november 2012, vol 1, no 5

The Role of Personalized Therapy in the Manage-ment of Multiple Myeloma: Case Study of a PatientWith a Cytogenetic Abnormality...................... Page 41

The Cancer Immunotherapy Trials Network: A National Strategy for the Development and Implementation of Immunotherapy for the Treatment of Cancer......................................Page 46

Cultivating Personalized Medicine Clinical Acumen inthe Management of Breast Cancer: An Interview With Edith Perez, MD.....................................7

November 2012

Volume 1 • Number 5

A Peer-Reviewed Journal

www.PersonalizedMedOnc.com© 2012 Green Hill Healthcare Communications, LLC

IMPLEMENTING THE PROMISE OFPROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARETM

MULTIPLE MYELOMA

IMMUNOTHERAPY

PERSONALIZEDMEDICINE INONCOLOGYM

OP

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INTERVIEW WITH THE INNOVATORS

The official publication of

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Clinical Approaches to Targeted Technologies: Implementing the Promise of Prognostic PrecisionInto Personalized Cancer Care.......................Page 26

CONTINUING MEDICAL EDUCATION

ALSO IN THIS ISSUE…• The Last Word by Robert E. Henry................ Page 56

In partnership with

LinkerAttaches the cytotoxic agent to the antibody. Newer linkersystems are designed to be

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Cytotoxic agentDesigned to kill target cells wheninternalized and released.4,8

AntibodySpecific for a tumor-associatedantigen that has restricted expression on normal cells.4,8

PERSONALIZED MEDICINE IN ONCOLOGY4 Volume 1 • No 5 November 2012

November 2012

Volume 1 • Number 5

MOP

News From ESMO PAGE 12

Frontline Therapy of Metastatic Renal Cell Carcinoma:

Pazopanib as Effective as Sunitinib

Crizotinib Extends Survival Versus Chemotherapy in

Advanced NSCLC

EGFR Mutations, Not KRAS Mutations, May Be

Predictive for Sorafenib Response in Advanced NSCLC

Whole Genome Testing Moves Forward in Breast Cancer

CONFERENCE NEWS

Cultivating Personalized Medicine Clinical Acumen in the Management of Breast Cancer: An Interview With Edith Perez, MD PAGE 17

PMO speaks with the Deputy Director of Mayo Clinic

Cancer Center in Florida to discuss the strategy and

tactics that she and her fellow colleagues are

employing in the fight against breast cancer.

PERSONALIZEDMEDICINE INONCOLOGY™

The Global Biomarkers Consortium™

(GBC) is a community of world-

renowned healthcare professionals who

will convene in multiple educational fo-

rums in order to better understand the

clinical application of predictive molec-

ular biomarkers and advanced personal-

ized care for patients.

Save the date for the Second Annual Conference,

October 4-6, 2013Visit

www.globalbiomarkersconsortium.comto register

Professional Experienceof GBC Attendees

INTERVIEW WITH THE INNOVATORS

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1-3 years

3-5 years

5-10 years

10-20 years

>20 years

56.7%

6.7%

26.7%

6.7%

3.3%

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Clinical Approaches to Targeted Technologies: Implementing the Promise of Prognostic Precision Into Personalized Cancer Care PAGE 26

Evolving regional standards of care and emerging

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for specific tumor types. This continuing medical

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and expert commentary on the application of biomarkers

in personalized care for patients with solid tumors.

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VISIT: CarisTargetNow.com

ON- AND OFF-COMPENDIUM DRUG ASSOCIATIONS AND CLINICAL TRIALS

ON-COMPENDIUM DRUG ASSOCIATIONS AND CLINICAL TRIALS

SENIOR VICE PRESIDENT, SALES AND MARKETINGPhilip Pawelko

[email protected]

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MANAGING DIRECTORPam Rattananont Ferris

EDITORIAL DIRECTORKristin Siyahian

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STRATEGIC EDITORRobert E. Henry

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BUSINESS MANAGERBlanche Marchitto

CIRCULATION [email protected]

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN ap-plied for (online) is published 6 times a year by Green Hill HealthcareCommunications, LLC, 1249 South River Road, Suite 202A, Cran-bury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy -right ©2012 by Green Hill Health care Com muni cations, LLC. Allrights reserved. Personalized Medicine in Oncology logo is a trademarkof Green Hill Healthcare Communications, LLC. No part of thispublication may be reproduced or transmitted in any form or by anymeans now or hereafter known, electronic or mechanical, includingphotocopy, recording, or any informational storage and retrieval sys-tem, without written permission from the publisher. Printed in theUnited States of America.

EDITORIAL CORRESPONDENCE should be ad dressed to ED-ITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO),1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLYSUBSCRIPTION RATES: United States and possessions: individ-uals, $50.00; institutions, $90.00; single issues, $5.00. Orders will bebilled at individual rate until proof of status is confirmed. Prices aresubject to change without notice. Correspondence regarding permis-sion to reprint all or part of any article published in this journal shouldbe addressed to REPRINT PERMISSIONS DEPART MENT,Green Hill Healthcare Communications, LLC, 1249 South RiverRoad, Suite 202A, Cranbury, NJ 08512. The ideas and opinions ex-pressed in PMO do not necessarily reflect those of the editorial board,the editorial director, or the publishers. Publication of an advertise-ment or other product mention in PMO should not be construed asan endorsement of the product or the manufacturer’s claims. Readersare encouraged to contact the manufacturer with questions about thefeatures or limitations of the products mentioned. Neither the edito-rial board nor the publishers assume any responsibility for any injuryand/or damage to persons or property arising out of or related to anyuse of the material contained in this periodical. The reader is advisedto check the appropriate medical literature and the product informa-tion currently provided by the manufacturer of each drug to be ad-ministered to verify the dosage, the method and duration ofadministration, or contraindications. It is the responsibility of thetreating physician or other healthcare professional, relying on inde-pendent experience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every effort has beenmade to check generic and trade names, and to verify dosages. Theultimate responsibility, however, lies with the prescribing physician.Please convey any errors to the editorial director.

PUBLISHING STAFF

MOP PERSONALIZED

MEDICINE INONCOLOGY™

MULTIPLE MYELOMA

The Role of Personalized Therapy in the Management of Multiple Myeloma: Case Study of a Patient With a Cytogenetic Abnormality PAGE 41

A report from the 2012 conference of the Global

Biomarkers Consortium.

IMMUNOTHERAPY

The Cancer Immunotherapy Trials Network: A National Strategy for the Development and Implementation of Immunotherapy for the Treatment of Cancer PAGE 46

The Cancer Immunotherapy Trials Network was

established to address the lack of widespread clinical

expertise with immunotherapy and to promote the rapid

development of new immunotherapy agents and

combination therapy using an integrated national network.

Holbrook E. Kohrt, MD, PhD; Howard L. Kaufman, MD; Mary L. Disis, MD

OUR MISSIONThe mission of Personalized Medicine in Oncology is to deliver practice-changing informationto clinicians about customizing healthcare based on molecular profiling technologies, eachpatient’s unique genetic blueprint, and their specific, individual psychosocial profile, prefer-ences, and circumstances relevant to the process of care.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, wheredecisions and practices are tailored for the individual – beginning with an incremental integrationof personalized techniques into the conventional practice paradigm currently in place.

Volume 1 • No 5 November 20126 PERSONALIZED MEDICINE IN ONCOLOGY

THE LAST WORD

A Personal Introduction and Invitation to Join My Journey Through the World of Personalized Medicine PAGE 56

The Strategic Editor of PMO offers thoughts on a

variety of topics in personalized medicine.

Robert E. Henry

©Copyright 2012 Agendia. All rights reserved. Agendia, MammaPrint, TargetPrint and TheraPrint are registered trademarks of Agendia. BluePrint and SYMPHONY are trademarks of Agendia.

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Editor in ChiefAL B. BENSON III, MDNorthwestern UniversityChicago, Illinois

Editorial Board

Breast CancerEDITH PEREZ, MD Mayo ClinicJacksonville, Florida

Hematologic MalignanciesGAUTAM BORTHAKUR, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

PathologyDAVID L. RIMM, MD, PHDYale Pathology Tissue Services Yale University School of MedicineNew Haven, Connecticut

Drug DevelopmentIGOR PUZANOV, MDVanderbilt UniversityVanderbilt-Ingram Cancer CenterNashville, Tennessee

Lung CancerVINCENT A. MILLER, MDFoundation MedicineCambridge, Massachusetts

Predictive ModelingMICHAEL KATTAN, PHD Case Western Reserve UniversityCleveland, Ohio

Gastrointestinal CancerEUNICE KWAK, MD Massachusetts General Hospital Cancer CenterHarvard Medical School Boston, Massachusetts

MelanomaDOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer CenterIndianapolis, Indiana

Prostate CancerOLIVER SARTOR, MD Tulane UniversityNew Orleans, Louisiana

SECTION EDITORS

SANJIV S. AGARWALA, MDSt. Luke’s HospitalBethlehem, Pennsylvania

GREGORY D. AYERS, MS Vanderbilt University School of MedicineNashville, Tennessee

LYUDMILA BAZHENOVA, MDUniversity of California, San DiegoSan Diego, California

LEIF BERGSAGEL, MDMayo ClinicScottsdale, Arizona

KENNETH BLOOM, MDClarient Inc.Aliso Viejo, California

MARK S. BOGUSKI, MD, PHDHarvard Medical SchoolBoston, Massachusetts

GILBERTO CASTRO, MDInstituto do Câncer do Estado de São Paulo São Paulo, Brazil

MADELEINE DUVIC, MD The University of TexasMD Anderson Cancer CenterHouston, Texas

BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCNCleveland Clinic Taussig Cancer CenterCleveland, Ohio

STEPHEN GATELY, MDTGen Drug Development (TD2)Scottsdale, Arizona

STEVEN D. GORE, MDThe Johns Hopkins University School of MedicineBaltimore, Maryland

K. PETER HIRTH, PHDPlexxikon, Inc.Berkeley, California

HOWARD L. KAUFMAN, MDRush UniversityChicago, Illinois

KATIE KELLEY, MDUCSF School of MedicineSan Francisco, California

MINETTA LIU, MD Georgetown University HospitalWashington, DC

KIM MARGOLIN, MDUniversity of WashingtonFred Hutchinson Cancer Research CenterSeattle, Washington

