tap vol 5 issue 2

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

Major Cancer Advances in 2013 Highlight Importance of Federal FundingBy Caroline McNeil

About one-third of the most important clinical advances in cancer last year were made possible

at least in part through federal funding, according to ASCO’s annual report on progress in cancer, pub-lished in the Journal of Clinical Oncology.1

Significant Declines in FundingThe report, “Clinical Cancer Advances 2013,” de-

scribes 76 major advances in prevention, treatment,

and survivorship chosen for their potential to improve patient care and quality of life. Of the 76 advances, 26 were studies directly supported by federal dollars. These include many genomic and molecular profiling studies, several large prevention and screening trials, and early trials of promising agents for aggressive or treatment-resistant cancers.

That so many of the advances were federally fund-ed points to the urgency of restoring funds for publicly

supported research, said Richard L. Schilsky, MD, Chief Medical Officer at ASCO. Declines in federal funding due to sequestra-tion and other measures have already slowed cur-rent research and could have a severe impact on future studies, especially

San Antonio Breast Cancer Symposium

There is no doubt that this is a halcyon pe-riod in oncology. The unraveling of the

genome has been tremendously important, and finally has helped us to move treatment selec-tion from an era of rational empiricism to one of refined, molecular prognostication.

In the care of breast cancer, the im-pact of our understanding of BRCA1 and BRCA2, and of the genes that predict re-sponse to agents targeting HER2/neu is un-questioned. Similarly, in colorectal cancer, application of our understanding of thy-midylate synthase and dihydropyrimidine dehydrogenase and their relationship to

Cancer Genes, Promiscuity, and the

National Debt

By Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

Oncology Meetings CoverageSan Antonio Breast Cancer Symposium �� 1, 13, 15 ASH Annual Meeting �� 3, 8, 12IPOS/AORTIC ��39, 40, 41

Andrew Zelenetz, MD, on Lenalidomide/Rituximab in NHL �� 8Matthew Ellis, MD, PhD, on PI3K in Breast Cancer ��16Direct From ASCO �� 24–27FDA Update ��33–35In Memoriam: John M. Goldman, MD ��54

MORE IN THIS ISSUE

continued on page 22

Health-Care Policy

Addition of Neoadjuvant Carboplatin in Triple-Negative Breast Cancer Supported by SABCS StudiesBy Caroline Helwick

The achievement of a pathologic complete re-sponse in patients with triple-negative breast

cancer was boosted by the addition of carboplatin to a standard neoadjuvant chemotherapy regimen, and by the addition of veliparib, an investigational oral PARP inhibitor, plus carboplatin to a standard chemothera-py regimen, in studies presented at the 2013 San An-tonio Breast Cancer Symposium.

William Sikov, MD, Associate Professor of Medi-cine at Brown University, Providence, Rhode Island,

reported the results from the Cancer and Leukemia Group B (CALGB)/Alliance 40603 study,1 concluding, “Based on these results, and those of the GeparSixto trial,2 if you decide that a patient with triple-negative

breast cancer should receive neoadjuvant chemother-apy, it would be reasonable to add carboplatin. You

will increase the likelihood of response in the breast and axillary nodes, and can do so with acceptable addi-tional toxicities, primarily an increase in neutropenia and thrombocytopenia.”

Bevacizumab (Avastin) was also evaluated in the study, and also increased pathologic responses when added to chemotherapy, but, considering its toxicity, was felt to be a less prom-ising approach.

CALGB/Alliance 40603 Study The phase II CALGB/Alliance 40603 study en-

rolled 454 patients with stage II/III triple-negative

William Sikov, MD

Health-Care Policy 1, 22, 38 | Biologic Doublets in Lymphomas 3, 8 | Global Oncology 21 VOLUME 5, ISSUE 2FEBRUARY 1, 2014



Many important questions can be answered only through publicly supported research, which is in real jeopardy.

—Richard L. Schilsky, MD

Dr. Raghavan is President, Levine Cancer Institute, Charlotte, North Carolina.

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]

The ASCO Post | FEBRUARY 1, 2014

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJoseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center

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 and Public Health

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 Continuum Cancer Centers of New York

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

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

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 H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

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

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

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ASCOPost.com | FEBRUARY 1, 2014 PAGE 3

ASH Annual Meeting

Lenalidomide/Rituximab Doublet a Potential Front-Line Treatment in Some LymphomasBy Caroline Helwick

The biologic doublet of lenalido-mide (Revlimid) plus rituximab

(Rituxan) can achieve high response rates and durable remissions in lympho-ma, according to a parade of phase II studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans.

The immunomodulatory agent le-nalidomide enhances rituximab-in-duced apoptosis in preclinical models, has single-agent activity in relapsed in-dolent lymphoma, and in combination with rituximab has shown strong activity in relapsed and previously untreated fol-

licular lymphoma. The combination of these agents—dubbed the “R-squared” regimen—has gained attention lately, and ongoing trials are evaluating wheth-er this treatment can take the place of traditional chemotherapy. It is also now serving as a backbone for a number of investigational regimens.

Mantle Cell LymphomaIn mantle cell lymphoma, Jia Ruan,

MD, PhD, of Weill Cornell Medical College, New York, presented the results of a multicenter phase II study of 32 treatment-naive patients whose objec-

tive response rate was 87%, with 57% of evaluable patients achieving complete responses.1

The high response rates translated into encouraging progression-free and overall survival. At a median follow-up of 16 months, the 12-month progres-sion-free survival rate was 93%, and the overall survival rate was estimated at 100%, Dr. Ruan reported. Responses deepened over time, with complete re-sponses increasing from just over 10% at 6 months to more than 50% by 21 months. All subjects remain alive as of last follow-up.

Induction included lenalidomide at 20 mg daily on days 1 to 21 of a 28-day

cycle for 12 cycles, with dose escalation to 25 mg daily if tolerated. The standard dose of rituximab was given weekly for four treatments during cycle 1, then once every other cycle, for a total of nine doses. During the maintenance phase, starting with cycle 13, lenalidomide was given at 15 mg daily on days 1 to 21 of a 28-day cycle, with rituximab given as maintenance once every other cycle un-til progression of disease.

Dose reductions were necessary in 40% of patients, usually to 15 mg daily; 17% tolerated an escalation of the dose to 25 mg.

The main toxicities were related to

Hematology

We believe our findings justify further evaluation of the lenalidomide plus rituximab regimen, both alone and as a platform in combination with other novel agents in [mantle cell lymphoma] therapy, and in both the upfront and relapsed settings.

—Jia Ruan, MD, PhD

Lenalidomide/Rituximab in Lymphoma

■ As the initial treatment of mantle cell lymphoma, a chemotherapy-free regimen of lenalidomide plus rituximab (“R-squared”) achieved an 87% response rate (57% complete responses), and 1-year progression-free survival was 93%.

■ R-squared combined with CHOP chemotherapy produced a response rate of 94%, including 44% complete responses and 30% unconfirmed complete responses, in patients with follicular lymphoma and bulky disease.

continued on page 8

‘R-Squared’ Lymphoma Treatment: Possible Markers of Response IdentifiedBy Caroline Helwick

A correlative analysis of a study eval-uating lenalidomide (Revlimid)

plus rituximab (Rituxan) in patients with indolent non-Hodgkin lymphoma found that increases in the levels of sev-eral cytokines correlated with response to treatment.

The study by investigators from the University of California Davis Cancer Center in Sacramento was presented at the 2013 American Society of He-matology Annual Meeting by Samuel Yamshon, a medical student.1 The se-nior author of the study was Joseph Tuscano, MD.

“Some of the differences in cyto-kine levels were quite large between

patients achieving a complete response and those who did not. It seems these cytokines have a strong correlation with a strong response,” Mr. Yamshon suggested.

Study DetailsThe phase II study included 45 pa-

tients (most with follicular lymphoma) with indolent non-Hodgkin lymphoma, including 30 previously treated (28 evaluable for response) and 15 previ-ously untreated (13 evaluable). Patients received the so-called “R-squared” regi-men of lenalidomide (20 mg/d) on days 1 to 21 of a 28-day cycle, continued until disease progression, plus rituximab (375

mg/m2) on day 15 of cycle 1 and repeat-ed weekly for a total of four doses.

The overall response rates were 75% for previously treated patients and 100% for treatment-naive patients, including complete responses in 44% and 61%, respectively. Progressive disease was observed in 11% and 0%, respectively. At a median follow-up time of 43 and 16 months, the median duration of re-sponse was 15.4 months for the previ-ously treated group and has not been reached in the treatment-naive cohort, respectively.

Correlative AnalysisCorrelative serum cytokine samples

were obtained from a subset of patients at baseline, day 15 (prior to treatment with rituximab), and days 30 and 60. These included interleukins (IL)-1, 2, 6, 8, 10, and 12; granulocyte-macrophage colony-stimulating factor (GM-CSF); interferon-gamma; tumor necrosis fac-tor (TNF)-alpha; and CXCL 10/IP-10 levels. Cytokine levels at each time point

were correlated with response to treat-ment.

Mr. Yamshon described the ratio-nale for the correlative analysis. “Le-nalidomide induces IL-2, interferon-gamma and TNF-alpha secretion, and it induces natural killer (NK) cells to pro-duce GM-CSF, TNF-alpha, and various immune-recruiting chemokines,” he noted. “It also enhances CD4 and CD8 cell costimulation in vitro and NK and NK T cells in vivo.”

For several cytokines, significant changes (in absolute percentage over baseline) were observed prior to rituximab treatment in patients who achieved a complete response, com-pared to those with anything less than a complete response.

Significant increases were observed for interferon-gamma (652% over baseline), GM-CSF (494%), CXCL-10 (737%) and IL-2 (242%) at day 15 (P < .005).

“These are huge changes in serum continued on page 8

Cytokine Levels and R-Squared Treatment

■ In indolent non-Hodgkin lymphoma patients treated with lenalidomide plus rituximab (R-squared regimen), increased levels of several cytokines were associated with response in a phase II study.

■ Cytokines that were increased several hundredfold included interferon-gama, GM-CSF, CXCL-10, and IL-2.

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ASH Annual Meeting

EXPERT POINT OF VIEW

“The future is increasingly bright for patients as we

move into an era of effective nonche-motherapy treatment options,” com-mented Nathan Fowler, MD, Asso-ciate Professor in the Department of Lymphoma/Myeloma at The Univer-

sity of Texas MD Anderson Cancer Center, Houston.

“Over the past several years, ad-vances in our understanding of lym-phoma biology make it clear that the immune microenvironment, or non-malignant components of a patient’s immune system, have an enormous

impact on outcome and survival,” he noted. “The ability to modulate or aug-ment immune responses to tumor in the presence of a therapeutic antibody has been a longtime goal, and emerg-ing data from these recent innovative studies confirm the profound activity

seen in our early trials combining le-nalidomide (Revlimid) and rituximab (Rituxan) in lymphoma.”

Dr. Fowler and his team also conducted a phase II study in new-ly diagnosed indolent lymphoma and observed high overall response rates, with complete response rates

achieved by more than 85% of follicu-lar lymphoma patients.

Treatment-Related RashCommenting on the observation

that rash is a common occurrence with R-squared treatment, he added, “In our experience, rash was ob-served in around half of patients. In most cases, the rash was not severe and was managed with supportive care and occasionally a dose inter-ruption.”

Larger studies are underway to confirm the benefits seen for le-nalidomide/rituximab in these and other studies, he indicated. The multinational randomized REL-EVANCE trial is comparing the R-squared regimen to traditional chemotherapy, and it represents one of the first large-scale attempts to re-place traditional chemotherapy for newly diagnosed patients with lym-phoma, he said. n

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

Emerging data from these recent innovative studies confirm the profound activity seen in our early trials combining lenalidomide and rituximab in lymphoma.

—Nathan Fowler, MD

inflammation, including grade ≥ 3 rash (22%), fatigue (9%), and tumor flare (9%). “The symptoms were largely related to inflammatory syndromes. These can be concerning to the patient, but they tend to occur in cycle 1. After their initial assessment, patients gener-ally cruise along with close and regular follow-ups,” according to Dr. Ruan.

“The initial treatment of [mantle cell lymphoma] is not standardized. Cur-rent conventional upfront chemoimmu-notherapies are generally not curative and can be deferred in some patients,” she said. “We believe our findings justify further evaluation of the lenalidomide plus rituximab regimen, both alone and as a platform in combination with other novel agents in [mantle cell lymphoma] therapy, and in both the upfront and re-lapsed settings.”

Follicular LymphomaFrench investigators reported

phase II results of adding lenalidomide to R-CHOP (rituximab, doxorubicin, vincristine, prednisone) in 80 patients with previously untreated follicular lym-phoma, grade 1, 2, or 3a with a high tu-mor burden.2

Patients received induction with six cycles of R-CHOP plus lenalidomide (lenalidomide at 25 mg on days 1–14 each cycle) followed by two additional rituximab infusions. Responders re-

ceived rituximab maintenance every 8 weeks for 2 years.

“This phase II study confirmed the safety of the combination. R-squared–CHOP yielded a high rate of complete

response in patients with high tumor burden follicular lymphoma,” said Hervé Tilly, MD, of the Centre Henri Becquerel in Rouen.

The response rate at the end of in-

duction by International Working Group criteria was 94%, including 44% with a complete response, 30% with an unconfirmed complete response, and

Biologic Doubletcontinued from page 3


cytokines that are strongly correlated with remission,” he noted. “Patients with a partial response or no response had limited or negative changes.”

Smaller IncreasesThe analysis also revealed increases

in activating CD4 and CD8 cells in pa-tients with complete responses, but the increases were not statistically signifi-cant. NK cell numbers also increased, but not significantly over patients with-out a complete response, and activating NK cells actually decreased, which was unexpected and could be the result of the timing of the assessment, he said. PD-1–positive T cells increased as well, which is consistent with previous find-ings that correlated this with improved outcomes in follicular lymphoma.

“The findings suggest it may be possible to predict complete response based on patients’ levels of these cyto-kines before starting rituximab,” he sug-gested. n

Disclosure: Mr. Yamshon reported no potential conflicts of interest. Dr. Tuscano has received honoraria and research funding from Celgene.

Reference1. Yamshon S, Qi L, Yu C, et al: Correla-

tive analysis and clinical update of a phase II study using lenalidomide and rituximab

in patients with indolent non-Hodgkin lymphoma. 2013 American Society of He-matology Annual Meeting. Abstract 249. Presented December 9, 2013.

Markers of Responsecontinued from page 3


Andrew D. Zelenetz, MD, PhD, Chair of the Non-Hodgkin Lym-

phoma Guideline Panel of the Nation-al Comprehensive Cancer Network

(NCCN) and former Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York,

commented on the study by Yamshon et al for The ASCO Post.

He said the finding that serum cy-tokines may predict response to “R-squared” treatment was “intellectually interesting” but perhaps not clinically relevant, at least in follicular lymphoma.

“When we give rituximab and le-nalidomide to patients with follicular lymphoma, the response rates are enor-mously high—close to 100%—and complete response rates are around 80% in previously untreated patients, in trials to date,” he noted.

In other words, biomarkers are use-ful for predicting response, but with near-universal responses, its utility is unclear. Serum cytokine levels could

conceivably be useful, however, in sub-types with less predictable response to the drugs, such as mantle cell lympho-ma, he suggested.

“I would say it may be a predic-tor of early response, but we already know this combination is highly ef-fective,” he said. “The question is, how robust are the data across differ-ent subtypes, and how practical and easy is it to perform these tests in the real world? Ultimately, it could be useful in certain circumstances, but it’s premature to say.” n

Disclosure: Dr. Zelenetz is on the advisory board of and receives research support from Genentech/Roche and is a consultant for Hospira, Dr. Reddy’s Laboratories, and Celgene.

Andrew Zelenetz, MD, PhD

FOR OVERALL SURVIVAL LOOK TO ZELBORAF

Signi� cant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety Information on New Primary MalignanciesCutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF.

The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.

Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

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Indication and UsageZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety InformationNew Primary Malignancies (cont’d)Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF.

Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.

Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms.

Monitor patients receiving ZELBORAF closely for signs or symptoms of other 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.

Con� rm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF.

Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension.

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval.

Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the � rst 3 months of treatment, and every 3 months thereafter or more often as clinically indicated.

Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modi� cation of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

OS at FDA approval (August 2011)†‡

HR=0.44(95% CI, 0.33-0.59), P<0.0001

HR=hazard ratioCI=con� dence interval* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2

† At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001)

Signi� cant improvement in OS in a randomized, open-label Phase III trial*

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias)

Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-� nding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid).

Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modi� cations for intolerable grade 2 or greater photosensitivity.Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm.

Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol.

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 for additional Important Safety Information.

75%of responses to ZELBORAF occurred by 1.6 months, approximately the time of the � rst postbaseline assessment

Baseline assessment

First postbaselineassessment

1 month

Signi� cant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine � rst line2

48.4% of treatment naive patients had con� rmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001)

—There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Learn more at Zelboraf.com/EXPERIENCE

References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on � le. Genentech, Inc.

© 2013 Genentech USA, Inc. All rights reserved. BRF0000653205

EXTEND SURVIVALWITH ZELBORAF

76312ha_a.indd 2-3 9/10/13 1:55 PM

0 42 86

7.9

10 12 140

20

40

60

80

100

Perce

ntage

survi

ving

OS (months)

Not reached

ZELBORAF (n=337) Dacarbazine (n=338)

Indication and UsageZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.Important Safety InformationNew Primary Malignancies (cont’d)Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF.

Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.

Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms.

Monitor patients receiving ZELBORAF closely for signs or symptoms of other 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.

Con� rm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF.

Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension.

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval.

Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the � rst 3 months of treatment, and every 3 months thereafter or more often as clinically indicated.

Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modi� cation of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

OS at FDA approval (August 2011)†‡

HR=0.44(95% CI, 0.33-0.59), P<0.0001

HR=hazard ratioCI=con� dence interval* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for � rst-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2

† At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001)

Signi� cant improvement in OS in a randomized, open-label Phase III trial*

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias)

Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-� nding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid).

Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modi� cations for intolerable grade 2 or greater photosensitivity.Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm.

Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol.

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 for additional Important Safety Information.

75%of responses to ZELBORAF occurred by 1.6 months, approximately the time of the � rst postbaseline assessment

Baseline assessment

First postbaselineassessment

1 month

Signi� cant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine � rst line2

48.4% of treatment naive patients had con� rmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001)

—There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Learn more at Zelboraf.com/EXPERIENCE

References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on � le. Genentech, Inc.

© 2013 Genentech USA, Inc. All rights reserved. BRF0000653205

EXTEND SURVIVALWITH ZELBORAF

76312ha_a.indd 2-3 9/10/13 1:55 PM


ASH Annual Meeting

20% with a partial response. At this eval-uation, PET scan was negative in 83% of the patients, according to Deauville criteria.

Hematologic toxicity was in the range of that observed with R-CHOP, with a 65% incidence of grade 4 neutro-

penia, 12.5% grade 4 thrombocytope-nia, 7.5% grade 3/4 febrile neutropenia, and no toxic deaths. Grade 3 rash was observed in < 5%.

“The future of this combination will depend on the results of ongoing trials exploring R-squared as front-line treatment in this population,” Dr. Tilly said.

FcγRIIIa Phenylalanine Carrier Status

Individuals with Fc-gamma receptor RIIIa polymorphisms at amino acid 158 (ie, FcγRIIIa-158 phenylalanine carriers) are reported to respond poorly to ritux-imab and to have limited progression-free survival. In a study from the University of Pennsylvania, the R-squared regimen

appeared to overcome the impact of this adverse genetic profile.3

“In our study, not only were patients relapsed or refractory to rituximab, but additionally they were FcγRIIIa-158 phe-nylalanine carriers. After a single 4-week course of rituximab during continuous le-nalidomide treatment, subjects achieved high response rates and prolonged 2-year progression-free survival,” reported Elise A. Chong, MD, of the Lymphoma Pro-gram, Abramson Cancer Center, Univer-sity of Pennsylvania, Philadelphia.

“Our findings suggest that the immu-nologic effects of lenalidomide may po-tentiate the action of rituximab,” she said.

The study was a single-center phase II trial of R-squared in 42 patients with rituximab-refractory or -resistant indolent B-cell lymphoma or mantle cell lympho-ma; 39 patients were also FcγRIIIa-158 phenylalanine carriers. Patients first re-ceived lenalidomide at 10 mg daily for 8 weeks; then patients were assessed for re-sponse. Rituximab was added from weeks 9 though 12, and response was reassessed at week 21.

The response rate to lenalidomide monotherapy was 32%, which increased to 65% with the addition of rituximab.

