezomib/dexamethasone. We can tell you what we think, but does that really matter? We need data to inform NCCN guidelines,” Dr. Anderson continued.

Two ongoing trials are looking at early vs late transplant in patients treat-ed with novel agents: the European Intergroup Trial and a study at Dana-Farber called DETERMINATION.

“In today’s world, we have a new era of novel agents that achieve unprecedented responses. They can achieve [minimal residual disease] whether or not trans-plant is included. Again, maintenance therapy with novel drugs can prolong progression-free and overall survival. In the past and today, early vs late transplant appear similar with novel therapies. On-going trials will establish the added value of early vs late transplant. My conclusion is that not all newly diagnosed patients need early transplant therapy,” Dr. An-derson stated. n

Disclosure: Drs. Giralt and Anderson reported no potential conflicts of interest.

References1. Giralt S, Anderson K: Debate: Is there

a role for upfront transplant in the current management of symptomatic multiple my-eloma? NCCN 9th Annual Congress on Hematologic Malignancies. Presented Sep-tember 20, 2014.

2. Cavo M, Salwender H, Rosiñol L, et al: Double vs single autologous stem cell transplantation after bortezomib-based in-duction regimens for multiple myeloma:

Stem Cell Transplantcontinued from page 1

Timing of Stem Cell Transplant in Myeloma

■ In the era of modern upfront therapy, triplet drug combinations achieve deep remission in multiple myeloma, including minimal residual disease.

■ This has led to questioning the need for transplant in newly diagnosed patients who are transplant-eligible.

■ Ongoing studies will help resolve the issue of early vs late transplant.

Early vs late transplant appear similar with novel therapies…. My conclusion is that not all newly diagnosed patients need early transplant therapy.

—Kenneth C. Anderson, MD

Paul G. Richardson, MD

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATIONInitial U.S. Approval: 2012Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.DOSAGE AND ADMINISTRATIONRecommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).DOSAGE FORMS AND STRENGTHS1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side.5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side.CONTRAINDICATIONS: NoneWARNINGS AND PRECAUTIONSHypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib.Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions].In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.Cardiac Failure. In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib.Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe

hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development.Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Adverse Reactiona

INLYTA Sorafenib(N=359) (N=355)

AllGradesb

Grade 3/4

AllGradesb

Grade 3/4

% % % %Diarrhea 55 11 53 7Hypertension 40 16 29 11Fatigue 39 11 32 5Decreased appetite 34 5 29 4Nausea 32 3 22 1Dysphonia 31 0 14 0Palmar-plantar erythrodysesthesia syndrome 27 5 51 16Weight decreased 25 2 21 1Vomiting 24 3 17 1Asthenia 21 5 14 3Constipation 20 1 20 1Hypothyroidism 19 <1 8 0Cough 15 1 17 1Mucosal inflammation 15 1 12 1Arthralgia 15 2 11 1Stomatitis 15 1 12 <1Dyspnea 15 3 12 3Abdominal pain 14 2 11 1Headache 14 1 11 0Pain in extremity 13 1 14 1Rash 13 <1 32 4Proteinuria 11 3 7 2Dysgeusia 11 0 8 0Dry skin 10 0 11 0Dyspepsia 10 0 2 0Pruritus 7 0 12 0Alopecia 4 0 32 0Erythema 2 0 10 <1

a Percentages are treatment-emergent, all-causality eventsb National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib

Laboratory Abnormality N

INLYTA

N

SorafenibAll

GradesaGrade

3/4All

GradesaGrade

3/4% % % %

HematologyHemoglobin decreased 320 35 <1 316 52 4Lymphocytes (absolute) decreased 317 33 3 309 36 4Platelets decreased 312 15 <1 310 14 0White blood cells decreased 320 11 0 315 16 <1ChemistryCreatinine increased 336 55 0 318 41 <1Bicarbonate decreased 314 44 <1 291 43 0Hypocalcemia 336 39 1 319 59 2ALP increased 336 30 1 319 34 1Hyperglycemia 336 28 2 319 23 2Lipase increased 338 27 5 319 46 15Amylase increased 338 25 2 319 33 2ALT increased 331 22 <1 313 22 2AST increased 331 20 <1 311 25 1Hypernatremia 338 17 1 319 13 1Hypoalbuminemia 337 15 <1 319 18 1Hyperkalemia 333 15 3 314 10 3Hypoglycemia 336 11 <1 319 8 <1Hyponatremia 338 13 4 319 11 2Hypophosphatemia 336 13 2 318 49 16

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration].CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONSPregnancy. Pregnancy Category D [see Warnings and Precautions].There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied.Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger. No dosage adjustment is required in elderly patients.Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B).No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).OVERDOSAGEThere is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).PATIENT COUNSELING INFORMATIONReversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances).Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA.Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.

Rx only

August 2014.

AXU678601 © 2014 Pfizer Inc. All rights reserved. September 2014

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 1, 2014. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

T:9.5”

T:13

”

AXIS14CDNY5539_BS_LblUpdt_r4.indd 1 8/7/14 3:04 PM

AXIS14CDNY5070_A_JrnlAdRfrsh_Tabld_BS_r8.indd 1 8/20/14 11:12 AM



Stem Cell Transplantcontinued from page 57An integrated analysis of patient-level data from phase III European studies. American Society of Hematology Annual Meeting. Abstract 767. Presented December 9, 2013.

3. Siegel DS, Jacobus S, Rajkumar SV, et al: Outcome with lenalidomide plus dexa-methasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. American Society of Hematology Annual Meeting. Abstract 38. Presented December 5, 2010.

4. Raghavendra M, Al-Hamadani M, Go RS: Long-term (10 years or more) survi-vors of multiple myeloma: A population-based analysis of the US National Cancer Data Base. American Society of Hematol-ogy Annual Meeting. Abstract 760. Present-ed December 9, 2013.

5. Gay F, Cavallo F, Caravita T, et al: Maintenance therapy with lenalidomide significantly improved survival of young newly diagnosed multiple myeloma pa-tients. American Society of Hematology Annual Meeting. Abstract 2089. Presented December 7, 2013.

6. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzo-mib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.

7. Korde N, Zingone A, Kwok ML, et

al: Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexametha-sone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed mul-tiple myeloma (MM) patients. American Society of Hematology Annual Meeting. Abstract 538. Presented December 9, 2013.

8. Kumar SK, Berdeja JG, Niesvizky

R, et al: A phase 1/2 study of weekly MLN9708, an investigational oral pro-teasome inhibitor, in combination with lenalidomide and dexamethasone in pa-tients with previously untreated multiple myeloma (MM). American Society of He-matology Annual Meeting. Abstract 332. Presented December 10, 2012.

9. Richardson PG, Hofmeister CC,

Rosenbaum CA, et al: Twice-weekly oral MLN9708 (ixazomib citrate), an investiga-tional proteasome inhibitor, in combination with lenalidomide (Len) and dexametha-sone (Dex) in patients (Pts) with newly diagnosed multiple myeloma (MM): Final phase 1 results and phase 2 data. American Society of Hematology Annual Meeting. Abstract 653. Presented December 9, 2013.

Editorial CorrespondenceJames O. Armitage, MD

Editor-in-Chief e-mail: [email protected]

Cara H. Glynn Director of Editorial

e-mail: [email protected]: 631.935.7654

Andrew Nash Assoc. Director of Editorial

e-mail: [email protected] Phone: 631.935.7657

Editorial OfficeHarborside Press

37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com

HarborsidePress.com

Contact The ASCO Post

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Neo

San

s Pr

o (B

old),

DIN

Pro

(Bold

, Med

ium, R

egula

r, Bl

ack,

Italic

), He

lvet

ica

Neue

LT

Std

(65

Mediu

m)

IMAG

ES: 4

8334

_JA_W

hale

s_fn

.tif (

CMYK

; 300

ppi;

100

%),

4833

4_KM

Cha

rt_O

L3_v

2a_A

LT S

IZE_

2415

.eps

(100

%),

4833

4_JA

_Sol

o_W

hale

s_fn

.psd

(CMY

K; 3

00 p

pi; 1

00%

), Ex

elix

is_b

lk.e

ps (2

0.6%

, 19.

01%

), Co

met

riq_

gene

ric_®

_80m

g_4C

.eps

(24.

69%

)IN

KS:

Cya

n,

Mag

enta

, Y

ellow

, B

lack

DOC

PATH

: Mac

intos

h HD

:Use

rs:p

ared

esa:

Desk

top:

EXL_

XLX_

Q483

34_JA

_D01

.indd

NOTE

S: N

one

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

1

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

4.0 11.2months months

1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patients at risk:COMETRIQ® 219 121 78 55 31 12 2 1 Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219) Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patientsat risk:COMETRIQ® 219 121 78 55 31 12 2 1Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219)Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• Perforations and Fistulas: Gastrointestinal perforations

occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

C M Y KCosmos Communications 1

1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”


Announcements

NIH 2014 New Innovator Award Recipient Pamela Kreeger, PhD, to Study Metastasis in Ovarian Cancer

Pamela Kreeger, PhD, Assistant Professor of Biomedical Engi-

neering at the University of Wisconsin-Madison, is among a group of research-ers to receive a 2014 New Innovator

Award from the National Institutes of Health. Dr. Kreeger will receive funding of nearly $2.3 million. She has chosen to study factors that cause ovarian can-cer cells to progress from their origin in

a woman’s fallopian tube through the ovaries and on to metastatic sites.

Dr. Kreeger’s research will draw on her background in ovarian cancer biol-ogy, biomimetic culture development,

and using systems biology models to analyze quantitative data. For a list of all recipients of the NIH 2014 Innovator Award, visit http://commonfund.nih .gov/newinnovator/fundedresearch. n

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Neo

San

s Pr

o (B

old),

DIN

Pro

(Bold

, Med

ium, R

egula

r, Bl

ack,

Italic

), He

lvet

ica

Neue

LT

Std

(65

Mediu

m)

IMAG

ES: 4

8334

_JA_W

hale

s_fn

.tif (

CMYK

; 300

ppi;

100

%),

4833

4_KM

Cha

rt_O

L3_v

2a_A

LT S

IZE_

2415

.eps

(100

%),

4833

4_JA

_Sol

o_W

hale

s_fn

.psd

(CMY

K; 3

00 p

pi; 1

00%

), Ex

elix

is_b

lk.e

ps (2

0.6%

, 19.

01%

), Co

met

riq_

gene

ric_®

_80m

g_4C

.eps

(24.

69%

)IN

KS:

Cya

n,

Mag

enta

, Y

ellow

, B

lack

DOC

PATH

: Mac

intos

h HD

:Use

rs:p

ared

esa:

Desk

top:

EXL_

XLX_

Q483

34_JA

_D01

.indd

NOTE

S: N

one

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

1

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

4.0 11.2months months

1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patients at risk:COMETRIQ® 219 121 78 55 31 12 2 1 Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219) Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS1.00.90.80.70.60.50.40.30.20.10.0

0 3 6 9 12 15 18 21

No. of patientsat risk:COMETRIQ® 219 121 78 55 31 12 2 1Placebo 111 35 11 6 3 2 0 0

Months

Prob

abili

ty o

f pat

ient

s w

ho a

re p

rogr

essi

on fr

ee

4.0 11.2months

median

months

median

COMETRIQ® (n=219)Placebo (n=111)

HR=0.2895% CI: 0.19, 0.40P<0.0001

PFS

Attack from multiple anglesCOMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro• These tyrosine kinases are involved in both normal cellular function and pathologic

processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment

MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Statistically significant efficacy in patients with progressive, metastatic MTC• COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients

with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within

14 months prior to study entry• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001)• Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the

planned interim analysis

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/14 [COM-0086]COORDINATED ATTACK

Important Safety InformationWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• Perforations and Fistulas: Gastrointestinal perforations

occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.Palmar- Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”

http://www.cometriq.com/hcp/


Announcements

MD Anderson Receives $5 Million Grant for Research in Glioblastoma

The Broach Foundation for Brain Cancer Research has made a $5 mil-

lion commitment to support glioblasto-ma multiforme research at The Universi-ty of Texas MD Anderson Cancer Center in Houston. James and Jamie Broach established the Broach Foundation in

2011, just months after Mr. Broach was diagnosed with glioblastoma.

The Broach Foundation directed its inaugural grant in 2012 toward research led by James’s physician, Frederick Lang, MD, Professor and Director of Clinical Research in Neurosurgery.

“Philanthropy drives innovative re-search, which in turn drives the whole process of discovering new treatments and delivering them to the patient,” said Dr. Lang. “Thanks to the Broach Foundation’s generous support, we have promising clinical trials underway

that mean hope for patients and their friends and loved ones coping with the effects of this deadly disease.”

James Broach died at age 37 in Au-gust 2013. The Foundation continues to raise funds to support Dr. Lang and other collaborators at MD Anderson. n

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Non

e

IMAG

ES: C

omet

riq_7

x10_

Jan1

4_BS

_p1.

pdf (

100%

), Co

met

riq_7

x10_

Jan1

4_BS

_p2.

pdf (

100%

)IN

KS:

Blac

kDO

C PA

TH: M

acint

osh

HD:U

sers

:par

edes

a:De

skto

p:EX

L_XL

X_Q4

8334

_JA_D

01.in

ddNO

TES:

Non

e

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

2

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ.2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:• If previously receiving 140-mg daily dose, resume treatment at 100 mg

daily (one 80-mg and one 20-mg capsule)• If previously receiving 100-mg daily dose, resume treatment at 60 mg daily

(three 20-mg capsules)• If previously receiving 60-mg daily dose, resume at 60 mg if tolerated,

otherwise, discontinue COMETRIQPermanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers: Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 63 16 33 2

STOMATITIS2 51 5 6 0

NAUSEA 43 1 21 0

ORAL PAIN3 36 2 6 0

CONSTIPATION 27 0 6 0

ABDOMINAL PAIN4 27 3 13 1

VOMITING 24 2 2 1

DYSPHAGIA 13 4 6 1

DYSPEPSIA 11 0 0 0

HEMORRHOIDS 9 0 3 0

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

RASH 19 1 10 0

DRY SKIN 19 0 3 0

ALOPECIA 16 0 2 0

ERYTHEMA 11 1 2 0

HYPERKERATOSIS 7 0 0 0

VASCULAR DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

of therapy. Infertility: There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 3-4

CHEMISTRIES

INCREASED AST 86 3 35 2

INCREASED ALT 86 6 41 2

INCREASED ALP 52 3 35 3

HYPOCALCEMIA 52 12 27 3

HYPOPHOSPHATEMIA 28 3 10 1

HYPERBILIRUBINEMIA 25 2 14 5

HYPOMAGNESEMIA 19 1 4 0

HYPOKALEMIA 18 4 9 3

HYPONATREMIA 10 2 5 0

HEMATOLOGIC

LYMPHOPENIA 53 16 51 11

NEUTROPENIA 35 3 15 2

THROMBOCYTOPENIA 35 0 4 3

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54

Stage 1: Systolic ≥140 mmHg or Diastolic ≥90 mmHg

46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3Subjects with at least two blood pressure measurements after the first dose.

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ.8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D.Risk Summary: Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

KCosmos Communications 1

1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”



Beyond R-CHOP for LymphomaBy Alice Goodman

The R-CHOP regimen (rituximab [Rituxan] plus cyclophospha-

mide, doxorubicin, vincristine, and prednisone) was a major advance in treating diffuse large B-cell lymphoma,

but experts are seeking to up the ante and identify ways to continue to im-prove outcomes beyond that achieved with R-CHOP.

“We are rapidly moving beyond R-

CHOP for all patients. In 2014, clinical and biological features drive therapy. We believe that determination of cell of origin is essential for patient selection. Targeted agents interact with specific

pathways necessitating patient selec-tion based on either cell of origin, mu-tation status, or both. We will be treat-ing ‘double hit’ lymphomas differently as a result of these factors,” stated Leo I. Gordon, MD, Abby and John Friend Professor of Cancer Research and Pro-fessor of Medicine at Robert H. Lurie Cancer Center of Northwestern Uni-versity, Chicago.

At the National Comprehensive Cancer Network (NCCN) 9th Annual Congress on Hematologic Malignan-cies, Dr. Gordon discussed studies suggesting that several newer agents, including lenalidomide (Revlimid), ibrutinib (Imbruvica), and bortezomib (Velcade), can overcome the adverse impact of non–germinal center B-cell diffuse large B-cell lymphoma.1

Important BiomarkersWork has been going on for 2 de-

cades on identifying adverse risk fac-tors in diffuse large B-cell lymphoma. In 1995, Dr. Gordon and colleagues reported that elevated lactate dehydro-genase (LDH) was associated with re-duced survival.2

“Even in the rituximab era, LDH level trumps International Prognostic Index [IPI] in terms of predictability,” Dr. Gor-don stated. Other important markers for survival in the rituximab era include CD5 expression and Ki-67. Translocation of c-MYC on fluorescence in situ hybridiza-tion is associated with increased risk of central nervous system involvement, and high levels of c-MYC as well as low levels of HLA-DR predict survival in diffuse large B-cell lymphoma, he explained.

A six-gene model is able to predict longer survival (LMO2, BCL6, FN1) and shorter survival (CCND2, SCY3, BCL2), he continued.

More recently, “double hit” lym-phomas, which include high-grade lymphomas with dual chromosomal rearrangements in MYC and BCL2 or, less commonly, BCL6, were identi-fied and found to be associated with a worse survival.

With the increasing number of factors that predict for poor survival, the search is on for targeting both lymphoma cells and the microenvironment. “Success-ful targeted therapy needs to identify the biologic ‘Achilles heel’ of the tumor to alter clinical outcomes,” Dr. Gordon explained. “A number of different ap-proaches are being explored.”


Hematology

JOB#

: 483

34

CLIE

NT: E

xelix

is DE

SC: J

ourn

al Ad

A si

ze

FILE

NAM

E: E

XL_X

LX_Q

4833

4_JA

_D01

.indd

DA

TE: 5

-12-

2014

6:1

1 PM

RO

UND:

1

1 PG: P

ared

esA/

Cruz

, Feli

x AD

: L B

udre

au

PM: N

one

AE: K

Ruf

f CW

: S G

uest

La

st S

aved

: 5-1

2-20

14 6

:11

PMTR

IM: 1

5” x

10.