GENE MORSE, PHARMDUniversity at BuffaloBuffalo, New York

AFSANEH MOTAMED-KHORASANI, PHDRadient PharmaceuticalsTustin, California

NIKHIL C. MUNSHI, MD Dana-Farber Cancer InstituteBoston, Massachusetts

STEVEN O’DAY, MDJohn Wayne Cancer Institute Santa Monica, California

DAVID A. PROIA, PHDSynta PharmaceuticalsLexington, Massachusetts

RAFAEL ROSELL, MD, PHDCatalan Institute of OncologyBarcelona, Spain

STEVEN T. ROSEN, MD, FACP Northwestern UniversityChicago, Illinois

HOPE S. RUGO, MD University of California, San FranciscoSan Francisco, California

DANIELLE SCELFO, MHSAGenomic HealthRedwood City, California

LEE SCHWARTZBERG, MD The West ClinicMemphis, Tennessee

JOHN SHAUGHNESSY, PHDUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas

LAWRENCE N. SHULMAN, MDDana-Farber Cancer Institute Boston, Massachusetts

JAMIE SHUTTER, MDSouth Beach Medical Consultants, LLCMiami Beach, Florida

DARREN SIGAL, MDScripps Clinic Medical GroupSan Diego, California

DAVID SPIGEL, MDSarah Cannon Research InstituteNashville, Tennessee

MOSHE TALPAZ, MDUniversity of Michigan Medical CenterAnn Arbor, Michigan

SHEILA D. WALCOFF, JDGoldbug Strategies, LLCRockville, Maryland

ANAS YOUNES, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

EDITORIAL BOARD

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CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsRoy A. Beveridge, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Linda Bosserman, MD, FACP; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: Advanced Care Directives: Palliative Care, Hospice, EthicsJ. Russell Hoverman, MD, PhDThomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD

3:45 pm - 4:15 pm Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm Cocktail Reception in the Exhibit Hall

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Large Oncology Group Practices—Successes, Issues, and Challenges

11:45 am - 12:00 pm Summary and Conclusion of Conference

*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by Medical Learning Institute Inc, the Association forValue-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core PrincipleSolutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATIONMedical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs)

of continuing pharmacy education credit. The Universal Activity Number for this activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing valuein cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to health-care reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

CONFERENCE REGISTRATIONDiscounted Pricing Available!

$375.00 until January 15, 2013$475.00 until March 15, 2013$675.00 after March 15, 2013

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

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Letter From the Board

Dear Reader,

Welcome to the 5th issue of Personalized Medicine in Oncology (PMO) –a journal dedicated to informing practicing oncologists and otherproviders on the clinical application of personalized medicine (PM)

research discoveries, and so guiding them in the appropriate usage of the biologi-cals and diagnostics so integral to PM.The healthcare system demands value, the balance of cost, quality, and access

that requires skillful resource allocation. PMO imparts to practicing oncologiststhe skills needed for value-based utilization of biologicals that are changing theface of cancer care. This includes knowing when and how to use the biologicals

that help drive the PM process of care and cause it to prosper. Their gratuitous usage, however, eliminatesthe value they bring and would threaten their continued usage. Never has “less is more” meant so much.Translating research into action is the tactical completion of the PM mission. Opposing this, however,

is a long-standing trend of delaying the application of new research, as stated in the Institute of Medicinereport, Crossing the Quality Chasm: A New Health System for the 21st Century: “In the current health caresystem, scientific knowledge about best care is not applied systematically or expeditiously to clinical prac-tice. An average of about 17 years is required for new knowledge generated by randomized controlled trialsto be incorporated into practice, and even then application is highly uneven.” Such inefficiency is incom-patible with today’s healthcare system, especially where biologicals and diagnostics are concerned. Theirusage must be tied to value. PMO helps providers master value-based usage of biologicals and diagnostics,thereby aligning PM with healthcare’s rules of engagement.To disseminate information on the principles of PM, we offer the oncology community our print and

online media as well as live events. Please save the date for the 2nd Annual Conference of the GlobalBiomarkers Consortium (GBC) on October 4-6, 2013, in Boston, Massachusetts. The GBC is a communityof world-renowned healthcare professionals who convene to discuss the clinical application of predictivemolecular biomarkers and advanced personalized care for patients. To register or for more information,please visit www.globalbiomarkersconsortium.com.

We are pleased to join you in the PM community.

Sincerely,

Oliver Sartor, MDTulane UniversityPMO Board Member

PMO and the PM Initiative: Value, Time, and Talent

Oliver Sartor, MD

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5:30 PM


According to a phase 3 noninferiority trial, paz -opanib is similarly effective as sunitinib, withsome advantages in its side effect profile. The

COMPARZ trial, reported at the 2012 ESMO Congress,met its primary end point by demonstrating that paz -opanib was noninferior to sunitinib, a standard frontlinetherapy in this setting. The distinct side effect profilesof these drugs should be considered when selectingfrontline therapy, according to experts.Lead author Robert Motzer, MD, Memorial Sloan-

Kettering Cancer Center (MSKCC), New York City,said that the study showed similar efficacy for pazopaniband sunitinib.

“The differentiated safety profile of pazopanib showsa lower incidence of hand-foot syndrome, fatigue, sto -matitis, and mucositis. Higher liver function abnormal-ities were observed with pazopanib,” Motzer said. Abenefit in quality of life (QOL) was also reported for paz -opanib in the COMPARZ study, which is the largestrandomized trial conducted in metastatic renal cell car-cinoma (mRCC) thus far.COMPARZ randomized 1110 patients with mRCC to

either pazopanib or sunitinib. Baseline demographic anddisease characteristics were well balanced between the 2arms. Median age was 61years, about 72% were male, and

83% had prior nephrectomy. Patients from all risk groupswere allowed in the trial; the majority had good and in-termediate risk according to MSKCC criteria.Median progression-free survival was 8.4 months

with pazopanib versus 9.5 months with sunitinib, a non-significant difference for noninferiority, with a hazardratio of 1.047.Adverse events differed according to treatment.

More frequent elevations in liver enzymes and whiten-ing of the hair were reported in patients treated with paz -opanib, while those treated with sunitinib had higherrates of fatigue, hand-foot syndrome, taste alteration,and thrombocytopenia. In Motzer’s opinion, the side ef-fect profiles “tip the scale in favor of pazopanib” as first-line treatment for mRCC.The QOL analysis showed greater patient satisfaction

with pazopanib therapy, with less fatigue and physicalsymptoms compared with sunitinib. Earlier this year atthe 2012 ASCO Annual Meeting, Escudier and col-leagues reported results of a patient preference studycalled PISCES. In this study, 70% of patients preferredpazopanib and 22% preferred sunitinib (AbstractCRA4502).Formal discussant of this trial, Tim Eisen, MD, Uni-

versity of Cambridge, UK, said that he found the dataon similar efficacy for the 2 drugs more convincing thanthe QOL data. He pointed out that QOL assessmentswere made every 28 days, which favors pazopanib; 28days is at peak exposure to sunitinib, which is given ona 4 weeks on, 2 weeks off schedule, while pazopanib isgiven continuously. He said the QOL from PISCESwere more convincing in favor of pazopanib. u

2012 ESMO Congress

Frontline Therapy of Metastatic Renal Cell Carcinoma:Pazopanib as Effective as SunitinibPhoebe Starr

The QOL analysis showed greater patientsatisfaction with pazopanib therapy, withless fatigue and physical symptomscompared with sunitinib.

We’re just aclick away!Please visit us at www.PersonalizedMedOnc.com

WWW.PERSONALIZEDMEDONC.COM 13Volume 1 • No 5 November 2012

The PROFILE 1007 trial, reported at the 2012ESMO Congress, showed positive results for atargeted therapy in patients whose tumors ex-

pressed that target. The first-in-class ALK inhibitorcrizotinib prolonged progression-free survival (PFS) andimproved response rates compared with single-agentchemotherapy in patients with advanced, previouslytreated, ALK-positive (ALK+), non–small cell lung can-cer (NSCLC). Patients treated with crizotinib hadgreater improvement in lung cancer symptoms and qual-ity of life (QOL) compared with patients receivingchemotherapy. PROFILE 1007 is the first trial to com-pare crizotinib head-to-head with chemotherapy inALK+ NSCLC. ALK rearrangements are found in about 5% of lung

cancers. Even though this is a small percentage, lungcancer is so prevalent that ALK positivity accounts forabout 50,000 new cases each year. Studies show thatyounger patients, those who never smoked, and adeno-carcinoma cases are more likely to be ALK+.“These results establish crizotinib as the standard of

care for patients with advanced previously treatedALK+ NSCLC,” stated lead author Alice Shaw, MD,Dana-Farber Cancer Institute/Harvard Cancer Center,Boston, Massachusetts. Crizotinib is approved for thetreatment of ALK+ NSCLC in the United States.The international PROFILE 1007 trial randomized

347 patients with ALK+, stage IIIb or IV NSCLC tocrizotinib 250 mg bid, pemetrexed 500 mg/m2, or do cetaxel 75 mg/m2 on a 21-day cycle. Patients treatedwith crizotinib received a median of 11 cycles, whilethose treated with chemotherapy received a median of4 cycles.For the primary end point, median PFS was 7.7

months with crizotinib versus 3 months withchemotherapy, reducing the risk of progression by 51%with crizotinib (P<.0001). Median PFS was 7.7 months

with crizotinib versus 4.2 months with pemetrexed(P=.0004) and 2.6 months with docetaxel (P<.0001).Overall response rate was tripled in the crizotinib

group: 65.3% versus 19.3% for single-agent chemother-apy (P<.0001).No overall survival (OS) benefit was seen with crizo-

tinib in an interim analysis. However, longer follow-upis needed so the data can mature, Shaw said. OS willlikely be confounded by crossover, she said, since pa-tients were allowed to cross over to crizotinib if progres-sion occurred.

Adverse events associated with crizotinib were mildand manageable in the study. The rate of toxicities grade3 or higher was under 5% for most toxicities; in thecrizotinib arm, elevated transaminases were reported in16% of patients and pulmonary embolism in 5%. Myelo-suppression was more frequent in the chemotherapyarms compared with crizotinib.Patient-reported outcomes suggested that QOL was

superior on crizotinib compared with chemotherapy.Time to deterioration in lung cancer symptoms was amedian of 5.6 months with crizotinib versus 1.4 monthswith chemotherapy (P<.0001).As with other targeted therapies, patients with ad-

vanced cancers will develop resistance to crizotinib. In-vestigational drugs such as LBK 178, AB6 273, and heatshock protein inhibitors may be able to overcome resis -tance that develops with crizotinib. u

2012 ESMO Congress

Crizotinib Extends Survival Versus Chemotherapy inAdvanced NSCLCPhoebe Starr

The first-in-class ALK inhibitor crizotinibprolonged PFS and improved responserates compared with single-agentchemotherapy in patients with advanced,previously treated, ALK-positive NSCLC.