“The improvement with rituximab was most pronounced in patients with follicular lymphoma (20% vs 66%)—a threefold increase—while in contrast, [mantle cell lymphoma patients] had the highest overall response rate to single-agent lenalidomide (60% vs 60%). This did not change with the addition of ritux-imab,” she said, “but two partial responses improved to complete responses.”

Median progression-free survival was 20.8 months for all patients. The 2-year progression-free survival rate was 44%. “Putting this in context, progression-free survival with rituximab monotherapy at 2 years is reported at 14%. We report 44%—a dramatic increase,” Dr. Chong noted.

The regimen was generally well tol-erated. n

Disclosure: Dr. Ruan is a consultant and member of the speakers bureau for and has received research funding from Celgene. Dr. Tilly has received honoraria from Roche, Celgene, Pfizer, and Janssen, research funding from Celgene and Amgen, and is an advisor for Celegene and Takeda. Dr. Chong reported no potential conflicts of interest.

References1. Ruan J, et al. 2013 ASH Annual Meet-

ing. Abstract 247. Presented December 9, 2013.

2. Tilly H, et al. 2013 ASH Annual Meet-ing. Abstract 248. Presented December 9, 2013.

3. Chong EA, et al. 2013 ASH Annual Meeting. Abstract 250. Presented Decem-ber 9, 2013.

Biologic Doubletcontinued from page 8

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ZELBORAF® (vemurafenib) tablet, oralInitial U.S. Approval: 2011This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGEZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesCutaneous MalignanciesCutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to <1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.Non-Cutaneous Squamous Cell CarcinomaNon-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.Other MalignanciesBased on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other 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 that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.3 Hypersensitivity ReactionsAnaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

5.4 Dermatologic ReactionsSevere dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].

5.5 QT ProlongationConcentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation.Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)].

5.6 HepatotoxicityLiver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)].Concurrent Administration with IpilimumabThe safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].

5.7 PhotosensitivityMild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)].

5.8 Ophthalmologic ReactionsUveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

5.9 Embryo-Fetal ToxicityZELBORAF 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. 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 Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

* Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.

a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2).

† Includes both squamous cell carcinoma of the skin and keratoacanthoma.

# Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysisMusculoskeletal and connective tissue disorders: arthritisNervous system disorders: neuropathy peripheral, VIIth nerve paralysisNeoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinomaInfections and infestations: folliculitisEye disorders: retinal vein occlusionVascular disorders: vasculitisCardiac disorders: atrial fibrillation

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on VemurafenibVemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

7.2 Effect of Vemurafenib on CYP1A2 SubstratesConcomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 IpilimumabIncreases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. 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.

8.3 Nursing MothersIt is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, 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.

8.4 Pediatric UseSafety and efficacy in pediatric patients below the age of 18 have not been established.

8.5 Geriatric UseClinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic ImpairmentNo formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

8.7 Renal ImpairmentNo formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.

10 OVERDOSAGEThere is no information on overdosage of ZELBORAF.

Manufactured by:Genentech, Inc.1 DNA Way BRF0000422003 South San Francisco, CA Initial U.S. Approval: August 2011 94080-4990 © 2013 Genentech, Inc

Change From Baseline to Grade 3/4

Parameter ZELBORAF (%) Dacarbazine (%)GGT 11.5 8.6AST 0.9 0.4ALT 2.8 1.9Alkaline phosphatase 2.9 0.4Bilirubin 1.9 0

Trial 1: Treatment Naïve Patients Trial 2: Patients with Failure of at Least One Prior

Systemic Therapy

ADRs ZELBORAFn= 336

Dacarbazinen= 287

ZELBORAFn= 132

All Grades

(%)

Grade 3a

(%)

All Grades

(%)

Grade 3

(%)

All Grades

(%)

Grade 3a

(%)Skin and subcutaneous tissue disordersRash 37 8 2 0 52 7Photosensitivity reaction 33 3 4 0 49 3Alopecia 45 <1 2 0 36 0Pruritus 23 1 1 0 30 2Hyperkeratosis 24 1 <1 0 28 0Rash maculo-papular 9 2 <1 0 21 6Actinic keratosis 8 0 3 0 17 0Dry skin 19 0 1 0 16 0Rash papular 5 <1 0 0 13 0Erythema 14 0 2 0 8 0Musculoskeletal and connective tissue disordersArthralgia 53 4 3 <1 67 8Myalgia 13 <1 1 0 24 <1Pain in extremity 18 <1 6 2 9 0Musculoskeletal pain 8 0 4 <1 11 0Back pain 8 <1 5 <1 11 <1General disorders and administration site conditionsFatigue 38 2 33 2 54 4Edema peripheral 17 <1 5 0 23 0Pyrexia 19 <1 9 <1 17 2Asthenia 11 <1 9 <1 2 0Gastrointestinal disordersNausea 35 2 43 2 37 2Diarrhea 28 <1 13 <1 29 <1Vomiting 18 1 26 1 26 2Constipation 12 <1 24 0 16 0Nervous system disordersHeadache 23 <1 10 0 27 0Dysgeusia 14 0 3 0 11 0Neoplasms benign, malignant and unspecified (includes cysts and polyps)Skin papilloma 21 <1 0 0 30 0Cutaneous SCC†# 24 22 <1 <1 24 24Seborrheic keratosis 10 <1 1 0 14 0InvestigationsGamma- glutamyltransferase increased

5 3 1 0 15 6

Metabolism and nutrition disordersDecreased appetite 18 0 8 <1 21 0Respiratory, thoracic and mediastinal disordersCough 8 0 7 0 12 0Injury, poisoning and procedural complicationsSunburn 10 0 0 0 14 0

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Common Mutations May Impact Neoadjuvant Treatment Outcomes in Breast CancerBy Caroline Helwick

Emerging research is suggesting that outcomes from neoadjuvant che-

motherapy may be correlated with two genetic mutations that are common in breast cancer—PIK3CA and TP53. Their presence may affect response to treatment, and mutational shift after treatment may affect survival, accord-ing to studies presented at the 2013 San Antonio Breast Cancer Symposium.

GeparSixto StudyWomen with HER2-positive, hor-

mone receptor–positive tumors with mutations in the PI3K/AKT pathway responded poorly to neoadjuvant ther-apy in the German Geparsixto study reported at the meeting.1

The PIK3CA mutation is the sec-ond most common in breast cancer, observed in about 20% of tumors, and alterations in this pathway are associat-ed with resistance to anti-HER2 agents. But the data have been discrepant with regard to its prognostic or predictive value, especially in HER2-positive tu-mors. The researchers, therefore, inves-tigated the frequency and prognostic associations of PIK3CA mutations in HER2-positive and triple-negative pri-mary breast cancer treated with neoad-juvant therapy.

The GeparSixto study was a pro-spective analysis of participants of the GeparSixto and GeparQuinto neoad-juvant trials. Patients received either trastuzumab (Herceptin) or lapatinib (Tykerb) in the GeparQuinto trial, or both inGeparSixto, in addition to 18 to 24 weeks of chemotherapy.

Mutational analysis (exons 9 and 20) of tissue samples was available on 360 women with HER2-positive tu-mors and on 285 women with triple-negative tumors. Within these groups, the PIK3CA mutation was identified in about 20% and 7%, respectively. By hor-mone receptor status in the HER2-pos-

itive patients, mutations were detected in about 21% of both receptor-negative and receptor-positive patients.

“We found that very few women with HER2-positive and hormone re-ceptor–positive breast cancer with a PIK3CA mutation experienced a patho-logic complete response after neoadju-vant therapy,” said Sibylle Loibl, MD, Associate Professor at the University

of Frankfurt and investigator with the German Breast Group in Neu-Isenburg, Germany.

PIK3CA Mutation Associated With Less Response

The combined analysis from both GeparQuinto and GeparSixto showed that, in HER2-positive patients, patho-logic complete response rates after dual HER2 blockade were significantly lower in the PIK3CA mutant group compared to patients with wild-type PIK3CA (17% vs 37%). In HER2-positive patients who were hormone receptor–positive and harbored a PIK3CA mutation, only 6.3% of pa-tients achieved pathologic complete response, Dr. Loibl reported.

“By hormone receptor status, this effect was exclusively confined to the hormone receptor–positive subgroup,” she said. “There was no difference in the

hormone receptor–negative group.”“The difference in [pathologic

complete response] rate between mu-tant and wild-type patients was largest among patients who received double HER2 blockade,” she added. “The [pathologic complete responses] were numerically higher without the muta-tion, and this seems confined to pa-tients receiving trastuzumab. There was no difference in the lapatinib-treated cohort, who had the same [pathologic complete response] rate irrespective of mutation status,” she said.

“The results are in concordance with NeoALTTO and Neosphere,” she noted. “Patients with PIK3CA-mutant HER2-positive and hormone receptor–positive breast cancer are resistant to chemotherapy and dual anti-HER2 treatment, and other treatment options need to be tested in this group.”

Dr. Loibl and her team are now con-ducting the randomized phase II neo-adjuvant NeoPHOEBE trial of the pan-PI3K inhibitor buparlisib.

Loss of PIK3CA and TP53 Mutations

Chinese investigators reported in San Antonio that the loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy heralds a favorable prog-nosis.2 Small studies have shown these mutations can be lost after neoadjuvant chemotherapy, and the researchers hy-pothesized that this “genetic evolution” could impact prognosis.

“We hypothesized that loss of TP53 and PIK3CA mutation status might be a common phenomenon after neoadju-vant chemotherapy and could serve as a prognostic biomarker,” said Zhi-Ming Shao, MD, of Fudan University Shang-hai Cancer Center,

The study included two neoadju-vant cohorts: 206 locally advanced breast cancer patients in the train-ing cohort and 158 in the validation cohort. All received four cycles of weekly paclitaxel and carboplatin, and underwent mutational analysis by exome sequencing before and after neoadjuvant treatment. A third co-hort included 81 patients with prior surgical resection who received adju-vant chemotherapy, and who under-went mutational analysis of microdis-sected tumor foci.

The study excluded patients who achieved a pathologic complete re-sponse, since this could confound the association with survival; instead, it correlated mutation status with partial response (Miller-Payne grade 3 or 4).

“We aimed to identify changes in mutation status, and the association be-tween mutational loss and chemothera-py response and survival,” Dr. Shao said.

Favorable Prognostic SignAt baseline, the distribution of the

mutations differed by breast cancer subtype. TP53 mutations were most common in basal-like tumors, while PIK3CA mutations were most frequent in luminal tumors. Mutation status for either gene had no influence on patient survival, but loss of the mutation did, Dr. Shao reported.

After neoadjuvant chemotherapy, mutation rates overall decreased sig-nificantly in both cohorts, from ap-proximately 25% to approximately 12% (P < .001). Loss of mutation was signifi-cantly associated with better pathologic response.

In cohort 1, a partial response or greater was observed in 77.8% of pa-tients who shifted from mutated status to wild-type, vs 45.9% who did not shift or who shifted from wild-type to mu-tated status. Similarly, in cohort 2 the response rates were 80% and 50.8%, re-spectively (P < .001 for both).

Furthermore, mutation shift, from mutated to wild-type, was associated with better disease-free survival (P = .033) and overall survival, which ex-ceeded 90% at 5 years (P = .045). By Cox proportional hazards model, a shift from mutation to wild-type, vs remain-ing wild-type, conferred hazard ratios of 0.62 (P = .004) in the training set and

Breast Cancer

We found that very few women with HER2-positive and hormone receptor–positive breast cancer with a PIK3CA mutation experienced a pathologic complete response after neoadjuvant therapy.

—Sibylle Loibl, MD

PIK3CA and TP53 Mutations and Neoadjuvant Therapy

■ PIK3CA and TP53 are the most common mutations in breast cancer, and emerging research suggests their presence or absence may affect outcomes after neoadjuvant treatment.

■ Analysis from the GeparSixto and GeparQuinto trials showed that women with HER2-positive, hormone receptor–positive breast cancer were less likely to respond to dual HER2 blockade if they had the PIK3CA mutation.

■ Exome sequencing by Chinese researchers revealed that patients with PIK3CA or TP53 mutations before paclitaxel-based neoadjuvant treatment, and who became wild-type after chemotherapy, had higher response rates and longer disease-free and overall survival than other patients.


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ZELBORAF® (vemurafenib) tablet, oralInitial U.S. Approval: 2011This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGEZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesCutaneous MalignanciesCutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to <1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.Non-Cutaneous Squamous Cell CarcinomaNon-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.Other MalignanciesBased on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other 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 that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.3 Hypersensitivity ReactionsAnaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

5.4 Dermatologic ReactionsSevere dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].

5.5 QT ProlongationConcentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation.Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)].

5.6 HepatotoxicityLiver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)].Concurrent Administration with IpilimumabThe safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].

5.7 PhotosensitivityMild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)].

5.8 Ophthalmologic ReactionsUveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

5.9 Embryo-Fetal ToxicityZELBORAF 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. 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 Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

* Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.

a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2).

† Includes both squamous cell carcinoma of the skin and keratoacanthoma.

# Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysisMusculoskeletal and connective tissue disorders: arthritisNervous system disorders: neuropathy peripheral, VIIth nerve paralysisNeoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinomaInfections and infestations: folliculitisEye disorders: retinal vein occlusionVascular disorders: vasculitisCardiac disorders: atrial fibrillation

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

7 DRUG INTERACTIONS7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on VemurafenibVemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

7.2 Effect of Vemurafenib on CYP1A2 SubstratesConcomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 IpilimumabIncreases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.9)].ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. 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.

8.3 Nursing MothersIt is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, 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.

8.4 Pediatric UseSafety and efficacy in pediatric patients below the age of 18 have not been established.

8.5 Geriatric UseClinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic ImpairmentNo formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

8.7 Renal ImpairmentNo formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.

10 OVERDOSAGEThere is no information on overdosage of ZELBORAF.

Manufactured by:Genentech, Inc.1 DNA Way BRF0000422003 South San Francisco, CA Initial U.S. Approval: August 2011 94080-4990 © 2013 Genentech, Inc

Change From Baseline to Grade 3/4

Parameter ZELBORAF (%) Dacarbazine (%)GGT 11.5 8.6AST 0.9 0.4ALT 2.8 1.9Alkaline phosphatase 2.9 0.4Bilirubin 1.9 0

Trial 1: Treatment Naïve Patients Trial 2: Patients with Failure of at Least One Prior

Systemic Therapy

ADRs ZELBORAFn= 336

Dacarbazinen= 287

ZELBORAFn= 132

All Grades

(%)

Grade 3a

(%)

All Grades

(%)

Grade 3

(%)

All Grades

(%)

Grade 3a

(%)Skin and subcutaneous tissue disordersRash 37 8 2 0 52 7Photosensitivity reaction 33 3 4 0 49 3Alopecia 45 <1 2 0 36 0Pruritus 23 1 1 0 30 2Hyperkeratosis 24 1 <1 0 28 0Rash maculo-papular 9 2 <1 0 21 6Actinic keratosis 8 0 3 0 17 0Dry skin 19 0 1 0 16 0Rash papular 5 <1 0 0 13 0Erythema 14 0 2 0 8 0Musculoskeletal and connective tissue disordersArthralgia 53 4 3 <1 67 8Myalgia 13 <1 1 0 24 <1Pain in extremity 18 <1 6 2 9 0Musculoskeletal pain 8 0 4 <1 11 0Back pain 8 <1 5 <1 11 <1General disorders and administration site conditionsFatigue 38 2 33 2 54 4Edema peripheral 17 <1 5 0 23 0Pyrexia 19 <1 9 <1 17 2Asthenia 11 <1 9 <1 2 0Gastrointestinal disordersNausea 35 2 43 2 37 2Diarrhea 28 <1 13 <1 29 <1Vomiting 18 1 26 1 26 2Constipation 12 <1 24 0 16 0Nervous system disordersHeadache 23 <1 10 0 27 0Dysgeusia 14 0 3 0 11 0Neoplasms benign, malignant and unspecified (includes cysts and polyps)Skin papilloma 21 <1 0 0 30 0Cutaneous SCC†# 24 22 <1 <1 24 24Seborrheic keratosis 10 <1 1 0 14 0InvestigationsGamma- glutamyltransferase increased

5 3 1 0 15 6

Metabolism and nutrition disordersDecreased appetite 18 0 8 <1 21 0Respiratory, thoracic and mediastinal disordersCough 8 0 7 0 12 0Injury, poisoning and procedural complicationsSunburn 10 0 0 0 14 0

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0.72 (P = .011) in the validation set, Dr. Shao reported.

Genetic analysis of cohort 3 revealed strong intratumoral heterogeneity in TP53 or PIK3CA mutations in 28% of the sam-ples. “Both mutant and nonmutant cancer cells coexist in the same tumor. This par-tially explains the genetic basis of the muta-tion shift after chemotherapy,” he said.

Dr. Zhao noted that chemotherapy sensitivity differs between mutant and wild-type cells. Loss of mutations may make cells more sensitive to chemo-therapy, conveying a favorable progno-sis. Patients with mutated status who remain mutated are more resistant to chemotherapy and have a worse prog-nosis, he suggested.

Ben Park, MD, PhD, Associate Pro-fessor of Oncology at Johns Hopkins, who moderated a poster session on PI3K pathway mutations, commented that “the next challenge will be to un-derstand how tumor biology changes

with tumor progression, or over the course of therapy, and how to develop methods to understand the whole cancer burden so that we can treat the clones that will be the bad actors.” n

Disclosure: This work was conducted with a grant from the EU FP 7 Programme. Drs. Loibl and Park reported no potential conflicts of interest.

References1. Loibl S, Denkert C, Schneeweis A, et

al: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-posi-tive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. 2013 San Antonio Breast Cancer Symposium.

Abstract S4-06. Presented December 12, 2013.

2. Shao Z-M, Jiang Y, Yu K-D: Exome sequencing identifies shift in TP53 and PIK3CA mutation status after paclitax-el-based neoadjuvant chemotherapy in breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S4-05. Pre-sented December 12, 2013.

Common Mutationscontinued from page 13

Ben Park, MD, PhD

Lung Cancer Screening Facts

The U.S. Preventive Services Task Force

has posted a supplemen-tal fact sheet for clinicians on its final recommenda-tion statement on screening for lung can-cer.1 This resource is meant to help health-care professionals talk about lung cancer screening with their patients and determine if screening is appropriate, as well as help clinicians understand how to implement the recently published final recommenda-tion.2 For more information, visit www .uspreventiveservicestaskforce.org. n

References1. U.S. Preventive Services Task Force:

Talking with your patients about screening for lung cancer. January 2014.

2. Humphrey LL, Deffebach M, Pappas M, et al: Screening for lung cancer with low-dose computed tomography. Ann Intern Med 159:411-420, 2013.

TCR

MHC

What if you could help the immunesystem respond to cancer cells?

Tumor expression of programmed death-ligand 1 (PD-L1), which binds

to the PD-1 and B7.1 receptors on

T cells, deactivates T-cell–mediated

cytotoxicity. This inhibits the immune

system and allows the tumor to continue

to grow.1 Nearly all cancer types show

increased expression of PD-L1.2

Genentech is investigating the strategy

of inhibiting the interaction between

tumor-expressed PD-L1 and its receptors

on T cells; blocking this interaction may

restore the body’s adaptive immune system

to respond to cancer cells.1 Research is also

under way to validate PD-L1 as a potential

biomarker for cancer immunotherapy.3

PD-L1 expression helps tumor cells evade the immune system

Blocking PD-L1 may restore the body’s adaptive immune response

Inactivated T cell

PD-L1

PD-1

B7.1

PD-L1Tumor cell

Activated T cell

Tumor cell deathPD-1

B7.1

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307-314. 3. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129-1132.

Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

© 2013 Genentech USA, Inc. All rights reserved. BIO0001911700 Printed in USA.

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MHC

76068ha_b.indd 1 7/12/13 2:22 PM

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Inactivated T cell

PD-L1

PD-1

B7.1

PD-L1Tumor cell

Activated T cell


B7.1




TCR

MHC

76068ha_b.indd 1 7/12/13 2:22 PM

http://www.biooncology.com



Drugging PI3K in Breast Cancer: Findings From SABCS 2013By Caroline Helwick

Components of the phosphati-dylinositide 3-kinase/mam-

malian target of rapamycin (PI3K/mTOR) pathway are deregulated in many human cancers, with about 30%

of breast cancers harboring PIK3CA gene mutations. Emerging research shows that these mutations may ren-der estrogen receptor alpha-positive tumors less sensitive to endocrine

agents, and HER2-positive tumors less responsive to anti-HER2 therapy. The good news is that compounds in development appear to overcome these effects, as reported at the 2013

San Antonio Breast Cancer Sympo-sium for the following four studies.