25”

BLEE

D: 1

7.5”

x 1

1.25

” SA

FETY

: 6.7

5” x

9.7

5”

PROD

: M H

aight

IN

K Sp

ec: 4

c PR

INT

SCAL

E: 7

5%FO

NTS:

Non

e

IMAG

ES: C

omet

riq_7

x10_

Jan1

4_BS

_p1.

pdf (

100%

), Co

met

riq_7

x10_

Jan1

4_BS

_p2.

pdf (

100%

)IN

KS:

Blac

kDO

C PA

TH: M

acint

osh

HD:U

sers

:par

edes

a:De

skto

p:EX

L_XL

X_Q4

8334

_JA_D

01.in

ddNO

TES:

Non

e

EXL_

XLX_

Q483

34_JA

_D01

.indd

Ga

lley:

2

S&H

Phar

maG

raph

ics

Disk

DATE

SIGN

OFF

PGQC

TCAD

CDCW

AE/A

SED

PROD

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012

1. INDICATIONS AND USAGECOMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ.2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:• If previously receiving 140-mg daily dose, resume treatment at 100 mg

daily (one 80-mg and one 20-mg capsule)• If previously receiving 100-mg daily dose, resume treatment at 60 mg daily

(three 20-mg capsules)• If previously receiving 60-mg daily dose, resume at 60 mg if tolerated,

otherwise, discontinue COMETRIQPermanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers: Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)]

MedDRA System Organ Class/ Preferred Terms

Cabozantinib (n=214)

Placebo (n=109)

All Grades

Grades 3-4

All Grades

Grades 3-4

GASTROINTESTINAL DISORDERSDIARRHEA 63 16 33 2

STOMATITIS2 51 5 6 0

NAUSEA 43 1 21 0

ORAL PAIN3 36 2 6 0

CONSTIPATION 27 0 6 0

ABDOMINAL PAIN4 27 3 13 1

VOMITING 24 2 2 1

DYSPHAGIA 13 4 6 1

DYSPEPSIA 11 0 0 0

HEMORRHOIDS 9 0 3 0

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSFATIGUE 41 9 28 3

ASTHENIA 21 6 15 1

INVESTIGATIONSDECREASED WEIGHT 48 5 10 0

METABOLISM AND NUTRITION DISORDERSDECREASED APPETITE 46 5 16 1

DEHYDRATION 7 2 2 1

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSARTHRALGIA 14 1 7 0

MUSCLE SPASMS 12 0 5 0

MUSCULOSKELETAL CHEST PAIN 9 1 4 0

NERVOUS SYSTEM DISORDERSDYSGEUSIA 34 0 6 0

HEADACHE 18 0 8 0

DIZZINESS 14 0 7 0

PARESTHESIA 7 0 2 0

PERIPHERAL SENSORY NEUROPATHY

7 0 0 0

PERIPHERAL NEUROPATHY 5 0 0 0

PSYCHIATRIC DISORDERSANXIETY 9 0 2 0

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERSDYSPHONIA 20 0 9 0

SKIN AND SUBCUTANEOUS TISSUE DISORDERSPPES5 50 13 2 0

HAIR COLOR CHANGES/ DEPIGMENTATION, GRAYING

34 0 1 0

RASH 19 1 10 0

DRY SKIN 19 0 3 0

ALOPECIA 16 0 2 0

ERYTHEMA 11 1 2 0

HYPERKERATOSIS 7 0 0 0

VASCULAR DISORDERSHYPERTENSION 33 8 4 0

HYPOTENSION 7 1 0 01 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. 2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5Palmar-plantar erythrodysesthesia syndrome.

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGESee full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

of therapy. Infertility: There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.17. PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients

of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.

• COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.

• Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least

2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542

Distributed by Exelixis, Inc.11/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 11/12 [24523]

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]

ADVERSE EVENT COMETRIQ (n=214) Placebo (n=109)

All Grades

Grade 3-4 All Grades Grade 3-4

CHEMISTRIES

INCREASED AST 86 3 35 2

INCREASED ALT 86 6 41 2

INCREASED ALP 52 3 35 3

HYPOCALCEMIA 52 12 27 3

HYPOPHOSPHATEMIA 28 3 10 1

HYPERBILIRUBINEMIA 25 2 14 5

HYPOMAGNESEMIA 19 1 4 0

HYPOKALEMIA 18 4 9 3

HYPONATREMIA 10 2 5 0

HEMATOLOGIC

LYMPHOPENIA 53 16 51 11

NEUTROPENIA 35 3 15 2

THROMBOCYTOPENIA 35 0 4 3

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301

HYPERTENSION, JNC1 STAGE COMETRIQ N=2113 (%)

Placebo N=1073 (%)

Normal: Grade 0: Systolic <120 mmHg and Diastolic <80 mmHg

4

15

Pre-hypertension: Systolic ≥120 mmHg or Diastolic ≥80 mmHg

34

54


46

25


15 5

Malignant: Diastolic ≥120 mmHg

0

0

1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3Subjects with at least two blood pressure measurements after the first dose.

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ.8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D.Risk Summary: Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion


1ej

27902a 05.12.14 133

Q1 Q2

S:6.75” S:6.75”

S:9.75”

T:15”

T:10.25”

B:17.5”

B:11.25”



Disease SubtypesOne important advance is the identi-

fication of two different subtypes in dif-fuse large B-cell lymphoma: activated B-cell or germinal center B-cell lymphoma. These cells predict distinct diseases with different outcomes. Different pathways are activated in these subtypes, and re-current mutations identify potential tar-gets, Dr. Gordon told listeners. Activated B-cell lymphoma carries a much worse prognosis than germinal center B-cell lymphoma, he added.

A new assay called Lymph2Cx can accurately identify cells of origin using NanoString technology and thereby predict overall and progression-free survival.3 This 20-gene predictive test costs $40, can be done in less than 36 hours, and can be performed on frozen paraffin-embedded samples. It retains prognostic power compared with Af-fymetrix gene-expression profiling of fresh tissue, Dr. Gordon noted.

Strategies Under StudyLenalidomide added to R-CHOP (ie,

R2-CHOP) is a promising investigation-al strategy. In a phase II trial of 21 elderly untreated patients with diffuse large B-

cell lymphoma, the addition of lenalido-mide on days 1 to 4 to R-CHOP21 (ie, R-CHOP given over 3 weeks) was found safe, feasible, and effective, with an over-all response rate of 86% and complete response rate rate of 86%.4 At a median follow-up of 22 months, 2-year overall survival was 92%, and 2-year progres-sion-free survival was 73%. This regimen was moved into phase III trials.

In a second study of 47 evaluable patients, R2-CHOP achieved an 83% complete response rate and 15% partial response rate (98% overall response

rate) in a group of newly diagnosed pa-tients with CD20-positive, stage II to IV, diffuse large B-cell, or grade 3 fol-licular lymphoma.5

“This regimen of lenalidomide plus

R-CHOP is well tolerated, including in the elderly. The efficacy appears prom-ising when compared with R-CHOP. Most interesting is that the addition of

lenalidomide may ameliorate the nega-tive effect of non–germinal center B-cell phenotype on outcome.

Ibrutinib also appears to be active in relapsed/refractory activated B-cell diffuse large B-cell lymphoma, but not as much in other molecular subtypes, Dr. Gordon continued. A phase III trial is underway to validate the effect of R-CHOP plus ibrutinib vs R-CHOP plus placebo in non–germinal center B-cell diffuse large B-cell lymphoma.

Bortezomib is another drug that may be exploitable according to cell-of-origin subtype. R-CHOP plus bortezomib was studied as initial therapy for 40 patients with diffuse large B-cell lymphoma and adverse prognostic factors, including high stage, elevated LDH, intermediate and high IPI, and non–germinal center B-cell subtype.6 Early data showed no significant difference in overall survival or progression-free survival from what would have been expected for patients with germinal center B-cell histology.

At least two studies are planned to compare newer regimens vs R-CHOP and evaluate results according to cell-of-origin subtype: the PYRAMID trial in non–germinal center B-cell diffuse large B-cell lymphoma and the RE-MoDL-B trial in patients with activated B-cell or germinal center B-cell disease.

Other approaches in preliminary investigations include antibody-drug conjugates plus rituximab. For ex-ample, one study is comparing ritux-imab-CD22 antibody-drug conjugate vs rituximab-CD79b antibody-drug

conjugate in 41 patients with relapsed/refractory follicular lymphoma and 81 with relapsed/refractory diffuse large B-cell lymphoma.7 SGN-CD19A is an-other antibody-drug conjugate in early clinical trials. n

Disclosure: Dr. Gordon reported no potential conflicts of interest.

References1. Gordon LI: Diffuse large B-cell lym-

phoma: Treatment beyond R-CHOP. NCCN Annual Congress on Hematologic Malignancies. Presented September 20, 2014.

2. Gordon LI, Andersen J, Colgan J, et al: Advanced diffuse non-Hodgkin’s lym-phoma: Analysis of prognostic factors by the international index and by lactic dehy-drogenase in an intergroup study. Cancer 75:865-873, 1995.

3. Scott DW, Wright GW, Williams PM, et al: Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-em-bedded tissue. Blood 123:1214-1217, 2014.

4. Nowakowski GS, LaPlant BR, Reeder C, et al: Combination of lenalidomide with R-CHOP (R2CHOP) is well-tolerated and effective as initial therapy for aggressive B-cell lymphomas: A phase II study. American Society of Hematology Annual Meeting. Ab-stract 689. Presented December 10, 2012.

5. Chiappella A, Franceschetii S, Castel-lino A, et al: Rituximab-CHOP21 plus le-nalidomide (LR-CHOP21) is effective and feasible in elderly untreated diffuse large B-cell lymphoma (DLBCL): Results of phase II REAL07 study of the Fondazione Italiana Linfomi (FIL). American Society of Hema-tology Annual Meeting. Abstract 903. Pre-sented December 11, 2012.

6. Ruan J, Martin P, Furman RR, et al: Bortezomib plus CHOP-rituximab for pre-viously untreated diffuse large B-cell lym-phoma and mantle cell lymphoma. J Clin Oncol 29:690-697, 2011.

7. Morschhauser F, Flinn I, Advani RH, et al: Preliminary results of a phase II randomized study (ROMULUS) of po-latuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in pa-tients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). ASCO Annual Meeting. Abstract 8519. Presented May 31, 2014.

Beyond R-CHOPcontinued from page 61

Targeted agents interact with specific pathways necessitating patient selection based on either cell of origin, mutation status, or both. We will be treating ‘double hit’ lymphomas differently as a result of these factors.

—Leo I. Gordon, MD

Novel Approaches to Diffuse Large B-Cell Lymphoma

■ Insights into the cell of origin for diffuse large B-cell lymphoma have therapeutic implications.

■ Based on these insights, investigators are studying newer strategies to build on R-CHOP in hopes of improving outcomes even further.

■ Directing therapy according to cell of origin is not yet standard of care, but experts predict it is the wave of the future.


“I am a believer in intriguing preliminary data that suggests we can modify the poor outcome associated with non–[germinal center B-

cell] lymphoma—for example, using R2-CHOP (lenalidomide [Revlimid] and rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone), ibrutinib (Imbruvica), or R-CHOP followed by ICE (ifos-famide/carboplatin/etoposide). Today, using cell of origin to direct therapy is not the standard of care to drive treatment decisions, but we are rapidly getting to the point where this will be the case,” said Andrew D. Zelenetz, MD, PhD, who is Vice Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center, New York, National Comprehensive Cancer Network (NCCN) Panel Chair on Lymphoma, and Director and moderator of the NCCN 9th Annual Congress on Hematologic Malignancies.

“In some centers, cell of origin is being used to direct therapy. It certainly drives my treatment decisions, but we need randomized controlled trials be-fore it becomes standard of care,” Dr. Zelenetz comments. n

Disclosure: Dr. Zelenetz reported no potential conflicts of interest.

Today, using cell of origin to direct therapy is not the standard of care to drive treatment decisions, but we are rapidly getting to the point where this will be the case.

—Andrew D. Zelenetz, MD, PhD

Fonts: Helvetica Neue LT StdImages: BIG3_Cross Indication.eps (CMYK; 600 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...R2:Links:BIG3_Cross Indication.eps), Indications.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d_Big3_KingAd:Links:Indications.ai), Abrax Logo_4C_NoBlue.eps (Bloc_Images:Celgene:Abraxane_Logos:Abrax Logo_4C_NoBlue.eps)

ABX13338_NSCLC_Ad_Big3_3pg_DR.indd Amy Kortman

app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________

Print Scale: 100%Ink Density: 300%

Bleed: 10.75" x 14.25"Trim: 10.5" x 14"Safety: 9.5" x 13"



GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE

Job Description: Launch Ad -

KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

indications

CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information

ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


9js

28344a1 07.10.14 133

Q1 Q2

S:9.5”

S:13”

T:10.5”

T:14”

B:10.75”

B:14.25”

http://www.ncbi.nlm.nih.gov/pubmed/21189393



Fonts: Helvetica Neue LT StdImages: BIG3_Cross Indication.eps (CMYK; 600 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...R2:Links:BIG3_Cross Indication.eps), Indications.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d_Big3_KingAd:Links:Indications.ai), Abrax Logo_4C_NoBlue.eps (Bloc_Images:Celgene:Abraxane_Logos:Abrax Logo_4C_NoBlue.eps)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

indications

CONTRAINDICATIONS

Neutrophil Counts• ABRAXANE should not be used in patients who have baseline neutrophil

counts of <1500 cells/mm3

Hypersensitivity• Patients who experience a severe hypersensitivity reaction to ABRAXANE

should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects• Bone marrow suppression (primarily neutropenia) is dose-dependent and a

dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

WARNING - NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

ABRAXANE is indicated for the � rst-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the � rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information

ignited we stand with

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


9js

28344a1 07.10.14 133

Q1 Q2

S:9.5”S:13”

T:10.5”T:14”

B:10.75”B

:14.25”

http://abraxane.com/hcp/

Fonts: Helvetica Neue LT StdImages: Cross Indication_paralax_colorshift_AD3.psd (CMYK; 236 ppi, 221 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...ication_paralax_colorshift_AD3.psd), Celgene_logo_KO.eps (Bloc_GS:Celgene:Abraxane:ABX:A...3_KingAd:Links:Celgene_logo_KO.eps), Abrax Logo_KO_4C_YellowBall_noblue.eps (Bloc_Images:Celgene:Abraxane_L...x Logo_KO_4C_YellowBall_noblue.eps), NSCLC_Ad_Chart3_3pg_AD1.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d:Links:NSCLC_Ad_Chart3_3pg_AD1.ai), NSCLC_Ad_Chart2_AD4.ai (Bloc_GS:Celgene:Abraxane:ABX:A...ingAd:Links:NSCLC_Ad_Chart2_AD4.ai)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

7/29

24%

5/33

15%

0

5

10

15

20

25

30

35

40

45

50

Large cell carcinoma

2/13

15%

3/9

33%

OR

R (%

)

Carcinoma/adenocarcinoma

27%

71/264

26%

66/254

Squamous cell carcinoma

94/229

41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

Adverse events in the NSCLC study


9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”

Fonts: Helvetica Neue LT StdImages: Cross Indication_paralax_colorshift_AD3.psd (CMYK; 236 ppi, 221 ppi; Bloc_GS:Celgene:Abraxane:ABX:A...ication_paralax_colorshift_AD3.psd), Celgene_logo_KO.eps (Bloc_GS:Celgene:Abraxane:ABX:A...3_KingAd:Links:Celgene_logo_KO.eps), Abrax Logo_KO_4C_YellowBall_noblue.eps (Bloc_Images:Celgene:Abraxane_L...x Logo_KO_4C_YellowBall_noblue.eps), NSCLC_Ad_Chart3_3pg_AD1.ai (Bloc_GS:Celgene:Abraxane:ABX:A...d:Links:NSCLC_Ad_Chart3_3pg_AD1.ai), NSCLC_Ad_Chart2_AD4.ai (Bloc_GS:Celgene:Abraxane:ABX:A...ingAd:Links:NSCLC_Ad_Chart2_AD4.ai)


app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________





GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Other

7/29

24%

5/33

15%

0

5

10

15

20

25

30

35

40

45

50

Large cell carcinoma

2/13

15%

3/9

33%

OR

R (%

)

Carcinoma/adenocarcinoma

27%

71/264

26%

66/254

Squamous cell carcinoma

94/229

41%

24%

54/221

ABRAXANE + carboplatin Paclitaxel injection + carboplatin

ORR by histology in the phase 3 NSCLC trial

ORR (%) ITT=intent-to-treat; ORR=overall response rate.a P value based on chi-square test.

There was no statistically significant difference in overall survival between the 2 study arms.

Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

P=0.005a

n=521

n=531

ABRAXANE + carboplatin

33% (170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin

25% (132/531) 95% CI: 21.2%-28.5%

0 5 10 15 20 25 30 35 40 45 50

Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)• Monitor for myelotoxicity by performing complete blood cell

counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3

• In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC

• In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3

• In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System• Sensory neuropathy is dose- and schedule-dependent

• The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modi� cation

• If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine

• Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis

• If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics

• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis• Pneumonitis, including some cases that were fatal,

occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine

• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity• Severe and sometimes fatal hypersensitivity reactions,

including anaphylactic reactions, have been reported• Patients who experience a severe hypersensitivity reaction to

ABRAXANE should not be rechallenged with this drugHepatic Impairment• Because the exposure and toxicity of paclitaxel can be

increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment

• For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment

Albumin (Human)• ABRAXANE contains albumin (human), a derivative of

human blood Use in Pregnancy: Pregnancy Category D• ABRAXANE can cause fetal harm when administered to a

pregnant woman • If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men• Men should be advised not to father a child while

receiving ABRAXANE

ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study• The most common adverse reactions (≥20%) with single-

agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively

• Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients

• Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), � uid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported

• Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)

• In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)

• Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension

• Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study• Among the most common (≥20%) adverse reactions in

the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group

• The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)

• Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)

• Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations• Severe and sometimes fatal hypersensitivity reactions have

been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied

• There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs

• There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible in� ltration during drug administration

DRUG INTERACTIONS• Caution should be exercised when administering ABRAXANE

concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONSNursing Mothers• It is not known whether paclitaxel is excreted in human

milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric • The safety and effectiveness of ABRAXANE in pediatric

patients have not been evaluatedGeriatric• No toxicities occurred notably more frequently among

patients ≥65 years of age who received ABRAXANE for MBC• Myelosuppression, peripheral neuropathy, and arthralgia

were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

• Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment• The use of ABRAXANE has not been studied in patients with

renal impairment

DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended

for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN

• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN

• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity

• Monitor patients closely

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue

• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)

• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)

• The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively

• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is indicated for the fi rst-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

signifi cantly superior ORR in fi rst-line ITT population with advanced NSCLC

STUDY DESIGN • Multicenter 1:1 randomized, phase 3

study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

41% ORR in squamous patients

A National Comprehensive Cancer Network® (NCCN®) Category 1 recommendation1,2,b,c

b First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

CATEGORY 1

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.For more information, please visit www.abraxane.com.ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

Adverse events in the NSCLC study


9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”

Fonts: NoneImages: ABRAXANE_3_King_Brief Summary_012714.pdf (Bloc_GS:Celgene:Abraxane:ABX:A...NE_3_King_Brief Summary_012714.pdf)

ABX13338_NSCLC_Ad_Big3_3pg_DR.indd Amy Kortmanap

pro

vals

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days

Third Discontinue Treatment

Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.



9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1


The following is a Brief Summary; refer to full Prescribing Information for complete productinformation.

1 INDICATIONS AND USAGE1.1 Metastatic Breast CancerABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapyfor metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy shouldhave included an anthracycline unless clinically contraindicated.1.2 Non-Small Cell Lung CancerABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small celllung cancer, in combination with carboplatin, in patients who are not candidates for curative surgeryor radiation therapy.1.3 Adenocarcinoma of the PancreasABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of thepancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION2.1 Metastatic Breast CancerAfter failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months ofadjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administeredintravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung CancerThe recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 daycycle immediately after ABRAXANE [see Clinical Studies (14.2)].2.3 Adenocarcinoma of the PancreasThe recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately afterABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].2.4 Dosage in Patients with Hepatic ImpairmentNo dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderateand severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities knownto paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations fordosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2

in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severehepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 astolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) andClinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic ImpairmentSGOT (AST) Bilirubin ABRAXANE Dosea

Levels LevelsMBC NSCLCc Pancreaticc

AdenocarcinomaMild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2

≤ 1.25 x ULNModerate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not

2 x ULN recommendedSevere < 10 x ULN AND 2.01 to 130 mg/m2 b 50 mg/m2 not

5 x ULN recommended> 10 x ULN OR > 5 x ULN not not not

recommended recommended recommendedMBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in

subsequent courses should be based on individual tolerance.b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual

tolerance.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials forpancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation RecommendationsMetastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severesensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequentcourses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least

1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until countsrecover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 andplatelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption ofdosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin atreduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completelyresolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLCWeekly Every 3-Week

Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL)

Neutropenic Fever (ANC less than500/mm3 with fever >38°C) First 75 4.5

ORDelay of next cycle by more than7 days for ANC less than 1500/mm3 Second 50 3

ORANC less than 500/mm3 for morethan 7 days


Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment

Severe sensory Neuropathy – First 75 4.5Grade 3 or 4 Second 50 3


Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the PancreasDose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2)Full dose 125 10001st dose reduction 100 8002nd dose reduction 75 600If additional dose reductionrequired Discontinue Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients withadenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas

Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / GemcitabineDay 1 < 1500 OR < 100,000 Delay doses until recoveryDay 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level

< 500 OR < 50,000 Withhold dosesDay 15: IF Day 8 doses were reduced or given without modification:

500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1< 500 OR < 50,000 Withhold doses

Abbreviations: ANC = Absolute Neutrophil Count.Recommended dose modifications for other adverse drug reactions in patients with adenocarcinomaof the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levelPeripheral Neuropathy: Withhold until improves to

Grade 3 or 4 ≤ Grade 1; resume at next No dose reductionlower dose level

Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatmentGrade 2 or 3 if toxicity persists

Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume atGrade 3 mucositis or diarrhea next lower dose level

4 CONTRAINDICATIONS• ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged

with the drug.5 WARNINGS AND PRECAUTIONS

5.1 Hematologic EffectsBone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity ofABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastaticbreast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patientswith pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior todosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do notadminister ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patientswith either MBC or NSCLC.In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recoversto a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2)at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANCrecovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to anANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of thecycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC isless than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the nextcycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 ofthe cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage andAdministration (2.5)].