Treatment with sorafenib did not improve overallsurvival (OS) in patients with heavily pre-treated advanced non–small cell lung cancer

(NSCLC) in the overall analysis of the MISSION trialreported at the 2012 ESMO Congress. A post hoc com-panion biomarker study of MISSION presented at thesame meeting suggested that EGFRmutated status maybe predictive of a benefit with sorafenib treatment; however, KRAS mutations were not predictive of response.“The biomarker analysis hinted that mutated EGFR

may be predictive for sorafenib, but interpret these datawith caution,” stated lead author Tony S. Mok, MD,Chinese University of Hong Kong. He pointed out thatthis analysis was based on a small sample size and wasexploratory.

The global multicenter, randomized, phase 3 MIS-SION trial compared sorafenib plus best supportive carewith best supportive care alone as third- or fourth-linetherapy in 703 patients with advanced NSCLC. Pa-tients were not preselected or prestratified according toEGFR or KRAS status.After the trial was completed, mutational analysis was

performed on 347 patients. EGFR mutations were de-tected in 26% and KRASmutations in 20%. Mutationalstatus was balanced between the 2 treatment arms.Mutated EGFR was identified in tumor tissue or

plasma in 44 patients treated with sorafenib and 45 re-

ceiving placebo. Wild-type EGFR was found in 122 ofsorafenib-treated patients and in 136 in the group re-ceiving placebo.Sorafenib demonstrated a significant progression-free

survival (PFS) benefit in patients with mutated EGFR:median PFS was 2.7 months with sorafenib versus 1.4months with placebo (P<.001). PFS was also signifi-cantly better with sorafenib in the wild-type EGFRpatients: median of 2.7 months versus 1.5 months, respectively (P<.001).Sorafenib-treated patients with EGFRmutations had

significantly superior OS compared with placebo; OSwas 13.9 months on sorafenib versus 6.5 months forthose receiving placebo (P=.002). However, no OS dif-ference was found between groups in patients with wild-type EGFR; median OS was 8.3 months with sorafeniband 8.4 months with placebo. The biomarker treatmentinteraction analysis had a P value of .015 for PFS and.023 for OS.The interaction analysis suggests that EGFR status is

a potential biomarker for sorafenib response, Moknoted.No significant PFS or OS benefit was observed for

sorafenib in either KRAS mutated or KRAS wild-typeNSCLC. For KRASmutation, the biomarker treatmentinteraction analysis had a P value of .696; for KRASwild-type, the biomarker interaction analysis had a P value of .743.“KRAS mutation status did not appear to influence

response to sorafenib. The interaction analysis was neg-ative for both PFS and OS,” Mok said.“Based on current data, we hypothesize that EGFR

mutation is a predictive biomarker for sorafenib in treat-ment of patients with advanced NSCLC,” Mok stated.He added that the search for biomarkers that predict re-sponse is critical for progress. “Otherwise we are treatingblindly in the dark,” he commented. u

2012 ESMO Congress

EGFR Mutations, Not KRAS Mutations, May BePredictive for Sorafenib Response in Advanced NSCLCPhoebe Starr

The global multicenter, randomized, phase3 MISSION trial compared sorafenib plusbest supportive care with best supportivecare alone as third- or fourth-line therapyin 703 patients with advanced NSCLC.


Researchers presented the first large study to testthe entire genome of individualized breast can-cers to help personalize cancer at the 2012

ESMO Congress. They found that this approach is fea-sible and enables identification of genetic alterationsthat can be targeted by available drugs. They also sawearly signs of clinical activity with this approach.“Now that a number of drugs are available that target

specific genetic alterations in cancers, genetic testing isusually performed. In most of these cases, these genetictesting approaches analyze only a limited number ofgenes,” said lead author of the study, Fabrice André,MD, Institut Gustav Roussy, Villejuif, France.Theoretically, whole genome testing can identify

both frequent and rare genetic alterations. “In addition,this approach allows us to quantify the level of genomicinstability, and to detect whether driver mutations areassociated with genomic alterations involved in resis -tance to specific targeted agents,” André explained.Also, whole genome approaches could reduce expen-

ditures related to genetic testing, because new bioassayswould not need to be developed for each new targetablegenetic alteration discovered in cancer. “An all-in-oneassay could substitute for multiple tests,” explainedMonica Arnedos, MD, one of the study coauthors.The SAFIR01 trial analyzed the entire genome from

a biopsy of a metastatic lesion prospectively. “We soughtto identify molecular alterations and try to match thesewith a targeted therapy for each patient,” Arnedos said.The investigators also wanted to determine the best

technology for looking at the whole genome, and thebest algorithm for identifying potential therapeutic tar-gets. Most important, they plan to evaluate whetherwhole genome testing improves outcomes. “First we did a pilot study in 108 patients where we

performed whole genome analysis to determine feasibility.The techniques we used were array CGH and Sanger se-quencing. Once feasibility was determined, we initiated

the French national program, funded by French NCI andsponsored by UNICANCER,” Arnedos told listeners.SAFIR01 was performed at 18 centers. As of Septem-

ber 23, 2012, biopsies were obtained from a metastatic le-sion in 402 breast cancer patients, including 26 patientswhose biopsies were under study. A genomic result wasgenerated in 276 patients, including whole genome analy-sis in 251 patients. A targetable genomic alteration wasidentified in 172 (69%) of those patients. No patients hadany evidence of disease progression while on treatment.“Seventy-six genetic alterations were considered rare,

low-frequency alterations. These alterations are unex-pected, highlighting the need for whole genome ap-proaches,” she said.At the time of the ESMO Congress, 26 patients had

received therapy targeted to their specific genetic alter-ations. Evidence of activity was observed in 8 of thesepatients. The data are still quite preliminary.“In the next 3 years, we expect to have treated 80 pa-

tients with metastatic breast cancer using matched ther-apy selected from whole genome analysis,” Arnedos said.The researchers plan to develop approaches to decrease

biopsy failure and to improve access to targeted therapies.Arnedos said these biopsies and tests are challenging.

In 105 cases, the tumor sample was not sufficient foranalysis, and in 19 cases the whole genome analysis wasnot interpretable.The next trial, called SAFIR 2, will be a randomized

trial comparing treatment based on whole genome test-ing versus treatment not driven by tumor biology. “This approach is extremely important. It will identify

patients who could benefit from a targeted drug not neces-sarily approved for that type of cancer. This approach willchange the way we approve drugs. We have seen surprisingcompounds emerge that are effective. This will affect theregulatory process,” stated the press conference moderator,Christoph Zielinski, MD, Medical University of Vienna,Austria, who was not involved in these studies. u

2012 ESMO Congress

Whole Genome Testing Moves Forward in Breast CancerPhoebe Starr

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If any cancer can be said to have launched personal-ized medicine into orbit and establish it as the stan-dard for all cancer therapy to aspire toward, it is

breast cancer. The discovery of the es-trogen receptor (ER) and HER2 bio-markers has astonished healthcareprofessionals and the public alike andraised forever the bar of cancer care.What conditions have arisen to makebreast cancer the envy of other cancerresearchers, and how is this field lev -eraging its discoveries to unlock newopportunities for researchers and clinicians alike? And most important,how can today’s practicing oncologistsput into practice the life saving tech-niques of breast cancer personalizedmedicine, ally them with the conventional medicinethat still dominates the field, and cultivate a base ofknowledge of this burgeoning, data-heavy field of med-ical science?To capture the essence of the breast cancer treat-

ment revolution, we interview Dr Edith Perez. Trans-lational research is the soul of Dr Perez’s work. Askedwhat she sees as the vision statement of personalized

medicine in breast cancer, she mentions not the ad-vances in science but the lives that will be savedthrough a new understanding and application of its sci-

ence. Asked about the “competing”model of predictive modeling versusbiomarkers, she instantly embraces itas a welcome and helpful adjunct tobiomarkers. This same inclusivenessextends to wellness-based healthcare,to patient-reported outcomes, to thelink between the clinical, business,and policy sectors of healthcare inmaking breast cancer research get trac-tion and stay on course.And what is that course? Without

hesitation, she advances the transla-tional research goal: a new molecular

classification of breast cancer that identifies the rele-vance of types of breast cancer to drive treatment deci-sions. For Dr Perez, it’s all about treatment. As one ofthe leading researchers in the area of cancer researchthat other cancer experts look to as a model of success,we sought her out to give not only an empirical view ofthe principles and drivers of breast cancer success andfuture research goals, but also to help define the issues


Interview With the Innovators

Cultivating Personalized Medicine Clinical Acumen inthe Management of Breast Cancer: An Interview With Edith Perez, MDEdith Perez, MDDeputy DirectorMayo Clinic Cancer Center, Florida

Edith Perez, MD

Dr Perez is Deputy Director, Mayo Clinic Cancer Center in Florida, and director of the Breast Program and the Serene M. andFrances C. Durling Professor of Medicine at Mayo Medical School. She is a cancer specialist and an internationally knowntranslational researcher at Mayo Clinic. Her roles extend nationally, including chairing the Breast Committee for the North Cen-tral Cancer Treatment Group, as well as other positions within the American Association for Cancer Research, the AmericanSociety of Clinical Oncology, and the National Cancer Institute. Dr Perez has developed and is involved in a wide range ofclinical trials exploring the use of new therapeutic agents for the treatment and prevention of breast cancer. She also has developedstudies to evaluate the role of genetic biomarkers in the development, aggressiveness, and therapeutic efficacy for breast cancer.


PMO How would you define or otherwise describepersonalized medicine and its role in the clinical man-agement of breast cancer?

Dr Perez It’s our ability to identify markers of thetumor of the host that impact pathogenesis so that wecan target them to optimize treatments for the individ-ual patients.

PMO How does predictive modeling assist in thispro cess, compared with the more specific matter of biomarkers?

Dr Perez Predictive modeling can be really fascinat-ing and provide us with some guide of the path that wewant to follow. The same applies to preclinical modeling,utilizing cell lines or newer models. In the area of predic-tive medicine for patients, or personalized medicine, wehave realized that all of these models really need to bevalidated with a robust number of patients who have beenfollowed for an adequate time, along with having appro-priate tumor specimens to test these biomarkers.We can chase a lot of ideas with theoretical concepts

and preclinical models, and even studies in a small num-ber of patients. But in the area of oncology, certainly inthe area of breast cancer, we have come to a realizationthat these tumors are heterogeneous. There are manygenes and proteins that impact the pathogenesis. Thus,

we need a fairly large number of patients with appropri-ate molecular testing to reach definite conclusions.I’m very enthusiastic, though, about the way the field

is moving, but at the same time I’m concerned about thevolume of reports that are published in abstract form orpeer-reviewed manuscripts every month in this field thatmay not have a robust number of patients to reach def-inite conclusions.