1. An in vitro combinatorial drug screen showed that the pairing of a PI3K inhibitor (the pan inhibitor GDC-0941, or the alpha-specific in-hibitor BYL-719) with a CDK4/6 inhibitor (LEE-011) was synergistic in PI3K inhibitor–resistant cell lines and a PIK3CA-mutated breast cancer model with de novo resistance to PI3K inhibitors. In the upfront setting, the combination led to tumor regression in this mouse model study from Mas-sachusetts General Hospital.1

2. In a phase I study from Wash-ington University, St. Louis, the pan-PI3K inhibitor BKM120 plus fulves-trant (Faslodex) produced partial response or disease stabilization for over 6 months in 10 of 18 patients with metastatic estrogen receptor–positive breast cancer.2 The results of this trial led to the ongoing phase III trials of this combination for patients with estrogen receptor–positive breast cancer who had disease pro-gression on an aromatase inhibitor.

3. To overcome resistance that develops to everolimus (Afinitor), researchers from the University of California, Los Angeles, administered BKM120 as a single agent or with ful-vestrant in a mouse model of evero-limus resistance and achieved strong tumor growth inhibition with either treatment.3

4. The combination of the alpha-specific PI3K inhibitor GDC-0032 combined with fulvestrant yielded a 73% response rate in an international phase Ib study.4 n

References1. Vora SR, King N, Costa C, et al:

Overcoming resistance to PI3K inhibitors in PIK3CA mutant breast cancer using CDK4/5 inhibition: Results from a com-binatorial drug screen. 2013 San Antonio Breast Cancer Symposium. Abstract S4-04. Presented December 12, 2013.

2. Ma CX, Wang J, Luo J, et al: A phase I study of BKM120 and fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast can-cer. 2013 San Antonio Breast Cancer Symposium. Abstract PD1-4. Presented December 12, 2013.

3. O’Brien NA, Tong L, Ayala R, et al: Targeting PI3K overcomes in vivo resis-tance to everolimus in estrogen receptor

Breast Cancer


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http://www.biooncology.com



(ER+) breast cancer. 2013 San Anto-

nio Breast Cancer Symposium. Abstract PD1-5. Presented December 11, 2013.

4. Juric D, Saura C, Cervantes A, et al:

Ph1b study of the PI3K inhibitor CDC-0032 in combination with fulvestrant in patients with hormone receptor-positive

advanced breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract PD1-3. Presented December 11, 2013.

Drugging PI3Kcontinued from page 15


Matthew Ellis, MB, PhD, Pro-fessor of Medicine and the An-

heuser-Busch Chair in Medical Oncol-ogy at Washington University School of Medicine, St. Louis, commented for The ASCO Post on the emerging field of research on drugging PI3K mutations.

Critical Mechanisms“Multiple somatic lesions in breast

cancer cells can activate the PI3 kinase pathway, and developing an under-standing of mechanisms whereby these events deregulate signaling is critical for accurate drug targeting. The field is still uncovering new ways where PI3 kinase gets activated,” he noted.

“For example,” Dr. Ellis continued, “in a study from the University of North Carolina, Dr. Perou’s team showed that SOX4 is a novel regulator of PI3K sig-naling in basal-like breast cancers. It was amplified in approximately 40% of basal-like tumors with high PI3K signaling, which is comparable to the frequency of PIK3CA or PTEN altera-tions.1 It’s not clear how SOX4 achieves PI3K pathway activation, but it appears to do so, which means we could poten-tially target the downstream effect of SOX4 overexpression with PI3K path-way–targeted agents,” he predicted.

“This sort of complexity explains why our initial efforts to link the effi-cacy of everolimus to the presence of

PIK3CA mutations have not yielded clear results, likely because other bio-logic events and mutations that also determine efficacy have not been taken into account,” he said.

Promising InhibitorsTargeting of PIK3CA will probably

best be achieved with a direct inhibi-tor, as reported by a number of inves-tigators in San Antonio. BYL-719 and other highly specific PI3K-alpha inhib-itors look promising, according to Dr. Ellis. While the BKM120 compound

is a broader inhibitor, Dr. Ellis’ group showed that patients who are resistant to endocrine therapy can respond to the combination of fulvestrant and BKM120.

“We are also learning that inhibiting cyclin D/CDK4 activity is important,”

he said, and is “clearly targetable” by the LEE-011 CDK4 inhibitor. A triple combination of an endocrine agent, a PI3K inhibitor, and a CDK4 inhibitor could be a potent approach to treat-ment, he predicted.

In HER2-positive tumors, the asso-ciations are similarly complex. In San Antonio, German researchers showed that PI3KCA mutations are associated with poor response to otherwise effec-tive HER2-targeting.2 However, since PI3KCA mutations are associated with luminal type biology, “we have to tease

all this out because direct cause and ef-fect is not demonstrated in these stud-ies,” Dr. Ellis added.

Other InsightsInsights have also been gained into

PI3KCA mutations in the hormone-

sensitive environment—affecting not only estrogen receptor–positive tumors, but also androgen receptor–positive tumors that are part of the triple-negative subset of patients. “The molecular apocrine tumors can also be PIK3CA-mutant,” Dr. Ellis noted.

“So it appears that this PIK3CA mu-tation story is associated with luminal biology and hormone receptor–driven tumors, and it is also associated with androgen receptor expression.” In this setting there is potential for yet an-other novel strategy: combining an an-tagonist of the androgen receptor with PIK3CA inhibition. n

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

References1. Gatza ML, Silva G, Hoadley KA, et al:

An integrated genomics approach identifies novel drivers of oncogenic pathway activity in human breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S4-01. Presented December 12, 2013.

2. Loibl S, Denkert C, Schneeweis A, et al: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-pos-itive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. 2013 San Antonio Breast Cancer Symposium. Abstract S4-06. Presented December 12, 2013.

Multiple somatic lesions in breast cancer cells can activate the PI3 kinase pathway, and developing an understanding of mechanisms whereby these events deregulate signaling is critical for accurate drug targeting.

—Matthew Ellis, MB, PhD

ASCO President Issues Statement on Major Decline in Lung Cancer Editor’s note: The Centers for Dis-

ease Control and Prevention (CDC) recently issued a report on lung cancer incidence trends in the United States.1 According to the report, incidence rates for lung cancer have decreased between 2005 and 2009, the period evaluated. Lung cancer incidence has decreased in all men, except those younger than 35 years. The decreased incidence in women was seen in those aged 35 to 44 years and 54 to 64 years. The most rapid decrease in lung cancer incidence was seen in the population aged 35 to 44, where lung cancer incidence decreased 6.5% among men and 5.8% among women. More information is available at www.cdc.gov/mmwr. ASCO President Clifford A. Hudis, MD, FACP, com-mented on the report as follows:

“Eliminating tobacco use is the most important thing we can

do to prevent lung and other cancers, as well as the many other diseases its use causes. [Recent] news confirms that we are making progress. However, the global health challenges from tobacco are still growing.

“This new CDC report1 shows how far we’ve come in the United States as we approach the 50th anniversaries of both the Surgeon General’s first report on tobacco and ASCO’s founding. Hav-ing shown that we can make substantial progress, we must continue to do ev-erything possible to expand tobacco

control programs in the United States and especially overseas, where tobacco use is taking an even greater toll.

“ASCO believes it is our respon-sibility as cancer doctors to help our patients quit and oppose tobacco use in all its forms. We are deeply commit-ted to proactive tobacco control glob-ally and have set an aggressive agenda for slashing tobacco use, deploying ev-ery public health, policy, and legal ap-proach available.” n

—Clifford A. Hudis, MD, FACP

Reference1. Henley JS, Richards TB, Underwood

MJ, et al: Lung cancer incidence trends among men and women: United States, 2005–2009. MMWR Morb Mortal Wkly Rep 63:1-5, 2014.

It is our responsibility as cancer doctors to help our patients quit and oppose tobacco use in all its forms.



San Antonio Breast Cancer SymposiumBreast Cancer

breast cancer, randomly assigning them to standard neoadjuvant chemotherapy or chemotherapy plus carboplatin, beva-cizumab, or the combination. Patients received weekly paclitaxel for 12 courses plus dose-dense anthracycline/cyclo-phosphamide alone, or with the addition of bevacizumab every 2 weeks for nine cycles or the addition of carboplatin AUC 6 every 3 weeks for four cycles.

The primary endpoint was patholog-ic complete response in the breast, and a secondary endpoint was pathologic complete response in the breast and the axillae. The investigators evaluated the effect of carboplatin on all patients re-ceiving it (alone or in combination) and the same for bevacizumab.

“The addition of carboplatin to stan-dard neoadjuvant chemotherapy signifi-cantly increased the pathologic complete response in the breast and also in the breast plus axillae,” Dr. Sikov reported.

For patients receiving carboplatin, 60% achieved a pathologic complete response in the breast, compared to 46% of those not receiving carboplatin. When defined as no disease in the breast or axillae, patho-logic complete response rates were 54% with carboplatin, vs 41% without carbopl-atin, a 71% increase (P = .0029), Dr. Sikov reported.

Bevacizumab was active as well, yielding a statistically significant differ-ence in the breast but not in the breast and axilla. When carboplatin and beva-cizumab were used in combination in addition to chemotherapy, 67% of pa-tients achieved a pathologic complete response in the breast. However, a sig-nificant treatment interaction between the two drugs was not shown.

Bevacizumab proved more toxic, as did chemotherapy plus both experi-mental agents. The total number of pa-tients with a serious adverse event was 15 in the chemotherapy-alone arm, 39 with chemotherapy plus bevacizumab, 29 with chemotherapy plus carboplatin, and 46 with chemotherapy plus the two agents. Bevacizumab was associated

with more grade 3 hypertension, infec-tions, and postsurgical complications, as well as a slight increase in thrombo-sis and bleeding problems. Patients re-ceiving carboplatin were more likely to experience neutropenia and thrombo-cytopenia. Most treatment discontinu-ations were seen with bevacizumab.

“Bevacizumab did increase patho-logic complete responses but at the cost of significant toxicities, and we don’t think it should be routinely added,” Dr. Sikov said at a press briefing.

I-SPY2 TrialThe I-SPY 2 trial is an ongoing multi-

drug, multicenter neoadjuvant phase II breast cancer trial. Findings reported at San Antonio included positive results for the PARP inhibitor veliparib, the first drug to complete testing in the tri-al. Adding carboplatin and veliparib to standard presurgery chemotherapy im-proved estimated pathologic complete

response rates for the subset of women with triple-negative breast cancer.3

I-SPY 2, devised by Laura J. Esserman, MD, and Don Berry, PhD, uses an adaptive randomized design to learn which patients respond better to which therapies as the trial proceeds. To be eligible, patients must have a breast tumor measuring at least 2.5 cm and be considered at high risk for early breast cancer recurrence by MammaP-rint evaluation, or have triple-negative or HER2-positive disease regardless of MammaPrint results.

For this portion of the trial, patients were randomly assigned to standard neoadjuvant chemotherapy—weekly paclitaxel for 12 weeks, followed by an-thracycline-based chemotherapy for four

courses—or to the same regimen plus veliparib at 100 mg/d plus carboplatin AUC 6 every 3 weeks during paclitaxel. Among 71 patients assigned to the velipar-ib-containing regimen, 38 had triple-nega-tive breast cancer and 33 had hormone re-ceptor–positive, HER2-negative disease.

The estimated pathologic complete response rate for patients with triple-negative breast cancer was 52% after receipt of chemotherapy plus veliparib/carboplatin and standard paclitaxel fol-lowed by anthracycline-based chemo-therapy vs 26% with control chemo-therapy alone, corresponding to a 99% probability that this regimen is superior to the control, reported Hope S. Rugo, MD, Professor of Medicine and Direc-tor of Breast Oncology and Clinical Tri-als Education at the Helen Diller Fami-ly Comprehensive Cancer Center at the University of California, San Francisco.

Thus, veliparib and carboplatin arm met the threshold for graduation—meaning a 90% chance of success when tested in a 300-patient phase III neoad-juvant trial. AbbVie is planning to open such a trial early this year, Dr. Rugo told The ASCO Post.

In “signatures” other than triple-negative breast cancer, the combination was predicted to be far less successful. For example, for the hormone recep-tor–positive/HER2-negative group, the estimated pathologic complete response rate was 14% for the combination and 19% for controls, she said.

“These data show that the adaptive design of I-SPY 2 can generate results that will power phase III registration tri-als,” said Dr. Rugo. “By identifying which

patients benefit, we can reduce trial size, accelerate drug development, and avoid overtreatment in the majority of patients, which is the future of drug development.”

Use of CarboplatinDr. Sikov noted that several studies

now show that the addition of carboplatin increases pathologic complete responses in patients with triple-negative disease, though recurrence-free and overall sur-vival benefits have not yet been observed, largely due to short follow-up and lack of statistical power. He said that the general assumption is that achievement of patho-logic complete response will, indeed, im-prove long-term outcomes, and he said he incorporates carboplatin in the neoadju-vant setting in his patients. n

Disclosure: Drs. Sikov and Rugo reported no potential conflicts of interest.

References1. Sikov WM, et al: Impact of the addition

of carboplatin and/or bevacizumab to neo-adjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013.

2. von Minckwitz G, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast can-cer (GeparSixto). 2013 ASCO Annual Meet-ing. Abstract 1004. Presented June 3, 2012.

3. Rugo HS, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Pre-sented December 13, 2013.

Triple-Negative Breast Cancercontinued from page 1

Carboplatin in Triple-Negative Breast Cancer

■ In early-stage triple-negative breast cancer, the addition of carboplatin to chemotherapy produced a pathologic complete response rate of 60% in the phase II CALGB/Alliance 40603 study.

■ Bevacizumab also increased pathologic complete responses, but the benefit was outweighed by toxicity.

■ In the adaptive-design I-SPY2 trial, the oral PARP inhibitor veliparib plus carboplatin added to standard neoadjuvant chemotherapy yielded a pathologic complete response rate of 52%.


Lajos Pusztai, MD, DPhil, Professor of Med-icine and Director of Breast Medical Oncol-

ogy at Yale University, New Haven, Connecticut, who was the formal discussant of the papers by Sikov et al and Rugo et al, said there is mounting evidence for using carboplatin. He and his own research team have estimated that carboplatin plus chemotherapy may result in about a 15% reduction in the risk for recurrence, but he also predicted, “this may not reach statistical signifi-cance in the CALGB 40603 trial,” largely attributed to the limited statisti-cal power due to modest sample size.

“This provides a valid new treatment option for patients with high-risk triple-negative disease,” Dr. Pusztai concluded. “The impact on survival may be mod-est, but I believe it will be observable with longer follow-up.” He also pointed out that more effective neoadjuvant chemotherapy also provides patient-level benefits other than survival, including smaller surgery, better cosmesis, addi-tional prognostic information, and an opportunity to seek out further adjuvant therapies (on clinical trials) in case of extensive residual cancer.” n

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

Lajos Pusztai, MD, DPhil

Hope S. Rugo, MD

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18.4 MONTHS MEDIAN OVERALL SURVIVAL

VS 13.6 MONTHS WITH PLACEBO1

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety InformationContraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot fl ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid

requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2

Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs

placebo (47% vs 53%, respectively)1

37% reduced risk of death• HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Eff ect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Eff ect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information.References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Learn more at XtandiHCP.com

© 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013E-076-7984-3 12/13XTANDI, Astellas, and the fl ying star logo are trademarks of Astellas Pharma Inc.

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https://www.xtandihcp.com

Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012BRIEF SUMMARYOF PRESCRIBING INFORMATIONThe following is a brief summary: please see the package insert for full prescribing information.INDICATIONS AND USAGEXTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.CONTRAINDICATIONSPregnancyXTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONSSeizureIn the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. ADVERSE REACTIONSClinical 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.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)General Disorders

Asthenic Conditionsa 50.6 9.0 44.4 9.3Peripheral Edema 15.4 1.0 13.3 0.8

Musculoskeletal And Connective Tissue DisordersBack Pain 26.4 5.3 24.3 4.0Arthralgia 20.5 2.5 17.3 1.8Musculoskeletal Pain 15.0 1.3 11.5 0.3Muscular Weakness 9.8 1.5 6.8 1.8Musculoskeletal Stiffness 2.6 0.3 0.3 0.0

Gastrointestinal DisordersDiarrhea 21.8 1.1 17.5 0.3

Vascular DisordersHot Flush 20.3 0.0 10.3 0.0Hypertension 6.4 2.1 2.8 1.3

Nervous System DisordersHeadache 12.1 0.9 5.5 0.0Dizzinessb 9.5 0.5 7.5 0.5Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 4.5 3.8

Paresthesia 6.6 0.0 4.5 0.0Mental Impairment Disordersc 4.3 0.3 1.8 0.0Hypoesthesia 4.0 0.3 1.8 0.0

Infections And InfestationsUpper Respiratory Tract Infectiond

10.9 0.0 6.5 0.3

Lower Respiratory Tract And Lung Infectione

8.5 2.4 4.8 1.3

Psychiatric DisordersInsomnia 8.8 0.0 6.0 0.5Anxiety 6.5 0.3 4.0 0.0

Renal And Urinary DisordersHematuria 6.9 1.8 4.5 1.0Pollakiuria 4.8 0.0 2.5 0.0

Injury, Poisoning And Procedural ComplicationsFall 4.6 0.3 1.3 0.0Non-pathologic Fractures 4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue DisordersPruritus 3.8 0.0 1.3 0.0Dry Skin 3.5 0.0 1.3 0.0

Respiratory DisordersEpistaxis 3.3 0.1 1.3 0.3

a Includes asthenia and fatigue.b Includes dizziness and vertigo.c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. InfectionsIn the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related InjuriesIn the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.HallucinationsIn the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

DRUG INTERACTIONSDrugs that Inhibit or Induce CYP2C8Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology].Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers [see Clinical Pharmacology (12.3)].The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology ].Effect of XTANDI on Drug Metabolizing EnzymesEnzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology ]. USE IN SPECIFIC POPULATIONSPregnancy- Pregnancy Category X [see Contraindications].XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Nursing MothersXTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric UseSafety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 and over, while 25 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal ImpairmentA dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology]. Patients with Hepatic ImpairmentA dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology].OVERDOSAGEIn the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (PATIENT INFORMATION).• Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without

food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.• Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of

treatment with XTANDI.• Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that

may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

• Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their

physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

• Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

• Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062Medivation, Inc., San Francisco, CA 94105Issued: August 201212A005-ENZ-BRSRx Only© 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 0131-076-8930

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IPOS/AORTIC Conference Aims to Bring Comprehensive Care to Patients in AfricaBy Jo Cavallo

More than 1,000 scientists from 66 countries, including 32 of

the 52 African countries, attended the African Organization for Research and Training in Cancer (AORTIC) 9th International Conference on Can-cer in Africa, held this past November in Durban, South Africa. The theme

of the 2013 meeting was Cancer in Africa: Bridging Science and Human-ity. The program featured concur-rent plenary and workshop sessions on a variety of topics, including from epidemiologic analyses to pathogenic mechanisms, biomolecular pathways, clinical data, and innovative thera-peutic strategies. In addition to fo-cusing on the cancer care of patients in Africa, the meeting also addressed the need for increasing the oncology workforce in the African continent.

Currently, the most commonly diagnosed cancers in African men include Kaposi’s sarcoma, constitut-ing 12.9% of all cancer in males; liver cancer, 14.8%; prostate cancer, 9.5%; bladder cancer, 6.1%; and non-Hodg-kin lymphoma, 5.7%. In African wom-en, the most common cancers include cervical cancer, constituting 23.3% of all cancer in females; breast cancer, 19.2%; Kaposi’s sarcoma, 5.1%; liver cancer, 5%; and non-Hodgkin lym-phoma, 3.7%.

Treating the Whole PatientHeld in conjunction with the

AORTIC conference was the Inter-national Psycho-Oncology Society (IPOS)/AORTIC Academy, which was co-chaired by Jimmie Holland, MD, founder of IPOS, and Attending Psychiatrist and Wayne E. Chapman Chair in Psycho-Oncology at Memo-

rial Sloan-Kettering Cancer Center, New York; Chioma Asuzu, PhD, Senior Lecturer in Psycho-Oncology at the University of Ibadan, Lagos, Nigeria; and Mark Lazenby, PhD, Director of the American Psychoso-cial Oncology Society and Assistant Professor of Nursing at Yale School

of Nursing, West Haven, Connecti-cut. The theme of the IPOS/AOR-TIC Academy meeting was “Treating the Whole Patient: Moving Psycho- Oncology Forward.”