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than

1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarilyneutropenia, which may be severe and result in infection, it is recommended that frequentperipheral blood cell counts be performed on all patients receiving ABRAXANE [seeContraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relativeto those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXELFORMULATIONS.

5.2 Nervous SystemSensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. Theoccurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage andAdministration (2.5)].5.3 SepsisSepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combinationwith gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatalsepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrumantibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].5.4 PneumonitisPneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANEin combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis andinterrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling outinfectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatmentwith ABRAXANE and gemcitabine.5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have beenreported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not bere-challenged with this drug.5. 6 Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased with hepatic impairment,administration of ABRAXANE in patients with hepatic impairment should be performed with caution.The starting dose should be reduced for patients with moderate or severe hepatic impairment [seeDosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].5.7 Albumin (Human)ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donorscreening and product manufacturing processes, it carries a remote risk for transmission of viraldiseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is consideredextremely remote. No cases of transmission of viral diseases or CJD have ever been identified foralbumin.5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxelprotein-bound particles to rats during pregnancy at doses lower than the maximum recommendedhuman dose, based on body surface area, caused embryofetal toxicities, including intrauterinemortality, increased resorptions, reduced numbers of live fetuses, and malformations.There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If thisdrug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, thepatient should be apprised of the potential hazard to the fetus. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in SpecificPopulations (8.1)].5.9 Use in MenMen should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology(13.1)].

6 ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastaticbreast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, anddiarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin fornon-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions ofABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) andpneumonia (3%). The most common adverse reactions resulting in permanent discontinuation ofABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). Themost common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading towithholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), andanemia (16%).In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreaticadenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5%higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy,nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, anddehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higherincidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The mostcommon adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheralneuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactionsresulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).The most common adverse reactions leading to withholding or delay in ABRAXANE dosing areneutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia(5%) and diarrhea (5%).6.1 Clinical Trials Experience in Metastatic Breast CancerTable 6 shows the frequency of important adverse events in the randomized comparative trial for thepatients who received either single-agent ABRAXANE or paclitaxel injection for the treatment ofmetastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized MetastaticBreast Cancer Study on an Every-3-Weeks Schedule

Percent of PatientsABRAXANE Paclitaxel Injection

260 mg/m2 over 30 min 175 mg/m2 over 3 hb

(n=229) (n=225)Bone Marrow

Neutropenia< 2.0 x 109/L 80 82< 0.5 x 109/L 9 22

Thrombocytopenia< 100 x 109/L 2 3< 50 x 109/L <1 <1

Anemia < 11 g/dL 33 25< 8 g/dL 1 <1

Infections 24 20Febrile Neutropenia 2 1Neutropenic Sepsis <1 <1Bleeding 2 2

Hypersensitivity Reactionc

All 4 12Severed 0 2

CardiovascularVital Sign Changes DuringAdministration

Bradycardia <1 <1Hypotension 5 5

Severe Cardiovascular Eventsd 3 4Abnormal ECG

All Patients 60 52Patients with Normal Baseline 35 30

RespiratoryCough 7 6Dyspnea 12 9

Sensory NeuropathyAny Symptoms 71 56Severe Symptomsd 10 2

Myalgia / ArthralgiaAny Symptoms 44 49Severe Symptomsd 8 4

AstheniaAny Symptoms 47 39Severe Symptomsd 8 3

Fluid Retention/EdemaAny Symptoms 10 8Severe Symptomsd 0 <1

GastrointestinalNausea

Any Symptoms 30 22Severe Symptomsd 3 <1

VomitingAny Symptoms 18 10Severe Symptomsd 4 1

DiarrheaAny Symptoms 27 15Severe Symptomsd <1 1

MucositisAny Symptoms 7 6Severe Symptomsd <1 0

Alopecia 90 94Hepatic (Patients with NormalBaseline)

Bilirubin Elevations 7 7Alkaline Phosphatase Elevations 36 31AST (SGOT) Elevations 39 32

Injection Site Reaction <1 1a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication.c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain,

hypotension) that began on a day of dosing.d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body SystemHematologic DisordersNeutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in therandomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patientstreated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a doseof 175 mg/m2. Pancytopenia has been observed in clinical trials.InfectionsInfectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,respiratory tract infections and pneumonia were the most frequently reported infectiouscomplications.



9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups

ABRAXANE Paclitaxel Injection(100 mg/m2 weekly) (200 mg/m2 every 3 weeks)

plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013



9js

28344a1 07.10.14 133

Q1 Q2

S:20”

S:13”

T:21”

T:14”

B:21.25”

B:14.25”



app

rova

ls

7-2-2014 1:45 PM _______________

______________

_______________

_______________

_______________

_______________

_______________




Colors: Black GS

GSM

ED

CW

AD

AE

PD

Client: CELGENE


KING

Job #: ABX13338

Stage: DISK RELEASE

Round: 1

Hypersensitivity Reactions (HSRs)Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patientspreviously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.CardiovascularHypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused nosymptoms and required neither specific therapy nor treatment discontinuation.Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest,supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli,and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have beenreported.Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalitieson study did not usually result in symptoms, were not dose-limiting, and required no intervention.ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to studyentry, 35% of all patients developed an abnormal tracing while on study. The most frequently reportedECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinustachycardia.RespiratoryDyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment withABRAXANE.NeurologicThe frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathywas the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treatedwith ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documentedimprovement after a median of 22 days; 10 patients resumed treatment at a reduced dose ofABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documentedimprovement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) wasobserved in either arm of the controlled trial.Vision DisordersOcular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1%were severe. The severe cases (keratitis and blurred vision) were reported in patients who receivedhigher doses than those recommended (300 or 375 mg/m2). These effects generally have beenreversible. Arthralgia/MyalgiaThe symptoms were usually transient, occurred two or three days after ABRAXANE administration,and resolved within a few days.HepaticGrade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% ofpatients treated with paclitaxel injection in the randomized trial.RenalOverall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dosereductions, or dose delays were caused by renal toxicities.Other Clinical EventsNail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edemaoccurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were alsoreported.6.2 Clinical Trials Experience in Non-Small Cell Lung CancerAdverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxelinjection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized,open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as anintravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatmentarms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the medianage was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous celllung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles oftreatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence inABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE pluscarboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with adifference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE pluscarboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups


plus carboplatin plus carboplatinGrades 1-4 Grade 3-4 Grades 1-4 Grade 3-4

(%) (%) (%) (%)Anemia1,2 98 28 91 7Neutropenia 1,3 85 47 83 58Thrombocytopenia1,3 68 18 55 9

1 508 patients assessed in ABRAXANE/carboplatin-treated group2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group

Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxelinjection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups


+ carboplatin (N=514) + carboplatin (N=524)Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4

MedDRA v 12.1 Toxicity Toxicity Toxicity ToxicitySystem Organ Class Preferred Term (%) (%) (%) (%)Nervous system Peripheral 48 3 64 12disorders neuropathya

General disorders Edema peripheral 10 0 4 <1and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0and mediastinaldisorders Musculoskeletal Arthralgia 13 <1 25 2and connective tissue disorders Myalgia 10 <1 19 2

a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathyimproved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation ofABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the PancreasAdverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinomaof the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patientsreceived a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8months in the gemcitabine group. For the treated population, the median relative dose intensity forgemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. Themedian relative dose intensity of ABRAXANE was 81%.Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plusgemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

ABRAXANE(125 mg/m2)/ GemcitabineGemcitabined

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Neutropeniaa,b 73 38 58 27Thrombocytopeniab,c 74 13 70 9

a 405 patients assessed in ABRAXANE/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated groupcompared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

ABRAXANE Gemcitabine (N=402)(125 mg/m2)

and gemcitabine (N=421)

Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher

Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%)Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%)Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%)Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%)Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%)Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%)Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%)Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%)Alopecia 212 (50%) 6 (1%) 21 (5%) 0Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%)Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%)Dysgeusia 68 (16%) 0 33 (8%) 0Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%)Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%)Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%)Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%)Cough 72 (17%) 0 30 (7%) 0Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%)Urinary tractinfectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%)Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%)Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%)Myalgia 44 (10%) 4 (1%) 15 (4%) 0

Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy(broad scope).b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis,urinary tract infection bacterial, and urinary tract infection enterococccal.


General disorders andadministration siteconditions

Gastrointestinal disorders

Skin and subcutaneoustissue disorders

Nervous system disorders

Metabolism and nutritiondisorders

Respiratory, thoracic andmediastinal disorders

Infections and infestations

Musculoskeletal andconnective tissuedisorders

Additional clinically relevant adverse reactions that were reported in < 10% of the patients withadenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:Infections & infestations: oral candidiasis, pneumoniaVascular disorders: hypertensionCardiac disorders: tachycardia, congestive cardiac failureEye disorders: cystoid macular edemaPeripheral NeuropathyGrade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibinecompared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheralneuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANEarm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement fromGrade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.SepsisSepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patientswho received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Riskfactors for sepsis included biliary obstruction or presence of biliary stent.PneumonitisPneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% ofpatients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitisdied.6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel FormulationsUnless otherwise noted, the following discussion refers to the adverse reactions that have beenidentified during post-approval use of ABRAXANE. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure. In some instances, severe events observed withpaclitaxel injection may be expected to occur with ABRAXANE.Hypersensitivity ReactionsSevere and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The useof ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or humanalbumin has not been studied. CardiovascularThere have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricularblock with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such asanthracyclines, or had underlying cardiac history.RespiratoryThere have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patientsreceiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injectionsafety and may also be observed with ABRAXANE.NeurologicCranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathyresulting in paralytic ileus.Vision DisordersReports in the literature of abnormal visual evoked potentials in patients treated with paclitaxelinjection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment withABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visualacuity may return to baseline.HepaticReports of hepatic necrosis and hepatic encephalopathy leading to death have been received as partof the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANEtreatment.Gastrointestinal (GI)There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemiccolitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injectionalone and in combination with other chemotherapeutic agents.Injection Site ReactionThere have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it isadvisable to monitor closely the ABRAXANE infusion site for possible infiltration during drugadministration.Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as partof the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injectionsite reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayedby a week to ten days. Recurrence of skin reactions at a site of previous extravasation followingadministration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical EventsSkin reactions including generalized or maculopapular rash, erythema, and pruritus have beenobserved with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recallphenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantarerythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.6.5 Accidental ExposureNo reports of accidental exposure to ABRAXANE have been received. However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Followingtopical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONSThe metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinicaldrug interaction studies, caution should be exercised when administering ABRAXANE concomitantlywith medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin,fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g.,rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on itsmechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to apregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant whilereceiving this drug, the patient should be apprised of the potential hazard to the fetus. Women ofchildbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 atdoses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2

basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (upto 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase infetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue andskeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximumrecommended human dose on a mg/m2 basis).8.3 Nursing MothersIt is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites wereexcreted into the milk of lactating rats. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infants, a decision should be made todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to themother.8.4 Pediatric UseThe safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.8.5 Geriatric UseOf the 229 patients in the randomized study who received ABRAXANE for the treatment of metastaticbreast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicitiesoccurred notably more frequently among patients who received ABRAXANE.Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-linetreatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years orolder compared to patients younger than 65 years old. No overall difference in effectiveness, asmeasured by response rates, was observed between patients 65 years or older compared to patientsyounger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-linetreatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.No overall differences in effectiveness were observed between patients who were 65 years of age orolder and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were morefrequent in patients 65 years or older compared with patients younger than 65 years old. Clinicalstudies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were75 years and older to determine whether they respond differently from younger patients.8.6 Patients with Hepatic ImpairmentBecause the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment,the administration of ABRAXANE should be performed with caution in patients with hepaticimpairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and ClinicalPharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for thetreatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.8.7 Patients with Renal ImpairmentThe use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGEThere is no known antidote for ABRAXANE overdosage. The primary anticipated complications ofoverdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedProduct No.: 103450NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.16.2 StorageStore the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package toprotect from bright light.16.3 Handling and DisposalProcedures for proper handling and disposal of anticancer drugs should be considered. Severalguidelines on this subject have been published [see References (15)]. There is no general agreementthat all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling• ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while

receiving this drug. Women of childbearing potential should use effective contraceptives whilereceiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].• Patients must be informed of the risk of low blood cell counts and severe and life-threatening

infections and instructed to contact their physician immediately for fever or evidence of infection.[see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signsof dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patientsshould advise their physicians of numbness, tingling, pain or weakness involving the extremities[see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently withABRAXANE

• Instruct patients to contact their physician for signs of an allergic reaction, which could be severeand sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough,or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for: Celgene CorporationSummit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC.©2005-2013 Abraxis BioScience, LLC.All Rights Reserved.Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013



9js

28344a1 07.10.14 133

Q1 Q2

S:20”S:13”

T:21”T:14”

B:21.25”B

:14.25”


Journal Spotlight

No Benefit Seen for Cetuximab Added to Cisplatin and Accelerated Radiotherapy in Advanced Head and Neck Carcinoma By Matthew Stenger

U se of cisplatin or cetuximab (Er-bitux) with radiotherapy im-

proves overall survival in stage III or IV head and neck carcinoma, and add-ing cetuximab to platinum therapy im-proves overall survival in metastatic dis-ease. In the phase III Radiation Therapy Oncology Group (RTOG) 0522 trial reported in the Journal of Clinical Oncol-ogy, K. Kian Ang, MD, PhD (now de-ceased), of The University of Texas MD

Anderson Cancer Center, Houston, and colleagues found no progression-free survival or overall survival benefit of adding cetuximab to radiation/cis-platin in stage III or IV disease.1

Rita S. Axelrod, MD, of Thomas Jefferson University Hospital, Philadel-phia, is the corresponding author for the Journal of Clinical Oncology article.

Study DetailsIn the trial, 891 patients with squa-

mous cell carcinoma of the oropharynx, hypopharynx, or larynx and Zubrod performance status 0 or 1 were random-ly assigned between November 2005 and May 2009 to receive accelerated ra-diotherapy plus cisplatin with (n = 444) or without cetuximab (n = 447). Ran-domization was stratified by tumor site, nodal stage, Zubrod performance sta-tus, use of intensity-modulated radio-therapy (IMRT), and use of pretreat-ment positron-emission tomography/computed tomography scans.

Accelerated radiotherapy included two schedules; in one, 72 Gy was deliv-ered in 42 fractions given over 6 weeks. This included 1.8 Gy/fraction per day for 5 days per week and 1.5 Gy/fraction as a second daily treatment for the last 12 treatment days. When IMRT was used, the schedule included 70 Gy in 35 fractions (2 Gy per fraction), with

twice-daily dosing once a week for 5 weeks. Cisplatin was given at 100 mg/m2 on days 1 and 22 of radiotherapy, and cetuximab was given at 400 mg/m2 the week before radiotherapy and then 250 mg/m2 per week during ra-diotherapy. The primary endpoint was progression-free survival in the inten-tion-to-treat population.

The cetuximab and control groups were generally balanced for age (medi-

an, 58 and 57 years), sex (90% and 87% male), race (90% and 92% white), Zu-brod performance status (0 in 66% and 65%), primary tumor site (oropharynx in 70% in both, hypopharynx in 7% in both, larynx in 23% in both), T catego-ry (T2 in 40% and 39%, T3 in 36% and 38%, T4 in 24% and 23%), N category (eg, N0 in 12% and 10%, N2b in 35% and 31%, N2c in 31% and 36%), stage (IV in 85% and 87%), p16-positive pri-mary oropharyngeal tumor (39% and 36%, unknown in 47% and 50%), and EGFR status (27% and 26% with < 80% positive tumor cells, 16% in both with ≥ 80% positive tumor cells, unknown in 57% in both).

No Survival DifferenceMedian follow-up was 3.8 years.

There were no significant differences between the cetuximab and control groups in 30-day mortality (2.0% vs 1.8%, P = .81) or in 3-year progression-free survival (58.9% vs 61.2%, hazard ratio [HR] = 1.08, P = .76), overall

survival (75.8% vs 72.9%, HR = 0.95, P = .32), locoregional failure (25.9% vs 19.9%, HR = 1.30, P = .97), or distant metastasis (9.7% vs 13.0%, HR = 0.76, P = .08). On subgroup analysis, an overall survival benefit of cetuximab was observed in patients aged ≤ 50 years (HR = 0.45, P = .02 for interac-tion), with the addition of cetuximab not appearing to affect outcome in other subgroups.

Trends for a differential effect of ce-tuximab according to p16 status were observed; hazard ratios were 1.57 for p16-positive disease and 0.86 for p16-negative disease for progression-free survival (P = .12 for interaction) and 1.42 and 0.69, respectively, for overall survival (P = .13 for interaction). After imputation and adjustment for prog-nostic factors, hazard ratios were re-duced to 1.29 and 0.92 for progression-free survival (P = .31 for interaction) and 1.10 and 0.63 for overall survival (P = .19 for interaction).

On multivariate analysis, primary laryngeal-hypopharyngeal carcinoma, p16-negative oropharyngeal cancer, N2b-3 category, T4 tumor, > 10 pack-years smoking history, age > 50 years, and Zubrod performance status of 1 were significantly associated with poorer progression-free and overall survival.

Effect of p16 and EGFR StatusAmong all patients, those with p16-

positive vs p16-negative oropharyn-geal carcinoma had significantly better

3-year progression-free survival (72.8% vs 49.2%, HR = 0.49, P < .001), overall survival (85.6% vs 60.1%, HR = 0.32, P < .001), locoregional failure (HR = 0.45, P < .001), and distant metasta-sis (HR = 0.37, P = .005). Epidermal growth factor receptor (EGFR) expres-sion ≥ 80% vs < 80% was not associated with 3-year progression-free survival (HR = 1.09, P = .60), overall survival (HR = 1.19, P = .37), locoregional fail-ure (HR = 0.93, P = .76), or distant me-tastasis (HR = 1.53, P = .14).

ToxicityGrade 3 or 4 acute toxicities that

were more common (all P < .05) in the cetuximab group included radiation mucositis (43% vs 33%), skin reaction outside portal (20% vs 1%), skin reac-tion inside portal (25% vs 15%), fatigue (14% vs 9%), anorexia (16% vs 11%), and hypokalemia (10% vs 5%). How-ever, late grade 3 or 4 toxicities (> 90 days from start of radiotherapy) were not observed more frequently in the ce-tuximab group.

More treatment-related grade 5 ad-verse events occurred in the cetuximab group (10 vs 3, P = .05). The cetuximab group was more likely to have interrup-tion of radiotherapy (26.9% vs 15.1%).

For the cetuximab vs control groups, rates of feeding tube dependency were 18.8% vs 21.2% at 1 year (P = .47), 11.9% vs 13.5% at 2 years (P = .56), and 7.0% vs 12.1% at 3 years (P = .05).