PMO Yes, and that’s what you’re looking for: an en-riched patient population.

Dr PerezYes, and we’ll get to that, but another area thatis tremendously important in terms of interpretation of theliterature is that it has become easier for journals to promi-nently publicize and publish material that reflects a possiblerelationship between a biomarker and patient outcome. It remains difficult to print data of negative associations.For the needs of patients, reports of negative associ-

ations are as important, so that researchers don’t haveto keep repeating the same work, as well as acknowledgethe work that is done by not only the patients volun-teering tumor specimens but also the investigators whohave done the calculation work.I would like to ask for a call to analyze and publicize

the data, even if they are negative, because that is theway to advance the field.

PMO Yes, everyone from the public to the researchcommunity is getting this skewed, overly positive per-spective on the degree of success – and the ease of suc-cess – that’s present in personalized medicine. Withoutsufficient recognition of the research failures, we willlose the impetus to continue pursuing research areas thatare going to overcome these setbacks.


It’s our ability to identify markers of thetumor of the host that impact pathogenesisso that we can target them to optimizetreatments for the individual patients.

helpful to all cancers. Above all, she applauds the prin-ciple of personalized medicine in oncology: to cultivatean understanding by practicing oncologists of the bio-logical basis of cancer and the pharmacodynamic basisof the drugs – biologicals and conventional alike – usedto combat it. Asked what the practicing oncologist mustglean from the informational overload of this new sci-ence to keep up, her advice was immediate and precise:

“The practicing oncologist needs to understand genes,the regulation of genes, protein expression, and thenmetabolomics.”We turn now to a tour of personalized medicine for

the practicing oncologist by Dr Edith Perez, who de-scribes the strategy and tactics that she and her fellowcolleagues are employing to transform what was once auniversal killer into a manageable, nonlethal condition.


Dr Perez Yes, but I wouldn’t actually use the wordfailure. When we have hypotheses, it’s our job as scien-tists and translational investigators to validate the hy-pothesis or not, and so our obligation is to be able topublish, to report on the information we have provided.That’s the way I look at the field.But I am very enthusiastic about the way we’re mov-

ing because we are all learning about better ways to dothe analysis. We have started to look more carefully atthe way the specimens are collected and stored, the needto validate any laboratory testing that we do with ap-propriate controls, and potentially even have more than1 pathologist look at stains or results of gene analysis.And also how carefully we have to analyze the data fromthese markers in a blinded way in the context of patientoutcomes, so that the results that we obtain truly couldrelate with patient performance.

PMO You’re seeing basically a success in changingnot just prognostic expectations that personalized med-icine provides, but even changing the culture of medi-cine regarding prevention, diagnosis, and treatment?

Dr PerezWell stated. Let me phrase the situation inthis way. It is clear that we have made advances overthe past 30 to 40 years, but at this time I think we are ina position for the advances to be of much greater mag-nitude than what we have been able to accomplish.Second, the 2 basic stories that are most positive in

the setting of breast cancer are following the only 2 tar-gets that we currently use for therapeutic decisions,which include the ER and HER2. At the same time weknow that we have to move beyond these 2 markers inthe context of 24,000 genes, validation of the expressionof these genes, then posttranslational modification approaches.

PMO What is the degree of the proliferation, if youwill, of personalized care in breast cancer compared withother cancers, and what would be the reason for the dif-ferences in the degree of personalized medicine prolif-eration across these cancers?

Dr Perez I think there’s a wide interest in the field ofpersonalized medicine for all malignancies. The 1 issuein the setting of breast cancer that makes it unique is

composed of 2 things. Number 1, breast cancer is a com-mon disease, and we have had some good therapies thathave allowed many patients to survive for longer timesthan other tumor types, which has then led to an advo-cacy coming from the patient’s standpoint to get re-searchers to do research in the setting of breast cancer.

Also a positive for breast cancer has been the factthat some of these therapies that we have found to bebeneficial really have impacted the lives of so many, soessentially we have used the low-hanging fruit. Somethings have worked very well, so we have a lot of impe-tus to keep moving in that direction.But clearly at the same time I’m really very happy that

this field of personalized medicine has started to pan outin the setting of some lung cancers and also some othercancers, especially melanoma, where we’re starting to seesome really fascinating data. But the issue is going to be,are these new data going to impact the 5-year survival


It is clear we have made advances overthe past 30 to 40 years, but at this time Ithink we’re in a position for the advancesto be of much greater magnitude...

An avid runner, Dr Perez, among her many contributions tobreast cancer research, participates in a race for the finish.


of those diseases, which remain way below 20%.So although the data with the EGFR inhibitors for

lung cancer, for the ALK inhibitors for lung cancer, andthe data for the BRAF inhibition in the setting ofmelanoma, look very interesting, we need a little bitlonger follow-up, whereas in breast cancer, we know thattargeting ER, targeting HER2, truly impacts the long-term outcome of patients in addition to having an im-pact on short-term response or progression-free survival.Initially it seems like the group of individuals in-

volved in breast cancer is quite cohesive at the globallevel, but this is happening also with other tumor types.But we have had long-term meetings where researchdata are discussed on an ongoing basis so that we don’tduplicate work, and at the same time we collaboratewith each other to make important data available.

PMO What would be some of the important exam-ples of personalized medicine algorithms of this type asthey’re generally understood? And next, what are someexamples of such algorithms that have been discoveredby researchers but have failed to be adopted by oncolo-gists expeditiously, and how can we expedite the uptakeof that kind of progress for breast cancer patients?

Dr Perez First of all, one of the issues that we have todeal with, and I deal with this all the time, is how to conveythe message of the work that is currently being done, aswell as the complexity of the work being done, to thephysicians who are mainly involved in practice, or to physi-cians or to philanthropists who we absolutely need for sup-port of some of this innovative work. We have to distill thetechnical jargon to understandable concepts that can beconveyed to people because they have to be part of theteam as we try to solve this puzzle of breast cancer.

PMO Yes, including the investors.Dr PerezAbsolutely. Then we as scientists also have

to keep in mind that the honesty related to our researchfindings is something that cannot be underestimated.We have to be judicious in the way we report our owndata and just absolutely always, always tell the truth, notmake more than what we have, not make less than whatwe have. We’ll always be 100% honest and accurate re-lated to the information we share with others.We cannot compromise on this issue because we may

send confusing messages to all of these stakeholders aswell as all the researchers.In terms of personalized medicine algorithms, I think

probably the most important thing I can say is that wehave to work with our pathologists to be able to collectthe tumor specimens in a consistent way, and for pathol-ogists to follow algorithms and recommendations thathave been generated by expert panels related to expo-sure of tissues to various elements so that the tissue re-mains appropriate for testing of these markers.At the same time it is very important to realize that

at least from the treatment standpoint, depending onthe data that we get from these molecular profiles, theclinical condition of the patient is also very important.So we don’t manage patients only based on laboratoryresults. We manage patients based on the prior therapythey may have had, the patient’s overall condition, andorgan function. We have to put all the pieces together,but I hope that in the next few years we’re going to learnso much about the molecular profile of these tumors thatwe’ll be able to be a lot smarter related to putting to-gether molecular profiles with patient profiles to comeup with the best treatments.When we think about personalized medicine and mo-

lecular markers, there are so many different things thatwe can look at. We can look at whole genome. We canlook at exomes. We can look at RNA. We can look atproteins. We can look at microRNAs, RNAs that mod-ulate function of genes. So this is a very vast field thatspeaks to the complexity of what we need to elucidate.In the area of microRNAs, there are hundreds of

RNAs that have now been identified, and RNAs appearto modulate the function of about a third of our genes.

PMO Given the limitations of personalized medi-


In the area of microRNAs, there arehundreds of RNAs that have now beenidentified, and RNAs appear to modulatethe function of about a third of our genes.


cine, empirical science continues to play a predominantrole in cancer care and in research, and we won’t beabandoning this approach anytime soon. Because of theneed for personalized medicine and empirical medicineto coexist, we’d welcome your comments to put person-alized medicine into an operational perspective.

Dr Perez I think in order to provide personalizedmedicine there will always be a portion of empiricism,because I don’t know if we are going to be able to devisea treatment that will target all molecular abnormalitiesthat may be driving a tumor for each individual patient.I think what we’re going to be able to do is subclassify

patients based on pathways, and I hope that will give usenough information to be able to have maybe 10 typesof breast cancer and guide therapy based on that. Ideally,if a tumor is found to have 3 abnormalities and we canfind 3 drugs that address those abnormalities, then obvi-ously we will be able to provide individualized care toeach patient. But I think the way things are going, eachbreast cancer may have many more than 3 abnormalities,so we may not be able to treat a patient with 20 drugs.A realistic approach means that, while most of what

we do now is empiric, the balance will change. But we’regoing to have to be realistic related to whether we will ad-dress every target in the tumor. Think about this: It’s morethan just being able to identify the abnormalities in thetumor with genomic analysis. We need to identify whetherthey are drivers of tumor growth or metastatic potential.

PMO Is there any strategic guidance that you mightoffer practicing oncologists to give appropriate emphasisto personalized medicine in order to integrate it intotheir clinical strategic process?

Dr Perez I think the guidance is going to be that weare going to need more access to more specimens in theevolution of the disease process to be able to manage pa-tients in an optimal way. Right now we’ve been practi-cally relying on the limited molecular testing that wecan do on the original tumor and expect that that willprovide us the guide on how to manage patients whenthey develop relapse, when they go into a metastatic set-ting, when they develop further progression, so I thinkthat has to be the guide.

We may need to be much more attentive and consis-tent in our recommendations to obtain biopsies so thatwe can do this molecular analysis at the different stagesof the disease process. Then people like me and otherswill figure out the best tools with which to evaluate themolecular changes. But without tissue that can be col-lated with patient outcome, we will not be able to ad-vance as quickly as we should.

PMO How would you advise oncologists so that


Dr Perez and her team are focusing on developing a newmolecular classification for breast cancer.

Dr Perez with E. Aubrey Thompson, PhD, Professor of Bio -chemistry and Molecular Biology at the Mayo Clinic in Florida.


they could develop a sophistication in their under-standing of personalized medicine techniques to distin-guish real innovation from just novelty?

Dr Perez Very good point. I think it’s going to be upto all of us. I think it’s our responsibility to educatephysicians, because the terminology is different fromwhat they learned in medical school. So we need differ-ent specimens to do different types of gene sequencing.We need to help them understand the difference be-tween doing an exome analysis versus a whole genomesequencing and the data that we can get. There’s a re-alization that we’ll need to work together to educatepracticing oncologists, and it will be done.

PMO Can you describe breast cancer patient sub-group risk stratification as part of the personalized med-icine revolution? What are the different categories ofbreast cancer prognostic expression signature sets?