Meeting Overview Approximately 50 members of

IPOS and eight travel scholars from five African countries were in at-tendance (see page 39 for more on “IPOS/AORTIC Travel Scholars”). Joe Harford, PhD, Director of the Office of International Affairs at the National Cancer Institute (NCI), led off the first session with a review of the scientific literature on the major

causes of delay in patients’ re-ceiving a timely cancer diag-nosis. They included patients’ late presentation to health-care providers and system delays. “These delays are the major cause preventing cura-tive treatment in Africa,” Dr. Holland said.

Dr. Asuzu followed Dr. Harford with a presentation of the results of her NCI-funded study on the role of traditional heal-ers in the care of patients with cancer and how it contributes to the delay in patients receiving evidence-based cancer care and, consequently, cura-tive therapy.

Improving Care Through Education and Better Communication

The second session focused on education and communication in the improvement of cancer care and included presentations by Vincent Odigie, MD, Professor of Surgery at Ahmadu Bello University Teaching Hospital in Zaria, Nigeria; Beatrice Wiafe-Affai, MD, PhD, Chief Execu-tive Officer at Peace and Love Hospi-tals in Ghana; and Margaret Fitch, PhD, Head, Oncology Nursing at the Odette Cancer Center of Sunnybrook and Women’s Health Science Center in Toronto, Canada; among others.

Dr. Odigie spoke about the results

from his study on the use of cell-phones to improve doctor-patient communication. According to Dr. Odigie’s study, in which breast cancer surgeons gave their cell phone num-bers to patients so they could call with questions or symptoms, over 86% of participants rated phone use very useful in obtaining information or rescheduling appointments.

Dr. Wiage-Addai, also a breast can-cer surgeon, described her work using breast cancer survivors as lay educa-tors and support group facilitators to provide psychological support for patients with breast cancer. Dr. Fitch spoke about the use of distance mo-dalities and the role of interpersonal education in teaching and learning patient- and family-centered care.

Managing Cancer GloballyThe final session, titled “Routes to

Change Through Collaboration,” was presented by Folakemi Odedina, PhD, Professor, Pharmaceutical Out-comes and Policy, at the University of Florida, and Shubhra Ghosh, MD, Project Director of Global Academic Programs at MD Anderson Cancer Center.

Dr. Odedina discussed the role of patient advocates in enhancing pa-tient care. Dr. Ghosh explained MD Anderson’s role in developing collab-orative programs in Zambia to pro-vide more training, service delivery, and research to increase the number of skilled providers in the manage-ment of comprehensive cancer care and improve and increase access to care to more patients.

Watch future issues of The ASCO Post for interviews with faculty from the IPOS/AORTIC Meeting. nFig. 1: Faculty scholars and attendees of the IPOS/AORTIC Academy in Durban, South Africa.

Psychosocial Oncology

Global Oncology

These delays are the major cause preventing curative treatment in Africa.

—Jimmie Holland, MD

Chioma Asuzu, PhD Mark Lazenby, PhD

Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012BRIEF SUMMARYOF PRESCRIBING INFORMATIONThe following is a brief summary: please see the package insert for full prescribing information.INDICATIONS AND USAGEXTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.CONTRAINDICATIONSPregnancyXTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONSSeizureIn the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. ADVERSE REACTIONSClinical 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.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%)General Disorders

Asthenic Conditionsa 50.6 9.0 44.4 9.3Peripheral Edema 15.4 1.0 13.3 0.8

Musculoskeletal And Connective Tissue DisordersBack Pain 26.4 5.3 24.3 4.0Arthralgia 20.5 2.5 17.3 1.8Musculoskeletal Pain 15.0 1.3 11.5 0.3Muscular Weakness 9.8 1.5 6.8 1.8Musculoskeletal Stiffness 2.6 0.3 0.3 0.0

Gastrointestinal DisordersDiarrhea 21.8 1.1 17.5 0.3

Vascular DisordersHot Flush 20.3 0.0 10.3 0.0Hypertension 6.4 2.1 2.8 1.3

Nervous System DisordersHeadache 12.1 0.9 5.5 0.0Dizzinessb 9.5 0.5 7.5 0.5Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 4.5 3.8

Paresthesia 6.6 0.0 4.5 0.0Mental Impairment Disordersc 4.3 0.3 1.8 0.0Hypoesthesia 4.0 0.3 1.8 0.0

Infections And InfestationsUpper Respiratory Tract Infectiond

10.9 0.0 6.5 0.3

Lower Respiratory Tract And Lung Infectione

8.5 2.4 4.8 1.3

Psychiatric DisordersInsomnia 8.8 0.0 6.0 0.5Anxiety 6.5 0.3 4.0 0.0

Renal And Urinary DisordersHematuria 6.9 1.8 4.5 1.0Pollakiuria 4.8 0.0 2.5 0.0

Injury, Poisoning And Procedural ComplicationsFall 4.6 0.3 1.3 0.0Non-pathologic Fractures 4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue DisordersPruritus 3.8 0.0 1.3 0.0Dry Skin 3.5 0.0 1.3 0.0

Respiratory DisordersEpistaxis 3.3 0.1 1.3 0.3

a Includes asthenia and fatigue.b Includes dizziness and vertigo.c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. InfectionsIn the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related InjuriesIn the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.HallucinationsIn the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

DRUG INTERACTIONSDrugs that Inhibit or Induce CYP2C8Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology].Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers [see Clinical Pharmacology (12.3)].The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology ].Effect of XTANDI on Drug Metabolizing EnzymesEnzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology ]. USE IN SPECIFIC POPULATIONSPregnancy- Pregnancy Category X [see Contraindications].XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Nursing MothersXTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric UseSafety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 and over, while 25 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal ImpairmentA dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology]. Patients with Hepatic ImpairmentA dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology].OVERDOSAGEIn the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (PATIENT INFORMATION).• Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without

food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.• Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of

treatment with XTANDI.• Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that

may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

• Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their

physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

• Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

• Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062Medivation, Inc., San Francisco, CA 94105Issued: August 201212A005-ENZ-BRSRx Only© 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 0131-076-8930

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Health-Care Policy

on those that are least likely to be un-dertaken by the private sector.

“Many important questions can be answered only through publicly sup-ported research, which is in real jeop-ardy,” Dr. Schilsky said.

Genomic ResearchExamples of such questions are

those that address a cancer’s entire ge-nome. Among 2013’s major advances was the comprehensive genomic analy-sis of 200 tumor samples from adults with de novo acute myeloid leukemia, which is associated with recurrent ge-netic abnormalities.

The analysis was the work of The Cancer Genome Atlas (TCGA) Re-search Network, a program of the Na-tional Cancer Institute. In 2013, TCGA also reported the results of comprehen-sive molecular analyses of kidney and endometrial cancers.

The resulting databases are avail-able to researchers worldwide and can facilitate the search for new targeted therapies. While developing targeted treatments is generally the province of drug and biotech companies, discovery of the target has often been in federal laboratories or with federal dollars, Dr. Schilsky noted.

“TCGA investigators will keep com-ing out with previously unrecognized genetic abnormalities,” he predicted. “Then enterprising companies can come up with the targeted agents. That lets biotech and drug companies do what they do best—product develop-ment. It’s the perfect synergy between private enterprise and public research.”

The ASCO report includes a policy section that discusses the impact of se-questration on National Institutes of Health (NIH)-funded studies and strong-ly recommends increased funding: It calls for $32 billion for NIH in next year’s bud-get, of which $5.2 billion would go to the National Cancer Institute (NCI).

Clinical TrialsThe report also recommends more

support for clinical trials in general and the NCI-sponsored cooperative groups, now consolidated into the National Clinical Trials Network, in particular. It notes that long-planned trials have not been able to open for patient enrollment and that as a result, the number of patients taking part in clinical trials has dropped from a high of more than 29,000 a year in 2009 to 20,000 in 2013.

As with genomic studies, the drop in federal funding for trials bodes ill for clinical questions that are not typically ad-

dressed in the private sector.“What gets lost when

people talk about the clinical trials is that there are certain kinds of trials that government can do and the private sector doesn’t do,” said Dr. Schilsky.

Trials of treatment strate-gies using drugs already ap-proved offer one example. Among the 76 most important ad-vances in 2013 was a breast cancer trial showing that adjuvant paclitaxel given weekly, in lower doses, was significantly less toxic than the standard dose-dense regimen given every 2 weeks. It was also less expensive. Though the drug has been on the market for many years, the new finding is expected to change prac-tice, making an important difference for hundreds of thousands of women.

Early studies of experimental thera-pies, many federally funded, are also highlighted in the report. In relapsed, therapy-resistant childhood acute lym-phoblastic leukemia (ALL), an immu-notherapy using genetically modified T cells to attack cancerous B cells was tried for the first time. The first two children who received the T cells expe-rienced complete remission, one for 11 months and one for 2 months.

“These early results show promise that in the future, engineered T cells may become a radical new strategy for advanced, treatment-resistant ALL,” ac-cording to the report.

Large-scale prevention and screen-ing trials are another example of studies that require public funding. The ASCO report singles out results from the NCI-sponsored National Lung Screening Trial, showing that low-dose computed tomography (CT) scans reduced the mortality of non–small cell lung can-

cer among smokers and recent former smokers by 20%. As a result, the U.S. Preventive Services Task Force started recommending CT screening for those at high risk.

About the ReportThe 76 advances in the annual report,

now in its ninth year, were identified by an editorial board led by Co-Executive Editors Jyoti D. Patel, MD, Northwest-ern University, and Bruce J. Roth, MD, Washington University at St. Louis. The editors reviewed research published in peer-reviewed scientific journals and presented at major scientific meetings over a 1-year period (October 2012 to September 2013), covering prevention, screening, treatment, patient and sur-vivor care, biomarkers, tumor biology, and cancer disparities.

In addition to its publication in the Journal of Clinical Oncology, the report is available with additional resources at www.cancerprogress.net/cca. n

Disclosure: Drs. Schilsky and Patel reported no potential conflicts of interest. Dr. Roth has received research funding from Exelixis, Medivation, and Oncogenix.

Reference1. Patel JD, Krilov L, Adams S, et al:

Clinical cancer advances 2013: Annual re-port on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 32:129-160, 2014.

2013 Cancer Advancescontinued from page 1

Federal Funding in Oncology

■ ASCO’s 9th annual Clinical Cancer Advances report identifies the 76 most important advances of 2013, many of which were supported with federal funds.

■ Federal investment in basic science brings insights that enable commercial companies to make important advances in product development.

■ Many important clinical questions can be answered only through publicly supported research.

Bruce J. Roth, MD Jyoti D. Patel, MD

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

Andrew Zelenetz, MD, PhD, on Markers of Response in Lymphoma see page 8

Mary M. Horowitz, MD, MS, on Options for Age and Donor Sources for Transplant see page 31

Matthew Ellis, MD, PhD, on PI3K in Breast Cancer see page 16

Derek Raghavan, MD, PhD, Cancer Genes, Promiscuity, and the National Debt see pages 1, 37

Lajos Pusztai, MD, DPhil, on Triple-Negative Breast Cancer see page 17

Mollie deShazo, MD, on Flu Vaccination in Patients With Cancer see page 46

Visit The ASCO Post online at ASCOPost.com

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Direct From ASCO

ASCO Member Helps to Strengthen Cancer Care Internationally Through Philanthropy and Volunteer ServiceA Global Approach to Cancer Care

Ian F. Tannock, MD, PhD, DSc, FASCO, Professor of Medical On-

cology at Princess Margaret Hospital and University of Toronto, has long been an advocate for ASCO as a truly global society and a leader in cancer care worldwide. It’s something he en-couraged during his time on ASCO’s Board of Directors, and which he con-tinues to reinforce as a volunteer and donor to the Conquer Cancer Foun-dation.

A truly global approach to cancer care is challenging given the enor-mous disparities in resources around the world. As Dr. Tannock frames it, “There is a huge difference in manag-ing cancer in countries like the United States and Canada, most of Western Europe, Australia, and Japan and de-veloping middle-income and lower-

income countries. I think that ASCO, if it’s to be a world leader, is making good steps in that direction, but has to recognize that a 3-month gain in survival from a targeted agent that costs at least $5,000 a month is to-tally irrelevant to most of the world’s population.”

Addressing DisparitiesThis year, in response to donor re-

quests, the Conquer Cancer Founda-tion created a new giving option for donors to allow them to designate their gifts directly to the international initiatives the Foundation supports through its Grants & Awards program and ASCO International.

These programs attempt to thought-fully address the disparities that Dr. Tannock describes, and range from di-rect research funding for investigators in low- and middle-income countries (the International Innovation Grant), to opportunities for ASCO member volunteers to travel overseas to help strengthen cancer care in low-resource

countries, to training and mentoring opportunities like the Long-Term In-ternational Fellowship (LIFe) and the International Development and Edu-cation Award (IDEA).

The International Development and Education Award

The IDEA provides support for early-career oncologists in low- and middle-income countries to estab-lish strong relationships with lead-ing ASCO members who serve as scientific mentors to each recipient. The recipients of this award attend ASCO’s Annual Meeting and partici-pate in a post-Meeting visit to their mentor’s institution in the United States or Canada. Recipients also re-ceive 3 years of complimentary ASCO

m e m b e r -ship, in-cluding a s u b s c r i p -tion to the Journal of Clinical On-cology.

Dr. Tannock has been involved in the IDEA Program as a volunteer men-tor from the very beginning. “I’ve been a mentor in the IDEA Program since its inception—I think every year but one. Some of those people have come back to work with me or with others as fellows, so it’s been a very produc-tive program,” he said. As an example of this, he cited one particular IDEA recipient whom he mentored, Rachel Riechelmann, MD, PhD, of the Insti-tuto do Estado de Sao Paulo, Brazil, who found the IDEA to be a transformative experience for her life and career.

The IDEA program has produced substantial results over the past 11 years. There are currently 231 IDEA alumni from over 40 countries, many of whom have assumed leadership po-sitions on ASCO committees and in their local societies; received fellow-ships and other research opportuni-ties; pursued longer-term collabo-rations with their mentors; helped organize ASCO training and other activities in their countries; and, in

some instances, created oncology so-cieties where none previously existed. In addition, on average, each IDEA alumnus shares the information and new skills learned with more than 80 colleagues in his or her home country.

Dr. Tannock reported that he has developed continuing collaborations with several of his IDEA mentees. Next year he plans to travel to Viet-nam to spend a few days teaching with a former mentee in Hanoi.

International Cancer CorpsAnother of ASCO’s international

programs that Dr. Tannock would like to see grow is the International Can-cer Corps, which, in collaboration with Health Volunteers Overseas, provides an opportunity to strength-en cancer care in medical centers in low-resource countries. By volun-teering for the International Cancer Corps, oncology professionals can share their medical expertise and build long-term, supportive relation-ships with the clinicians who provide cancer care in these countries.

Health Volunteers Overseas pairs eligible oncology professionals with a medical center where the training needs of the facility match the ex-pertise of the volunteer. Volunteers spend 1 to 4 weeks onsite, where they teach and train staff, residents, and students, and gain insight into the center’s cancer management needs and challenges. The International

Cancer Corps has now expanded to five countries, with training sites in Paraguay, Bhutan, Costa Rica, Hon-duras, and Vietnam.

Making a Difference Worldwide Through Philanthropy

As a long-time member of the fac-ulty at the ASCO Annual Meeting, Dr. Tannock had previously declined his honoraria payments so that the funds would remit to support the Conquer Cancer Foundation. When ASCO changed its policy to no longer offer speaker honoraria, Dr. Tannock decided to continue to support the Foundation with a direct donation to its International Programs. As he put it, “When ASCO stopped pay-ing honorarium I thought, well, I can afford to give a few hundred dollars each year to support these programs, and I’m happy to continue to do that.”

To learn more about these pro-grams and support them with a donation to the Conquer Can-cer Foundation, please visit www .c o n q u e rc a n c e r f o u n d at i o n .o r g /global. To volunteer to act as a men-tor in the IDEA program or to learn more about any of the ASCO Inter-national programs supported through the Foundation, please email [email protected]. n

© 2014. American Society of Clinical Oncology. All rights reserved.

Philanthropy Spotlight

Ian F. Tannock, MD, PhD, DSc, FASCO, and Rachel Riechelmann, MD, PhD

http://www.hvousa.org/


Direct From ASCO

Conquer Cancer Foundation Funds Research in Low- and Middle-Income Countries for the First TimeRecipients of the Foundation’s New International Innovation Grant Announced

The Conquer Cancer Foundation of the American Society of Clini-

cal Oncology has announced the four recipients of the inaugural 2014 Inter-national Innovation Grant, which is a new program that underscores the Foundation’s continued commitment to improving the care of patients world-wide. The 1-year grants of up to $20,000 will support novel and innovative re-search projects led by ASCO members in Nigeria, Tanzania, Colombia, and Myanmar. The grant funds research that can significantly impact cancer control in low- and middle-income countries.

As the global cancer burden contin-ues to increase, there is a great need for programs that deliver creative solutions to improving cancer care in countries with limited resources. To help address this need, the International Innovation Grant was designed to fund projects that can impact people locally while also hav-ing the potential to be transferrable to other low- and middle-income settings.

“We considered how we could im-prove the lives of cancer patients in low-to-middle income countries in a cost-effective, scalable, and meaning-ful way,” said Anees B. Chagpar, MD, Chair of the International Innovation Grant Selection Subcommittee. “We discovered that what was needed, be-

yond improving awareness and oncol-ogy practice, was innovation—people thinking about how they could best help patients with cancer in their own environments.”

International Innovation Grant Recipients

The recipients of the 2014 Interna-tional Innovation Grants are:• Chibuike Ogwuegbu Chigbu,

MBBS, FWACS University of Nigeria Teaching Hospital, Ituku/Ozalla Dr. Chigbu will serve as the prin-cipal investigator on a three-phase study to examine the effect of com-munity health educators on uptake of cervical and breast cancer screen-ing and human papillomavirus vac-cination in rural southeast Nigeria.

• Bertha Tsingay Maegga, PhD Tanzania Public Health Association Nearly two-thirds of tobacco use in Tanzania starts before age 12. Dr. Maegga will serve as the principal investigator on the 80 Children Strong research project that will implement an intensive 1-week, school-based tobacco awareness campaign designed to reduce the percentage of children age 14 and younger who use tobacco products

in Dar es Salaam, Tanzania. • Armando Sardi, MD, FACS

Fundación Para la Prevención y Tratamiento del Cáncer, Colombia Dr. Sardi will lead a project investi-gating a model telehealth education intervention to improve cervi-cal cancer service provision and health outcomes. In Colombia, the incidence of cervical cancer is twice that of the United States with mor-tality rates that are 4.5 times greater.

• Mya Thida, MBBS University of Medicine 1, Myanmar Dr. Thida will lead a study look-ing at the effectiveness of a visual inspection with acetic acid– and cryotherapy-based single-visit ap-proach to cervical cancer preven-tion in Taikkyi Township, Myan-mar, where only an estimated 0.9% of women are currently screened.“The applications were all outstand-

ing and I am thrilled with the first set of grants awarded,” Dr. Chagpar said. “I can’t wait to see how these investiga-tors put these projects into action and am excited to see the impact on cancer worldwide.”

Reducing the Global Cancer Burden

According to Dr. Chagpar, the In-

ternational Innovation Grant embod-ies the mission of the Conquer Cancer Foundation, which encourages and supports ASCO members in work-ing to make a lasting and meaningful difference in reduc-ing the cancer burden and improving the lives of patients in all regions of the world. In addition, it is the newest in a number of ASCO Interna-tional programs dedicated to foster-ing global collaboration to improve cancer care.

The 2014 International Innovation Grants were made possible by the gen-erous support of the Conquer Cancer Foundation Mission Endowment, Do-ris Duke Charitable Foundation, and Thomas G. Roberts, Jr, MD, and Susan M. DaSilva.

Visit www.conquercancerfoundation .org/global to watch a video about the Innovation Grant and other interna-tional programs funded by the Con-quer Cancer Foundation, and to make a donation that will have a global reach and personal impact on people with cancer. n



Direct From ASCO

ASCO Cosponsors Inaugural Palliative Care in Oncology Symposium

In October, ASCO will cosponsor the inaugural Palliative Care in Oncology

Symposium with the American Acad-emy of Hospice and Palliative Medicine (AAHPM), the American Society for Radiation Oncology (ASTRO), and the Multinational Association of Sup-

portive Care in Cancer (MASCC). The Symposium is designed to promote discussion and integration of palliative care, and to highlight the latest research findings and state-of-the-art practices in this important area of oncology. The 2-day symposium will take place

October 24 to 25 in Boston.“Palliative care has really come of

age,” said Jamie Von Roenn, MD, Se-nior Director of Education, Science, and Professional Development at ASCO. “You cannot provide optimal oncology care without integrating ag-

gressive symptom assessment, man-agement, and prevention as part of the upfront treatment.”