The investigators concluded: “Add-ing cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. [Progression-free and overall survival] were higher in patients with p16-pos-itive [oropharyngeal carcinoma], but outcomes did not differ by EGFR ex-pression.” n

Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference1. Ang KK, Zhang Q, Rosenthal DI, et al:

Randomized phase III trial of concurrent ac-celerated radiation plus cisplatin with or with-out cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. August 25, 2014 (early release online).

Head/Neck Cancer

RTOG 0522 Results

■ The addition of cetuximab to radiotherapy and cisplatin did not improve progression-free or overall survival.

■ Outcomes were better in patients with p16-positive oropharyngeal carcinoma but did not differ according to EGFR status.

Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely.

—K. Kian Ang, MD, PhD

Rita S. Axelrod, MD


Perspective

Adding Cetuximab to Chemoradiation Did Not Benefit Patients With Advanced Head and Neck Cancer: What Were the Reasons?By Avraham Eisbruch, MD

Two landmark randomized stud-ies demonstrated improved sur-

vival of patients with head and neck cancer receiving the epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux) concurrent with radiotherapy compared with radiotherapy alone,1 and similar improvement in patients with recurrent/meta-static disease receiving cetux-imab and chemotherapy com-pared with chemotherapy alone.2

These results prompted the hypothesis that a combination of radiotherapy and concurrent che-motherapy and cetuximab may improve the outcome of head and neck cancer patients compared with radiotherapy and chemother-apy, regarded as today’s standard of care for advanced disease. This hy-pothesis was supported by preclin-ical findings that cetuximab sensi-tizes tumor cells to cisplatin3 and radiotherapy4 as well as data on its activity in recurrent/metastatic head and neck cancer refractory to platinum-based chemotherapy.5

Failure to Improve Outcome

However, a randomized Radi-ation Therapy Oncology Group (RTOG) study testing this hy-pothesis has failed to confirm the presumed superiority of the combined therapy. As reviewed in this issue of The ASCO Post, Ang et al6 reported the results of a large study (N = 891) in pa-tients with stage III/IV head and neck cancer randomly assigned to radiotherapy plus concurrent cisplatin, with and without con-current cetuximab. They noted higher rates of acute toxicity, no-tably mucositis, and higher rates of treatment interruptions in the cetuximab-containing arm, but no significant differences in dis-ease-free or overall survival.

What were the possible reasons for the failure to improve outcome by adding cetuximab? The authors

raised a number of possibilities, one being that the higher toxicity observed in the cetuximab-containing arm may

have increased interruptions in radio-therapy, neutralizing any potential tu-mor control benefit from the drug.

Another potential explanation is the similar mechanism of radiation sensiti-


Dr. Eisbruch is Professor of Radia-tion Oncology at the University of Michigan Health System, Ann Arbor.

Primary Endpoint: • Objective response rate

Secondary Endpoints: • Duration of response

• Progression-free survival

• Overall survival

• Safety: incidence of adverse events

• Incidence of antitherapeutic antibodies to MPDL3280A

• Maximum serum concentration (Cmax) of MPDL3280A

Key Inclusion Criteria2: • Documented locally advanced or metastatic

transitional cell carcinoma of the urothelium

• Representative tumor specimens


• Life expectancy ≥12 weeks

• Measurable disease, as defined by RECIST v1.1

• Adequate hematologic and end-organ function

• Refractory or ineligible for platinum-based chemotherapy

Key Exclusion Criteria2: • History of autoimmune disease

• Active hepatitis B or hepatitis C

• HIV-positive

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1

• Prior treatment with CD137 agonists, or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

A Phase II study for patients with locally advanced or metastatic UBC who are treatment-naïve and

ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy

A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

MPDL3280A1

(an engineered anti-PDL1 antibody)

N=330

Now Enrolling

For more information

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.



Call: Genentech Trial Information

Support Line: 1-888-662-6728 (US only)

E-mail: [email protected]


BLADDER

77659ha_f.indd 1 7/25/14 1:57 PM



Perspective

zation by cisplatin and cetuximab (in-hibition of repair of radiation-induced DNA damage) that may have prevented an additive or synergistic effect. If this explanation is valid, then the combina-tion of cetuximab and a drug with a dif-ferent sensitization mechanism, such as docetaxel, would be expected to be more effective, as has recently been suggested in a randomized study of postoperative radiotherapy with cisplatin and cetux-imab or with docetaxel and cetuximab.7

Tumor p16 StatusThe results of this study confirmed

that patients with human papillomavirus (HPV)-related oropharyngeal cancer had significantly better outcomes com-pared with patients with non-HPV re-lated cancers. No significant relationship was found between the effect of adding cetuximab and tumor HPV status.

This contrasts with the effect of an-other fully humanized IgG2 EGFR-specific monoclonal antibody, pani-tumumab (Vectibix), which did not show a survival benefit when added to cisplatin and fluorouracil in a random-ized study in metastatic head and neck cancer. However, disease-free survival was improved by adding panitumumab, and most of the improvement was dem-onstrated in patients with p16-negative tumors.8

Taking into account the fact that EGFR overexpression is a characteris-tic of p16-negative tumors,9 this finding suggests that EGFR inhibition may be more effective in tumors that overex-press EGFR. However, in the Ang et al study, no such interaction between adding cetuximab and HPV tumor status was noted. Neither was such an interaction observed in a randomized study of chemotherapy with or without cetuximab for metastatic head and neck cancer, in which a survival benefit was observed in the chemotherapy-cetux-imab arm compared with chemotherapy alone across both HPV-related and -un-related cancers.10

While other studies found that pa-tients with p16-positive oropharyngeal cancers may benefit more from the cetuximab-radiotherapy combination compared with chemoradiation,11 the evidence for no such interaction is much stronger.

Acute MucositisThe main added toxicity observed

with the cetuximab-chemoradiothera-

py combination compared with chemo-radiotherapy alone in RTOG 0522 was acute mucositis. The lack of excess mucositis in the radiation-concurrent-with-cetuximab arm compared with radiotherapy alone reported in the ran-domized study by Bonner et al1 raised the expectation that the main toxicity of aggressive chemoradiation for head and neck cancer can be prevented by sub-stituting cetuximab for chemotherapy and that adding cetuximab to chemora-

diation would not worsen this toxicity. However, emerging data suggest

that acute mucositis is quite prevalent in cetuximab-radiotherapy regimens, based on anecdotal data.12,13 Tsien et al treated patients planned for surgical resection with the EGFR tyrosine ki-nase inhibitor erlotinib and examined EGFR levels before and at post-erlo-tinib surgery in both cancer and mu-cosa samples.14 They found heterogene-ity in mucosal EGFR expression both pretherapy and after erlotinib therapy, with similar heterogeneity found in the tumor specimens.

Substantial suppression of mucosal EGFR activity may explain higher mu-cositis rates, since the normal mucosa depends on EGFR activity for its prolif-eration. Moreover, the substantial het-erogeneity in EGFR levels and response to EGFR inhibition suggest that some patients may be more prone to mucosi-tis during cetuximab-radiotherapy than other patients. This issue needs to be investigated further.

Overcoming Cetuximab Resistance

What should be the next step? The combination of radiotherapy, cetuximab, and docetaxel may be more active than radiotherapy, cetuximab, and cisplatin, as detailed above, and RTOG plans a phase III study to assess this. In addition, recent studies have examined possible ways to enhance cetuximab activity.

The presence of PIK3CA and RAS mutations and other alterations affect-ing the mTOR pathway activity in head and neck cancer may serve to select the patients that may benefit most from concomitant administration of cetux-imab and PI3K or mTOR inhibitors.15 Another strategy to overcome cetux-imab resistance may be interrupting the RAS-MAPK pathway, which is activat-ed in resistant cells, using an ERK1/2 inhibitor.16 Such strategies, if successful,

will renew future interest in combining chemotherapy and EGFR inhibitors in advanced head and neck cancer. n

Disclosure: Dr. Eisbruch reported no potential conflicts of interest.

References1. Bonner JA, Harari PM, Giralt J, et

al: Radiotherapy plus cetuximab for squa-mous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.

2. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus ce-tuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008.

3. Fan Z, Baselga J, Masui H, et al: An-titumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well es-tablished A431 cell xenografts. Cancer Res 53:4637-4642, 1993.

4. Huang SM, Bock JM, Harari PM, et al: Epidermal growth factor receptor block-ade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Can-cer Res 59:1935-1940, 1999.

5. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepi-dermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005.

6. Ang KK, Zhang Q, Rosenthal DI, et

al: Randomized phase III trial of concur-rent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940-2950, 2014.

7. Harari PM, Harris J, Kies MS, et al: Postoperative chemoradiotherapy and ce-tuximab for high-risk squamous cell car-cinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol 32:2486-2495, 2014.

8. Vermorken JB, Stöhlmacher-Williams J, Davidenko I, et al: Cisplatin and fluoroura-cil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPEC-TRUM): An open-label phase 3 randomised trial. Lancet Oncol 14:697-710, 2013.

9. Vainshtein JM, Spector ME, McHugh JB, et al: Refining risk stratification for lo-coregional failure after chemoradiotherapy in human papillomavirus-associated oro-pharyngeal cancer. Oral Oncol 50:513-519, 2014.

10. Vermorken JB, Psyrri A, Mesía R, et al: Impact of tumor HPV status on out-come in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: Retrospective analysis of the phase III EXTREME trial. Ann Oncol 25:801-807, 2014.

11. Pajares B, Trigo JM, Toledo MD, et al: Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papilloma-virus-related head and neck cancer. BMC Cancer 13:26, 2013.

12. Pryor DI, Burmeister E, Burmeister BH, et al: Distinct patterns of stomatitis with concurrent cetuximab and radiother-apy for head and neck squamous cell carci-noma. Oral Oncol 47:984-987, 2011.

13. Walsh L, Gillham C, Dunne M, et al: Toxicity of cetuximab versus cisplatin con-current with radiotherapy in locally advanced head and neck squamous cell cancer (LA-HNSCC). Radiother Oncol 98:38-41, 2011.

14. Tsien CI, Nyati MK, Ahsan A, et al: Effect of erlotinib on epidermal growth fac-tor receptor and downstream signaling in oral cavity squamous cell carcinoma. Head Neck 35:1323-1330, 2013.

15. Wang Z, Martin D, Molinolo AA, et al: mTOR co-targeting in cetuximab re-sistance in head and neck cancers harbor-ing PIK3CA and RAS mutations. J Natl Cancer Inst 106(9):dju215, 2014.

16. Boeckx C, Op de Beeck K, Wout-ers A, et al: Overcoming cetuximab re-sistance in HNSCC: The role of AURKB and DUSP proteins. Cancer Lett 354:365-377, 2014.

Avraham Eisbruch, MDcontinued from page 71

The combination of radiotherapy, cetuximab, and docetaxel may be more active than radiotherapy, cetuximab, and cisplatin, … and RTOG plans a phase III study to assess this. In addition, recent studies have examined possible ways to enhance cetuximab activity.

—Avraham Eisbruch, MD


Testicular cancer is one of oncology’s true success stories. It is a highly

treatable disease, usually curable, that most often develops in young and mid-dle-aged men. Despite the success in tes-ticular cancer, there are still clinical chal-lenges ranging from staging to optimum therapeutic approaches. To explore these challenges, The ASCO Post recently spoke with internationally regarded testes can-cer expert Lawrence H. Einhorn, MD, Distinguished Professor of Medicine at Indiana University School of Medicine, Indianapolis.

Key AdvanceWhat has been the most important ad-

vance during your career in testicular can-cer?

The most important advance in testes cancer goes all the way back to the early 1970s, with the discovery of the first heavy metal platinum ever used as an an-tineoplastic agent. Ironically, despite the activity platinum showed in a variety of human tumors, the toxicity was so severe that platinum came dangerously close to being discarded as a therapeutic option.

In some early phase I trials, however, a few testicular cancer patients in whom other treatments had failed were given single-agent platinum, and their tumors regressed substantially. Since the plati-num in these patients was given as third-line therapy, the responses were transient and the cancer returned. But follow-ing this positive response, we looked at platinum combined with other drugs in first-line therapy. And in 1974, when we began our studies with platinum plus vin-blastine plus bleomycin, the cure rate in these young men improved from about 5% to 55%.

In effect, just as platinum has saved the lives of so many men with testicular cancer, testicular cancer “saved” plati-num. Because if not for its success in tes-ticular cancer, platinum probably would have been discarded as a highly toxic,

minimally effective drug. Now, 40 years later, platinum has become a component of first-line chemotherapy for 11 differ-ent tumor types—more than any other single agent.

Early-Stage DiseaseClinical stage I testicular cancer is the

most prevalent presentation. Have we reached a point of consensus on how best to approach the disease at this stage? And as a follow-up, are we underutilizing active sur-veillance?

When I see a new patient diag-nosed with clinical stage I nonsemi-noma testes cancer whose computed tomography (CT) scans, serum hu-man chorionic gonadotropin (hCG), and physical exams are normal, I have a discussion about the pros and cons of surveillance vs having a good urolo-gist do a nerve-sparing retroperitoneal

lymph node dissection or having one course of adjuvant chemotherapy. To me, the preferred option in this setting is ac-tive surveillance.

In fact, late last year, I was one of 23 authors who published a consensus statement in the Journal of Clinical On-cology that examined all the options in clinical stage I disease and concluded that surveillance was the preferred clini-cal option. That said, performing a nerve-sparing retroperitoneal lymph node dissection or delivering one course of adjuvant chemotherapy in the stage I set-ting should still be part of the treatment option discussion between physicians and their patients.

However, in clinical stage I seminoma,

where there are three options—a single day of carboplatin, radiation therapy, or surveillance—there is near-unanimous support for the use of surveillance unless there is some compelling reason to the contrary.

Retroperitoneal Lymph Node Dissection

What is the clinical status of retroperito-neal lymph node dissection today?

In clinical stage I disease, the advan-tage of having a retroperitoneal lymph node dissection is that it indicates whether the lymph nodes are positive or negative for metastatic cancer. Metastatic testes cancer is the most curable of meta-static cancers with chemotherapy, and it is also the most surgically curable cancer in the presence of nodal metastases.

To that end, retroperitoneal lymph node dissection is not just for staging; it’s

also a therapeutic procedure. If a patient undergoes retroperitoneal lymph node dissection, as opposed to surveillance, he never has to have another CT scan of the abdomen because you’ve removed those lymph nodes.

So there are benefits to doing retro-peritoneal lymph node dissection, but we are doing fewer and fewer in stage I disease, as surveillance has become the preferred option. But if a retroperito-neal lymph node dissection is called for in a younger patient, it’s important to have a urologist who has expertise in doing nerve-sparing retroperito-neal lymph node dissection, in order to spare the patient from retrograde ejaculation and infertility.

Recurrence RiskWhere are we in the management of pa-

tients at high risk of recurrence?Patients who have stage I disease with

vascular invasion are at high risk for re-currence. We are still very comfortable with active surveillance in this setting despite a 50% chance of disease recur-rence, because even if disease recurs, we can cure 99% to 100% of these patients with standard chemotherapy for meta-static disease.

Patients with a high risk for recurrence are those who have a high risk of never going into complete remission with their chemotherapy. For many decades, four courses of the combination regimen BEP (bleomycin, etoposide, and cisplatin) has been standard first-line therapy for meta-static testes cancer.

In fact, at last year’s ASCO Annual Meeting, a French group presented a study in which the half-lives of serum hCG and alpha-fetoprotein were assessed during the first course of therapy.1 Pa-tients in whom these measures were not decreasing appropriately (based on a fair-ly complicated algorithm) were random-ly assigned to continued BEP vs a six- or seven-drug concoction with additional courses of chemotherapy. There was no difference in overall survival between study arms, but there was an advantage in progression-free survival among those receiving the additional agents.

We haven’t adopted that approach in the United States, and we are still look-ing to find a better treatment than stan-dard BEP in first-line chemotherapy. However, when a patient does relapse, we have curative options—standard-dose platinum along either with drugs they haven’t had before or with very high-dose chemotherapy followed by a stem-cell transplant. Even in the sal-vage setting, we’re still going to cure more than 50% of these patients who relapsed after their first-line treatments.

State of the Art


I think the advances in testes cancer in the next decade are going to be on the genetic front—identifying patients with a genetic susceptibility that predisposes them to toxicity from

the platinum-based therapies that can offer cure. —Lawrence H. Einhorn, MD


A Conversation With Lawrence H. Einhorn, MD By Ronald Pi ana

Treating Testicular Cancer in 2014


State of the Art

Ongoing ResearchAre there ongoing studies that the read-

ers should be aware of?In testes cancer, most of our patients

present with clinical stage I disease, and statistically we cure more than 99% of those patients. We’re not going to im-prove outcomes in that setting. More-over, we cure about 95% of patients with good-risk metastatic disease. We’re not going to improve those out-comes, either. But we’re always looking for ways to improve the 50% cure rate of patients with very advanced disease and new methods of delivering salvage chemotherapy.

In our group, we’re looking at the late consequences of platinum-based chemotherapy, such as neuropathy, car-diovascular toxicity, and second malig-nancies. These are survivorship issues that we don’t think about at the time of diagnosis because we’re just trying to get our patients through their therapy and cure the cancer. But these are im-portant quality-of-life issues in the post-therapy setting that need to be studied.

Looking AheadAny last thoughts on this clinical area

that you’ve devoted much of your career to?I think the advances in testes can-

cer in the next decade are going to be

on the genetic front—identifying pa-tients with a genetic susceptibility that predisposes them to toxicity from the platinum-based therapies that can offer cure. In the early days of platinum ther-apy, drugs were eventually developed to ameliorate the horrendous side effects of nausea and vomiting. I see a time in

the near future when we’ll be able to identify patients at risk for the chronic side effects of therapy, and have the personalized tools to treat those side effects. So the future is bright in testes cancer. n

Disclosure: Dr. Einhorn reported no potential conflicts of interest.

Reference1. Fizazi K, Pagliaro LC, Flechon A, et

al: A phase III trial of personalized chemo-therapy based on serum tumor marker de-cline in poor-prognosis germ cell tumors: Results of GETUG 13. ASCO Annual Meeting. Abstract LBA4500. Presented June 1, 2013.

Lawrence H. Einhorn, MDcontinued from page 73

$1 Million Raised in Honor of 40th Anniversary of Milestone

Gifts totaling $1 million in honor of the 40th anni-

versary of the cure for testicular cancer were recently announced at a celebration for the physician scientist who developed the treat-ment. Family, friends, colleagues, and men grateful for their lives gathered at the Indianapolis Mu-seum of Art to honor Lawrence Einhorn, MD, Distinguished Professor and Livestrong Founda-tion Professor of Oncology at the Indiana University (IU) School of Medicine and a researcher at the IU Melvin and Bren Simon Can-cer Center.

It was in September 1974 when Dr. Einhorn tested the


CODE: JJ-14-2 B size PUB/POST: Advertorial Spread Ad (3 Sizes), PRODUCTION: Roseann P. LIVE: 15” x 10.25”

DESCRIPTION: Advertorial Spread Ad (Size B) WORKORDER #: 006672 TRIM: 15.5” x 10.75”

Delivery Support: 212.237.7000 FILE: 02B-006620-02C-770584-B SIZE SPREAD.indd SAP #: S.TEMP.02388 BLEED: 16” x 11.25”

Art: 37187_A_JA_Storm_Within_fn.tif (CMYK; 306 ppi; Up to Date), 6_18_14_OGI BTK 4013_BTK 3D Illustrations_MainImage_noText2.tif (CMYK; 581 ppi, 498 ppi, 447 ppi; Up to Date), 06-12-13OGI-BTK 11113 Unbranded-Microenvironment Image NOText FINAL-4C.tif (CMYK; 422 ppi; Up to Date), JNJ-Janssen PCoJnJ-Horz-4C.ai (Up to Date), JNJ-pharmacyclics-4C.ai (Up to Date)

TLR BCR CXCR4/5Microenvironment

© Pharmacyclics, Inc. 2014

© Janssen Biotech, Inc. 2014

07/14 PRC-00437

A PERFECT STORM Connections between intracellular signaling and the microenvironment

The microenvironment provides a proliferative, protective niche for malignant cells.2,4-6

The microenvironment supplies survival signals and may contribute to the development of resistance in malignant cells.2,4-6 Internal aberrant prosurvival signaling and increased homing to and retention within supportive microenvironments likewise reinforce the prosurvival signals in malignant B cells,1-3,5 promoting a cycle that maintains disease.