Dr Perez They’re currently being defined. That’s ac-tually 1 of the challenges in the field. Different peopleare using different technologies to come up with signa-tures, and the genes from one signature do not correlatewith the genes found with the other mechanisms, sothese signatures seem to be nonconsistent, in my opin-ion. That’s because the platforms used to develop the sig-natures are different. So I think as we get more and moreinto understanding the exome, and we get to understandthe whole genome sequencing, this will get better, be-cause right now we just have a smatter of signatures andno real clear-cut relation between one versus the other.To complicate matters even more, not many studies havebeen done in which a specific set of tumors has beentested using different techniques to see if the signaturesthat are derived are the same or different.

PMO How do they reflect tumor status?Dr PerezWell, right now we and others are working

on redeveloping signatures for what’s ER-positive versusER-negative breast cancer. I think we will eventuallydevelop signatures for patients with HER2-positivebreast cancer that will have a likelihood of respondingto trastuzumab or lapatinib or other agents.Right now the status of the signature is that no one

can tell me whether it’s a primary tumor or a metastaticsite. That’s not the area that we are going to be pursuing.We’re just going to take a tumor wherever it is, try tounderstand the biology so that we can offer the besttherapy for our patients.

PMO Drilling down 1 step further. These signaturesets, how do they help delineate outcome?

Dr Perez When we find mutations in the signaturesets that are important for the pathophysiology of thebreast cancer, then we’ll be able to really devise thera-peutic strategies using combinations of agents, and that will be directly correlated with improved patientoutcome. At least that’s the way I envision this.

PMO Historically, how reliable are they?Dr PerezWell, we haven’t had the tools in the past.

Right now the best we can do when we have a patientwith advanced cancer is to choose any of the drugs thathave been approved by regulatory agencies. Each drughas approximately a 20% to 30% activity, and that’s justnot good enough. I hope that we’ll get to the pointwhere we’ll be able to do the analysis of the tumors andtell the patient, “hey, your tumor has an 80% chance ofbenefiting.” Even with that I’m going to be very happy.

PMO Are these codified in algorithms by the Na-tional Comprehensive Cancer Network or AmericanSociety of Clinical Oncology?

Dr Perez Not yet, because there are so many signa-tures that are being published, based on what I considerto be evolving technologies, that they have not beenvalidated by others enough to really have big names yet.

PMO What are the specific breast cancer patienttypes – and tumor types? Is the revelation of personalizedmedicine processes in breast cancer leading to subspe-cialization based on these patient types and tumor types?

Dr Perez This will happen, but right now they’re re-ally not validated enough for me to tell you that there


Right now the best we can do when wehave a patient with advanced cancer isto choose any of the drugs that havebeen approved by regulatory agencies.


are going to be 4 subtypes of breast cancer, or 10. I thinkthis is going to require a little bit more work.Right now we’re still using ER/PR [progesterone re-

ceptor] and HER2 to make the decisions for patients.Everything else is to be validated.

PMO In what way would this profiling aid the on-cologist in risk stratification, in establishing prognosticexpectations, and in identifying personalized medicinediagnostic tests and treatment?

Dr Perez Just to give you an example of how this isgoing to be revolutionized: Right now when a new pa-tient is diagnosed with breast cancer, we do surgery andtake the tumor out, and then we give adjuvant therapy,or we may decide to give neoadjuvant therapy. But thereare essentially about 5 drugs that are used where I thinkthere may be 40 abnormalities in the breast cancer thatmay be important to drive pathogenesis. I think in thefuture we’re going to have many more agents that arereally directed toward their normal targets. Instead ofhaving 1 general recommendation for adjuvant ther-apy, we may have 10. Because right now everybody’streated the same way, bottom line. Everybody getschemotherapy, that is anthracycline, taxane-basedchemotherapy. That’s it. That is the backbone of treat-ment for patients with cancer, even with early-stagebreast cancer, and we need to be much more specificthan you’re seeing, you know, 2 classes of drugs that aremost effective.

PMO If you could, please discuss the discovery andadvancement of the approved biomarkers for breast can-cer, and the investigational ones.

Dr Perez In terms of a routine management of pa-tients with breast cancer, there are only 3 markers thatare done: ER, PR, and HER2. And it’s not evenHER2/neu. HER2/neu refers to the HER2 gene, so weprefer to call it HER2 because HER2 addresses evalua-tion of the protein or the gene, and we can do either fora therapeutic decision. We don’t have to do both.EGFR has been looked at, and it has not panned out

yet as a marker to drive therapy in patients with breastcancer. Regarding p53, certainly we know it’s expressedas abnormal in a majority of tumors, but it’s not tumor-

specific enough to guide therapy, and people have triedto look at p53 in the context of anthracyclines, butagain nothing specific.So we just wonder when looking at AKT, looking at

PA3 kinase, looking at IGF, are those markers going tobe important, but right now we don’t know. MET maybe a very important marker in breast cancer. Protein ki-nase D1 may be important, but again, all these thingsare a part of research right now. Nodule may be impor-tant. But we need to figure out what those markersmean in the context of the physiology of this disease.

PMOWhy are these attracting the most interest andresearch?

Dr Perez One of the reasons is that companies havedrugs that target a particular marker, because the othermarkers that we haven’t talked a lot about today are themicroRNAs, which may control 30% of our genome,and theoretically they could be extremely important.But more work needs to be done in that area.


Offering patients optimal therapies with minimal side effects isat the heart of Dr Perez’s work.


Another area certainly is phosphorylated proteins,but that is very difficult to test for because phosphory-lation occurs, and in 1 minute it’s gone, so you cannotassay for the impact of phosphorylated proteins in thecontext of tumors. We can do that very well in cell lines,but that’s very different than in humans, so I think that’sgoing to be a very challenging area to conquer.The other biomarker of interest has been circulating

tumor cells. Before we can really explore this more, weneed to first understand if the genomic markers in cir-culating tumor cells are equivalent to the genomicmarkers of the tumors that are invading different organs.And second, can we assay for a variety of molecularmarkers in circulating tumor cells when we may havejust 5 cells per mL? When is the technology going to begood enough that we can take 2 cells and do enoughbiomarkers in those 2 cells to be able to drive a betterunderstanding of breast cancer?If we can avoid having to do invasive biopsies and

just assay the circulating tumor cells, that would begreat. But before we do this we again need to addressthose 2 issues: are they the same cells, or is there some-thing different about the cells that decide to shed andbe in the circulation compared with the tumors that areinvading the liver and causing death?

PMO What would you regard as landmark researchin personalized medicine in breast cancer and the clin-ical basis for its significance?

Dr Perez The term “personalized medicine” is a verybroad term, but essentially the most important bio-marker in addition to ER really has been HER2. HER2was identified, and then we developed a strategy in themetastatic setting to target HER2, clearly improving sur-vival. And then we were able to take that marker anduse these agents in the adjuvant setting, and we de-creased relapse by 50%, and we are improving survivalby 38%. So now by using this biomarker, this is part ofpersonalized medicine. We’ve been able to change thenatural history of HER2-positive breast cancer from avery aggressive type of breast cancer to one that is verymanageable and potentially curable.

PMO Are there any particular clinical, business, or

policy factors impeding progress in breast cancer, espe-cially involving personalized medicine?

Dr Perez It’s really time and money, because we needto put enough resources not only to have sequencingmachines but to have the patient resources to haveenough tumor specimens to not only put the specimensin a machine but also to have the bioinformatics per-sonnel to put the story together. There has to be a fo-cused and concerted effort to devote enough resourcesto this area in a timely fashion to really get the answers.

PMO Are there particular areas of consensus andparticular areas of controversy concerning biomarkersin particular and personalized medicine in general in-volving breast cancer that you see as standing out, veryobvious ones?

Dr PerezThe controversy is, in my opinion, that somepeople feel a lot of gene work has been done and “it hasn’ttranslated into anything yet.” Some people have becomenaysayers because they’re not as involved as some of usare, trying to really make specific advances on this.I think that is the main controversy. This is a new

field, and people don’t understand it. Breast cancer is agenetic disease, and we really need to unravel the ge-netics of this disease, what drives gene function, whatis the product of those genes, so that we can realize thisdream, going back to the dream of personalized medi-cine for our patients with breast cancer.

PMO In your research priorities, are you going tofocus in 1 area?

Dr PerezAbsolutely, although our interests are veryvast. I hope that our work will eventually lead to a newmolecular classification of breast cancer and we’ll iden-tify the relevance of types of breast cancer to drive treat-ment decisions. Along those lines, this finding of fusiongenes in breast cancer may be very important. But firstof all, we need to identify what the redundant fusiongenes are, and number 2, do they have any associatedprotein products, and can they be utilized for the devel-opment of new treatments.

PMO That gives us a perfect place to end our discus-sion today. Thank you for your time.

Dr Perez My pleasure. u


AGENDA*

FRIDAY, JULY 26, 20133:00 pm – 7:00 pm Registration5:30 pm – 7:30 pm Welcome Reception/Exhibits

SATURDAY, JULY 27, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Welcome to the Second Annual World Cutaneous Malignancies

Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies• Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway

• Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 4:30 pm General Session II: Current Treatment Guidelines in Cutaneous

Malignancies• Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients

• Panel Discussion Management Controversies and AcceptedGuidelines for the Personalized Management of Cutaneous Malignancies

• Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm Meet the Experts/Networking/Exhibits

SUNDAY, JULY 28, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Review of Saturday’s Presentations and Preview of Today’s Sessions8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for

Cutaneous MalignanciesGeneral Session IV: Challenges for the Cutaneous Malignancies Clinician• Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 2:45 pm General Session V: “Hot Data” — What I Learned at Recent Meetings:

Focus on Cutaneous Malignancies2:45 pm – 3:00 pm Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

A 2-day congress dedicated to informing, educating, and fostering the exchangeof clinically relevant information in the field of cutaneous malignancies on topics inmelanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carci-noma, and Merkel cell carcinoma, including:

• Epidemiology and genetic/environmental factors

• Molecular biology and cytogenetics related to the pathogenesis of cutaneousmalignancies

• Risk stratification based on patient and tumor characteristics

• Principles of cancer prevention of melanoma and basal cell carcinoma

• Current treatment guidelines

• Emerging treatment options for personalized therapy

• Future strategies in management based on translational data from current clinicaltrials and basic research

PROGRAM OVERVIEW

This activity was developed for medical and surgical oncologists, dermatologists,radiation oncologists, and pathologists actively involved in the treatment of cu-taneous malignancies. Advanced practice oncology or dermatololgy nurses,oncology pharmacists, and researchers interested in the molecular biology andmanagement of cutaneous malignancies are also encouraged to participate.