Growing Emphasis on Palliative Care

In February 2012, a panel of oncol-ogy and palliative care experts con-vened by ASCO released a provisional clinical opinion titled “The Integration of Palliative Care Into Standard Oncol-ogy Care,” which was prompted by a growing body of evidence showing that the integration of palliative care into treatment early in the course of care for patients with metastatic cancer leads to better patient and caregiver outcomes. Additionally, the Institute of Medicine recently released its report “Delivering

Cancer.Net’s Newest Resource— the Cancer.Net Blog

S tarting this year, Cancer.Net added a new interactive blog to its list of

resources. Using the blog, Cancer.Net will be able to share information in a more timely manner and respond to current events, including breaking news about cancer advances and other topics important to people affected by cancer.

Cancer.Net Blog posts will provide practical tips for living with cancer, suggestions to help patients and fami-lies cope with the disease, and research news and guidelines from ASCO. The blog will also feature guest posts by ASCO experts, stories from patients and patient advocates, podcasts, and interviews. To learn more, read an in-troduction by Cancer.Net’s Editor-in-Chief, Robert S. Miller, MD, FACP, at www.cancer.net/blog. n



Jamie Von Roenn, MD


Direct From ASCO

High-Quality Cancer Care: Charting a New Course for a System in Crisis,” which also highlighted the importance of integrating palliative care from the time of diagnosis through to survivor-ship or end-of-life care.

Based on these calls to action, ASCO leadership determined that the cancer care community, includ-ing the growing number of board-certified palliative care professionals, could benefit from a meeting focused on this important area. Previously the

only major palliative care in oncology meeting was the Chicago Supportive Oncology Conference, which held its last meeting in 2012.

“This program will not only fill an educational gap, but it is responding to this larger emphasis on palliative care in oncology,” said Michael J. Fisch, MD, MPH, Chair of the meeting’s planning committee and Chair of the Department of General Oncology at The University of Texas MD Anderson Cancer Center.

Focus of SymposiumThe Symposium will include scien-

tific oral abstracts and posters, educa-tion sessions, and a keynote lecture. In addition, attendees can expect an intimate setting for high-quality inter-actions between attendees and faculty.

The meeting program will focus on five overarching areas of content• Patient experience of symptoms and

toxicities of treatment, including at-tention to basic mechanisms and pathways involved;

• Novel models of early integration;

• Psycho-oncology, including assess-ment and management of distress, anxiety, and depression;

• End-of-life care, including advanced directives, patient- and family-cen-tered care, and use of hospice; and,

• Survivorship care, focusing on chron-ic and late effects of cancer treatment, and the use of survivorship care plans.

Social Media PresenceDr. Fisch encourages attendees and

parties interested in the meeting to take advantage of social media during the meeting dates. Dr. Fisch will be tweet-

ing live from the meeting at his Twitter handle @fischmd and attendees are en-couraged to post relevant updates using the meeting’s official hashtag #pallonc.

“There is quite a range of interactions that can occur through social media,” Dr. Fisch said. “It is a great way to engage professionals, patients, and their fami-lies who cannot attend but are interested to see what new research is emerging.”

To find out more about the meeting and to request meeting updates, please visit pallonc.org. n


Key DatesEarly May – Abstract Submitter, Registration, and Hotel Reservations OpenJuly 1– Abstract Submission DeadlineOctober 24-25 – Palliative Care in Oncology Symposium

Palliative Care Symposiumcontinued from page 24

Nearly 40 Practices Receive QOPI® Recertification for High-Quality Cancer Care

Nearly 40 practices have achieved certification through the Quality

Oncology Practice Initiative (QOPI®) Certification Program (QCP™) for a sec-ond 3-year term. The QOPI Certifica-tion Program began certifying practices in 2010 and is now seeing the first wave of practices applying for a second term.

More than 95% of practices eligible to apply for recertification have commit-ted to the process, and on-site reviews of previously reviewed practices reveal many of the changes made to achieve the initial certification remain intact.

“Practices that earn recertification through QOPI have demonstrated an unwavering commitment to delivering the highest quality of care,” said ASCO President Clifford A. Hudis, MD, FACP. “As the QOPI Certification Pro-

gram continues to reach new milestones, ASCO can ensure that more patients receive treatments that meet the highest national quality standards.”

Certification ProcessThe QOPI Certification Program as-

sesses the practice’s compliance with cer-tification standards based on the ASCO/Oncology Nursing Society (ONS) Stan-dards for Safe Chemotherapy Adminis-tration. As part of the certification pro-cess, practices submit to an evaluation of their entire practice and documenta-tion standards. The QCP staff and QCP Oversight Council and Steering Group members then verify through on-site in-spection and peer-review that the evalua-tion and documents are correct and that the practices met core standards in all areas of treatment.

Each certification remains valid for 3 years, at which point the practice must apply for recertification from the QOPI Certification Program.

For a list of certified practices, please visit http://qopi.asco.org /certifiedpractices.htm. n


ASCO Proposes New Framework for Medicare Reimbursement

In the fifth installment of the Physician Payment Reform Educational Series,

ASCO presents an alternative for oncol-ogy reimbursement that recognizes and rewards high quality, high value care for patients with cancer. ASCO hopes this proposal will spark conversation within the oncology community and among

policy makers regarding the complex is-sue of Medicare payment reform.

The full series can be accessed at: http://www.asco.org/advocacy/ physician-payment-reform. n


Clifford A. Hudis, MD, FACP

[Social media] is a great way to engage professionals, patients, and their families who cannot attend but are interested to see what new research is emerging.

—Michael J. Fisch, MD, MPH

ASCO 50th Annual MeetingMay 30 - June 3, 2014

McCormick Place

Chicago, Illinois

Save the Date

http://qopi.asco.org/certifiedpractices.htm

http://qopi.asco.org/certifiedpractices.htm

http://www.asco.org/advocacy/physician-payment-reform

http://www.asco.org/advocacy/physician-payment-reform

6.7 months median PFS with INLYTAvs 4.7 months with sorafenib

EVIDENCE What truly matters to you in 2nd-line mRCC?

INLYTA was the 1st agent to demonstrate

to sorafenibSUPERIOR EFFICACY

In the phase 3, head-to-head study of exclusively 2nd-line patients with mRCC...

95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

(n=361) (n=362)

Primary endpoint: PFS HR=0.67 (95% CI: 0.54, 0.81; P<.0001)

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 ORR, OS, and safety and tolerability.1,2

median PFS

6.7months

median PFS

4.7months

vs

INLYTA sorafenib

for the treatment of advanced RCC after failure of one prior systemic therapy

INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Important Safety InformationHypertension 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.

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, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation.

The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue.

The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Please see brief summary on the following page.

AXIS3X0205_A_SimpleStoryTabSpread_Female_KING_r8.indd All Pages 11/14/13 2:27 PM







(n=361) (n=362)



median PFS

6.7months

median PFS

4.7months

vs

INLYTA sorafenib



























(n=361) (n=362)



median PFS

6.7months

median PFS

4.7months

vs

INLYTA sorafenib



























(n=361) (n=362)



median PFS

6.7months

median PFS

4.7months

vs

INLYTA sorafenib





















http://www.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.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

September 2013

AXU606812 © 2013 Pfizer Inc. All rights reserved. November 2013

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on fi le. Pfi zer Inc, New York, NY.mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

AXIS3X0205_A_SimpleStoryTabSpread_Female_KING_BS_r8.indd 1 11/14/13 2:01 PM


ASH Annual Meeting

Expanded Options for Age and Donor Sources for TransplantBy Alice Goodman

A lthough many oncologists consid-er matched sibling donors as the

best source of grafts for hematopoietic cell transplantation, two separate stud-ies presented at the recent American Society of Hematology Annual Meet-ing support the use of alternative donor grafts for patients with lymphoma and acute myelogenous leukemia (AML).1,2 Additionally, the studies show that old-er patients with hematologic malignan-cies can safely undergo transplantation using these alternative donor sources.

“Many practicing oncologists have not shifted their criteria for referring pa-tients for transplant. Patients can ben-efit from allogeneic transplants even if they don’t have a matched family mem-ber and this includes older patients, but many in the community have not kept pace with newer data,” stated Mary M. Horowitz, MD, MS, Professor of Medicine, Robert A. Uihlein, Jr Chair in Hematologic Research, and Chief, Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee.

Lymphoma StudyThe first study included 1,593 non-

Hodgkin and Hodgkin lymphoma patients with no age restriction (ages ranged from 17 to 73 years) who under-went donor hematopoietic cell trans-plantation with alternative donor grafts from one of three different sources: umbilical cord blood (n = 142), 8/8 HLA-matched unrelated donor (“well matched,” n = 1,176), and 7/8 matched unrelated donor (“partial matched,” n = 275). Outcomes from 2000 to 2010 were compared as reported to the Cen-ter for International Blood and Marrow Transplant Research.

“Our results suggest that umbilical cord blood and 7/8 unrelated donor grafts provide similar survival to 8/8 unrelated donor grafts. This extends al-logeneic hematopoietic cell transplan-tation to most patients with no suitable matched sibling donors,” stated lead author Veronika Bachanova, MD,

PhD, Assistant Professor of Medicine, Division of Hematology, Oncology and Transplantation, at the University of Minnesota, Minneapolis. She said that determining graft source depends on availability, the urgency of transplant, and transplant center experience.

In this study, one-third of patients are alive beyond 2 years. These are patients who have shown disease progression on early therapies, and half of them had prior autologous stem cell transplan-tation. They all underwent transplant with a nonfamily donor. They were chosen for transplantation because they

are still responsive to therapy and are in suitable physical condition.

Leukemia StudyThe second study included 740

AML adults over age 50 in first com-plete remission and compared the ef-fectiveness of the same three nonfamily donor sources in achieving a success-ful transplant: umbilical cord blood (n = 205), 7/8 HLA matched (n = 94), and 8/8 HLA matched (n = 441). Outcomes were reported to the Center for International Blood and Marrow Transplant Research on transplants per-formed from 2005 to 2010. Median age was 58 years, and ages ranged from 50 to 75 years.

Median follow-up was 50 months in the well-matched group, 61 in the par-tial matched group, and 37 months in the umbilical cord donor group. Neu-trophil and platelet recovery was slower in the latter group compared with the other two groups. The incidence of neu-trophil recovery in the umbilical cord group was 85% on day 42 compared with 98% in the well-matched group and 92% in the partial matched group.

No significant differences between the three groups were seen in grades II to IV acute graft-vs-host disease; the 3-year incidence of chronic graft-

vs-host disease was significantly lower with umbilical cord transplant (28% vs 53% and 58%, respectively).

Leukemia-free survival for all three donor groups was between 30% and

43% at 3 years. Relapse risk was greatest in patients with unfavorable cytogenet-ics regardless of graft type; overall sur-vival was worse in these patients as well as in those over age 60.

Expanded Pool of Donors“Both studies found that umbilical

cord blood was about as good as either of the unrelated donor graft sources. In the lymphoma study, all endpoints ex-cept engraftment were similar with all three sources, including toxicities, re-lapse, and survival. In the AML study, which was focused on one disease

and had more restrictive criteria for older age and disease status, the par-tial matched and umbilical cord trans-plants were about the same, but the fully matched patients did better,” said Daniel Weisdorf, MD, Professor of Medicine at University of Minnesota,

Minneapolis. Dr. Weisdorf was lead au-thor of the AML study and coauthor of the lymphoma study.

Both studies show that donor source is not a limitation for transplant and that older age per se should not pre-clude transplant, he emphasized.

When asked which donor source was preferable, he said: “This is not a horse race. We are not offering the same treatment to the same person. We are saying there are several different and suitable options for people who do not have a family donor. Matched sibling donor is the first choice, but we have shown that in two major diseases where transplantation is performed with sub-stantial frequency, we now have three choices. All of them are good, and post-transplant survivals are similar.”

AML is mainly a disease of people over age 50. “Now we can be comfort-able looking at an expanded pool of donors for people with lymphoma and AML who need transplant, whether unrelated adult volunteers or umbili-cal cord donors for people with AML,” Dr. Weisdorf said. “There is reason to believe that this would be the case for people with acute lymphoblastic leuke-mia as well,” he added.

Option for Older Patients“Transplant physicians and referring

hematology physicians have been re-luctant to consider transplant as an op-tion for older patients. Transplantation should be considered for older patients whose disease justifies it and who don’t have an available family donor,” he em-phasized.

“We and other investigators have done a number of studies to demon-strate that older patients with AML or myelodysplastic syndrome have en-couraging outcomes [after transplan-tation]. A birth date does not predict survival. Overall fitness, lack of comor-bidities, and willingness to undergo intensive therapies should determine transplant,” he emphasized.

Hematology

We can find a donor for almost any patient, and older patients who might benefit from transplant should be referred as soon as possible to ensure that the procedure is done at a point in their disease when the likelihood of success is highest.

—Mary M. Horowitz, MD, MS

Shifting Criteria in Hematopoietic Cell Transplantation

■ Criteria for successful allogeneic transplant have broadened to include older patients and alternative donor sources, including umbilical cord and partial HLA-matched grafts from volunteers.

■ Oncologists who refer patients for transplant need to incorporate these expanded criteria into their practice.

continued on page 32Veronika Bachanova, MD

Daniel Weisdorf, 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.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

September 2013

AXU606812 © 2013 Pfizer Inc. All rights reserved. November 2013

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on fi le. Pfi zer Inc, New York, NY.mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

AXIS3X0205_A_SimpleStoryTabSpread_Female_KING_BS_r8.indd 1 11/14/13 2:01 PM


ASH Annual Meeting

Shedding PreconceptionsAgreeing with Dr. Weisdorf, Dr.

Horowitz emphasized the importance of referring older patients and patients without a matched related donor for transplant. “The 5-year survival of older patients with AML on chemotherapy is less than 10%. Previous data show that the outcome of unrelated donor transplant with a limited degree of mis-matching is similar to related matched transplant. Survival of older adults with AML who undergo transplantation is about 30% at 5 years,” she said.

“Physicians have to drop their pre-conceived notions of age < 50 for allo-

geneic transplant and matched sibling as donor source. We can find a donor for almost any patient, and older pa-tients who might benefit from trans-plant should be referred as soon as possible to ensure that the procedure is done at a point in their disease when the likelihood of success is highest,” she added. n

Disclosure: Drs. Horowitz, Bachanova, and Weisdorf reported no potential conflicts of interest.

References1. Bachanova V, Brunstein C, Burns LJ,

et al: Alternative donor transplantation for adults with lymphoma: Comparison of um-bilical cord blood vs 8/8 HLA-matched donor

(URD) vs 7/8 URD. ASH Annual Meeting. Abstract 161. Presented December 8, 2013.

2. Weisdorf D, Eapen M, Ruggieri A, et al: Alternative donor hematopoietic trans-plantation for patients older than 50 years with AML in first complete remission: Unre-lated donor and umbilical cord blood trans-plantation outcomes. ASH Annual Meeting. Abstract 302. Presented December 9, 2013.

Expanded Options for Transplantcontinued from page 31

Editorial CorrespondenceJames O. Armitage, MD

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Contact The ASCO Post

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COMETRIQ.com

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

© 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/13 [03-13-00091-A]

* Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

Perforations and Fistulas: Gastrointestinal (GI) perforations and fi stulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fi stula was fatal (<1%). Non-GI fi stulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fi stulas. Discontinue COMETRIQ in patients who experience a perforation or a fi stula.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. 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 signifi cant 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 (modifi ed JNC criteria stage 1 or 2 hypertension identifi ed in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). 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: 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.Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ 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.Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, 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 (<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: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm di© erence of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, 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.Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the fi rst dose compared to 19% of patients receiving placebo (regardless of baseline value).In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

You are encouraged to report negative side e© ects of prescription drugs to the FDA. Visit fda.gov/medwatch or call 1-800-FDA-1088.

Please see brief summary of full Prescribing Informationon next page.

> Signifi cantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001)

> COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo— Median PFS was 11.2 months with COMETRIQ™

vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™

vs 0% with placebo (P<0.0001)— Median duration of objective response was

14.7 months (95% CI: 11.1, 19.3)> Adverse reactions occurring in ≥25% of patients

treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm di© erence) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, 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 ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

COMETRIQ™ demonstrated signifi cant e� cacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confi rmed disease progression.*

COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

median

4.0months

median

11.2months

COMETRIQ™ (n=219)

Progression-free survival (PFS)

IMPORTANT SAFETY INFORMATIONWARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE• Perforations and Fistulas: Gastrointestinal

perforations occurred in 3% and fi stula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fi stula.

• 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.

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http://www.cometriq.com/hcp/index.php


FDA Update

Dabrafenib Receives FDA Breakthrough Therapy Designation for BRAF-Mutated NSCLC

The U.S. Food and Drug Admin-istration (FDA) has granted

Breakthrough Therapy designation for dabrafenib (Tafinlar) for the treatment of patients with metastat-

ic BRAF V600E mutation–positive non–small cell lung cancer (NSCLC) who have received at least one prior line of platinum-containing chemo-therapy.

The Breakthrough Therapy desig-nation was based on interim efficacy and safety results from an ongoing phase II study of dabrafenib in pa-tients who had NSCLC with the

BRAF V600E mutation and who had received at least one previous course of chemotherapy. These interim re-sults were presented at the 2013 ASCO Annual Meeting. n

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FDA Update

FDA Approves Combination Therapy for Unresectable or Metastatic Melanoma With BRAF V600E/K Mutations

The U.S. Food and Drug Adminis-tration (FDA) has approved tra-

metinib (Mekinist) for use in combina-tion with dabrafenib (Tafinlar) for the treatment of patients with unresectable

melanoma or metastatic melanoma with BRAF V600E or V600K muta-tions. These mutations must be detect-ed by an FDA-approved test.

The approval of the combination is

based on the demonstration of response rate and median duration of response in a phase I/II study. Improvement in dis-ease-related symptoms or overall sur-vival has not been demonstrated. The

accelerated approval is contingent on the results of an ongoing phase III trial.

Phase II ResultsResults from the randomized phase

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 COMETRIQ

Permanently 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; 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% in 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%) of 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 medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity 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 0

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)

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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.1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.02 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration,

mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth

syndrome, glossodynia4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain

upper, abdominal rigidity, abdominal tenderness, esophageal pain5 Palmar-plantar erythrodysesthesia syndrome

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

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Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg

46

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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.

3 Subjects 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 (AUC

0-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 (AUC

0-inf) by 77%. Avoid chronic co-

administration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, 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 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.

Distributed by Exelixis, Inc.12/2012

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

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FDA Update

II part of a phase I/II open-label study evaluating the combination of tra-metinib and dabrafenib vs single-agent dabrafenib, demonstrated an investiga-tor-assessed overall response rate of 76% (95% confidence interval [CI] = 62–87) for patients treated with the combina-tion vs 54% (95% CI = 40–67) for those treated with single-agent dabrafenib. The

median duration of response was 10.5 months (95% CI = 7–15) for patients treated with the combination, and 5.6 months (95% CI = 5–7) for patients treated with single-agent dabrafenib.

Data analyses of the blinded inde-pendent radiologic review committee supported the investigator results, with an overall response rate of 57% (95% CI

= 43–71) for patients treated with the combination, and 46% (95% CI = 33–60) for patients receiving single-agent dabrafenib. The median duration of re-sponse as assessed by the independent radiologic review committee was 7.6 months (95% CI = 7 to not reached) for patients treated with the combina-tion, and 7.6 months (95% CI = 6 to

not reached) for patients treated with single-agent dabrafenib.

Adverse EventsTrametinib in combination with dab-

rafenib can cause serious side effects, some of which can be life-threatening, including new primary cutaneous malig-nancies, tumor promotion in wild-type BRAF melanoma, hemorrhagic events, venous thromboembolic events, cardio-myopathy, ocular toxicities, interstitial lung disease, serious febrile drug reac-tions, serious skin toxicity, hyperglyce-mia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase de-ficiency, and embryofetal toxicity.

The most frequently occurring adverse reactions included pyrexia

(71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhea (36%), abdominal pain (33%), peripheral edema (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%), and myalgia (22%).

The most common grade 3 or 4 ad-verse events observed in the combina-tion group in this study were renal fail-ure (7%), pyrexia (5%), back pain (5%), hemorrhage (5%), fatigue (4%), chills (2%), nausea (2%), vomiting (2%), diar-rhea (2%), abdominal pain (2%), myalgia (2%), and urinary tract infection (2%). n

Health IT Safety Guide

A new set of guides and interactive tools to help health-care providers

more safely use electronic health infor-mation technology products, such as electronic health records (EHRs), are now available at www.HealthIT.gov.