In B-cell malignancies, intracellular dysfunction and external factors enable the disease state.1,2 Intracellular signaling pathways that control survival and proliferation can be dysregulated, resulting in inappropriate survival.1 These internal prosurvival processes are augmented by external signals from supportive cells and factors in the microenvironment such as the lymph nodes and bone marrow.2,3

New research is revealing how intracellular signaling and the microenvironment are involved in B-cell malignancies. Pharmacyclics, Inc. and Janssen Biotech, Inc., are committed to furthering the understanding of these important connections in B-cell malignancies.

For more information, including the new animation “Intracellular Signaling and the Microenvironment in B-cell Malignancies,” visit www.BCellSignals.com.

TLR=toll-like receptor; BCR=B-cell receptor; CXCR4/5=C-X-C (motif) chemokine receptor 4, C-X-C (motif) chemokine receptor 5. Creative representations of select simplifi ed signaling pathways. Illustrations not to scale.

References: 1. Shaffer AL III, Young RM, Staudt LM. Annu Rev Immunol. 2012;30:565-610. 2. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. Blood. 2009;114:3367-3375. 3. Davids MS, Burger JA. Open J Hematol. 2012;3. 4. Burger JA, Kipps TJ. Blood. 2006;107:1761-1767. 5. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Blood. 2009;113:4604-4613. 6. Kurtova AV, Balakrishnan K, Chen R, et al. Blood. 2009;114:4441-4450.

Intracellular signaling pathways

http://www.bcellsignals.com


State of the Art

platinum-based drug cisplatin with two additional drugs that were effec-tive in killing testis cancer cells. The combination became the cure for this once deadly disease. Today, there are

more than 300,000 survivors because of Dr. Einhorn’s research.

“When Dr. Einhorn began his work 4 decades ago, there was no term ‘cancer survivor,’” Patrick J. Loehrer, MD, Director of the IU Simon Cancer Center, said. “Now,

thanks to his research and leader-ship, 95% of the most common cancer in young men is curable. To-day, the IU Simon Cancer Center is uniquely positioned to develop a program of significant magnitude for all cancer survivors.”

Survivorship Research Program

The new survivorship research program will use gene-sequencing technology. Dr. Einhorn’s personal-ized medicine approach will allow a treatment team to evaluate the risks

for adverse side effects before therapy and map a treatment plan that reduces toxicity and an-ticipates and manages unavoid-able complications throughout each patient’s lifetime.

A total of $700,000, which will launch the program, has been contributed by multiple grateful patients and friends of Dr. Einhorn. This includes a lead-ership gift of more than $500,000 from A. Farhad Moshiri of Mo-naco. Mr. Moshiri had previ-ously created the Lawrence H. Einhorn Chair with a $2 million gift. The Einhorn Chair will be held by the Survivorship Pro-gram Director.

The children of Sidney and Lois Eskenazi also have pledged $300,000 to honor Dr. Einhorn and celebrate their parents’ 60th wedding anniversary. The gift from Sandy, Dori (Meyers), and David Eskenazi and their spouses establishes the Sidney and Lois Eskenazi Fellowship at the IU School of Medicine.

“IU is home to unique exper-tise in personalized medicine that focuses on genetic risks for side effects, and blending ge-netics data for both tumor and patient will be the ‘platinum’ standard of future treatment and lifelong health management for survivors,” Dr. Loehrer added. n

$1 Million Raisedcontinued from page 74

13th International Conference on Malignant

Lymphoma (ICML)June 17–20, 2015

Lugano, Switzerland

For more information, visit www.lymphcon.ch/imcl/index.php2

Save the Date

CODE: JJ-14-2 B size PUB/POST: Advertorial Spread Ad (3 Sizes), PRODUCTION: Roseann P. LIVE: 15” x 10.25”

DESCRIPTION: Advertorial Spread Ad (Size B) WORKORDER #: 006672 TRIM: 15.5” x 10.75”

Delivery Support: 212.237.7000 FILE: 02B-006620-02C-770584-B SIZE SPREAD.indd SAP #: S.TEMP.02388 BLEED: 16” x 11.25”

Art: 37187_A_JA_Storm_Within_fn.tif (CMYK; 306 ppi; Up to Date), 6_18_14_OGI BTK 4013_BTK 3D Illustrations_MainImage_noText2.tif (CMYK; 581 ppi, 498 ppi, 447 ppi; Up to Date), 06-12-13OGI-BTK 11113 Unbranded-Microenvironment Image NOText FINAL-4C.tif (CMYK; 422 ppi; Up to Date), JNJ-Janssen PCoJnJ-Horz-4C.ai (Up to Date), JNJ-pharmacyclics-4C.ai (Up to Date)

TLR BCR CXCR4/5Microenvironment

© Pharmacyclics, Inc. 2014

© Janssen Biotech, Inc. 2014

07/14 PRC-00437

A PERFECT STORM Connections between intracellular signaling and the microenvironment

The microenvironment provides a proliferative, protective niche for malignant cells.2,4-6

The microenvironment supplies survival signals and may contribute to the development of resistance in malignant cells.2,4-6 Internal aberrant prosurvival signaling and increased homing to and retention within supportive microenvironments likewise reinforce the prosurvival signals in malignant B cells,1-3,5 promoting a cycle that maintains disease.

In B-cell malignancies, intracellular dysfunction and external factors enable the disease state.1,2 Intracellular signaling pathways that control survival and proliferation can be dysregulated, resulting in inappropriate survival.1 These internal prosurvival processes are augmented by external signals from supportive cells and factors in the microenvironment such as the lymph nodes and bone marrow.2,3

New research is revealing how intracellular signaling and the microenvironment are involved in B-cell malignancies. Pharmacyclics, Inc. and Janssen Biotech, Inc., are committed to furthering the understanding of these important connections in B-cell malignancies.

For more information, including the new animation “Intracellular Signaling and the Microenvironment in B-cell Malignancies,” visit www.BCellSignals.com.

TLR=toll-like receptor; BCR=B-cell receptor; CXCR4/5=C-X-C (motif) chemokine receptor 4, C-X-C (motif) chemokine receptor 5. Creative representations of select simplifi ed signaling pathways. Illustrations not to scale.

References: 1. Shaffer AL III, Young RM, Staudt LM. Annu Rev Immunol. 2012;30:565-610. 2. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. Blood. 2009;114:3367-3375. 3. Davids MS, Burger JA. Open J Hematol. 2012;3. 4. Burger JA, Kipps TJ. Blood. 2006;107:1761-1767. 5. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Blood. 2009;113:4604-4613. 6. Kurtova AV, Balakrishnan K, Chen R, et al. Blood. 2009;114:4441-4450.

Intracellular signaling pathways

http://www.pharmacyclics.com

http://www.janssenbiotech.com


News

Nearly 800 New Cancer Medicines and Vaccines in Development, PhRMA Reports

America’s biopharmaceutical re-search companies are currently

developing nearly 800 new medicines and vaccines for cancer, according to a report released recently by the Phar-maceutical Research and Manufactur-ers of America (PhRMA).1

Perseverance Needed“In recent decades, we have seen

great progress in developing effective cancer treatments that help extend lives, improve quality of life, and in-crease productivity,” said PhRMA President and CEO John J. Castellani. Mr. Castellani discussed the impor-tance of collaborations and commit-ment of biopharmaceutical research-ers to persevere despite scientific challenges and setbacks at a national conference, “Turning the Tide Against Cancer,” held this past October.

As detailed in the new report, bio-pharmaceutical research companies continue to explore new avenues to treat cancer. Researchers are also identifying ways to use existing medi-cines, either alone or in combination with other therapies, to treat various types of cancers more effectively than current standards of care. “Continued research has expanded our knowledge of how cancer develops and how to target medicines for specific cancer types, which has resulted in more ef-fective therapies for patients,” Mr. Castellani said.

“Although the death rate from can-cer has been steadily declining for the past 4 decades, its toll is still stagger-ing,” said Mr. Castellani.

Of the 771 medicines and vaccines either in clinical trials or awaiting re-view by the U.S. Food and Drug Ad-ministration, there are 98 for lung can-cer, 87 for leukemia, 78 for lymphoma, 73 for breast cancer, 56 for skin cancer, and 48 for ovarian cancer.

Public-Private PartnershipsThe report highlights how biophar-

maceutical research companies are working together and collaborating with academic medical centers, govern-ment, and nonprofit organizations to make progress against cancer a reality. These public-private partnerships help to leverage diversity of thought and experience and reduce potential dupli-cation. The goal is to increase the num-ber of new therapies for patients while reducing the time necessary to develop

them. “Despite the complexity of the challenge, researchers at biopharma-ceutical companies remain committed to developing new treatment options for patients,” Mr. Castellani said. n

Disclosure: Mr. Castellani is President and CEO of the Pharmaceutical Research and Manufacturers of America (PhRMA).

Reference1. Pharmaceutical Research and Manu-

facturers of America: 2014 Report: Medi-cines and Vaccines in Development for Cancer. Available at http://www.phrma.org/sites/default/files/pdf/2014-cancer-report.pdf Accessed October 14, 2014.

25695_clovco_fa2_rash_ASCOpst.indd 1 9/23/14 3:31 PM

We want to change the face of EGFR-targeted therapy

In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are well-established side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5

At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014.

Clovis Oncology is leading the fight

Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2014 Clovis Oncology. DARO-101 8/14


http://www.phrma.org/sites/default/files/pdf/2014-cancer-report.pdf





Announcements

Professional Associations Collaborate to Launch Stereotactic Radiosurgery Patient Registry

The American Association of Neuro-logical Surgeons (AANS) and the

American Society for Radiation Oncol-ogy (ASTRO) are partnering to launch and support a national registry for ste-

reotactic radiosurgery (SRS) treatments. The partnership was announced recently at the ASTRO Annual Meeting.

The SRS patient registry will define national patterns of care in radiosurgery,

with an eye to improving health-care outcomes, supporting informed deci-sion-making, and potentially lowering the cost-of-care for patients. The registry project will gather data from 30 diverse,

high-volume sites with data specific to stereotactic radiosurgery during the next 3 years. The registry will log de-identified SRS treatment information of thousands of patients affected by brain metastases, benign brain tumors, and arteriovenous malformations (AVMs).

Jason Sheehan, MD, PhD, FAANS, Harrison Distinguished Professor and Vice-Chair of the Neurological Surgery at the University of Virginia, said “The registry underscores the commitment by AANS and ASTRO to enhancing qual-

ity care for our patients. It also provides new opportunities for achieving major advances in the management of patients with brain tumors, vascular malforma-tions, and functional disorders.”

ASTRO Health Policy Council Chair and a Radiation Oncologist at the University of Colorado, Denver, Brian Kavanagh, MD, MPH, added, “Radio-surgery is one of the most important, high-value services we can provide to a wide-range of patients for an assort-ment of benign and malignant cancers. The registry will give us ’big data’ that we can use to refine our current tech-nical and patient selection guidelines with the nuanced observations that can only be derived from large patient co-horts who are followed prospectively in a registry platform.”

ASTRO and AANS will lead the Scientific Advisory Committee charged with providing strategic oversight for the registry. Major sponsorship for the project has been provided by BrainLAB. Additional sponsors are being sought to support the long-term efforts and expan-sion of the registry. n

Jason Sheehan, MD, PhD, FAANS

Brian Kavanagh, MD, MPH


We want to change the face of EGFR-targeted therapy

In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are well-established side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5

At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014.

Clovis Oncology is leading the fight

Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2014 Clovis Oncology. DARO-101 8/14


http://www.clovisoncology.com


2014-2015 Oncology Meetings 2014-2015NovemberChemotherapy Foundation SymposiumNovember 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

Diagnostic Error in Medicine 5th International ConferenceNovember 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail.aspx/80028747

CNS Anticancer Drug Discovery/Development ConferenceNovember 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

Multidisciplinary Update in Breast Disease 2014November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgical-specialties-2014s306

19th Annual Meeting of the Society for Neuro-OncologyNovember 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer TherapeuticsNovember 18-21 • Barcelona, Spain For more information: www.aacr.org

ESMO Symposium on Immuno-OncologyNovember 21-22 • Geneva, Switzerland For more information: www.esmo.org/Conferences/Immuno-Oncology-2014

European Multidisciplinary Colorectal Cancer Congress (EMCCC)November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl

RSNA 2014: Radiological Society of North AmericaNovember 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

DecemberAmerican Association for Cancer Research: Tumor ImmunologyDecember 1-4 • Orlando, Florida For more information: www.aacr.org

Society of Urologic Oncology 15th Annual MeetingDecember 3-5 • Bethesda, Maryland For more information: http://suonet.org/meetings/2014/default.aspx

UICC World Cancer CongressDecember 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

24th World Congress of the International Association of Surgeons, Gastroenterologists and OncologistsDecember 5-7 • Vienna, Austria For more information: iasgo2014.org

ASH Annual Meeting and ExpositionDecember 6-9 • San Francisco, California For more information: hematology.org

37th Annual San Antonio Breast Cancer SymposiumDecember 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015Melanoma 2015: 25th Annual Cutaneous Malignancy UpdateJanuary 10-11 • San Diego, California For more information: www.scripps.org/events/melanoma-annual-cutaneous-malignancy-update-january-10-2015

Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

11th Annual Clinical Breakthroughs and Challenges in Hematologic MalignanciesJanuary 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

The Society of Thoracic Surgeons 51st Annual MeetingJanuary 24-28 • San Diego, California For more information: www.sts.org/education-meetings/educational-meetings-activities/future-meetings

February2015 BMT Tandem Meeting American Society for Blood and Marrow TransplantationFebruary 11-15 • San Diego, California For more information: www.asbmt.org

5th International Conference on Innovative Approaches in Head & Neck OncologyFebruary 12-14 • Nice, France For more information: www.estro.org/congresses-meetings/items/5th-ichno

The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer ResearchFebruary 19-21 • San Diego, California For more information: www.imedex.com/anti-angiogenesis-and-immune-therapies/

Genitourinary Cancers SymposiumFebruary 26-28 • Orlando, Florida For more information: www.gucasym.org

6th Current Concepts in the Management of Thyroid and Parathyroid NeoplasmsFebruary 26-28 • Houston, Texas For more information: www.mdanderson.org

32nd Annual Miami Breast Cancer Conference®February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/meetings/32nd-Annual-Miami-Breast-Cancer-Conference

March13th International Congress on Targeted Anticancer TherapiesMarch 2-4 • Paris, France For more information: www.tatcongress.org

Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to BiomarkersMarch 5-8 • Orlando, Florida For more information: www.aacr.org

16th European Congress: Perspectives in Lung CancerMarch 6-7 • Torino, Italy For more information: www.imedex.com/lung-cancer-congress-europe/index.asp

Advances in the Management of Multiple MyelomaMarch 6-7 • Saint Petersburg, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer CenterMarch 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse


2014-2015 Oncology Meetings 2014-2015Advanced Prostate Cancer Consensus ConferenceMarch 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

NCCN Annual Conference: Advancing the Standard of Cancer CareMarch 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/meetings/annual_conference.asp

8th Annual Interdisciplinary Prostate Cancer Congress™March 14 • New York, New York For more information: http://www.gotoper.com/conferences/ipcc/meetings/8th-Annual-Interdisciplinary-Prostate-Cancer-Congress

American Society of Preventive Oncology (ASPO) Annual MeetingMarch 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting

ACCC 41st Annual National MeetingMarch 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/calendar.asp

State-of-the-Art Neuro-Oncology Conference: 3rd Annual MeetingMarch 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicians-healthcare-professionals/conferences/conferences

21st Annual Blood-Brain Barrier and Neuro-Oncology MeetingMarch 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb

Society of Surgical Oncology Annual MeetingMarch 25-28 • Houston, Texas For more information: www.surgonc.org/

EORTC-EANO-ESMO 2015March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_EANO_ESMO-2015

46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

AprilAmerican Brachytherapy Society Annual MeetingApril 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm

Hematologic Malignancies: New Therapies and the Evolving Role of TransplantApril 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematology-and-oncology-2015r919

7th Asian Oncology Summit and the 11th Annual Conference of the Organisation for Oncology and Translational Research April 10-12 • Shanghai, China For more information: www.asianoncologysummit.com

ESMO European Lung Cancer ConferenceApril 15-18 • Geneva, Switzerland For more information: http://www.esmo.org/Conferences/ELCC-2015-Lung-Cancer

American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org

ONS 40th Annual Congress April 23–26 • Orlando, Florida For more information: www.ons.org/conferences/congress-2015

3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congresses-meetings/items/3rd-estro-forum

MayThe 28th Annual Meeting of the American Society of Pediatric Hematology/OncologyMay 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/annualmeeting.html

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

ASCO Annual MeetingMay 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

JuneInternational Cancer Screening Network (ICSN) Triennial MeetingJune 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

2015 Clinical Update: 21st Century Prevention of HPV-Associated CancerJune 5-7 • Baltimore, Maryland For more information: www.asccp.org/Education/2015-21st-Century-Prevention-of-HPV-Associated-Cancer

Society of Nuclear Medicine and Molecular Imaging Annual MeetingJune 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML)June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

Anticancer Drug Action and Resistance: from Cancer Biology to the ClinicJune 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

MASCC/ISOO Annual Meeting on Supportive Care in CancerJune 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-OncologyJuly 28–August 1 • Washington, DC For more information: http://www.apos-society.org/professionals/meetings-ed/annualconference.aspx

Best of ASCO® BostonJuly 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

AugustBest of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://boa.asco.org/

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

SeptemberASCO Breast Cancer Symposium September 25-27 • San Francisco, California For more information: breastcasym.org

The European Cancer CongressSeptember 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/European-Cancer-Congress-2015


Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Lung CancerCompiled by Jo Cavallo

PHASE IB/II

Study Type: Phase Ib/II/interven-tional/single-group assignment

Study Title: Phase Ib/II Trial of Carfilzomib With Irinotecan in Irinote-can-Sensitive Malignancies (Phase Ib) and Small Cell Lung Cancer Patients (Phase II) Who Have Progressed on Prior Platinum-Based Chemotherapy

Study Sponsor and Collabora-tors: Cancer Research and Biostatistics Clinical Trials Consortium, Lucille P. Markey Cancer Center at the Universi-ty of Kentucky, Washington University School of Medicine

Purpose: To determine a well-tol-erated dose of carfilzomib (Kyprolis) in combination with irinotecan in subjects with relapsed small cell and non–small cell lung cancer or other irinotecan-sen-sitive cancers and to assess the 6-month survival of relapsed small cell lung can-cer patients treated with this combina-tion therapy

Ages Eligible for Study: 18 years and older

Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures:

Phase Ib: Determine maximum toler-ated dose of carflizomib in combination with irinotecan in subjects with relapsed small and non–small cell lung cancer or other irinotecan-sensitive cancers (time frame: 28 days). Phase II: Assess 6-month survival of relapsed small cell lung cancer patients treated with carfil-zomib in combination with irinotecan

(time frame: up to 6 months).Principal Investigator: Susanne M.