TARGET AUDIENCE

Upon completion of this activity, the participant will be able to:

• Review the molecular biology and pathogenesis of cutaneous malignancies asthey relate to the treatment of cutaneous T-cell lymphoma, basal cell carci-noma, Merkel cell tumors, and malignant melanoma

• Compare risk stratification of patients with cutaneous malignancies, and how totailor treatment based on patient and tumor characteristics

• Summarize a personalized treatment strategy that incorporates current stan-dards of care and emerging treatment options for therapy of patients with cu-taneous malignancies

LEARNING OBJECTIVES

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DESIGNATION OF CREDIT STATEMENTS

PHYSICIAN CREDIT DESIGNATION

SPONSORS

REGISTERED NURSE DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 12.0AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

This activity is jointly sponsored by Medical Learning Institute Inc, Center of ExcellenceMedia, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

Medical Learning Institute IncProvider approved by the California Board of Registered Nursing, Provider Number15106, for 12.0 contact hours.

Sanjiv S. Agarwala, MDProfessor of Medicine Temple University School ofMedicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

Steven J. O’Day, MDHematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer CenterClinical Associate Professor of MedicineUSC Keck School of MedicineLos Angeles, California

Professor Dr. Med. AxelHauschildProfessor, Department of DermatologyUniversity of KielKiel, Germany

CONFERENCE CO-CHAIRS

July 26-28, 2013Hyatt Regency La Jolla • San Diego, California

• Melanoma

• Basal Cell Carcinoma

• Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma

• Merkel Cell Carcinoma

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN!$175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharmacyeducation. Completion of this knowledge-based activity provides for 12.0contact hours (1.2 CEUs) of continuing pharmacy education credit. The

Universal Activity Number for this activity is (To be determined).

For complete agenda please visit www.CutaneousMalignancies.com

� � ��


The Evolution of PersonalizedBiomarker-Based Therapy forAdvanced Non–Small Cell LungCancerRoy S. Herbst, MD, PhD, from the Yale Compre-

hensive Cancer Center and Yale School of Medicinein New Haven, Connecticut, began the symposium by

discussing the magnitude of the problem of non–smallcell lung cancer (NSCLC).Lung cancer (both small cell and non–small cell) is the

second most common cancer in both men and women(not counting skin cancer). In men, prostate cancer ismore common, while in women breast cancer is morecommon. In the United States alone, approximately

Continuing Medical Education

Clinical Approaches to Targeted Technologies:Implementing the Promise of Prognostic Precision IntoPersonalized Cancer CareAn ancillary educational symposium, Clinical Approaches to Targeted Technologies: Implementing thePromise of Prognostic Precision Into Personalized Cancer Care, was held June 2, 2012, in conjunction withthe 2012 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. The symposiumfocused on evolving regional standards of care and cutting-edge information and emerging data onmolecular markers that can impact treatment strategies for specific tumor types. This continuing medicaleducation activity brings together highlights, summaries, and expert commentary from the symposium onthe current and future direction of the application of biomarkers in personalized care for patients with solid tumors.

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc, CorePrinciple Solutions, LLC, and Center of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Boehringer Ingelheim and Eisai Pharmaceuticals.

Target AudienceThis educational activity is directed toward medical oncologists,pathologists, geneticists, advanced practice oncology nurses, re-search nurses, clinical oncology pharmacists, genetic counselors,and other healthcare providers involved in the management of pa-tients with solid tumors and interested in the use of moleculartumor biomarkers to help optimize patient care.

Purpose StatementThe purpose of this activity is to enhance competence of medical on-cologists, pathologists, geneticists, advanced practice oncologynurses, research nurses, clinical oncology pharmacists, genetic coun-selors, and other healthcare providers concerning the application ofbiomarkers in personalized care for patients with solid tumors.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring materialfor a maximum of 1.25 AMA PRA Category 1 Credits™. Physiciansshould claim only the credit commensurate with the extent of theirparticipation in the activity. This activity has been planned and imple-

mented in accordance with the Essential Areas and policies of the Ac-creditation Council for Continuing Medical Education through the jointsponsorship of the Medical Learning Institute Inc, Core Principle So-lutions, LLC, and the Center of Excellence Media, LLC. The MedicalLearning Institute Inc is accredited by the Accreditation Council forContinuing Medical Education to provide continuing medical educationfor physicians.

Registered Nurse DesignationMedical Learning Institute Inc.Provider approved by the California Board of Registered Nursing,Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the Accred-itation Council for Pharmacy Education as a provider of con-

tinuing pharmacy education. Completion of this knowledge-basedactivity provides for 1.25 contact hours (0.125 CEUs) of continuingpharmacy education credit. The Universal Activity Number for this ac-tivity is 0468-9999-12-032-H01-P.

Learning ObjectivesUpon completing this activity, the participants will be able to:• Assess emerging data and recent advances in the discovery of solidtumor biomarkers, their impact on the treatment of patients withsolid tumors, and how to integrate key findings into clinical practice • Discuss the role of tumor biomarkers in designing personalizedtherapy for patients with solid tumor cancers, including manage-ment of treatment-related adverse events

To receive credit, complete the posttest at www.mlicme.org/P12038E.html.


226,160 new cases of lung cancer (116,470 in men and109,690 in women) will be diagnosed in 2012.1 Lung can-cer is by far the leading cause of cancer death among bothmen and women. Each year, more people die of lung can-cer than of colon, breast, and prostate cancers combined.In the United States, an estimated 160,340 deaths willoccur in 2012 from lung cancer (87,750 in men and72,590 among women).1 Five-year survival rates for pa-tients with advanced NSCLC are extremely low (Figure1),2 indicating an urgent need for better therapies.However, the development of new therapies is fraught

with challenges, including long timelines, great attrition,and huge expense. As illustrated in Figure 2, it takes ap-proximately 24 drug candidates and a period of 14 or moreyears of research and development to result in the launchof just 1 new drug.3,4 According to Herbst, “The goal is toidentify a biomarker early on, so we can test the right drug

in the right patient at the right time, thus decreasing theamount of time the drug takes in clinical trials.”

To receive credit, complete the posttest at www.mlicme.org/P12038E.html.

DisclosuresBefore the activity, all faculty and anyone who is in a position to havecontrol over the content of this activity and their spouse/life partner willdisclose the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcaregoods/services to be discussed during their presentation(s): honoraria,expenses, grants, consulting roles, speakers bureau membership, stockownership, or other special relationships. Presenters will inform partic-ipants of any off-label discussions. All identified conflicts of interest arethoroughly vetted by Medical Learning Institute Inc for fair balance, sci-entific objectivity of studies mentioned in the materials or used as thebasis for content, and appropriateness of patient care recommendations.

Planners and Managers DisclosuresKaren Cooksey, Medical Writer, has nothing to disclose.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Teresa Haile, RPh, MBA, MLI Reviewer, has nothing to disclose.Kathryn Gada, MSN, MLI Reviewer, has nothing to disclose.

Faculty DisclosuresRoy S. Herbst, MD, PhD, Professor of Medicine and Pharmacology,receives grant support/research funding from Amgen, AstraZeneca,Bristol-Myers Squibb, Genentech, Geron, Imclone, Novartis, On-cothyreon, OSI Pharmaceuticals, Pfizer, and Sanofi Aventis; is a paidconsultant for Allos Therapeutics, Argennix Inc, Boehringer Ingelheim,Genentech, and OSI Pharmaceuticals; and is on scientific advisoryboards for Biothera, DiaTech Oncology, Genetics Squared, MedTrust,N-of-One, SynDevRx, and Targeted Molecular Diagnostics.

The associates of Medical Learning Institute Inc, the accreditedprovider for this activity, Core Principle Solutions, LLC, and Center ofExcellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest

related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

DisclaimerThe information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the inde-pendent medical judgment of a healthcare provider relative to diag-nostic and treatment options of a specific patient’s medical condition.Recommendations for the use of particular therapeutic agents arebased on the best available scientific evidence and current clinicalguidelines. No bias toward or promotion for any agent discussed inthis program should be inferred.

Instructions for Credit

There is no fee for this activity. To receive credit after reading thisCME/CPE/CE activity in its entirety, participants must complete thepretest, posttest, and evaluation. The pretest, posttest, and evaluationcan be completed online at www.mlicme.org/P12038E.html. Uponcompletion of the evaluation and scoring 70% or better on the posttest,you will immediately receive your certificate online. If you do notachieve a score of 70% or better on the posttest, you will be asked totake it again. Please retain a copy of the Certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 [email protected].

Estimated time to complete this activity: 1.25 hoursDate of initial release: November 13, 2012Valid for CME/CPE/CE credit through: November 13, 2013

Figure 1. Five-Year Survival Rates for PatientsWith NSCLC by Stage2

NSCLC indicates non–small cell lung cancer.

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Evolution of ChemotherapyModern chemotherapy was born in 1942 at Yale Uni-

versity, when the first oncology patient received treat-ment with nitrogen mustard.5 A timeline showing otherkey developments in the war against cancer is presentedin Figure 3.6

Lung cancer chemotherapy reached the modern agein the mid 1990s, when a number of promising newagents, including the taxanes, gemcitabine, and vinorel-bine, became available for the treatment of metastaticNSCLC. However, a study by Schiller and colleagues in2002 compared the survival rates achieved by 4chemotherapy regimens (cisplatin plus paclitaxel, cis-platin plus gemcitabine, cisplatin plus docetaxel, or car-boplatin plus paclitaxel) in the treatment of advancedNSCLC and found that none of the 4 chemotherapyregimens offered a significant advantage over the others(Figure 4).7 These results indicated that a ceiling hadbeen reached in efficacy with these chemotherapy regi-mens, and a paradigm shift was needed.

Targeting the Tyrosine Kinase InhibitorsBecause of this need for novel therapeutic approaches,

research began using small-molecule tyrosine kinase in-hibitors to target lung cancer. In 1997, the first orally ad-ministered epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors – gefitinib and erlotinib – en-tered clinical studies. In 2002, phase 1 results from a studywith gefitinib showed antitumor activity at all doses inboth chemotherapy-naive and heavily pretreated pa-tients.8 Gefitinib was granted accelerated approval by theFDA in May 2003 for the treatment of patients withNSCLC who were refractory to established cancer treat-ments (ie, both a platinum drug and docetaxel) on thebasis of a surrogate end point, tumor response rate, for clin-ical efficacy. The response rate in patients taking the drugwas approximately 10%.9 In November 2004, the FDAapproved erlotinib for the treatment of patients with lo-cally advanced or metastatic NSCLC after failure of atleast 1 prior chemotherapy regimen. Unlike gefitinib, er-lotinib was approved based on improved overall survival.10


Figure 2. Drug Development Timeline

p(TS) indicates probability of technical success of that phase; WIP, work in progress, ie, the number of projects (targets) pursued.