The Office of the National Coordi-nator for Health Information Technol-ogy (ONC) at HHS recently released the Safety Assurance Factors for EHR

Resilience (SAFER) Guides. These guides are a suite of tools that include checklists and recommended prac-tices designed to help

health-care providers and the organiza-tions that support them assess and opti-mize the safety and safe use of EHRs. n

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 COMETRIQ

Permanently 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; 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% in 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%) of 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 medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity 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 0

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)

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Perspective

malignancies, using well standardized techniques.

Two pharmaceutical companies approached the U.S. Food and Drug Administration (FDA) requesting a restriction of labeling of their anti–epi-dermal growth factor targeted therapies to those that had wild-type KRAS ex-pression because of the lack of response among tumors with mutated genes. There is also exciting information about the relevance of ALK for a subset of lung cancers.

Making Old MistakesThat said, I am increasingly con-

cerned about the current stance on ge-nomics in oncology, as we seem to be making old mistakes. I think back to the early days of the evolution of chemo-therapy—novel agents were tested in a sequential fashion, progressing step-wise from phase I to phase II to phase III, after the presentation of encourag-ing preclinical information to decision networks. Support was provided by the National Institutes of Health and/or the pharmaceutical industry, usually with the production of free drugs, and support for the costs of clinical trials. We now know the imperfections and abuses of the system, but it actually made sense overall.

So what’s the problem in the new, genomic era? First, we have a collection of laboratories with the capacity to pro-vide “routine” genetic testing, offered to oncologists in either clinical practices or academic centers, and sometimes to patients themselves. In the former situation, my concern is that the vast majority of algorithms for the use of gene-expression studies remain un-proven, supported only by level 2/3 or presumptive evidence.

Need for Standardization In addition, there is no national

standardization of the assays for gene expression, although we know that the quality of the techniques employed re-

ally does matter. Yet these laboratories seek reimbursement routinely, either from centers engaged in investigative work or from patients directly, at great cost, and our system seems content to go along with this. This seems sadly reminiscent of the early days of direct chemosensitivity testing, which has not been validated by level 1 evidence focused on value or survival outcomes.

Would it not make more sense for our national system of health care to re-quire the same type of corporate invest-ment that has characterized the devel-opment of unproven anticancer agents?

Should there not be a system of stan-dardization, both of the assay systems and of the clinical trial mechanisms employed to assess them? Can some-one explain to me the evidence-based standard algorithm for routine math-ematical evaluation of gene-expression studies, including a way of dealing with the range of expressed mutations? Once that is done, perhaps we can start to consider a standard approach to the clinical interpretation of next-genera-tion sequencing.

Need for RegulationWe have recently heard that the

FDA has taken a stance on direct-to-patient marketing of gene-expression studies. That action may be the first regulatory step to limit implementa-tion and the potential to create anxiety and panic among uninformed lay pop-

ulations who have not had the benefit of counseling on the implications of such studies.

As is widely recognized, there is in-creasing urgency for us to start to think carefully about profligate expenditure in health care, which is becoming a huge component of the national debt. If we consider that more than 200,000 patients are diagnosed with lung cancer each year, and that a typical charge for a panel of genetic testing is in the range of $1,500 to $10,000 or more, it really isn’t rocket science to work out that the po-tential costs to the nation, for unproven

sets of tests, will be vast. It is high time that some form of regulation, predi-cated on technology and interpretation standards as well as level 1 clinical evi-dence should be introduced.

Speaking of the FDA, I note that they have recently given authoriza-tion for a next-generation sequencer, and it will be important to see if and how they plan to be involved in quality assurance and standardization in the future evolution of this complex and lucrative technology.

Need for SpeedThe other domain of serious con-

cern is the need for speed. Some of those at the forefront of genomic re-search seem to be in a real hurry to publish preliminary data—we see this on a regular basis in grant applications in which “hypothesis-generating” un-

derpowered genomic studies are add-ed to well-designed clinical trials. The purported intent of these translational studies is to help to model future stud-ies, but, in fact, they have so little sta-tistical power that they are unlikely to be informative at all.

Against a background in which we are just beginning to understand the promiscuity of interactions between targeted therapies and gene pathways, as well as the extraordinarily complex interactions and relationships between genes and different genetic pathways, we are seeing increased use of trial de-signs that are extrapolated from funda-mental Bayesian theory. The Bayesians have made great contributions to our understanding of parsimonious use of limited patient resources, but it may well be that the range of discontinu-ation designs, complicated by inade-quate understanding of the aforemen-tioned pathways and interactions, will lead us to discard important agents. It seems to me that this is exactly the time not to underpower studies in haste, but rather to secure clearly defined, repro-ducible pathway information before experimenting with less conventional, statistically weak trial algorithms.

Need for Rational ThinkingIn closing, let me be very clear—I

am very supportive of the importance of learning how to apply and imple-ment routine genetic testing (of pa-tients and tumor samples). At the Levine Cancer Institute, we have con-vened a working party of clinicians, molecular biologists, ethicists, and genomic biostatisticians to try to de-velop a rational stance and incorporate its principles into our system of elec-tronic treatment pathways.

However, at a national level, under-standing that our budget is under siege and that health-care dollars are not lim-itless, I just hope that, as a community, we increase the level of rational think-ing about how to do this well. Hopeful-ly government will involve real experts before setting up their system of over-sight and regulation. n

Genes, Promiscuity, and Debtcontinued from page 1

I am very supportive of the importance of learning how to apply and implement routine genetic testing…. I just hope that, as a community, we increase the level of rational thinking about how to do this well, and that the government involves real experts before setting up their system of oversight and regulation.

—Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

Visit The ASCO Post website at ASCOPost.com


Health-Care Policy

50th Anniversary of the First U.S. Surgeon General’s Report on Smoking and HealthStatement by ASCO President Clifford A. Hudis, MD, FACP

“When the first Surgeon Gen-eral’s Report was released in

1964, more than half of American men and over a third of women smoked and

lung cancer had gone from an obscure disease to a leading cause of death. In is-suing this pioneering report summariz-ing the known health risks of smoking, our nation’s researchers, policymak-ers, and physicians were galvanized to

take bold action against one of public health’s greatest threats.

“In the 50 years since the report’s release, tobacco use has declined con-

siderably. More research on the harmful effects of smoking, as well as the dan-gers of secondhand smoke, have raised awareness and discouraged large num-bers of Americans from using tobacco. Most importantly, it has prompted fed-

eral, state and local government to pass laws regulating cigarettes, protecting Americans from secondhand smoke ex-posure and establishing excise taxes and other regulations that discourage teens from starting to use tobacco.

“Unfortunately, tobacco still kills more than 440,000 Americans each year and costs our economy close to $193 billion annually. We must contin-ue to be vigilant in our fight against this deadly addiction. Our efforts to fight the largest preventable cause of death and disability cannot cease or diminish.

“Smoking cessation remains espe-cially critical for cancer patients. Pa-tients who continue smoking after a cancer diagnosis are at risk for worse treatment outcomes, increased cancer recurrence, second primary cancers, poor quality of life and more side ef-fects than patients who do not smoke. It

is crucial that tobacco cessation be inte-grated into daily oncology care and that smokers be given the necessary support and resources to quit. ASCO has issued recommendations on public policy needs, provider education, and research in this area and continues to collaborate with physicians and lawmakers to see that they are implemented.

“We commend the office of the U.S. Surgeon General for its leadership and tireless efforts on this critically impor-tant public health issue. This milestone represents an opportunity to both cel-ebrate accomplishments and reflect on the need for additional efforts to reduce tobacco-related morbidity and mortal-ity. ASCO will continue to work with the medical community until tobacco-related disease is ultimately eliminated and fewer people die from its use.” n


Surgeon General’s New Report Attributes Smoking as Cause of Death in More Than 20 Million Americans Over Past 50 Years

According to a new Surgeon Gen-eral’s report issued last month,

more than 20 million Americans have died from smoking over the past 50 years. The new report concludes that cigarette smoking kills nearly half a

million Americans a year, with an addi-tional 16 million suf-fering from smoking-related conditions. It puts the price tag of

smoking in this country at more than $289 billion a year in direct medical care and other economic costs.

Further, approximately 5.6 million American children alive today, or one out of every 13 children under age 18, will die prematurely from smoking-related diseases unless current smok-ing rates drop.

The recent report, The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon Gen-eral, comes a half century after the historic 1964 Surgeon General’s re-port, which concluded that cigarette smoking causes lung cancer. Since that time, smoking has been identi-

fied as a cause of serious diseases of nearly all the body’s organs. Today, scientists add diabetes, colorectal and liver cancers, rheumatoid arthri-tis, erectile dysfunction, age-related macular degeneration, and other con-

ditions to the list of diseases that ciga-rette smoking causes. In addition, the report concludes that second-hand smoke exposure is now known to cause strokes in nonsmokers.

“Smokers today have a greater risk of developing lung cancer than they did when the first Surgeon Gen-eral’s report was released in 1964, even though they smoke fewer ciga-rettes,” said Acting Surgeon General

Boris Lushniak, MD, MPH. “Of all forms of tobacco, cigarettes are the most deadly and cause medical and financial burdens for millions of Americans.”

Although youth smoking rates de-

clined by half between 1997 and 2011, each day another 3,200 children un-der age 18 smoke their first cigarette, and another 2,100 youth and young adults become daily smokers.

“Over the last 50 years tobacco control efforts have saved 8 million lives but the job is far from over,” said HHS Assistant Secretary for Health Howard K. Koh, MD, MPH. “This report provides the impetus to accel-

erate public health and clinical strate-gies to drop overall smoking rates to less than 10% in the next decade. Our nation is now at a crossroads, and we must choose to end the tobacco epi-demic once and for all,” Dr. Koh said.

See the next issue of The ASCO Post for more on the Surgeon Gen-eral’s New Report on smoking and health. n

Over the last 50 years tobacco control efforts have saved 8 million lives but the job is far from over.

—Howard K. Koh, MD, MPH HHS Assistant Secretary for Health

Tobacco still kills more than 440,000 Americans each year and costs our economy close to $193 billion annually.


Tobacco Cessation


Reports From the IPOS/AORTIC Travel Scholars

Eight individuals were awarded travel scholarships allowing them

to attend the IPOS/AORTIC Pro-gram (International Psycho-Oncolo-gy Society/African Organization for Research and Training in Cancer) and share their experiences and efforts to-ward improving the psychosocial care of patients with cancer in Africa. The program was held this past Novem-ber in Durban, South Africa (see page 21). They included the following:

Anncommy Ekortarh, an inde-pendent consultant for international and national homestudy studies,

reported that she spends 6 days a month in the city of Douala, Camer-oon providing psychosocial services to patients with cancer. She believes that the importance of psychosocial services to cancer patients is gradu-ally being recognized in Cameroon, but that hospital administrators need to be better educated about the benefits in order to move such ser-vices forward.

Elizabeth Akin-Odanye, a psy-chologist with the Department of Psy-chology at the University of Ibadan in Nigeria, reported that the Psycho-Oncology Society of Nigeria recently held its third national conference and

workshop. The essence of the work-shop was to build psycho-oncology teams in each of the geopolitical zones in the country and later expand it to include as many states as possible as

manpower capacity increases. Zippora Ali, National Coordina-

tor at Kenya Hospices and Palliative Care Association, Kenya, reported that currently there is no unit specifically

concerned with psycho-oncology, but that efforts are being made to inte-grate psychosocial services into pallia-tive care. In 2013 in conjunction with

Global Oncology


Anncommy Ekortarh

Elizabeth Akin-Odanye

Zippora Ali



Global Oncology

IPOS/AORTIC Scholarscontinued from page 39other groups, Kenya Hospices and Palliative Care Association developed and launched a number of important guidelines and programs, including the national palliative care guidelines, na-tional palliative care training curricu-lum, and a diploma in palliative care for

nurses and medical students. Fadipe Babatunde, MD,

a psychiatrist at Lagos Uni-versity Teaching Hospital, works with a psychiatrist there on psychosocial issues in cancer patients. Together they have carried out a study in which they found a preva-

lence of depression among 49% of cancer patients. The next step is to collaborate with the oncology team there and gather data to show the need for psychosocial services in pa-tients with cancer.

Sokhna Ndiaye, a psychologist in Senegal, provides individual and group counseling for children, their Fadipe Babatunde, MD Sokhna Ndiaye



families, and members of staff. Al-though she is the only psychologist on the unit, she works with others on a regular basis, including an art thera-pist, pediatric psychologist, and a family therapist to assist and counsel patients, family members, and staff.

Tshirelesto Molefe, is an oncol-ogy nurse working in the chemother-

apy department of a private hospital in Botswana, but they also see patients from government hospitals on referral. She reported there is a need for collaboration with the government to see that patients are helped and there is much still to

be done in regard to psychosocial services. Patients in need of such ser-vices are currently referred to another center.

Two other scholars, Kaimukilwa Diocles, of Tanzania, and Philip Odiyo, Kenya, were absent from the proceedings and/or joined following the meeting. n

Global Oncology



Announcements

Gary Lyman, MD, Joins Scott Ramsey, MD, PhD, in Co-Leading Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson

The Hutchinson Institute for Can-cer Outcomes Research (HICOR)

has named Gary Lyman, MD, MPH, the Institute’s Co-Director with Scott Ramsey, MD, PhD, an internist and

health-care economist, and a member of the Cancer Prevention Program in the Public Health Sciences Division at Fred Hutchinson Cancer Research In-stitute. Dr. Lyman comes to HICOR

having previously served as Professor of Medicine and Senior Fellow at the Duke Center for Clinical Health Policy Research and Director of the Com-parative Effectiveness and Outcomes

Research Program in Oncology at the Duke Cancer Institute.

HICOR is a research institute based at Fred Hutchinson Cancer Research Center that is charged with evaluating and improving the effectiveness and value of cancer prevention and treat-ment strategies through collaborative research. Dr. Lyman started in this new position on January 2, 2014.

The HICOR TeamDr. Lyman is recognized for his

leadership in comparative effective-ness and health services and out-comes research. Co-Director Dr. Ramsey said “We are privileged to have Dr. Lyman on the HICOR

team. Gary’s wealth of oncology ex-pertise, his strong clinical and health outcomes research portfolio, and his leadership in developing and increasing adherence to oncology clinical practice guidelines will be a significant asset to HICOR’s commitment to reducing cost, while improving the quality of cancer care for insurers, providers, and patients.”

Dr. Lyman will hold appointments within the Cancer Prevention Program at the Hutchinson Research Center, the Division of Medical Oncology at the University of Washington School of Medicine, and affiliate appointments within the Department of Health Ser-vices at the University of Washington School of Public Health and in the School of Pharmacy. Dr. Lyman also will practice as a medical oncologist in the Breast Cancer Program at Seattle Cancer Care Alliance.

Dr. Lyman said, “I was particularly drawn to HICOR’s focus on how can-cer treatment affects the entire patient, from the medical to the financial. The work that HICOR is doing will un-doubtedly have a dramatic impact on improving the practice of oncology in the future. I am proud to be a part of this groundbreaking opportunity.” n

Gary Lyman, MD



Historical Timeline

To help tell the story of progress against cancer, ASCO launched

CancerProgress.Net in 2011. The site is intended as a resource for media, poli-cymakers, oncologists, advocates, and the public. One central feature of the site is an interactive timeline of major milestones in cancer treatment, preven-tion, and detection, covering 17 differ-ent cancer types. The site was devel-oped under the guidance of an ASCO editorial board of expert oncologists.

In recognition of ASCO’s 50th An-niversary, The ASCO Post is publishing selected milestones as noted in the in-teractive timeline throughout 2014. To view the complete interactive timeline, please visit CancerProgress.net. n

Major Cancer Milestones in History, From ASCO’s CancerProgress.NetVisit CancerProgress.Net to View the Interactive Timeline

Editor’s note: The ASCO Post invites readers to share their own recollections of clinical mile-stones and personal experiences in oncology over the past 50 years. To do so, please write to [email protected]. Photos encouraged in high-resolution jpg or tiff file. All correspondence will be acknowledged and may be considered for publication.

Fig. 1: The first use of ether as an anaesthetic in dental surgery by W.T.G. Morton in 1846. Oil painting by Ernest Board. Wellcome Library, Lon-don. Used with permission.

Fig. 3: Pierre and Marie Curie at work in a labo-ratory. Photograph, Iconographic Collections. Wellcome Library, London. Used with permission.

Fig. 2: W.S. Halsted operating in the New Surgical Ampithetre in 1904. From William Stewart Halsted, by W.G. MacCallum. Johns HopkinsBaltimore 1930. Wellcome Library, London. Used with permission.

Advent of general anesthesia opens the door for modern cancer surgeryIn October 1846, a Boston dentist named William T.G. Morton provides the first public demonstration of ether as a general anesthetic, allowing surgeons to remove a tumor from a patient’s jaw without pain. This advance gains imme-diate and widespread attention, ultimately eliminating the excruciating pain experienced by surgical patients until that time, and making the modern era of surgery possible (Fig. 1).

Radical mastectomy ushers in more aggressive surgical approaches for cancerBaltimore surgeon William Halsted pioneers a new ap-proach to removing breast tumors, radical mastectomy, in which the entire breast and the surrounding lymph nodes and chest muscles are removed. This helps reduce recur-rences of the disease, which was previously nearly always fatal. Halsted’s work also leads to similar approaches for other cancers, in which both the tumor and surrounding tissue are removed. These techniques are still an important part of treatment for some cancers today. For breast cancer, however, surgeries have become far more conservative and effective, enabling many women to avoid mastectomy alto-gether (Fig. 2).

First use of radiation to treat cancerFive years after Marie Curie’s discovery of radium, doctors report the first successful of use of this radioactive element to treat cancer, in two Russian patients with skin cancer. In the following decades, radiation becomes widely used to treat many different cancers, including cervical, prostate, breast, and other tumors. In these first decades, doctors use an approach known as brachytherapy, in which small pieces of radioactive material are implanted inside or next to tumors, delivering radiation to cancer cells at close range. Brachytherapy remains an essential part of cancer treatment today, but has been refined to more precisely target tumor cells while leaving healthy tissue unharmed (Fig. 3).

1846

1880s

1903

Weigh in on which milestones of the last

50 years were the most important by voting on

your “Top 5 Advances” at CancerProgress.Net/vote.

Voting will continue through the 2014 ASCO

Annual Meeting and results will be announced

shortly thereafter.


Perspective

An Overview of the REGAL Trial and Anti-VEGF Therapies in Recurrent GlioblastomaBy Annick Desjardins, MD, FRCPC

As published in the Journal of Clini-cal Oncology by Batchelor and col-

leagues1 and reviewed in a recent issue of The ASCO Post (November 15, 2013, page 106), the REGAL trial was a randomized, phase III, placebo-controlled, partially blinded trial evaluating the efficacy of cediranib, an investigational oral pan–vas-cular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine (CeeNu) vs lomustine mono-therapy in patients with first recurrence of glioblastoma. The primary endpoint was progression-free survival.

In total, 325 patients with a median age of 54 years were included in this inter-national study. Progression-free survival was not significantly different for either cediranib alone or cediranib in combina-tion with lomustine vs lomustine with placebo. More grade 3 or higher adverse events occurred in the combination arm of cediranib with lomustine (80%) com-pared to the cediranib monotherapy arm (61%) and the lomustine arm (61%).

Anti-VEGF Therapies and Recurrent Gliomas

Since vascular proliferation is a his-topathologic hallmark of glioblastoma and levels of overexpression of VEGF in malignant glioma correlate directly with tumor vascularity and grade and in-versely with prognosis, anti-VEGF thera-pies have emerged as therapies of choice in malignant gliomas.2-5 Bevacizumab (Avastin), an anti-VEGF monoclonal an-tibody, was granted accelerated approval by the U.S. Food and Drug Administra-tion for the treatment of recurrent glio-blastoma in May 2009 on the basis of radiographic response rate and quality-of-life data.6,7 Since then, multiple anti-VEGF agents have been tested.8-10

As demonstrated with other VEGF-directed therapies, Batchelor and col-leagues found a response rate of 28% to 38% in the cediranib-containing arms, which is similar to the 28.2% to 37.8% objective response rates observed with bevacizumab in the BRAIN study.6 Comparatively, no imaging improve-ment was obtained in the lomustine with placebo arm, which is also consistent with the minimal radiographic response rate expected with chemotherapy mono-

therapy in this patient population.11 Furthermore, as also observed in other

clinical trials evaluating anti-VEGF thera-pies for recurrent glioblastoma patients, corticosteroid usage was reduced at the time of progression compared to baseline for patients on the cediranib-containing arms vs the lomustine-alone arm.6,10 Also, patients on the cediranib arms showed a slower deterioration of their neurologic status compared with patients on the lo-

mustine arm. The steroid-sparing effect of anti-VEGF therapies has been observed in a multitude of clinical trials evaluating recurrent glioblastoma patients, as has the ability of such treatments to delay neuro-logic deterioration.6,10

Concerns and QuestionsThe REGAL trial did not meet its pri-

mary endpoint of prolongation of pro-gession-free survival, and unfortunately, the concern will remain that the reduc-tion in the dose of cediranib in the com-bination arm from 30 mg to 20 mg due to toxicity seen in a metastatic lung carci-noma trial12 might be in part responsible for the negative results seen in this study.