Arnold, MD, Lucille P. Markey Cancer Center at the University of Kentucky; 859-323-8043, [email protected]

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01941316

PHASE II

Study Type: Phase II/intervention-al/randomized

Study Title: Randomized Phase II Trial of Individualized Adaptive Radio-therapy Using During-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non–Small Cell Lung Cancer (NSCLC)

Study Sponsor and Collaborators: National Cancer Institute

Purpose: To study how well posi-tron-emission tomography/computer tomography scan works in guiding ra-diation therapy compared to standard therapy treatment in patients with stage III non–small cell lung cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Lo-

cal-regional, progression-free rate (time frame: 2 years)

Principal Investigator: Feng-Ming (Spring) P. Kong, Radiation Therapy Oncology Group; 706-721-1663, [email protected]


Study Type: Phase II/intervention-al/single-group assignment

Study Title: STEREOtactic Radia-tion and Adjuvant Chemotherapy in Lung Cancer (STEREO)

Study Sponsor and Collaborators: James Graham Brown Cancer Center

Purpose: To test the feasibility of adjuvant chemotherapy after stereo-tactic body radiation therapy for early stage non–small cell lung cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: To

measure the feasibility of adjuvant che-motherapy after stereotactic body radi-ation therapy for early stage non–small cell lung cancer (time frame: 3 years af-

ter subject enrollment)Principal Investigator: Goetz H.

Kloecker, MD; 502-562-4358, [email protected]


Study Type: Phase II/intervention-al/nonrandomized

Study Title: Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non–Small Cell Lung Cancer

Study Sponsor and Collaborators: University of Florida

Purpose: To determine whether hypofractionated image-guided radia-tion therapy (hypoIGRT) with proton therapy is a good way to treat early-stage lung tumors for patients who will not have surgery



Confirm grade 3 or higher toxicity rate of hypoIGRT proton therapy in pa-tients with stage I non–small cell lung cancer (time frame: 1 year after the end of radiation therapy)

Principal Investigator: Bradford S. Hoppe, MD, MPH, University of Flor-ida Proton Therapy Institute; contact Intake Coordinator, 877-686-6009


PHASE III

Study Type: Phase III/interven-tional/randomized

Study Title: A Phase III, Multicen-tre, Randomized Trial to Evaluate the Symptomatic and Quality of Life Im-provements in Lung Cancer Patients Receiving External Beam Radiation With or Without High-Dose Rate Intra-luminal Brachytherapy

Study Sponsor and Collaborators: Ontario Clinical Oncology Group, Ca-nadian Cancer Society Research Insti-tute

Purpose: To improve the quality of life of patients with advanced non–small cell lung cancer by evaluating the symptomatic improvement in patients with lung cancer receiving external ra-diation with or without high-dose inter-nal radiation



For each subject, a lung cancer-relat-ed symptomatic improvement at 6 weeks postrandomization, defined as a 10-point improvement on a 100 point scale from the summary question of lung cancer symptoms (time frame: 6 weeks from randomization)

Principal Investigator: Ranjan Sur, MD, PhD, Juravinski Cancer Centre; contact Jim Wright, 905-387-9495, ext. 64706; [email protected]


OBSERVATIONAL

Study Type: Observational Study Title: Molecular Predictors

of Lung Cancer BehaviorStudy Sponsor and Collaborators:

Vanderbilt-Ingram Cancer CenterPurpose: To investigate molecular

predictors of cancer in patients at high risk for developing lung cancer



quantitate the molecular changes dur-ing lung cancer development (time frame: after collection of designated samples)

Principal Investigator: Pierre Mas-sion, MD, Vanderbilt-Ingram Cancer Center; contact Rena Burns, RN; 615-873-7658, [email protected]


Study Type: ObservationalStudy Title: Genetic Epidemiology

of Lung Cancer Study Sponsor and Collaborators:

National Human Genome Research In-stitute

Purpose: This study will search for genes that greatly increase the risk of developing lung cancer in conjunction with cigarette smoking or other envi-ronmental agents, or both. While lung cancer has been frequently cited as an example of cancer determined only by the environment, certain occupations,

The information contained in this Clinical Trials Resource

Guide includes actively recruiting clinical studies of people with lung neoplasms, including stage I and II small cell and non–small cell lung cancers. The studies include phase Ib, II, III, observational, and inter-ventional trials evaluating com-binations of therapies; molecular predictors of lung cancer; molecu-lar strategies for early detection; guided radiation therapy; genetic epidemiology; immunoregulation of lung cancer by NK cells; sur-gery; and DNA/RNA sequencing to predict treatment response. All of the studies are listed on the Na-tional Institutes of Health website at ClinicalTrials.gov.



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GSKProduct: TafinlarJob#: 6GSK_DATR_10182326Colors: 4C Sizes: Bleed: 11.125”w x 15.25”h

Sm Trim: 10.5”w x 13.75”hLive: 9.5”w x 13”h

Publications:Hem/Onc TodayCAP TodayThe ASCO PostTargeted Therapies in OncologyValue Based Cancer Care

KING Size

New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST.Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

The fi rst and only FDA-approved combination therapy

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST.

Important Safety Information for TAFINLAR and MEKINIST when used in combination

To learn more, visit TAFINLARMEKINISTHCP.com

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATEDEMONSTRATED DURABLE RESPONSE RATEIN A PHASE II STUDY 1,2

overall response

rate1

overall response

rate1

median durationof response1

median durationof response1

months(95% CI: 7, 15)

months(95% CI: 5, 7)

(95% CI: 62, 87)

(95% CI: 40, 67)

10.510.510.510.55.65.65.65.6

76%76%76%76%

54%54%TAFINLAR as a single agent

Investigator-assessed analysis

TAFINLAR150 mg twice daily

MEKINIST2 mg once daily

in combination

+

MEL156R0_ICAD_FR2.indd 1 7/24/14 4:06 PM

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

(trametinib)0.5 mg, 1 mg, 2 mg tablets

®

(dabrafenib)50 mg, 75 mg capsules

®

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

0

10

20

30

40

50

60

70

80

TAFINLAR as a single agent(N=54)

Res

pons

e R

ates

4%

CompleteResponse

PartialResponse

50%

CompleteResponse

9%

PartialResponse

67%

Overall Response

54%(95% CI: 40, 67)

Overall Response

76%(95% CI: 62, 87)

+ MEKINIST2 mg once daily

TAFINLAR150 mg twice daily

(N=54)

Major effi cacy outcome: Investigator-assessed response rate1

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Months

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

10.5 months(95% CI: 7, 15)

Months

(N=54)

Effi cacy outcome: Investigator-assessed median duration of response1

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC


Sm Trim: 21.0”w x 13.75”hLive: 22”w x 15.25”h


KING Size

MEL156R0_ICAD_FR2.indd 2-3 7/24/14 4:06 PM


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC


Sm Trim: 10.5”w x 13.75”hLive: 9.5”w x 13”h


KING Size

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).Drug InteractionsEffects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.comTAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(trametinib)0.5 mg, 1 mg, 2 mg tablets

®

(dabrafenib)50 mg, 75 mg capsules

®




Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC

Client: GSKProduct: Tafinlar Job#: 6GSK_DATR_10182326Colors: 4C Sizes: Bleed: 11.125”w x 15.25”h

Sm Trim: 10.5”w x 13.75”h Live: 9.5”w x 13”h


KING Size

BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.


https://www.gsksource.com/gskprm/en/US/images/gsk_content/TAFMEK/index.html


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests

TAFINLAR plus MEKINIST 2 mg

N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions


N = 55


N = 54TAFINLAR

N = 53

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0



Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKlineResearch Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR:4BRS© 2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014



Clinical Trials Resource Guide

and dietary habits, researchers have long had a hypothesis that people vary in their risk of becoming affected when exposed to these factors. Also, some evidence has shown that lung cancer in families may be due to the com-bined effects of inheritance of a major gene and cigarette smoking. Individu-als with a confirmed diagnosis of lung cancer or a family history of lung can-cer may be eligible to enroll their fami-lies in this study.


Genders Eligible for Study: BothAccepts Health Volunteers: YesPrimary Outcome Measures: De-

tection of gene(s) contributing to lung cancer risk

Principal Investigator: Joan Bai-ley-Wilson, PhD, National Human Genome Research Institute; 443-740-2921, [email protected]


Study Type: ObservationalStudy Title: Mechanisms of Immu-

nosurveillance for Lung CancerStudy Sponsor and Collaborators:

Washington University School of Medi-cine, Saint Louis VA Medical Center

Purpose: To investigate the differ-ences in natural killer (NK) blood cells, a type of white blood cell that fights infection in the body, among different types of patients who have lung surgery. The four different groups of patients in-clude smokers with lung cancer, smok-ers without lung cancer, nonsmokers with lung cancer, and nonsmokers without lung cancer.


Genders Eligible for Study: BothAccepts Health Volunteers: YesPrimary Outcome Measures:

Number of NK cells (time frame: within 5 minutes of blood arrival to lab, processing begins, and blood is frozen; flow cytometry will be completed 1 to 3 months after blood is frozen; data pre-sentation in 1 to 2 years)

Principal Investigator: Alexander S. Krupnick, MD, Washington Univer-sity School of Medicine; contact Joanne F. Musick, BSN; 314-747-0707, [email protected]


Study Type: ObservationalStudy Title: Molecular Fingerprint-

ing of Lung CancerStudy Sponsor and Collaborators:

Vanderbilt-Ingram Cancer Center, Na-tional Cancer Institute

Purpose: To collect and analyze lung tissue samples from patients un-dergoing surgery for non–small cell lung cancer


Genders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures: Pro-

tein and RNA expression fingerprints from collected samples (time frame: after collection of designated samples)

Principal Investigator: Pierre P. Massion, MD, Vanderbilt-Ingram Can-cer Center; contact VICC Clinical Trials Information Program, 800-811-8480


Study Type: ObservationalStudy Title: Nashville Early Diag-

nosis Lung Cancer ProjectStudy Sponsor and Collaborators:

Vanderbilt-Ingram Cancer Center, Na-tional Cancer Institute

Purpose: This screening will ad-dress the lack of molecular strategies for the early detection of lung cancer and integrate those with epidemiologic and imaging strategies. The goal of the investigators is to provide screening for lung cancer in a high-risk population. This study will test whether repeated measure of biomarkers of risk allows early detection of lung cancer.

Ages Eligible for Study: 55 to 74 years


compare candidate biomarkers over time among participants who did and did not develop lung cancer (time frame: at baseline and yearly to year 5)

Principal Investigator: Pierre P. Massion, MD, Vanderbilt-Ingram Can-cer Center; contact Anel Muterspaugh, 615-936-4244


Study Type: ObservationalStudy Title: Specimen Banking

From Patients With Lung CancerStudy Sponsor and Collaborators:

University of Colorado, Denver; Na-tional Cancer Institute

Purpose: To develop a comprehen-sive specimen banking program from pa-tients with lung cancer for future trans-lational research, which will enable the investigators to detect lung cancer ear-lier, develop better therapies and explore screening and prevention strategies

Ages Eligible for Study: 18 to 85 years


develop a comprehensive specimen banking program from patients with lung cancer for future translational re-search (time frame: 6 years)

Principal Investigator: Wilbur Franklin, MD, University of Colorado, Denver; contact Mary K. Jackson; 303-724-1650, [email protected]


Study Type: ObservationalStudy Title: Molecular Fingerprints

in Lung Cancer: Predicting Tumor Re-sponse to Therapy

Study Sponsor and Collaborators: Vanderbilt-Ingram Cancer Center; Na-tional Cancer Institute

Purpose: Studying samples of tu-mor tissue and blood in the laboratory from patients with cancer may help in-vestigators learn more about changes that occur in genetic material (DNA and RNA) and may also identify pro-

tein expression patterns related to can-cer. It may also help clinicians predict how patients will respond to treatment.

Ages Eligible for Study: N/AGenders Eligible for Study: BothAccepts Health Volunteers: NoPrimary Outcome Measures:

DNA, RNA, and protein expression patterns and mutational analysis (time frame: after lung tumor tissue and blood collection)

Principal Investigator: Christine Lovly, MD, PhD, Vanderbilt-Ingram Can-cer Center; contact VICC Clinical Trial Information Program, 800-811-8480


INTERVENTIONAL

Study Type: Interventional/single-group assignment

Study Title: Image-Guided Hypo-fractionated Radiotherapy With Ste-reotactic Boost and Chemotherapy for Inoperable Stage II-III Non–Small Cell Lung Cancer

Study Sponsor and Collaborators: Jonsson Comprehensive Cancer Center

Purpose: To study image-guided hypofractionated radiation therapy (RT) when given together with hypo-fractionated RT boost and combination chemotherapy in treating patients with stage II–III non–small cell lung cancer that cannot be removed by surgery. Giving RT together with combination chemotherapy may kill tumor cells and allow doctors to save the part of the body where the cancer started.



determine the maximal tolerated dose using hypofractionated radiotherapy in patients with stage II–III non–small cell lung cancer (time frame: up to 90 days)

Principal Investigator: Percy Lee, MD, Jonsson Comprehensive Cancer Center; 310-825-9771

For More Information: Visit Clini-calTrials.gov and refer to this study by its identifier: NCT01345851 n

Lung Cancercontinued from page 80

The Value of Federally Funded Cancer ResearchASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide. The plenary presentations at ASCO’s Annual Meeting all were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge here to indicate the clinical trials listed here include data resulting from federally funded research.


Mac Op

QC

Editing

Copywriting

Art Director

Art Buying

Account

Traffic

Production

DQC




KING Size

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKlineResearch Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR:4BRS© 2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014



Book Review

A History of Medical Oncology By Ronald Piana

According to Pierre R. Band, MD, author of the recently published

book, Therapeutic Revolution: The History of Medical Oncology From Early Days to the Creation of the Subspecialty, “Many books have been written about cancer and many articles have been published on the his-tory of chemotherapy, but none to our knowledge on the history of medical on-cology, that is, the events that led to this new subspecialty of internal medicine.”

Dr. Band is correct: many books have been written about cancer. Dr. Band is also correct that the history of medical oncol-ogy has rarely, if ever, been tackled in book form. Moreover, he is the perfect author to write such a history. As noted in the book’s forward—written by his colleague and friend, James F. Holland, MD—Dr. Band is not a historian distant in time from the conflicts of what he writes about because “he was fully engaged in the extraordinary turbulence that permeated the early years of medical oncology.”

Personal BackgroundFor historical perspective, Dr. Band

introduces himself to the readers in chap-ter 1. He was born in Paris to Hungarian parents who immigrated to Canada when he was 15. The adolescent upheaval was traumatic, and Dr. Band dropped out of high school to work in a restaurant. A year later, he reentered high school and perse-vered his way to medical school, attaining his medical degree from the University of Montreal.

During his internship in 1961, he de-cided to pursue a career in cancer medi-cine. The enthusiastic young doctor sent letters of inquiry to the American Cancer Society asking what American institu-tions provided residencies in cancer medicine and what kind of training they offered. He received an unexpected re-ply: “There really isn’t any recommended special training for oncology because the oncologic specialty system of medical practice determines the course of treat-ment of the cancer patient, thus making a ‘cancer specialist,’ a non-entity.”

Pursuing a career as a ‘non-entity’ in-tensified Dr. Band’s realization that oncol-ogy was a new frontier, with endless pos-sibilities—a perfect fit for his restless and inquisitive mind. After serving as a resi-dent in Montreal, Dr. Band seized an op-portunity in 1966 to join the Department of Medicine headed by Dr. Holland, then Chief of Medicine at Roswell Park Cancer Institute in Buffalo, New York. “Holland’s contributions to cancer medicine will fig-

ure prominently in this book,” writes Dr. Band. And they do, as the book begins an intricate tour, from the inside out, of the history of medical oncology.

Remarkable HistoryIn chapter 2, Dr. Band gives what he

calls a brief overview “From Dinosaurs to the Dawn of Chemotherapy.” This is dense and intense content that discusses, among other topics, lymphatic theory, cell theory, and hormonal procedures. It is meant for small bites of reading, which better allow the reader to fully digest the remarkable history being told.

For instance, Dr. Band writes about Hippocrates’ descriptions of visible or readily palpable cancer including those of the skin, head and neck, breast, and cervix, noting that his description of virilization in two women who died of their disease is of special interest: “Menstruation ceased and the body took on a virile appearance, this woman became hairy all over, she grew a beard, her voice acquired harshness … this woman died in short time.”

Dr. Band stresses that these cases may be “the first-ever reported of virilizing ovarian or adrenal cancers, which at the

time could not be diagnosed as such.” (These cancers were thought to be ex-plained by the theory of the four humors, involving an excess of black bile.) But Dr. Band’s underlying message here to cur-rent oncology practitioners and research-ers is that these investigations took place in 300 BC. That is not only humbling, it’s a call to action.

Archaeologic DigThis is a scholarly work, but it is con-

structed with such care that it pulls you into the past of oncology, giving the feel of an archaeologic dig, which is one of the book’s true pleasures. In this chapter, we’re taken from the Hippocratic school through the Renaissance, to the “incom-parable genius” of Paul Ehrlich, MD (of “magic bullet” fame), to groundbreaking studies in hormonal therapies.

Once again, Dr. Band gives some his-torical perspective, which medical oncol-ogy fellows and residents should find of interest: “In the mid-sixties, at the time the author began his training in oncol-ogy, hormonal treatment whether surgi-cal or medical, was the mainstay against

advanced breast cancer. At the time, che-motherapy was offered as a last resort.”

The connection between warfare and cancer treatment is outlined superbly in chapter 3. And although the influence of mustard gas on the development of nitro-gen mustard—marking the dawn of mod-ern chemotherapy—is well documented, the connection between the scientific ef-forts to combat malaria in World War II and the development of U.S. cancer programs is less well known. Dr. Band points out that the malarial war program was “a gigantic cooperative effort … involving a number of disciplines and techniques, including chemistry, drug screening in experimental animal systems and human pharmacology and toxicology clinical trials.”

Giants in the FieldSeeing the success of the coopera-

tive malarial efforts, several American researchers sought to bring the same vi-sion and organization to oncology at the National Institutes of Health. The ran-domized clinical cancer trial was born, arguably one of the greatest advances in cancer research and treatment. Giants in the field stepped forward. “One of them was Dr. Charles Gordon Zubrod,” writes Dr. Band.

At this point, the narrative accelerates, suddenly arriving at chapter 5: “The Years of Creativity: 1953-1965. Pre-Clinical.” This epoch in cancer research, discovery, and sheer force of personality might be unmatched. The reader meets the great experimentalists such as Drs. Zubrod, Holland, Emil Frei III, Lloyd Law, and Emil J. Freireich, to name just a few.

Readers will find this particular trip into the history of U.S. medical oncol-ogy refreshing and slightly sad, in that the open field of exploration known to these pioneers has been clogged by un-due regulation and red tape. This chapter also offers the book’s most compelling and insightful anecdotes about these pio-neering researchers who worked side-by-side as colleagues and friends while they changed the face of oncology.

Moreover, chapter 5 offers today’s can-cer researchers a glimpse into an ethos that should be the foundation of the collective march toward better clinical research and outcomes for patients. Dr. Band’s firm control of the subject gives needed balance between anecdotes and scientific content, again, adding pleasure to what at times is somewhat dry material.

The story of medical oncology was written by men and women of courage, and conviction … [and] above all passion, that led us to where we are today.

—Pierre R. Band, MD

BookmarkTitle: Therapeutic Revolution: The History of Medical Oncology From Early Days to the Creation of the Subspecialty

Author: Pierre R. Band

Publisher: Bentham Science

Publication date: 2014

Price: $39.00 (eBook); $78.00 (print on demand); 213 pages

Available at: eurekaselect.com



Announcements

Fitting DesignDrs. Sidney Farber, David Karnofsky,

Vincent DeVita, Denis Burkitt, Lawrence Einhorn, Bernard Fisher, Gianni Bo-nadonna, and others well known to the readers of The ASCO Post appear in the chronologic order marked by their huge and lasting contributions. This architec-ture of the book fits its ambitious goal.

The chapters are remarkably concise. Given the overwhelming amount of infor-mation, that in and of itself is a triumph. This is not a book for the meek reader. However, it is a book for anyone who has a serious interest in the field of oncology.