Reprinted by permission from Macmillan Publishers Ltd: Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceuticalindustry’s grand challenge. Nat Rev Drug Discov. 2010;9:203-214. Copyright 2010.

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Studies found that the EGFR gene is mutated inmany NSCLCs, and that these mutations are associatedwith increased sensitivity to gefitinib or erlotinib. In ad-dition, EGFR gene mutations were found to be morecommon among females, patients from Japan, neversmokers, and patients with adenocarcinomas, which arethe same groups that have the highest response rates totyrosine kinase inhibitors.11-13

In 2005, a study by Shigematsu and colleagues foundthat mutations in either of 2 genes (EGFR or KRAS)are involved in the development of lung cancer.14 Theyfound that, in lung cancer patients, mutations in the ty-rosine kinase domain of the EGFR gene were more com-mon in never smokers than in smokers or nonsmokers

(51% vs 10%), adenocarcinomas versus other types oflung cancer (40% vs 3%), patients of East Asian ances-try versus other ethnicities (30% vs 8%), and females

versus males (42% vs 14%). Mutation status was not as-sociated with age at diagnosis, clinical stage, the pres-ence of certain histologic features, or overall survival,and mutations were not found in any normal tissue ortissue from other cancer types. EGFR tyrosine kinase


Figure 3. Timeline Showing the History of Chemotherapy

Reprinted by permission from Macmillan Publishers Ltd: Chabner BA, Roberts TG Jr. Timeline: chemotherapy and the war on cancer. Nat Rev Cancer. 2005;5:65-72. Copyright2005.

In 1997, the first orally administered EGFRtyrosine kinase inhibitors entered clinicalstudies.

Louis Goodmanand Alfred Gilmanuse nitrogen mustard to treat apatient with non-Hodgkin’s lymphoma anddemonstrate forthe first time thatchemotherapy caninduce tumor regression.

The NationalChemotherapyProgram beginsat the NationalCancer Institute(NCI); a systematic program for drug screeningcommences.

The Food and Drug Administration(FDA) approves thealkylatingagent cyclophos-phamide.

Vincent DeVita and colleaguescure lymphomaswith combinationchemo therapy.

A combinationof cyclophos-phamide,methotrexate,and fluorouracil(CMF) wasshown to be effective as adjuvant treatment fornode-positivebreast cancer.

The NCI introduces“disease oriented”screeningusing 60 celllines derivedfrom differenttypes of humantumor.

Studies by BrianDruker lead toFDA approvalof imatinib mesylate(Gleevec) forchronic myelogenousleukemia, a newparadigm fortargeted therapyin oncology.

The FDA approves bevacizumab(Avastin), thefirst clinicallyproven antiangiogenicagent, for thetreatment ofcolon cancer.

Sidney Farber usesantifolates to successfully induceremissions in children withacute lymphoblasticleukemia (ALL).

Roy Hertz andMin Chiu Lidemonstrate thatmethotrexate as asingle agent cancure choriocarci-noma, the firstsolid tumor to becured bychemotherapy.

Combinationchemotherapy(POMP regimen)is able to inducelong-term remissions inchildren withALL.

Emil Frei andcolleaguesdemonstrate thatchemotherapygiven after surgical removalof osteosarcomacan improve curerates (adjuvantchemotherapy).

The FDA approves cisplatinfor the treatmentof ovarian cancer,a drug that wouldprove to have activity across abroad range ofsolid tumors.

The FDA approves paclitaxel(Taxol), whichbecomes the first“blockbuster”oncology drug.

Researchers at Harvard Universitydefine mutations inthe epidermal growthfactor receptor thatconfer selectiveresponsiveness to thetargeted agent gefitinib, indicatingthat molecular testingmight be able toprospectively identifysubsets of patientsthat will respond totargeted agents.

George Hitchings and Gertude Elion synthesize the purine analogue 6-mercaptopurine.

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domain mutations are the first known mutations tooccur in never smokers. In addition, they found muta-tions in the KRAS gene, an EGFR signaling pathwaygene, in 8% of lung cancers but not in any that had anEGFR gene mutation.

Based on these and other data, in 2011, ASCO issueda provisional clinical opinion recommending EGFRmu-tation testing for patients with advanced NSCLC.15

Also in 2011, the National Comprehensive CancerNetwork (NCCN) similarly called for EGFR testing ofNSCLC patients with tumors of all histologies exceptsquamous cell carcinoma.16

Targeting Anaplastic Lymphoma Kinase InhibitorsThe benefit of testing for mutations of the anaplastic

lymphoma kinase (ALK) gene, such as the EML4-ALKfusion, was demonstrated in a phase 1 study17 and a phase2 study18 of the ALK inhibitor crizotinib. In these studies,

patients with the EML4-ALK fusion, nearly all of whomhad progressed despite at least 1 prior line of therapy,showed response rates of 50% to 60% with crizotinib.17,18

Based on the results of these 2 studies, in August2011, the FDA granted accelerated approval to crizo-tinib for the treatment of patients with locally advancedor metastatic NSCLC that is ALK-positive as detectedby a concurrently FDA-approved diagnostic test. In ad-dition, based on a retrospective, nonrandomized analysiscomparing overall survival of patients enrolled in the 2trials with historical controls to estimate the clinicalbenefit of crizotinib therapy,19 the NCCN recommendstesting for ALK rearrangement in patients with meta -s tatic NSCLC adenocarcinoma, and treatment with the ALK inhibitor crizotinib is recommended for ALK-positive patients.16

Multiple Pathways of Lung Cancer PathogenesisLung cancer is a heterogeneous disease. Because lung

cancer tumors differ from one another pathologicallyand molecularly, personalized lung cancer therapy is crit-ical in the battle against this disease. Multiple pathwaysof lung cancer pathogenesis have been uncovered, muchdue to the work done in the Tumor Sequencing Project(TSP). The TSP team sequenced 623 genes that wereknown or suspected to contribute to cancer formationin 188 lung cancer patients and matched controls.20 Bycombining mutation information with copy number andexpression data for 41 lung adenocarcinomas, they werealso able to determine whether specific mutations affected gene activity and/or copy number. The researchers detected 1013 nonsynonymous somatic mutations in 163 of these lung tumors. Most (>900)were point mutations, although insertions, deletions,and dinucleotide mutations were also detected. Overall,they found 26 genes that were most often mutated inlung adenocarcinoma (Figure 5). Among them weresome genes that had not previously been tied to lungcancer but which have been linked to other types ofcancer. These findings shed further light on several im-portant signaling pathways involved in lung adenocar-cinoma and suggest new molecular targets for treatment.


Figure 4. Overall Survival by Treatment Group

From Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regi-mens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. Copyright© 2002 Massachusetts Medical Society. Reprinted with permission from MassachusettsMedical Society.

EGFR tyrosine kinase domain mutations are the first known mutations to occur innever smokers.

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Latest Clinical Data on MolecularBiomarkers and Their Impact on the Management of Patients With Solid TumorsBiomarkers in Colorectal CancerLeonard B. Saltz, MD, from the Memorial Sloan-

Kettering Cancer Center in New York, New York, pre-sented data along with his personal opinions about theusefulness of biomarkers in the management of colorec-tal cancer. He began by stating, “most biomarkers thatare currently available for patients with colorectal can-cer do not provide actionable information and thereforeshould not be used in routine practice.”One clinical or surrogate “biomarker” that Saltz said

is useful in predicting survival in patients receiving the

EGFR-targeted monoclonal antibodies cetuximab andpanitumumab is the presence of a skin rash (Figure 6).In a number of studies, the presence of an acne-like

skin rash, predominantly on the face and upper torso,correlates with survival in patients treated with cetux-imab and may serve as a clinical biomarker to identifypatients likely to respond to cetuximab therapy (Figure7).21-25 Said Saltz, “Absence of skin rash with cetuximabor panitumumab at 4 weeks strongly suggests lack of ac-tivity of the anti-EGFR agent, and the clinician shouldconsider cessation of the agent.”The KRAS mutation, which may be present in 35%

to 45% of patients with colorectal cancer, has emergedas a predictive marker of resistance to panitumumab orcetuximab treatment.26-29 For example, in a study by


Figure 5. Mutation Analysis Shows That Multiple Mutations Along Multiple Pathways Drive thePathogenesis of Lung Cancer

Reprinted by permission from Macmillan Publishers Ltd: Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature.2008;455:1069-1075. Copyright 2008.

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Amado and colleagues, a strong correlation was demon-strated between the KRAS mutation and response topanitumumab (Figure 8).27

In a study by Bokemeyer and colleagues, a strong cor-relation was demonstrated between the KRASmutationand response to cetuximab (Figure 9).29 These results

show compelling evidence that KRASmutation is a bio-marker that predicts lack of response to both pani -tumumab and cetuximab; therefore, KRAS genotypinghas been incorporated into clinical practice.26

In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA oncogenesor loss of PTEN tumor suppressor gene expression maybe associated with resistance to EGFR-targeted mono-clonal antibody treatment.26 BRAF mutations are re-sponsible for an additional 12% to 15% of patients whofail to respond to anti-EGFR treatment. Because theRas-Raf-MAPK pathway lies just downstream of EGFR,a mutation in KRAS could render cells independent ofupstream EGFR activation or inhibition of the receptorthrough anti-EGFR therapies. Recent studies now showa strong correlation of KRAS and BRAFmutations withresponse to panitumumab and cetuximab. These studiesshow compelling evidence that KRAS and BRAF mu-tations are biomarkers of nonresponse to either of thesedrugs in patients with metastatic colorectal cancer. Thisfinding suggests that genotyping for the BRAF V600Emutation complements KRAS mutation analysis andmay be as important as KRAS testing for treatment decisions.30

Biomarkers in Prostate CancerOliver Sartor, MD, from the Tulane Cancer Center

and Tulane Medical School in New Orleans, Louisiana,explained that “the brave new era of biomarker-driventherapeutic decision making has yet to arrive forprostate cancer, as clinically useful biomarkers otherthan prostate-specific antigen (PSA) have been slow todevelop in this common malignancy.”PSA screening has led to a significant rise in the

number of men diagnosed with prostate cancer and anassociated increase in biopsies performed. Despite itslimitations, including a positive predictive value of only25% to 40%, PSA remains the only generally acceptedbiomarker for prostate cancer.31

In recent years, studies have shown that a change incirculating tumor cell (CTC) count could indicatewhether a therapy for metastatic breast,32-34 colorectal,35