Furthermore, overall survival was evaluated as a secondary endpoint and also showed an absence of benefit for the cediranib arms compared to lomus-tine, with a median overall survival of 8.0, 9.4, and 9.8 months for the cedira-nib monotherapy arm, cediranib plus lo-mustine arm, and lomustine arm, respec-tively. The lack of overall survival benefit might be secondary to a high number of patients receiving bevacizumab at the time of progression on trial, including 51% of patients on the cediranib plus lomustine arm and on the lomustine arm and 27% of patients on the cedira-nib monotherapy arm. Despite overall survival being recognized as the ultimate standard for demonstration of efficacy, the widespread use of bevacizumab at the time of recurrence in the United

States has made it almost impossible to truly evaluate in this country the survival advantage of patients exposed to anti-VEGF therapies vs those never exposed to anti-VEGF therapies.

The REGAL trial, like other clinical trials in this setting, has failed to iden-tify good predictors of response to anti-VEGF therapies. The ability to rapidly identify patient subgroups benefiting or not from anti-VEGF therapies remains

elusive in this patient population, but remains an area of active research.

Further ConsiderationsDespite the fact that the REGAL

study failed to reach its primary objec-tive, this study and another contem-porary study reported by Wick and colleagues13 have highlighted the ob-servation that lomustine monotherapy produces an improved median and 6-month progression-free survival com-pared to what was observed in historical controls with recurrent glioblastoma.

As mentioned by the authors, the REGAL trial was limited to patients at first recurrence, whereas the historical series included patients treated at mul-tiple recurrences. The results support the use of lomustine monotherapy in recurrent glioblastoma patients, but also raise an important recurring is-sue in neuro-oncology—ie, that the improvement in progression-free and overall survival of glioblastoma patients compared to historical controls is not due to the emergence of new and very active therapies, but to an improvement in our understanding and use of new supportive care interventions.

ConclusionsDespite its negative findings, the

REGAL trial still teaches us a lot about the use of anti-VEGF therapies in recur-rent glioblastoma patients. It confirms the positive response rates of other anti-

VEGF therapies, as well as their ability to decrease the length of time patients are ex-posed to corticosteroids and thus poten-tially decrease the extent of side effects in-duced by corticosteroids. It also confirms the prolongation of time before neurolog-ic decline offered by anti-VEGF therapies, and thus, an improvement in the severity of the physical and emotional burden the disease causes not only on patients, but also on caregivers. However, the ability to identify subgroups of patients experienc-ing the greatest benefit from anti-VEGF therapies remains extremely limited.

Finally, this multi-institutional group should be commended for enrolling—in a little less than 1 year—325 glioblas-toma patients at first recurrence, prior to any exposure to anti-VEGF therapies. n

Disclosure: Dr. Desjardins reported no potential conflicts of interest for cediranib. She serves on an advisory board for Genentech/Roche.

References1. Batchelor TT, et al: Phase III random-

ized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212-3218, 2013.

2. Chaudhry IH, et al: Vascular endothelial growth factor expression correlates with tu-mour grade and vascularity in gliomas. Histo-pathology 39:409-415, 2001.

3. Ke LD, et al: The relevance of cell pro-liferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin Cancer Res 6:2562-2572, 2000.

4. Plate KH, et al: Vascular endothelial growth factor is a potential tumour angiogen-esis factor in human gliomas in vivo. Nature 359:845-848, 1992.

5. Samoto K, et al: Expression of vascular endothelial growth factor and its possible rela-tion with neovascularization in human brain tumors. Cancer Res 55:1189-1193, 1995.

6. Friedman HS, et al: Bevacizumab alone and in combination with irinotecan in recur-rent glioblastoma. J Clin Oncol 27:4733-4740, 2009.

7. Kreisl TN, et al: Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recur-rent glioblastoma. J Clin Oncol 27:740-745, 2009.

8. de Groot JF, et al: Phase II study of aflibercept in recurrent malignant glioma. J Clin Oncol 29:2689-2695, 2011.

Neuro-oncology

Dr. Desjardins is Associate Professor of Medicine, Duke University Medical Center, Durham, North Carolina.

Despite its negative findings, the REGAL trial still teaches us a lot about the use of anti-VEGF therapies in recurrent glioblastoma patients.

—Annick Desjardins, MD, FRCPC



Awards

Grant to Develop Website and Mobile App to Track Radiation Therapy Toxicity Awarded to Radiation Oncology Resident

The Radiation Oncology Insti-tute has selected Malolan S.

Rajagopalan, MD, a radiation oncology resident at the University of Pittsburgh Cancer Institute, to receive a $20,000 grant for a project to compile best prac-

tices regarding the management of ra-diation therapy toxicity. Dr. Rajagopalan’s project proposal includes development of a website and mobile app that will give the Radiation Oncology Institute the capabil-ity to continually update this material so that it will remain current. Combined, the website and mobile app will be compre-hensive tools that will improve patient quality of life and treatment outcomes.

Vetted By ExpertsDr. Rajagopalan’s team will form a mul-

tidisciplinary panel of radiation oncology specialists and various other fields such as palliative care and pulmonology to review all materials to ensure the quality and com-prehensiveness of the information and re-

sources provided. Each panel of approxi-mately four to six members will include radiation oncologists from various insti-tutions and, to provide diversity, at least one member who is not a radiation on-

cologist. The first two symptoms that will be addressed are common side effects of radiation therapy, namely dermatitis and oral mucositis.

Dr. Rajagopalan plans to unveil both

the website and app for beta review and testing at the American Society for Ra-diation Oncology 46th Annual Meet-ing, September 14-17, 2014, in San Francisco. n

Malolan S. Rajagopalan, MD

9. Schiff D, et al: Phase II study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma (rGBM) [abstract]. J Clin Oncol 28(15 suppl):182s, 2010.

10. Wen PY, et al: Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEG-FR2, and RET, in patients (pts) with progres-sive glioblastoma (GB) [abstract]. J Clin On-col 28(15 suppl):181s, 2010.

11. Wong ET, et al: Outcomes and prog-nostic factors in recurrent glioma patients en-rolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999.

12. Goss GD, et al: Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in ad-vanced non-small-cell lung cancer. J Clin On-col 28:49-55, 2010.

13. Wick W, et al: Phase III study of enza-staurin compared with lomustine in the treat-ment of recurrent intracranial glioblastoma. J Clin Oncol 28:1168-1174, 2010.

REGAL Trialcontinued from page 44



In the News

Cancer Patients Are at Increased Risk of Complications From the Flu and Should Receive Flu Shots, but Not the Nasal Spray By Charlotte Bath

Widespread influenza activity continues to be reported by the

Centers for Disease Control and Pre-vention (CDC), with a recent increase in flu-related hospitalizations.1,2 Patients with cancer are at increased risk from flu complications and should receive the flu shot, but not the flu nasal spray vaccine, which contains live flu viruses.

“We do not know if cancer patients are at greater risk for infection with the flu,” the CDC acknowledged. “Howev-er, we do know that cancer patients and survivors are at higher risk for complica-tions from flu, including hospitalization and death.”3

Cancer patients who are actively being treated for cancer can safely re-ceive flu shots, Mollie deShazo, MD, told The ASCO Post. “It is not going to be dangerous for them. The question is how effective it will be.” Dr. deShazo is Associate Professor of Medicine in the Division of Hematology and Oncol-ogy and Medical Director of Inpatient Oncology at the University of Alabama at Birmingham.

Reduce Hospitalizations“The debate is over how effective the

flu shot is really going to be in patients who are undergoing active chemothera-py,” Dr. deShazo said. “The way the flu shot works is basically to train the im-mune system to react to the flu if it does get exposed to it. With cancer patients,

you don’t know how effectively their im-mune system is going to react to the flu shot,” she explained.

“But my belief is that a little effect is better than none, and if cancer patients get some immune protection from the flu shot, it could shorten the course of

their illness if they do get the flu, and it may keep them out of the hospital. People can debate endlessly about how effective the shot is, and there is just no proof either way. Most people believe there is probably some activity and some effect, so that is why we recommend it.”

Dr. deShazo added that flu shots are

not usually administered to inpatients. “That goes back to the immune system question. If patients are in the hospital and have been acutely ill, that would de-crease their chances of mounting the ap-propriate immune system response,” she said, although the shot “wouldn’t make them worse.”

In the past, she has advised patients to follow up a week or so after they are discharged from the hospital to see about getting the flu shot later. “But we are getting so late in the season, and the flu rates have risen so much lately. So we really are encouraging people to get it now and not wait much longer because of the risk of being exposed without having the flu shot on board.”

It’s Not Too LateAlthough it is late in the season, it is

not too late to get a flu shot. “Flu activ-ity most commonly peaks in the United States in January or February. However, seasonal flu activity can begin as early as October and continue to occur as late as May,” according to a CDC information sheet on the current flu season.4

In a recent update, the CDC noted, “Thirty-five states are now experiencing widespread activity, and 20 states are reporting high levels of influenza-like ill-ness. H1N1 viruses continue to predom-inate across the country. Anyone aged 6 months and older who has not gotten a flu vaccine yet this season should get one now. All flu vaccines are designed to pro-tect against H1N1 viruses.”1

The flu season “was kind of a late start-er this year, but the rates have definitely

increased much more rapidly in the last couple of weeks,” Dr. deShazo said. “A lot of the severe flu cases that are ending up in the hospital are the H1N1. The flu this year is having severe complications for younger people—those in their late 20s and 30s—which is more unusual, and they think that is due to H1N1.”

She added that she is glad that the is-sue of flu shots “is staying in the news, because it is very important.”

Additional PrecautionsDr. deShazo listed a number of other

precautionary steps that patients with cancer can take to decrease their chanc-es of getting the flu. “Staying away from sick people” topped the list. “My rule of thumb is that patients should stay at least 6 feet from someone who is cough-ing. They don’t have to put themselves in a bubble, but they do have to be rea-sonable,” she said.

“Small children are just walking bac-teria,” she added. “If you are actively undergoing treatment, be very cautious around small children, especially those who are in group settings like day care or school, where they are exposed to germs all the time.”

Other common-sense approaches include washing your hands often and having all family members and other caregivers receive flu shots. Caregivers getting flu shots should “absolutely” in-clude hospital staff, Dr. deShazo said. n

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

References1. Centers for Disease Control and Pre-

vention: Situation Update: Summary of Weekly FluView, updated January 10, 2014. Available at www.cdc.gov/flu/weekly sum-mary.htm. Accessed January 15, 2014.

2. Centers for Disease Control and Pre-vention: U.S. Flu Season Is Here, CDC Urges Vaccination, updated January 3, 2014. Available at www.cdc.gov/flu/news/flu-sea-son-here.htm. Accessed January 15, 2014.

3. Centers for Disease Control and Pre-vention: Cancer, the Flu, and You, updated December 20, 2013. Available at www.cdc.gov/cancer/flu. Accessed January 15, 2014.

4. Centers for Disease Control and Prevention: What You Should Know for the 2013-2014 Influenza Season. Updated January 8, 2014. Available at www.cdc.gov/flu/about/season/flu-season-2013-2014.htm. Accessed January 15, 2014.

If cancer patients get some immune protection from the flu shot, it could shorten the course of their illness if they do get the flu, and it may keep them out of the hospital.

—Mollie deShazo, MD

Expect Questions, and Some Reluctance, About Getting a Flu Shot

P eople with weakened immune systems due to diseases like cancer are at increased risk of severe complications from the flu virus and should get

flu shots annually. The Centers for Disease Control and Prevention (CDC) strongly encourages this practice, and most oncologists would recommend that for their patients with cancer, Mollie deShazo, MD, said in an interview with The ASCO Post. Dr. deShazo is Associate Professor of Medicine in the Division of Hematology and Oncology and Medical Director of Inpatient Oncology at the University of Alabama at Birmingham.

Reluctant PatientsSome patients, however, may need a push. “I think cancer patients are

always wary about taking a medicine that they haven’t talked to their doctor about. So while the general population will run into a drug store and get a flu shot, a cancer patient is a little more resistant to that,” she said.

“But I think most oncologists would recommend the flu shot to cancer patients,” she continued. “It is definitely advisable and their best source of preventing the flu or at least reducing complications if they were to get it. I have sensed some reluctance about getting the flu shot among some of my patients, but I encourage all of them to do so.”

On the Checklist“‘Did you get a flu shot?’ is on a checklist of what our nurses ask the pa-

tients,” Dr. deShazo said. “And I personally ask every single one of them if they have had the flu shot. If caregivers are there, I ask them too. Anyone in the room on a patient visit means they have enough exposure to my patient that I want them to have gotten the flu shot.” n


Announcements

Texas Children’s Hospital Announces New Chief of Interventional Radiology

The Department of Pediatric Radi-ology at Texas Children’s Hospital

recently announced that Kamlesh U. Kukreja, MD, has been named the new Chief of Interventional Radiology. Dr. Kukreja has also been appointed as As-sistant Professor of Radiology at Baylor College of Medicine.

“For more than a decade, Dr. Kukre-ja has distinguished himself as an expert in clinical and research initiatives and we’re confident that his leadership will continue to advance the national prom-inence of our interventional radiology team,” says George Bisset III, MD, the Edward B. Singleton Chief of Pediatric Radiology at Texas Children’s and Pro-

fessor of Radiology at Baylor.Dr. Kukreja’s clinical interests include

pediatric interventional oncology and management of thrombosis in children. His research focus is on pediatric cancer and venous thrombosis. He has authored more than 19 book chapters and publica-

tions in various academic and medical journals, and is the recipient of numerous honors and awards, including the Caffey Award for best electronic poster at the In-ternational Pediatric Radiology meeting in May 2006.

Dr. Kukreja previously served as a

pediatric interventional radiologist at Cincinnati Children’s Hospital Medi-cal Center. Dr. Kukreja completed his fellowship in pediatric radiology at Mi-ami Children’s Hospital, and his inter-ventional radiology fellowship at Jack-son Memorial Hospital in Miami. n

Champions Oncology Names Chief Medical OfficerChampions Oncology, a company

engaged in the development of advanced technology solutions and services to personalize the develop-ment and use of oncology drugs, has announced the appointment of Angela Davies, MD, as Chief Medical Officer.

Dr. Davies has demonstrated experi-ence in both academic clinical practice and as an executive in the pharmaceuti-cal industry. Previously, she was Chief Medical Officer of OSI Pharmaceuti-cals where she led the clinical develop-ment program for erlotinib (Tarceva).

Earlier in her career she was an As-sociate Professor of Medicine at the University of California, Davis, where she practiced as a medical oncologist and was a principal investigator on NCI sponsored and investigator initiated clinical trials, specializing in thoracic malignancies and development thera-peutics.

Dr. Davies will continue clinical practice as adjunct clinical faculty at Smilow Cancer Hospital at Yale-New Haven. n

Angela Davies, MD



In the Literature

Emerging Clinical Data on Cancer Management

BREAST CANCER

Final Overall Survival Data Show Better Results With Higher Dose of Fulvestrant

Among patients with locally ad-vanced or metastatic estrogen recep-tor–positive breast cancer, fulvestrant (Faslodex) given at 500 mg “is associ-ated with a 19% reduction in risk of death and a 4.1-month difference in median overall survival compared with fulvestrant 250 mg,” according to final results of the phase III CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial.

A total of 736 women from 128 centers in 17 countries participated. The median age was 61 years. “Pa-tients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramus-cular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter,” Angelo Di Leo, MD, PhD, of the Sandro Piti-gliani Medical Oncology Unit in Prato, Italy, and colleagues explained in the Journal of the National Cancer Institute.

The primary study endpoint was progression-free survival, and the ini-tial results showed that the 500-mg dose of fulvestrant was associated with a statistically significant increase in progression-free survival compared

to the 250-mg dose. “Based on these data, the 500-mg dose of fulvestrant is now the approved dose in the Europe-an Union (approved in March 2010), United States (approved in September 2010), Japan (approved in November 2011), and other countries world-wide,” the researchers noted.

Final AnalysisAt the time of the initial analysis,

approximately 50% of patients had died. “A final analysis of [overall sur-vival] was subsequentially planned for when 75% of patients had died,” the authors stated. “At the final survival analysis, 554 of 736 (75.3%) patients had died. Median [overall survival] was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (haz-ard ratio = 0.81; 95% confidence inter-val = 0.69–0.96; nominal P = .02),” the researchers reported.

Throughout the entire treatment period, 35 patients (9.7%) in the ful-vestrant 500-mg group and 27 patients (7.2%) in the fulvestrant 250-mg group had serious adverse events. “[Serious adverse events] that were causally re-lated to study treatment were reported for eight (2.2%) and four (1.1%) pa-tients, and [serious adverse events] with an outcome of death were report-ed for five (1.4%) and seven (1.9%) patients in the fulvestrant 500-mg and fulvestrant 250-mg groups, respective-ly,” the investigators stated.

“The results of this study raise a number of questions that need to be addressed in future trials,” the authors

noted. These questions include wheth-er fulvestrant 500 mg might be a bet-ter option than aromatase inhibitors as first-line treatment for postmeno-pausal women with estrogen receptor–positive advanced breast cancer and whether fulvestrant should be part of a polyendocrine therapy approach.

Based on the CONFIRM trial’s progression-free and overall survival results, the investigators stated that whenever fulvestrant treatment is nec-essary, it should be initiated at the dose of 500 mg.

DiLeo A, et al: J Natl Cancer Inst 106(1):djt337, 2014.

LUNG CANCER

Some Lung Cancers Detected by Low-Dose CT in National Lung Screening Trial May Be Indolent

More than 18% of all lung can-cers detected by low-dose computed tomography in the National Lung Screening Trial (NLST) may be clini-cally insignificant. Overdiagnosis should be considered when describ-ing the risks of [low-dose computed tomography] screening for lung can-cer, according to a review of extended follow-up data from the NLST. The results were published in JAMA In-ternal Medicine by a team of investiga-tors led by Edward F. Patz, Jr, MD, of Duke University Medical Center in Durham, North Carolina.

The NLST compared screening with low-dose computed tomography vs chest radiography among 53,452 persons at high risk for lung cancer who were observed for 6.4 years. “During follow-up, 1,089 lung can-cers were reported in the [low-dose computed tomography] arm and 969 in the [chest radiography] arm of the NLST,” the investigators reported. They determined that the probability was 18.5% (95% confidence interval [CI] = 5.4%–30.6%) that any lung cancer detected by screening with low-dose computed tomography was an overdiagnosis, 22.5% (95% CI = 9.7%–34.3%) that a non–small cell lung cancer detected by low-dose computed tomography was an overdiagnosis, and 78.9% (95%CI = 62.2%–93.5%) that a bronchioal-veolar lung cancer detected by low-dose computed tomography was an overdiagnosis.

Study MethodologyThose participating in the NLST

had at least a 30 pack-year history of cigarette smoking and were between the ages of 55 and 74 when enrolled. Subjects were randomly assigned to receive either three annual low-dose computed tomography studies (n = 26,722) or three annual single-view posterior-anterior chest x-rays (n = 26,730) and then observed for up to 5 more years. Low-dose computed to-mography “demonstrated an encour-aging 20% relative reduction in lung cancer–specific mortality compared with screening using chest radiogra-phy,” the researchers commented.

Findings from the NLST “were met with enthusiasm, but before a wide-spread public health screening pro-gram is implemented, risks of screen-ing also need to be considered,” the authors wrote. Their analyses “were performed to provide an empirical es-timate of, or at least an upper bound on, the magnitude of overdiagnosis in the NLST so that the impact on mass screening programs could be under-stood.”

The magnitude of overdiagnosis “should be considered when guide-lines for mass screening programs are constructed,” the researchers stated. “In the future, once there are better biomarkers and imaging techniques to predict which individuals with a di-agnosis of lung cancer will have more or less aggressive disease, treatment options can be optimized, and a mass screening program can become more valuable,” the authors concluded.

Patz EF Jr, et al: JAMA Intern Med. December 9, 2013 (early release online).