As the author notes in the closing paragraph, “The story of medical oncol-ogy was written by men and women of courage, and conviction … [and] above all passion, that led us to where we are today.” Dr. Band was one of those men, and his fine scholarly work deserves a place in the canon of oncology. n

See the August 15 issue of The ASCO Post for a conversation with Pierre R. Band, MD, titled, “Pioneering Medical Oncologist Remembers a Time Before the Subspecialty Was Created.”

AACR Honors Zhu Chen, MD, PhD, for Distinguished Public Service and Global Impact in Cancer Research

The American Association for Can-cer Research (AACR) honored

Zhu Chen, MD, PhD, with the 2014 AACR Award for Distinguished Public Service and Global Impact in Cancer

Research in Biomedical Science at the AACR’s inaugural meeting in China, called New Horizons in Cancer Re-search: Harnessing Breakthroughs—Targeting Cures. Dr. Chen received the award when he delivered the opening plenary lecture at the inaugural meeting.

Dr. Chen, a fellow of the AACR Acad-emy, is the Vice Chairman of the 12th Standing Committee of the National People’s Congress. From 2007 to 2013, he served as China’s Minister of Health.

“Dr. Chen epitomizes the scientific work of this vast nation, and it is our

honor to recognize him for his achieve-ments,” said Carlos L. Arteaga, MD, President of the AACR.

In a career dedicated to translational research, Dr. Chen pioneered the con-

cept of combination targeted therapies for cancer and, by combining tradi-tional Chinese medicine with Western medicine, he provided the first suc-cessful model in the treatment of acute

promyelocytic leukemia with all-trans retinoic acid and arsenic trioxide. This treatment turned this previously fatal hematologic malignancy into a largely curable disease. n

Book Reviewcontinued from page 90

Zhu Chen, MD, PhD

Proceed with confidence

Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy.

Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.

© 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today.

• Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1

Confidence begins with a highly accurate risk assessment

For HR+, early-stage invasive breast cancer

18434_nanpro_fa2_ascopst_ad.indd 1 3/24/14 1:43 PM

http://prosigna.com


Patient’s Corner

Lessons From CancerAn AML diagnosis has taught me that while I can’t always control what happens to me, I can control how I respond to new challenges—and that is empowering.By Kelly Traw, as told to Jo Cavallo

For a year before I was diagnosed with acute myeloid leukemia

(AML) in December 2011, I had what I thought were the lingering remnants of a bad case of bronchitis. My breath-ing was labored, I had a chronic cough, and occasionally my voice would give out. Every time I saw my pulmon-ologist, I would tell him about my symptoms and ask him why they were persisting for so long. I never got a sat-isfactory answer.

I guess because of my relatively young age—I was just 46 at the time—and otherwise good health, my symptoms weren’t triggering any red flags. The doc-tor would send me home with more pre-scriptions for inhalers and instructions to see him again in a few weeks.

My deteriorating health finally got his attention when strange bruises started appearing on my legs. Results from blood tests showed that I had too many white blood cells and not enough red blood cells or platelets, suggesting I had leukemia. A bone marrow biopsy confirmed that I had AML and that the subtype was acute myelomonocytic leukemia (M4).

The Shock of Having CancerBy the time I got the diagnosis, I

was so sick I had to be admitted to a cancer center for immediate intensive chemotherapy. I was given high doses of a combination of cytarabine, dau-norubicin, and etoposide and had such serious side effects from the treatment I remained in the hospital for 42 days.

Although the therapy put me in re-mission, I remained on the regimen until July 2012 to increase my chances of staying that way. Unfortunately, 6 months later I relapsed and, after anoth-er round of induction chemotherapy, I had an autologous bone marrow trans-

plant. While waiting for my immune system to kick in, I overcame two nearly fatal illnesses—pneumonia and sep-sis—but the transplant was a success,

and I’ve been in remission ever since.The whole process has left me in a

state of shock, and I’m still processing what happened to me. During treat-ment, I tried to make sense of the ram-ifications of getting such a life-threat-ening illness and figure out how to live the rest of my life. I knew I couldn’t project too far into the future—that was still too uncertain—nor did I want to dwell too much on the past. My only recourse was to live as much in the present as I could, and that’s what I still try to do, but it’s not easy.

Living With IntentionAlthough I feel healthy, and a re-

cent follow-up bone marrow biopsy showed I remain cancer-free, I’m still grappling with the emotional fallout of having cancer, and I’m not quite sure how to plan for a future that was so re-cently threatened.

Once you have cancer, it’s impos-sible not to think about death, and the experience has made me want to live a more purposeful life. Having leukemia dragged me deeper into myself and

I’ve learned a lot. Now I’m more aware of who I am and what I believe and what I can and cannot control. While I may not always have control over what

happens to me, I do have control over how I respond to new challenges, and that’s empowering.

Facing the FutureDuring my treatment and recovery

from the transplant, I was fortunate to have a wonderful medical team taking

care of me, and I can’t express enough the power that their kind and encour-aging words had on me. Having cancer was an extremely lonely experience, especially before, during, and after each round of chemotherapy and my transplant, when I was so vulnerable to infection and had to be kept in protec-tive isolation. At such times, the atten-tive care of my medical team meant a lot.

That said, I wish the cancer center had dedicated psychosocial support programs in place to help me over-come my anxiety. I also could have used more help with the transition from cancer patient to cancer survivor.

As I reflect on the past 2 years, I feel grateful for every new day. I’m getting stronger emotionally and physically, and my life is finally returning to nor-mal. While I’m determined to live as much as possible in the present, I’m cautiously starting to raise my head higher to see what might be ahead, and I’m beginning to feel less afraid. n

As I reflect on the past 2 years, I feel grateful for every new day…. While I’m determined to live as much as possible in the present, I’m cautiously starting to raise my head higher to see what might be ahead, and I’m beginning to feel less afraid.

—Kelly Traw

In MemoriamKelly TrawOctober 30, 1964 - September 2, 2014

R egretfully, The ASCO Post has learned that Kelly Traw, 49, passed away on September 2, 2014, at Johns Hopkins Hospital in Baltimore. While

her obituary did not mention a cause of death, it said that, “She will be great-ly missed by her extended family and by the many friends who supported her through her 3-year battle with leukemia.”

Ms. Traw was anxious to tell her story of her diagnosis of acute myeloid leukemia in December 2011 and how the experience changed her life. Al-though Ms. Traw did not get to see her story published in The ASCO Post, she read and approved the final version, which appears above.

She is survived by her husband, Tom White; her parents, Chuck and A.K. ( Jones) Traw; her sister Nikki Traw and partner Debbie Engelstad; and her nephews, Caden and Owen, and niece, Jacey. n


Announcements

NCI Awards $2 Million Grant to University of Pittsburgh School of Dental Medicine to Study How Cancer Spreads to Bone

W ith a $2 million, 5-year grant from the National Cancer Insti-

tute (NCI), researchers at the University of Pittsburgh School of Dental Medicine will examine the molecular mechanisms that allow certain cancers, particularly multiple myeloma, to spread to the bone. The project could lead to new interven-tions to prevent such metastases and per-haps slow down primary tumor growth.

Myeloma Sometimes Diagnosed After Dental Issues

About 30% of multiple myeloma pa-tients are diagnosed after going to the den-tist with jaw pain or suspicious lesions in the oral cavity, said the project’s Principal Investigator Hongjiao Ouyang, DDS, PhD, DMD, Associate Professor of the Departments of Restorative Dentistry/Comprehensive Care and Oral Biology, and a member of the Center for Craniofa-cial Regeneration, University of Pittsburgh School of Dental Medicine. Multiple myeloma is a cancer of plasma cells that begins in the bone marrow and is known for eating away the bone. Even with treat-ment, the bone lesions rarely heal.

“This bone destruction is a signifi-cant cause of pain and mortality in this disease,” said Dr. Ouyang, an endodon-tist and bone biologist. “A better under-standing of the molecular pathways that underlie this process could lead us to novel targets for treatment.”

Bone marrow stromal cells reside in the bone marrow and with appropriate stimulation can give rise to bone-forming osteoblasts, fat cells, and other cells. In multiple myeloma, bone marrow stromal cells produce growth factors and inflam-matory proteins that boost tumor cells and activate osteoclasts, which break down bone while osteoblasts rebuild it as part of normal metabolism. In cancer, osteoclast activation makes holes in the bone that do not heal.

Dr. Ouyang’s team has found that the bone marrow stromal cells in mul-tiple myeloma patients, unlike those in healthy people, produce much more X-box binding protein, a molecule that has been shown in other tissues to regulate the production of inflammatory proteins. Their lab experiments showed that induc-ing healthy cells to produce X-box bind-ing protein leads to changes in the bone microenvironment that support growth of multiple myeloma cells and osteoclast formation. Conversely, knocking out X-box binding protein production in mul-tiple myeloma patient bone marrow stem

cells corrected the abnormalities.For the newly funded project, the

team will determine the molecular mechanisms of the stromal X-box bind-ing protein signaling in altering the bone

microenvironment to favor multiple my-eloma growth and bone destruction, as well as employ pharmacologic and ge-netic strategies to repress this molecule as a proof-of-concept for approaches to

treat multiple myeloma bone disease.“This could be helpful not only in

treatment of multiple myeloma, but also in other cancers that spread to bone,” Dr. Ouyang said. n

EXCLUSIVE FOR MEMBERSRegister and Reserve Your Hotel

May 29-June 2, 2015McCormick Place | Chicago, Illinois

ASCO members enjoy early access to the closest and most sought-after hotels, discounted registration rates, and first choice of ticketed sessions.

Take full advantage of your ASCO membership: register and reserve your hotel today.

Key DatesAbstract Submitter Opens

General Registration and Hotel Reservations Open

Abstract Submission Deadline

Early Registration and Hotel Reservation Deadline

November 14, 2014

December 3, 2014

February 3, 2015, at 11:59 PM (EST)

April 22, 2015, at 11:59 PM (EDT)

Not an ASCO Member?Join ASCO at benefits.asco.org

am.asco.org

http://upmc.pr-optout.com/Tracking.aspx?Data=HHL%3d%3e341%3f%26JDG%3c948-4%25TIK84%2f%3b3&RE=MC&RI=4192456&Preview=False&DistributionActionID=54992&Action=Follow+Link






http://am.asco.org


Lab Notes

Ongoing Molecular Research in the Science of Oncology

TARGETED THERAPY

EGFR a Potential Target in Muscle-Invasive Bladder Cancer With Basal-Like Phenotype

As reported by Rebouissou and col-leagues in Science Translational Medi-cine, a subset of muscle-invasive bladder cancers that present with a basal-like phenotype is associated with poorer survival, EGFR pathway activation, and sensitivity to EGFR inhibition.

Assessment of data from 383 tu-mors revealed that 23.5% displayed a basal-like phenotype characterized by expression of epithelial basal cell markers and shorter survival. These basal-like tumors exhibited activation of the EGFR pathway associated with frequent EGFR gains and activation of an EGFR autocrine loop. The tumor cells were found to be sensitive to anti-EGFR therapy using both a 40-gene ex-pression classifier derived from human tumors to identify bladder cancer cell lines and a mouse model of chemically induced bladder cancer corresponding to human basal-like bladder cancer.

The authors concluded, “Our find-ings provide preclinical proof of con-cept that anti-EGFR therapy can be used to target a subset of particularly aggressive [muscle-invasive bladder cancer] tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.”

Rebouissou S, et al: Sci Transl Med 6:244ra91, 2014.

MECHANISMS OF ACTION

MHC-Matched Graft-vs-Host Disease Requires Recipient Intestinal Barrier Loss and Natural Killer Cell Inactivation

Although available data indicate an as-sociation among pretransplantation con-ditioning intensity, intestinal barrier loss, and severity of graft-vs-host disease, the multiple effects of irradiation and other types of conditioning have made it diffi-cult to precisely identify the role of intesti-nal barrier loss in graft-vs-host disease.

In a study reported in Science Trans-lational Medicine, Nalle and colleagues developed graft-vs-host disease mod-els that permitted identification of in-dividual pretransplantation variables. It was found that intestinal damage was required for development of MHC minor-mismatch graft-vs-host disease but not for major-mismatch graft-vs-host disease. Natural killer cells in the transplant recipient were found to prevent minor-mismatch graft-vs-host disease via a perforin-dependent pro-cess that limited the expansion of al-loreactive T cells and their infiltration into the target organ.

Myeloid differentiation primary re-sponse protein 88 (MyD88)-mediated Toll-like receptor 4 signaling on donor cells was required for minor-mismatch graft-vs-host disease. Intestinal dam-age could be bypassed by parenteral lipopolysaccharide administration, indicating that the influx of bacterial components associated with intestinal

barrier loss is a central component in minor-mismatch graft-vs-host disease pathogenesis.

The authors concluded, “In all, the data demonstrate that pretransplant conditioning plays a dual role in pro-moting minor mismatch [graft-vs-host disease] by both depleting recipient [natural killer] cells and inducing intes-tinal barrier loss.”

Nalle SC, et al: Sci Transl Med 6:243ra87, 2014.

IMMUNOTHERAPY

Successful Immunotherapy With Mutation-Specific CD4-Positive T Cells in Patient With Epithelial Cancer

There is limited evidence of muta-tion-specific T-cell response to epitheli-al cancers. In a study reported in Science, Tran and colleagues used whole-exome sequencing to show that tumor-infil-trating lymphocytes included CD4-positive Th1 cells that recognized a mutation in erbb2 interacting protein (ERBB2IP) expressed by a tumor in a patient with metastatic cholangiocarci-noma.

In the setting of progressive disease, adoptive transfer of tumor-infiltrating lymphocytes containing approximately 25% mutation-specific polyfunctional Th1 cells produced tumor regression at 2 months, with lung and liver lesions reaching a maximum reduction of 30% at 7 months. Disease was stabilized for 13 months after infusion, with sub-sequent progression observed in the lungs but not the liver.

At progression, the patient was re-treated with a > 95% pure population of mutation-reactive Th1 cells. Treat-ment again produced tumor regression, which was evident at 1 month and was maintained at the last follow-up at 6 months.

The investigators concluded, “These results provide evidence that a CD4[-positive] T cell response against a mu-tated antigen can be harnessed to medi-ate regression of a metastatic epithelial cancer…. The ability to immunologi-cally target unique mutations in cancers can potentially extend highly personal-ized immunotherapies to patients with epithelial cancers, which account for about 90% of cancer deaths in the Unit-ed States.”

Tran E, et al: Science 344:641-645, 2014.

TREATMENT RESISTANCE

Chemotherapy-Induced Immunosuppressive Myeloid Cells Inhibit Tumor Control via PD-1–PD-L1 Axis

In a study reported in Cancer Research, Ding and colleagues identified mecha-nisms by which cyclophosphamide in-duces suppressor cells that inhibit im-mune response and predispose to loss of tumor control. They found that cyclo-phosphamide treatment induces expan-sion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that exert immunosuppressive activities.

Adoptive transfer of tumor-specific CD4-positive T cells after cyclophospha-mide treatment in mice with advanced lymphoma resulted in initial antitumor immune response, but also increased ex-pansion of the inflammatory monocytic myeloid cells. This expansion resulted in loss of long-term tumor control and permitted recurrence by supporting functional tolerance of the antitumor CD4-positive effector cells via the PD-1–PD-L1 axis. Blockade of PD-1/PD-L1 after treatment with cyclophosphamide and adoptive transfer of the tumor-spe-cific CD4-positive T cells resulted in per-sistence of the CD4-positive effector cells and durable antitumor effects.

In addition, use of low-dose gem-citabine to reduce levels of the proliferative monocytes prevented tumor recurrence after treatment with cyclophosphamide and adoptive transfer. Further, inhibi-tion of the monocytes via disruption of the CCR2 signaling pathway augmented the efficacy of cyclophosphamide. The investigators found that melphalan and doxorubicin can also induce expansion of monocytic myeloid suppressor cells.

The investigators concluded, “These findings reveal a counter-regulation mech-anism elicited by certain chemotherapeu-tic agents and highlight the importance of overcoming this barrier to prevent late tu-mor relapse after chemoimmunotherapy.”

Ding ZC, et al: Cancer Res 74:3441-3453, 2014.

BIOMARKERS

Androgen, Estrogen, and Stem Cell Markers Help Predict Recurrence and Survival in Metastatic Prostate Cancer

In a study reported in Clinical Cancer Research, Fujimura and colleagues devel-oped and tested models to predict pros-©Mick Stevens/The New Yorker Collection/www.cartoonbank.com


Lab Notes

tate-specific antigen (PSA) recurrence and cancer-specific survival in patients with treatment-naive prostate cancer and bone metastases using mRNA expression of genes involved in androgen and estrogen signaling and genes in stem cell-like cells.

Cancer and stromal tissues were col-lected via laser-captured microdissection. Markers analyzed for association with clinical outcome consisted of: androgen receptor and related genes APP, FOX family, TRIM36, Oct1, and ACSL3; stem cell-like cell genes Klf4, c-Myc, Oct3/4, and Sox2; estrogen receptor (ER) and Her2 expression; and PSA and C-reactive protein (CRP).

Analysis of the ability to predict PSA recurrence showed an area under the curve value of 1.0 in both training (n = 46) and validation (n = 30) cohorts for Sox2, Her2, and CRP expression in cancer cells, androgen receptor and ERα expression in stromal cells, and clinical parameters. A model using Oct1, TRIM36, Sox2, and c-Myc expression in cancer cells, andro-gen receptor, Klf4, and ERα expression in stromal cells, PSA, Gleason score, and extent of disease identified favorable-, in-termediate-, and poor-risk groups, with 5-year cancer-specific survival rates of 90%, 32%, and 12% in the training set and 75%, 48%, and 0% in the validation set.

The investigators concluded, “Expres-sion levels of androgen and estrogen sig-naling components and [stem cell] mark-ers are powerful prognostic tools.”

Fujimura T, et al: Clin Cancer Res. July 1, 2014 (early release online).

OUTCOME PREDICTORS

Polymorphisms and Cetuximab Benefit in Locally Advanced Rectal Cancer

Polymorphisms in FcγR (receptor for the constant region of immunoglobulin G) have been reported to be associated with improved immune-mediated effects of ce-tuximab (Erbitux) in metastatic colorectal cancer. In a study reported in Clinical Can-cer Research, Sclafani and colleagues ana-lyzed the association of FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in peripheral blood samples with outcome in a subgroup of patients in the phase II EXPERT-C trial in patients with high-risk locally advanced rectal cancer; in this trial, patients received neoadjuvant CAPOX (capecitabine and oxaliplatin), chemora-diotherapy, and surgery followed by adju-vant CAPOX with or without cetuximab.

A total of 51 patients who received ce-tuximab and 50 who did not were included in the analysis. There was no association between the polymorphisms and tumor

RAS status. Both FcγRIIa-131R (HR = 0.38, P = .058) and FcγRIIIa-158F alleles (HR = 0.21, P = .007) predicted improved progression-free survival in patients receiv-ing cetuximab. Among cetuximab recipi-ents, carriers of both 131R and 158F alleles vs those homozygous for either had a sig-nificant improvement in 5-year progres-sion-free survival (78.4% vs 35.7%, HR =

0.22, P = .002) and 5-year overall survival (86.4% vs 57.1%, HR = 0.24, P = .018). The interaction between cetuximab benefit and 131R and 158F alleles was significant (P = .017) and remained so after adjustment for prognostic variables (P = .003).

The investigators concluded, “This is the first study investigating FcγRIIa and FcγRIIIa polymorphisms in early stage

colorectal cancer patients treated with ce-tuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.” n

Sclafani F, et al: Clin Cancer Res. July 1, 2014 (early release online).

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

JOIN US!