LEUKEMIA

Bosutinib Shows ‘Acceptable Safety’ in Philadelphia Chromosome–Positive Leukemia

Bosutinib (Bosulif ) demonstrat-ed “acceptable safety with manage-able toxicities” in a phase I/II study among patients with chronic-phase chronic myeloid leukemia (CML) or advanced Philadelphia chromo-some–positive leukemia (accelerat-ed-phase/blast-phase CML or acute lymphoblastic leukemia). Patients had resistance/intolerance to ima-tinib (Gleevec) and possibly other tyrosine kinase inhibitors such as ©Charles Barsotti/The New Yorker Collection/www.cartoonbank.com


In the Literature

dasatinib (Sprycel) and nilotinib (Tasigna). “Our findings support the continued clinical development of bosutinib as monotherapy for the treatment of [Philadelphia chromo-some–positive] CML patients,” con-cluded the researchers, led by Hagop M. Kantarjian, MD, of The Univer-sity of Texas MD Anderson Cancer Center, Houston, in Blood.

The first phase of the trial was a dose-escalation study that established a recommended dose of bosutinib at 500 mg/d in primarily imatinib-resis-tant chronic-phase CML patients, the researchers explained. The phase II safety and efficacy evaluation permit-ted dose escalation to 600 mg/d “for lack of efficacy,” defined as complete hematologic response not reached by week 8 or complete cytogenetic re-sponse not reached by week 12, if no drug-related grade 3/4 adverse event occurred.

The three patient cohorts includ-ed second-line chronic-phase CML (n = 286), third/fourth–line chronic-phase CML (n = 118), and advanced leukemia (n = 166). All patients were at least 18 years old and resistant to full-dose imatinib or intolerant to any dose of imatinib. Patients in the third/fourth–line cohort were resis-tant to dasatinib at 100 mg/d or nilo-tinib at 800 mg/d and/or intolerant to any dose of dasatinib; patients in the advanced leukemia cohort may also have been resistant or intolerant to dasatinib and/or nilotinib, the re-searchers reported. The median dura-tion of bosutinib treatment was 11.1 months (range, 0.03–83.4 months).

Adverse Events“Treatment-emergent adverse

events in each cohort were primar-ily gastrointestinal,” the investigators stated. Diarrhea occurred in 86% of the second-line cohort, 83% of the third/fourth–line cohort, and 74% of the advanced leukemia cohort; nau-sea occurred in 46%, 48%, and 48% of the respective cohorts; and vomiting in 37%, 38%, and 43%.

“Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppres-sion … [was] reported in 41% of pa-tients; among affected patients, 46% and 32% were managed with bosuti-nib interruption and dose reduction, respectively. Alanine aminotrans-ferase elevation … occurred in 17% of patients, including 7% with grade

3/4 events; among patients managed with dose interruption, bosutinib rechallenge was successful in 74%,” the researchers reported. “Additional experience with bosutinib treatment may further improve the manage-ment of observed toxicities,” the au-thors added.

A total of 44 deaths occurred with-

in 30 days of the last bosutinib dose. Most (32) deaths occurred among patients in the advanced disease co-hort. Common reasons for death included CML disease progression and adverse events considered by the investigators to be unrelated to bosutinib, such as pneumonia/pneu-monitis and cardiac events. The three

deaths that were attributed to adverse events considered related to bosuti-nib were from lower gastrointestinal hemorrhage with thrombocytopenia, myocardial infarction, and acidosis with respiratory failure complicated by sepsis. n

Kantarjian HM, et al: Blood. De-cember 17, 2013 (early release online).



2014 Oncology Meetings 2014February

25th International Congress on Anti-Cancer TreatmentFebruary 4-6 • Paris, France

For more information: www.icact.fr

APOS 11th Annual ConferenceFebruary 13-15 • Tampa, Florida

For more information:

www.apos-society.org/apos2014/

European Society for Medical Oncology Sarcoma and GIST 2014February 18-19 • Milan, Italy


www.esmo.org

2014 BMT Tandem MeetingAmerican Society for Blood and Marrow TransplantationFebruary 19 - 23 • Orlando, Florida


www.asbmt.org

Multidisciplinary Head and Neck Cancer SymposiumFebruary 20-22 • Scottsdale,

Arizona


www.headandnecksymposium.org

Society of Gynecological Oncology 2014 Winter MeetingFebruary 20-22 • Breckenridge,

Colorado


www.sgo.org

North Carolina Oncology Association/South Carolina Oncology Society Joint Membership ConferenceFebruary 21-22 • Charlotte, North

Carolina


www.ncoa-northcarolina.com/

American Association for Cancer Research: RAS Oncogenes: From Biology to TherapyFebruary 24-27 • Lake Buena Vista,

Florida


www.aacr.og

March31st Annual Miami Breast Cancer Conference®March 6-9 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/meetings/31st-Annual-Miami-Breast-Cancer-Conference

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer CenterMarch 7-10 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse

38th Annual Meeting of the American Society of Preventive OncologyMarch 8-11 • Arlington, Virginia For more information: www.aspo.org

NCCN 19th Annual Conference: Advancing the Standard of Cancer Care™March 13–15 • Hollywood, Florida For more information: www.nccn.org/professionals/meetings/annual_conference.asp

Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 • Phoenix, Arizona For more information: www.surgonc.org

7th Annual Interdisciplinary Prostate Cancer Congress™March 15 • New York, New York For more information: www.gotoper.com/conferences/ipcc/meetings/7th-Annual-Interdisciplinary-Prostate-Cancer-Congress

24th Annual Interdisciplinary Breast Cancer ConferenceMarch 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/

9th European Breast Cancer ConferenceMarch 19-21 • Glasglow, Scotland For more information: www.ecco-org.eu

20th Annual Blood-Brain Barrier and Neuro-Oncology MeetingMarch 20-22 • Sunriver, Oregon For more information: www.ohsu.edu/bbb

Illinois Medical Oncology Society 2014 Membership ConferenceMarch 21 • Chicago, Illinois For more information: www.imos-illinois.com/

ELCC 2014 European Lung Cancer ConferenceMarch 26-29 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2014-Lung-Cancer

ACCC 40th Annual National MeetingMarch 31-April 2 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/AM2014.asp

April ESTRO 33April 4-8 • Vienna, Austria For more information: www.estro.org/congresses-meetings/items/estro-33

American Association for Cancer Research Annual Meeting April 5-9 • San Diego, California For more information: www.aacr.org

15th Annual Meeting of the American Society of Breast SurgeonsApril 30-May 4 • Las Vegas, Nevada For more information: www.breastsurgeons.org/index.php

MayOncology Nursing Society 39th Annual CongressMay 1-4 • Anaheim, California For more information: www.ons.org

Association for Value-Based Cancer Care – 4th Annual ConferenceMay 6-9 • Los Angeles, California For more information: http://avbcconline.org/

Accelerating Anticancer Agent Development and Validation WorkshopMay 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/

ASPHO’s 27th Annual MeetingMay 14-17 • Chicago, Illinois For more information: www.aspho.org

Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics SymposiumMay 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences

2014 State of the Art Radiation Therapy: Practical Treatment, Biology and ImagingMay 16-18 • San Antonio, Texas For more information: www.astro.org

ASCO 50th Annual MeetingMay 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone DiseaseJune 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/


Visit CancerProgress.Net to explore ASCO’s 50 year history and progress against cancer:

> ASCO timeline of the evolution of the Society

> Progress timeline of milestones for 17 cancers and all types of patient care

> Stories of cancer survivors, physician perspectives, and more

> Slide decks and fact sheets of progress milestones

> Data visualizer tools to explore cancer statistics

> Voting ballot on the top 5 advances in oncology

Celebrating 50 years of the American Society of Clinical Oncology and progress against cancer


2014 Oncology Meetings 201416th International Symposium on Pediatric Neuro-OncologyJune 28-July 2 • Singapore For more information: www.ispno2014.com

July2014 Pan Pacific Lymphoma ConferenceJuly 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/panpacificlymphoma.htm

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck SocietyJuly 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php

AACR/ASCO Methods in Clinical Cancer Research WorkshopJuly 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

Best of ASCO® BostonAugust 8-9 • Boston, Massachusetts For more information: boa.asco.org/

Best of ASCO® ChicagoAugust 15-16 • Chicago, Illinois For more information: boa.asco.org/

Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org/

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

SeptemberAssociation of Pediatric Hematology/Oncology Nurses 38th Annual ConferenceSeptember 4-6 • Portland, Oregon For more information: www.aphon.org

Breast Cancer SymposiumSeptember 4-6 • San Francisco, California For more information: breastcasym.org

American Society for Radiation Oncology Annual MeetingSeptember 14-17 • San Francisco, California For more information: www.astro.org

Academy of Oncology Nurse and Patient Navigators 5th Annual ConferenceSeptember 18-21 • Orlando, Florida For more information: http://aonnonline.org

Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/meetings--workshops/special-conferences/advances-in-melanoma-from-biology-to-therapy.aspx

European Society for Medical Oncology 2014 CongressSeptember 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO-2014-Congress

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to BiomarkersSeptember 29 - October 2 • Cambridge, Massachusetts For more information: http://steelelab.mgh.harvard.edu

OctoberACCC 31st National Oncology ConferenceOctober 8-11 • San Diego, California For more information: www.accc-cancer.org

2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: http://cme.baptisthealth.net/breastcancer/pages/index.aspx

2014 Quality Care SymposiumOctober 17-18 • Boston, Massachusetts For more information: quality.asco.org

ASCO’s Palliative Care in Oncology SymposiumOctober 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org

American College of Surgeons Clinical CongressOctober 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/future_congress/future

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: http://www.cutaneousmalignancies.com

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/home/programs/physicians

2014 Chicago Multidisciplinary Symposium in Thoracic OncologyOctober 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

3rd Annual Global Biomarkers Consortium ConferenceOctober 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium.com

NovemberChemotherapy Foundation SymposiumNovember 4 - 8 • New York, New York For more information: www.chemotherapyfoundationsymp-osium.org

Diagnostic Error in Medicine 5th International ConferenceNovember 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail.aspx/80028747

Multidisciplinary Update in Breast Disease 2014November 12-15 • Atlantic Beach, Florida For more information: http://www.mayo.edu/cme/surgical-specialties-2014s306

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer TherapeuticsNovember 18-21 • Barcelona, Spain For more information: www.aacr.org

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

World Cancer CongressDecember 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

37th Annual San Antonio Breast Cancer SymposiumDecember 9-13 • San Antonio, Texas For more information: www.sabcs.org

continued from page 50

Learn more at www.amgenoncology.comExpanding the potential of biomarker analysis means helping physicians not only determine what options are appropriate for patients but, equally as important, understanding what options are not appropriate for patients. Amgen is investigating extended RAS testing to further biomarker analysis in mCRC.

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In Memoriam

Leukemia Pioneer John M. Goldman, DM, Dies at 75By Ronald Piana

“He gave his honours to the world again,his blessed part to heaven, and slept in peace.”—William Shakespeare, Henry VIII

In 1971, John M. Goldman, DM, FRCP, FRCPath, FMedSci, began

research in chronic myeloid leukemia (CML), a uniformly fatal disease at the

time. Over the ensuing decades, Dr. Goldman’s pioneering work in the labo-ratory and clinic was instrumental in turning CML into a controllable condi-tion for many patients, saving countless thousands of lives. After a brief illness, Dr. Goldman died on December 24, 2013.

Dr. Goldman was the son of Jewish parents who fled from Germany to Eng-land in 1933 to escape the threat of the Nazi’s racial laws. They arrived in London with a £5 note and their worldly belong-ings in a suitcase. Dr. Goldman’s father Carl Heinz was a doctor, and he would go on to establish a successful practice in internal medicine. His status in the com-munity allowed him to help many of his relatives escape Germany before the out-break of war.

Early Career HighlightsDr. Goldman was born in London,

in 1938. An eager student, his academic skills propelled him through primary school toward an advanced degree. He attended Magdalen College, Oxford, to study classics, only later turning to

medicine. Dr. Goldman did his medical training at St. Bartholomew Hospital in London.

A serendipitous opportunity brought him to the United States, where he took positions in hospitals in Miami and later at Harvard University. An avid flyer, Dr. Goldman also found time during this en-ergized period in his career to obtain his pilot’s license.

Dr. Goldman eventually returned to his native Great Britain, and in 1971, he joined the prestigious group of hematol-ogists in the Department of Hematology at Hammersmith Hospital in London. Internationally renowned for clinical re-search, Hammersmith Hospital is where

Dr. Goldman began his work in CML, and it would serve as the base for his long and illustrious career.

In 1980 Dr. Goldman started alloge-neic hematopoietic cell transplantation for patients with CML. He also initiated the use of unrelated donors for stem cell transplantation in CML patients and was at the forefront of developing polymerase chain reaction (PCR) technology for monitoring residual leukemia.

Along with research and clinical work, Dr. Goldman was a proactive figure in the international oncology community. Seeing an unmet demand in match-ing donors for CML patients needing transplantation, Dr. Goldman and his colleagues established the Anthony No-lan bone marrow register, which today includes more than 500,000 potential donors. Named for a boy who died at

age 8 of Wiskott-Aldrich syndrome, a rare blood disorder, the Anthony Nolan register has been instrumental in helping CML patients in the United Kingdom as well as 15 other countries worldwide ob-tain lifesaving transplants.

Role in Imatinib DevelopmentDr. Goldman performed early clini-

cal studies of the original tyrosine kinase inhibitor (STI571, imatinib), and he began using it in the clinic in 1999. He also vigorously promoted the research of Brian Druker, MD, who had helped develop imatinib.

Although the targeted agent pro-duced substantial survival benefits in

CML, major drug companies were re-luctant to invest in developing a drug for a limited patient population of about 5,000 per year. Determined to see ima-tinib’s promise realized, Dr. Goldman flew to Novartis’s headquarters in Basel, Switzerland, and persuaded the com-pany’s CEO to manufacture the drug. It has since become the oncology success story that researchers hope to replicate in other cancers.

Dr. Goldman was a founder of several professional societies that promoted re-search in blood cancers and transplanta-tion, including the European Hematolo-gy Association and the European Group for Blood and Marrow Transplantation. He also created charities, such as Leu-ka, to help fund leukemia research. Dr. Goldman published more than 800 sci-entific papers and book chapters.

Worldwide InfluencePerhaps most telling about his de-

votion to CML patients was a state-ment by his friend and colleague, Robert Peter Gale, MD, PhD, Visiting Professor of Haematology at the Impe-rial College London: “His American medical colleagues thought nothing of calling John at 2:00 AM London time to discuss an idea or a complex medical case. No one is certain when (or if ) he ever slept.”

In the tributes for Dr. Goldman, the word “gentleman” is often men-tioned. Besides being a renowned researcher and clinician, Dr. Gold-man was a lover of life. He enjoyed traveling, reading, and skiing, and among those fortunate enough to call him their friend, he was known for his generosity and modesty. After his death, remembrances flooded in from across the globe. Websites such as that of the International Chronic My-eloid Leukemia Foundation carried hundreds of comments from doctors and patients.

One of his many mentees wrote, “John has mentored many hematolo-gists and scientists over the past few decades. Their stories are deeply per-sonal, but they have common themes. His influence was worldwide, as evi-denced by the scores of influential scientists and clinicians that name him as their key mentor. John’s joy in scientific discovery will serve as an in-spiration for us and the future genera-tions of doctor-researchers.”

Dr. Goldman is survived by his wife, two daughters, and a son. His daughter Cassie carried his love of fly-ing to greater heights—she’s a 747 pi-lot. The good doctor is also survived by the thousands of patients whose lives were made longer and better by his tireless work to cure leukemia. n

His American medical colleagues thought nothing of calling John at 2:00 AM London time to discuss

an idea or a complex medical case. No one is certain when (or if ) he ever slept.

—Robert Peter Gale, MD, PhD

In Memoriam

John M. Goldman, DMNovember 30, 1938 – December 24, 2013

John M. Goldman, DM

NCCN Academy for Excellence & Leadership in Oncology™

School of Pharmaceutical & Biotech Business

ENROLL TODAY at NCCN.org/academy and Save $100Early Bird Registration for NCCN Academy expires Monday, February 3, 2014.

JNCCN-N-0188-1213

Register now at NCCN.org/academy!A one-day session held in conjunction with the NCCN 19th Annual Conference

NCCNHEAL

TH CARE LEADERSHIP

ONCOLOGY EXCELLENCE

A C A D E M Y

Module I: Advocacy and Industry: Exploring Effective Communication and Successful CollaborationsModule II: Utilization of Guidelines and Pathways: Learnings and Best Practices Module III: Meet the Experts – NCCN Guidelines® Hot Topics

Growth Factors, Non-Hodgkin’s Lymphomas, and Non-Small Cell Lung Cancer

Curriculum*

WEDNESDAY, MARCH 12, 2014 The Westin Diplomat | Hollywood, Florida9:00 am – 3:00 pm (Registration and breakfast begin at 8:00 am)

Moderated by:Clifford Goodman, PhDThe Lewin Group

* Subject to change.


Letters to the Editor

Artemis Project® for a Preventive Breast Cancer Vaccine

I read with interest the article, “Breast Cancer Vaccines for Primary Pre-

vention Move Toward Clinical Use,” which appeared in the December 15th issue of The ASCO Post (page 28). How-ever, information presented regarding the National Breast Cancer Coalition’s (NBCC’s) Artemis Project for a breast cancer prevention vaccine is only a small part of this project.

The article states that “NBCCs Arte-mis Project for a breast cancer prevention

vaccine has awarded seed grants to several researchers to search through breast can-cer genomes for evidence of infectious agents not found in normal breast.” In re-ality, NBCC has awarded one small grant to do so, but the majority of the project and grant awards have focused on search-ing for the safest, most efficacious self- and neoantigens within both invasive and in situ carcinoma tissues and related da-tasets. We have made significant progress and now have a short list of antigen candi-

dates that will be tested in the next phase of the project with immunologic studies.

By definition, a preventive vaccine is intended for a population of healthy women. Therefore, safety is our utmost concern. We want to develop the safest vaccine that is the most efficacious. A rush to clinical trials without appropriate pre-clinical testing is a concern for advocates. We intend to move the Artemis Project forward as quickly as possible, but with the utmost care and attention to obtain-

ing the appropriate safety and efficacy data before meeting with the U.S. Food and Drug Administration prior to launch of a clinical trial. n

—Fran Visco, JD President,

National Breast Cancer Coalition Washington, DC

Editor’s note: For additional information on the National Breast Cancer Coalition, please visit www .breastcancerdeadline2020.org.

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at [email protected]

NCCN Academy for Excellence & Leadership in Oncology™

School of Pharmaceutical & Biotech Business

ENROLL TODAY at NCCN.org/academy and Save $100Early Bird Registration for NCCN Academy expires Monday, February 3, 2014.

JNCCN-N-0188-1213

Register now at NCCN.org/academy!A one-day session held in conjunction with the NCCN 19th Annual Conference

NCCNHEAL

TH CARE LEADERSHIP

ONCOLOGY EXCELLENCE

A C A D E M Y

Module I: Advocacy and Industry: Exploring Effective Communication and Successful CollaborationsModule II: Utilization of Guidelines and Pathways: Learnings and Best Practices Module III: Meet the Experts – NCCN Guidelines® Hot Topics

Growth Factors, Non-Hodgkin’s Lymphomas, and Non-Small Cell Lung Cancer

Curriculum*

WEDNESDAY, MARCH 12, 2014 The Westin Diplomat | Hollywood, Florida9:00 am – 3:00 pm (Registration and breakfast begin at 8:00 am)

Moderated by:Clifford Goodman, PhDThe Lewin Group

* Subject to change.

In Ph+ CML

National Comprehensive Cancer Network® (NCCN®) recommends INTERNATIONAL SCALE RQ-PCR with 4.5-log sensitivity every 3 months1

A BCR-ABL assay thatreads between the lanes

Standardized to the International Scale (IS)

Ability to truly assess major molecular response (MMR)

High sensitivity to 4.5 logs (below baseline) to assess whether undetectable disease has been achieved1

Only routine, highly sensitive molecular monitoring standardized to the International Scale (IS) gives you the con� dence to make clinical decisions.2

LOOK DEEPER at www.GenoTRACE.com

A N OVA R T I S C O M PA N Y © 2013 Genoptix, Inc. 7/13 GNP-1070093

GenoTRACE® reveals what you don’t want to miss

Ph+ CML, Philadelphia chromosome–positive chronic myeloid leukemia; RQ-PCR, real-time quantitative polymerase chain reaction.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia Version 4.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed July 19, 2013. To view the most recent and complete version of the guidelines, go online to www.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. Jabbour EJ, Quintás-Cardama A. Molecular monitoring 101: helping your patients with chronic myeloid leukemia to understand the meaning of molecular response. Leuk Lymphoma. 2012;53(8):1452-1460.

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http://www.genoptix.com

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