LEARN MORE AT APSHO.org

AD_APSHO_JNCCN-AD_8.125x10.875.indd 1 8/29/14 1:27 PM

http://apsho.org


In the Literature

Emerging Clinical Data on Cancer Management

CERVICAL CANCER

Cervical Cancer Risks After Negative HPV Test Lower at 3 Years Than After Negative Pap Result

Three-year risks for cervical cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were lower following a negative test for human papillomavirus (HPV) than following a negative Pap test, according to a large study comparing three cervical cancer screening strategies, HPV or Pap testing every 3 years, or cotesting every 5 years). The study also found that 3-year risks following a negative result with HPV testing alone were lower than the 5-year risks following a negative result with cotesting.

Julia C. Gage, PhD, MPH, of the Na-tional Cancer Institute, Bethesda, Mary-land, and colleagues analyzed data from the Kaiser Permanente Northern California, a large integrated health delivery system with a large well-established cervical cancer screening program that screened women at approximately 3-year intervals, with a mean follow-up time of 4.36 years. “With newly available data through 2012, we were able to estimate risks among more than 1 mil-lion women,” the investigators noted.

For each testing strategy, the investiga-tors used logistic regression and Weibull survival models to estimate the cumula-tive risk of cervical cancer after a negative test result. The 3-year risk for cervical fol-lowing a negative HPV result was lower than the 3-year risk following a negative Pap test (0.011% vs 0.020%, P < .0001) and lower than the 5-year risk following an HPV-negative/Pap-negative cotest (0.011% vs 0.014%, P = .21). The 3-year risk for CIN3+ was also lower follow-ing a negative HPV result than a negative Pap test (0.069% vs 0.19%, P < .0001) and lower than the 5-year risk following an HPV-negative/Pap-negative cotest (0.069% vs 0.11%, P < .0001).

Optimal Screening Interval for HPV Testing

“This analysis focused on 3-year risks after a negative HPV test, because a 3-year screening interval is under consideration for initial introduction of primary HPV testing in the U.S,” the authors wrote. “Yet, the optimal screening interval for primary HPV testing has not yet been established and might exceed 3 years, as has been ad-vocated in Europe. European screening trialists suggest that HPV screening can be safely implemented with at least a 5-year interval, and countries are implementing

extended screening intervals.”The investigators concluded that “pri-

mary HPV testing every 3 years might provide as much, if not more, reassurance against precancer and cancer, compared to primary Pap testing every 3 years and cotesting every 5 years.” The researchers also cautioned that “further consideration is required to define the optimal screening interval within the context of patient bene-fits (ie, cancer prevention) and harms (eg, increased screening visits, colposcopy and treatment). Analyses should also incor-porate risks and resource utilization after multiple screening rounds across screen-ing strategies.”

In an accompanying editorial, Jane J. Kim, PhD, of the Harvard School of Pub-lic Health, Boston, noted that the HPV test approved for primary screening spe-cifically assays the two highest-risk HPV types (16 and 18) that account for 70% of cervical cancers but pools the assay for the other 12 HPV strains.

“There is not yet enough evidence to indicate that HPV primary testing is the optimal approach to cervical cancer screening,” Dr. Kim wrote. “But increas-ingly, we are seeing robust evidence—in clinical trials and now in real-world prac-tice—that gives confidence in the safety and effectiveness of primary HPV testing, at least relative to Pap testing as is currently recommended in the United States.”

Gage JC, et al: J Natl Cancer Inst 106(8):dju153, 2014.

Kim JJ: J Natl Cancer Inst 106(8):dju213, 2014.

PANCREATIC CANCER

Vitamin D Deficiency Is Prevalent Among Patients With Advanced Pancreatic Cancer

Vitamin D deficiency was highly preva-lent among patients newly diagnosed with advanced pancreatic cancer, and black pa-tients had statistically significantly lower levels than white patients, according to a recent study reported by Katherine Van Loon, MD, MPH, of the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, and colleagues in the Journal of the National Cancer Institute. However, baseline levels among a cohort of patients receiving gemcitabine-based che-motherapy were not associated with pro-gression-free survival or overall survival.

Study DetailsPatients were enrolled in Cancer and

Leukemia Group G (CALGB) 80303,

a randomized trial finding no difference in overall survival among patients with advanced pancreatic cancer treated with gemcitabine plus placebo (5.9 months) vs gemcitabine plus bevacizumab (Avastin) (5.8 months).

Among a total of 602 patients en-rolled in that study, investigators obtained baseline serum 25-hydroxyvitamin D (25[OH]D) measurements for 256 and found that 44.5% were vitamin D de-ficient (< 20 ng/mL), and 32.4% were insufficient (≥ 20 and < 30 ng/mL). Vitamin D levels were lower in black vs white patients and patients of other/un-disclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline Vitamind D levels were not associated with progression-free survival (hazard ratio [HR] = 1.00, 95% confidence interval [CI] = 0.99–1.01, P = .60) or overall survival (HR = 1.00, 95% CI = 0.99–1.01, P = .95).

The authors commented: The apparent propensity toward extreme deficiency in patients with advanced pan-creatic cancer may reflect malabsorption of this fat-soluble vitamin in those with pancreatic exocrine insufficiency. How-ever, vitamin D concentration is primarily dependent on endogenous production by skin following exposure to ultraviolet rays and, to a lesser extent, on dietary consump-tion of vitamin D. The greater prevalence of vitamin D deficiency among black patients in our cohort is consistent with other stud-ies and likely due to reduced vitamin D photosynthesis in pigmented skin because of greater melanin content and increased absorption of UVB radiation. Between 2006 and 2010, black Americans had an age-adjusted incidence rate of pancreatic cancer that was 31% higher than in white Americans and an age-adjusted mortality rate that was 27% higher.

Van Loon K, et al: J Natl Cancer Inst 106(8):dju185, 2014.

MULTIPLE MYELOMA

Updated GEM2005 Trial Confirms Benefit of Melphalan/Bortezomib Combination in Elderly Multiple Myeloma Patients

Melphalan in combination with bort-ezomib (Velcade) should be maintained as one of the standards of care for the treatment of elderly patients with mul-tiple myeloma, concluded Spanish trial-ists reporting updated results from the GEM2005 study comparing bortezomib/

melphalan/prednisone with bortezomib/thalidomide (Thalomid)/prednisone as induction therapy.

Previously reported results showed that newly diagnosed elderly mul-tiple myeloma patients receiving bort-ezomib/melphalan/prednisone had slightly longer progression-free and overall survival and reduced frequency of side effects. “However, this conclu-sion was based on a relatively short me-dian follow-up of 32 months,” Maria- Victoria Mateos, MD, PhD, of Univer-sity Hospital of Salamanca/IBSAL, and colleagues wrote in Blood. “We now pro-vide an update of this phase 3 random-ized trial after a median follow-up of 6 years, confirming the role of the alkylator as part of bortezomib-based combina-tions for transplant-ineligible [multiple myeloma] patients.”

Study DetailsA total of 260 patients in 63 Spanish

centers were randomly assigned to receive 6 cycles of bortezomib/melphalan/pred-nisone or bortezomib/thalidomide/pred-nisone as induction therapy; those who completed induction therapy were ran-domly assigned to maintenance therapy with bortezomib/thalidomide or bortezo-mib/prednisone.

Patients in the bortezomib/mel-phalan/prednisone arm had a median progression-free survival of 32 months compared with 23 months for the bort-ezomib/thalidomide/prednisone arm (P = .09). Treatment with bortezomib/melphalan/prednisone resulted in a sig-nificant improvement in overall survival compared with bortezomib/thalido-mide/prednisone (median of 63 and 43 months, respectively; hazard ratio [HR] = 0.67, P = .01).

Achieving complete response and immunophenotypic complete response was associated with a significantly longer overall survival, especially in the bort-ezomib/melphalan/prednisone arm, where 66% remain alive after 8 years, stated the authors.

Value of Prolonged Treatment in Elderly Patients

Bortezomib/melphalan/prednisone demonstrated superior progression-free survival in both the group of pa-tients between 65 and 75 years (31 vs 27 months for bortezomib/melphalan/prednisone and bortezomib/thalido-mide/prednisone, respectively) and the group of patients older than 75 years (32 months vs 18 months; HR = 1.6,


In the Literature

95% CI = 1.1–2.5, P =.04). Median overall survival for patients be-

tween 65 and 75 years was 66 months for those receiving bortezomib/melphalan/prednisone vs 50 months for those receiv-ing bortezomib/thalidomide/prednisone. For patients older than 75 years, median overall survival was 51 months for those receiving bortezomib/melphalan/pred-nisone vs 34 months for those receiving bortezomib/thalidomide/prednisone (HR = 1.7, 95% CI = 1.1–2.9, P = .02).

“Our study has two major findings,” the investigators concluded. “First, melphalan remains an important and cost-effective drug for the treatment of newly diagnosed elderly myeloma patients, and second, the value of prolonged treatment and depth of response in elderly patients is confirmed.”

The trial is registered with www.Clini-calTrials.gov (NCT00443235).

Mateos M, et al: Blood. September 18, 2014 (early release online).

LEUKEMIA

Obinutuzumab Could Have Synergistic Action With New Tyrosine Kinase Inhibitors

Final results from the phase I/II GAUGUIN study showed that obinutu-zumab (Gazyva) monotherapy was ac-tive in patients with heavily pretreated re-lapsed or refractory chronic lymphocytic leukemia, European researchers reported in Blood. In phase II, median progression-free survival was 10.7 months and median duration of response was 8.9 months.

“For clinical use, obinutuzumab monotherapy is likely to be suitable in situations where rituximab [Rituxan] or ofatumumab [Arzerra] monotherapy are currently used, due to its higher propen-sity for B-cell depletion, and in patients not suitable for cytotoxic chemotherapy,” the researchers wrote. “However, argu-ably the most exciting development for obinutuzumab will lie in its potential for combination with new kinase inhibitors such as ibrutinib [Imbruvica] or idelalisib [Zydelig], where its efficiency with regard to eliminating circulating B cells may be synergistic with the strong ability of such kinase inhibitors to induce the migration of clonal cells from lymph node and bone marrow to the blood.”

During the phase I dose escalation por-tion of the study, 13 patients from seven centers across France received obinutu-zumab at 400 to 1,200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2–8). In the phase II portion, 20 patients from 20 centers across France and Germany received a fixed dose of 1,000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2–8). The median ages of

the patients were 64 in phase I and 62.5 in phase II. The median number of previous treatments was three for patients in both phases of the study and 8 patients (62%) in phase I. Ten patients (50%) in phase II had received prior rituximab treatment.

The overall end-of-treatment re-sponse rates (all partial responses) were 62% in phase I and 15% in phase II, and

the respective best overall response rates were 62% and 30%. The researchers speculated that that lower best overall response in phase II was “possibly due to higher baseline tumor burden resulting in lower treatment exposure.”

Nearly all patients had infusion-related reactions, although few grade 3/4. Adverse events were independent of dose, and no

dose-limiting toxicities were reported. GAUGUIN is registered at Clini-

calTrials.gov with the identifier NCT00517530. n

Cartron G, et al: Blood 124:2196-2202, 2014.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

JNCCN-N-0199-1014

NCCN.org/AC2015

Exhibition and Sponsorship Opportunities are [email protected]

The Diplomat • Hollywood, FL • March 12 – 14, 2015

NCCN.org/AC2015

SAVE THE DATEMarch 12 – 14, 20152015

th

AnnualADVANCING THESTANDARD OFCANCER CARETM

ConferenceCall for AbstractsAbstract Submission Deadline is Friday, October 31, 2014

NCCN will host its 3rd annual General Poster Session* to be presented during the NCCN 20th Annual Conference.*CE credits are not available for this poster session.

http://www.nccn.org/professionals/meetings/annual_conference.aspx

Participate in the

ASCO Election

and Help Shape the

Future of ASCO!

Visit asco.org/election to Cast Your Vote Today for the 2015 ASCO Election!

YOUR VOTE MATTERS!

Vote today for• President-Elect (one seat) • Treasurer (one seat)• Board of Directors (three seats) • Nominating Committee (two seats)

Simply login at asco.org/election using your ASCO username and password to learn more about the candidates and cast your online proxy ballot. All proxy ballots must be cast by November 26, 2014, at 11:59 PM EST.

For technical support with the online proxy ballot (M-F 8:00 AM - 5:00 PM CMT), call +1-952-974-2339 or email [email protected]. For questions about the election, please email [email protected].

Terms begin June 1, 2015 for those elected.

http://www.asco.org/about-asco/2015-asco-election


Perspective

CLL can serve as a valid model for cancer management in general by highlighting the dramatic progress that can be made within a short time frame when linking biology to therapy.

—Stephan Stilgenbauer, MD

rituximab [Rituxan]) for young/fit pa-tients and chlorambucil (Leukeran) plus obinutuzumab (Gazyva) or ofatumum-ab (Arzerra) for elderly/unfit patients.

Despite the dramatic improvements in efficacy with these regimens, a num-ber of critical issues remain. There is considerable long- and short-term tox-icity, mostly in terms of hematologic toxicity and infections. Moreover, there is a relentless pattern of relapse despite often initially deep remissions, making cure unlikely with these regimens.

Furthermore, biologic markers define risk groups that do not benefit as much as others from these treatments. 17p de-letion and/or TP53 mutation remain the strongest prognostic markers in multivari-able analyses despite the improvement in treatment. NOTCH1 mutation may be a predictive marker indicating decreased benefit from the addition of antibody.

Agents Targeting Disease Biology

As exemplified by the findings on ge-nomics, signaling pathways, and apop-tosis dysregulation, an improved un-derstanding of disease biology in CLL has led to the identification of biologi-cally targeted therapeutic approaches. Among the most promising treatment approaches are inhibitors of B-cell (and possibly other) receptor signaling and apoptosis targeting agents.

In recent clinical trials, agents target-ing Bruton’s tyrosine kinase (such as ibrutinib [Imbruvica]), PI3-kinase (such as idelalisib [Zydelig]), BCL2 (such as ABT-199), and CD20 (such as obinutu-zumab, ofatumumab) have generated a

lot of excitement. In phase I to III clinical trials, these agents have demonstrated not only compelling evidence for dramatic efficacy, but also for outstanding toler-ability. Much of the data, excitement, and also some controversy in interpretation and impact of these results have been dis-cussed in multiple recent contributions to The ASCO Post (see sidebar).

Challenging QuestionsAs is often the case with break-

throughs, the answers gleaned from these studies lead to new questions, and it appears that the magnitude of these questions is at least as big as the advances made through the new un-derstanding of CLL biology and treat-ment. Among the topics that need to be

addressed are the following issues and corresponding questions:

1. As few patients experience treat-ment failure with these novel agents and specific mutations in treatment tar-gets (eg, Bruton’s tyrosine kinase) have been identified, what are the resistance mechanisms and to what extent will they impact treatment decisions?

2. Given that the outcome of some biologic disease subgroups (eg, 17p deletion CLL with ibrutinib treat-

ment) appears improved compared to chemo(immuno)therapy but is still inferior compared to other subgroups, how can “ultra-high risk” disease be identified and treated?

3. Similarly, as allogeneic stem cell transplantation is considered a standard treatment option for young/fit patients with “ultra-high risk” CLL (eg, early re-lapse after chemoimmunotherapy and/or 17p deletion/TP53 mutation), what is the role of transplant in the current and future treatment algorithm?

4. As Richter’s transformation is a re-current reason for treatment failure (al-though there is no evidence that it may be induced by the new agents), how can this poor-prognosis syndrome be man-aged and/or prevented?

5. With some novel agents, “benign” disease persistence (early lymphocyto-sis with B-cell receptor antagonists) is a frequent phenomenon, whereas other agents (eg, BCL2 antagonists) produce rapid disease abolition. What are the prin-ciples guiding treatment with regard to an aim of disease control vs eradication?

6. As new, rare adverse events (eg, bleeding, atrial fibrillation, colitis) have been identified in spite of the generally outstanding treatment tolerability, what

are the long-term side effects of novel treatments?

7. As single-agent treatment, at least with classical chemo(immuno)therapy, has not proven to be the way forward, and indefinite treatment duration is not desirable, which combinations will offer the best results with regard to efficacy and tolerability?

8. Given that on one hand, combina-tion treatments have proven beneficial, while on the other hand, the novel com-pounds have already shown excellent single-agent activity, will a combination approach or sequential use of the novel agents lead to better long-term results?

9. Along these lines, will “total ther-apy” combining everything together in one regimen be superior to “tailored treat-ment” with a targeted approach for indi-vidual disease subtypes?

10. In light of individual patient and disease characteristics as well as specific features of each novel compound, how can subgroups be identified for greatest tailored benefit?

11. As novel treatments with Bruton’s tyrosine kinase and PI3-kinase inhibitors (and likely, in the future, BCL2 antago-nists) are approved in the relapsed/refrac-tory setting with only minor subgroups (17p deletion CLL) as exceptions, how will the first-line treatment algorithm evolve in clinical trials, and more impor-tantly, in general practice?

12. Given the cost and often indefinite treatment duration with the currently li-censed novel agents and the worldwide demand for efficacious cancer therapy, how will the issue of cost and equal access to these treatments be handled?

Bright PerspectivesThese are obviously only a few

among the many questions that can be raised with the use of the novel agents. When contemplating these issues, how-ever, one should not forget that such questions can be raised only because of the dramatic advance that the novel agents offer and due to the better un-derstanding of disease biology.

Clearly, to move beyond the success already witnessed, more well-designed clinical trials are needed with the ultimate goal of cure. Of equal importance, and underlined by the development of these targeted agents in CLL, is the advance of laboratory science in a translational ap-proach. CLL can serve as a valid model for cancer management in general by highlighting the dramatic progress that can be made within a short time frame when linking biology to therapy. n

Disclosure: Dr. Stilgenbauer reported no potential conflicts of interest.

Chronic Lymphocytic Leukemiacontinued from page 1

Recent Reports and Perspectives on Chronic Lymphocytic Leukemia

Recent articles on developments and controversies in the treatment of chronic lymphocytic leukemia in-

clude the following features from The ASCO Post, which are also available at www.ascopost.com:• “Recent FDA Approvals Foster Growing Treatment

Armamentarium for Chronic Lymphocytic Leuke-mia and Rare B-Cell Lymphomas,” August 15, 2014

• “Ibrutinib Surpasses Ofatumumab as Second-Line Treatment of Chronic Lymphocytic Leukemia,” by Alice Goodman, June 25, 2014

• “Potent Activity Shown for First-in-Class PI3K-delta Inhibitor in Chronic Lymphocytic Leukemia,” by Caroline Helwick, June 10, 2014

• “Looking Ahead in Treating Chronic Lymphocytic Leukemia,” by Caroline Helwick, June 10, 2014

• “Ibrutinib for Previously Treated Chronic Lympho-cytic Leukemia,” by Matthew Stenger, March 15, 2014

• “Encouraging Early Results With Novel Agents in

CLL,” by Alice Goodman, March 1, 2014• “First-Line Obinutuzumab/Chlorambucil Improves

Outcomes Over Rituximab/Chlorambucil in Older CLL Patients With Comorbidities,” by Alice Good-man, March 1, 2014

• “Obinutuzumab in Previously Untreated Chron-ic Lymphocytic Leukemia,” by Matthew Stenger, December 1, 2013

• “High Rate of Durable Remissions With Ibrutinib in Patients With Relapsed Chronic Lymphocytic Leukemia,” by Matthew Stenger, August 15, 2013

• “Ibrutinib CLL Trial: Where Is the Equipoise?” by Susan O’Brien, MD, May 1, 2013

• “The Ethical Imperative of Clinical Equipoise,” by Steven J. Schuster, MD, May 1, 2013

• “A Promising New Agent’s Road to Approval in CLL Raises Questions, Stirs Controversy,” by Ronald Piana, May 1, 2013

Advertisement not displayed in digital edition at advertiser’s request

tap vol 5 issue 17

Documents

testicular cancer

cancer management

recurrent cervical cancer

line treatment of her2

lung cancer trials

washington cancer institute

md ascopost

cll therapy