Figure 6. Cetuximab-Associated Skin Rash

Figure 7. Correlation of Severity of Skin Rash WithSurvival of Cetuximab-Treated Patients21

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Saltz LB, Meropol NJ, Loehrer PJ Sr, et al. Phase II trial of cetuximab in patients with re-fractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol.2004;22:1201-1208. Reprinted with permission. © 2004 American Society of Clinical Oncology. All rights reserved.


or prostate cancer36,37 is effective.38-40

A semiautomated system, the CellSearch Circulat-ing Tumor Cell Kit, has been developed using an ep-

ithelial cell adhesion molecule (EpCAM) antibody-based immunomagnetic capture and automated stain-ing methodology for the enumeration of CTCs of


Figure 8. Increased Progression-Free Survival Observed With Panitumumab in PatientsWith (A) KRAS Mutant Tumors Versus Those With (B) KRAS Wild-Type Tumors

BSC indicates best supportive care; HR, hazard ratio; Panit., panitumumab. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol.2008;26:1626-1634. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.


epithelial origin (CD45–, EpCAM+, and cytokeratins8, 18+, and/or 19+) in whole blood.41 The system andreagents have been approved by the FDA for predictingprogression-free and overall survival in patients withmetastatic breast, colorectal, or prostate cancer. In apivotal trial, the detection of >5 CTCs per 7.5 mL ofblood at the start of chemotherapy and after each cycleof therapy was associated with shorter progression-free

and overall survival in patients with metastatic breastcancer. CTC counts were more predictive of the out-comes than were standard clinical parameters.42,43 Forprostate cancer, preliminary analysis of the correlationof CTC counts with mRNAs for PSA or prostate-specific membrane antigen and available clinical pre-dictors have been encouraging.41,44,45 However, sincepublished literature has yet to demonstrate that the useof CTC measurements improves quality of life or in-

creases survival, ASCO does not recommend use ofCTC measurements for diagnostic or treatment deci-sion making.34 Sartor concluded his discussion of CTCswith this remark, “CTCs are FDA approved but not yetdemonstrably useful.”

Biomarkers in Breast CancerLisa A. Carey, MD, from the Lineberger Comprehen-

sive Cancer Center at the University of North Carolinaat Chapel Hill, North Carolina, presented a discussion ofthe molecular classification and profiling of breast cancer. Breast cancer is a heterogeneous disease; the recent

identification of molecular subtypes of breast cancer hasled to a paradigm shift in the way we think about breastcancer and may increase our ability to predict responseto current and novel therapies and ultimately improveoutcomes for breast cancer patients (Figure 10).46 In thepast decade, genomic studies have identified severalbreast cancer intrinsic subtypes (luminal A, luminal B,HER2-enriched, claudin-low, basal-like) and a normalbreast-like group.47-52

The molecular subtypes display highly significant dif-ferences in prediction of overall survival, as well as re-


The molecular subtypes display highlysignificant differences in prediction ofoverall survival as well as relapse-freesurvival.

Cens. indicates censored; Cet., cetuximab; FOLFOX-4, oxaliplatin, leucovorin, and fluorouracil; HR, hazard ratio; mo., months; pts., patients; Progr., progression.Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectalcancer. J Clin Oncol. 2009;27:663-671. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.

Progression-Free

Survival (pro

portion)

Progression-Free

Survival (pro

portion)

Time (months) Time (months)

Figure 9. Increased Progression-Free Survival Observed in Patients Receiving Cetuximab WithKRAS Wild-Type Tumors Versus Those With KRAS Mutant Tumors


lapse-free survival, with the luminal A subtype havingthe longest survival (Figure 11).47

Harrell and colleagues recently found that, in addi-tion to differences in survival among the various subtypesof breast cancer, differences occur in the overall risk ofrelapse, the timing of relapse, and the organs to whichthe tumors metastasize.53 For example, basal-like andclaudin-low breast cancers both exhibit a high probabil-

ity to metastasize to the brain and lung, while HER2-en-riched subtype tumors preferentially colonize the liver.53

Overall, the authors concluded that, depending on theorgan of relapse, a combination of gene expression sig-natures most accurately predicts metastatic behavior.Using gene expression profiling, van ’t Veer and col-

leagues at The Netherlands Cancer Institute developeda 70-gene signature (MammaPrint) that accurately dis-


Figure 10. Molecular Classification of Breast Cancer46

Figure 11. Differences in Prognosis Among the Various Molecular Subtypes of Breast Cancer

Reprinted from Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5:5-23. Copyright 2011, with permission from Elsevier.

ER–, Claudin-3/4/7low,

vimentin+,E-cadherinlow,

Zeb1+

ERlow, HER2low,proliferationhigh

ER–, PR–, HER2–,K5/14+, EGFR+

Adipose tissuegene signature+

Claudin-low(12%-14%)

Luminal B(~20%)

HER2-enriched(10%-15%)

Luminal A(~40%)

Normal BreastLike

Breast Cancer

HER2+

ER–

p=7.67e-06 p=4.67e-06

Basal-likeClaudin-lowHER2-enrichedLuminal ALuminal B

Ove

rall Su

rvival

Relapse

-Free Survival

Basal-like(15%-20%)

Months Months

ERhigh,HER2low


tinguished breast cancer patients who were likely to re-main free of distant metastases (good profile) from breastcancer patients at high risk of developing distant metas-tases (poor profile).54 The first validation of the 70-geneprofile was performed by van de Vijver and colleagueson a consecutive series of 295 breast cancer tumors; 144tumors from lymph node–positive and 151 tumors fromlymph node–negative breast cancer patients.55 Amongthe 295 patients, 180 had a poor-prognosis signature and115 had a good-prognosis signature, and the mean over-all 10-year survival rates were 55% and 95%, respec-tively. At 10 years, the probability of remaining free of

distant metastases was 51% in the group with a poor-prognosis signature and 85% in the group with a good-prognosis signature. The estimated hazard ratio (HR)for distant metastases in the group with a poor-prognosissignature, compared with the group with the good-prog-nosis signature, was 5.1 (95% CI, 2.9-9.0; P<.001).The 70-gene MammaPrint signature was later vali-

dated by an independent multinational collaborativeteam conducted under the aegis of the TRANSBIG

consortium.56 Their analyses confirmed that the70-gene signature is a strong prognostic factor fortime to distant metastases and overall survival inuntreated patients with node-negative breastcancer, with unadjusted HRs of 2.32 (95% CI,1.35-4.00) and 2.79 (95% CI, 1.60-4.87), respec-tively. In addition, when adjusted for the clinicalrisk groups based on 10-year survival probabilityas calculated by the Adjuvant! Online software,the gene signature HRs were 2.13 (95% CI, 1.19-3.82) for time to distant metastases, 2.63 (95%CI, 1.45-4.79) for overall survival, and 1.36(95% CI, 0.91-2.03) for disease-free survival.These results indicate that the gene signatureadds independent prognostic information to that

provided by a risk assessment based solely on clinico-pathologic factors.MammaPrint is being evaluated in a clinical trial

known as MINDACT (Microarray In Node-negative and1-3 node-positive Disease may Avoid ChemoTherapy),which is a randomized European study comparingMammaPrint with clinical assessment.57 MINDACT hasenrolled over 6000 patients, who have been classified intohigh or low genomic risk by MammaPrint and clinico-pathologic risk through Adjuvant! Online. Patients withboth genomic and clinical high risks are offered adjuvantchemotherapy; those with both genomic and clinical lowrisks do not receive chemotherapy; patients with discor-dant risk are randomized for the decision of adjuvantchemotherapy based on genomic or clinical risk.57 MIN-DACT is due to complete data collection in 2019.The researchers developing the Oncotype DX assay

took a different approach from that used by the devel-opers of MammaPrint. Carey explained, “They startedwith 250 candidate genes and then they tailored it downto 16. Once they found the best genes, they then vali-dated it prospectively.” Paik and colleagues at the Na-tional Surgical Adjuvant Breast and Bowel Project(NSABP) tested whether the results of a reverse-tran-scriptase polymerase chain reaction assay of 21 prospec-tively selected genes in paraffin-embedded tumor tissuewould correlate with the likelihood of distant recurrence


Rate of Distant Risk Category Percentage of Patients Recurrence at 10 YearsLow 51% 6.8%Intermediate 22% 14.3%High 27% 30.5%

*A low risk was defined as a recurrence score of <18, an intermediate risk as a score of 18-<31, and ahigh risk as a score of ≥31.

From Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. Copyright © 2004 Massachusetts MedicalSociety. Reprinted with permission from Massachusetts Medical Society.

Table 1. Kaplan-Meier Estimates of the Rate of Distant Recurrence at 10 Years, According to Recurrence ScoreRisk Categories Among Node-Negative, Tamoxifen-TreatedBreast Cancer Patients*

The researchers developing Oncotype DXtook a different approach from that usedby the developers of MammaPrint.


in patients with node-negative, tamoxifen-treated breastcancer who were enrolled in the NSABP study B-14.58

The levels of expression of 16 cancer-related genes and5 reference genes were used in a prospectively definedalgorithm to calculate a “Recurrence Score” (RS) andto determine a risk group (low, intermediate, or high)for each patient (Table 1). Low risk was defined as anRS <18, intermediate risk as a score of ≥18 but <31, andhigh risk as a score of ≥31. There were 28 recurrences

in the low-risk group, 25 in the intermediate-risk group,and 56 in the high-risk group. The difference among thegroups is significant (P<.001).In addition to quantifying breast cancer recurrence

risk, the Oncotype DX assay also assesses the benefitfrom chemotherapy.

Node-Negative, ER-Positive Breast CancerThe data from which the assay was developed were


Figure 12. Kaplan-Meier Plots for Distant Recurrence Comparing Treatment With Tamoxifen(Tam) Alone Versus Treatment With Tamoxifen Plus Chemotherapy (Tam + chemo)

A, all patients; B, low risk (Recurrence Score [RS] <18); C, intermediate risk (RS 18-30); D, high risk (RS ≥31).

Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol. 2006;24:3726-3734. Reprinted with permission. © 2006 American Society of Clinical Oncology. All rights reserved.


retrospectively analyzed from a prospective randomizedtrial, the NSABP study B-20, which compared the com-bination of chemotherapy (ie, 6 cycles of cyclophos-phamide, methotrexate, and 5-fluorouracil [CMF]) plus

hormonal therapy (ie, tamoxifen) with hormonaltherapy alone in 651 women with lymph node–negative, estrogen receptor (ER)-positive breastcancer (Figure 12).59

Node-Positive, ER-Positive, Postmenopausal Breast CancerFor lymph node–positive, ER-positive post -

meno pausal patients treated with tamoxifen, theOncotype DX report form now includes data retrospectively analyzed from the prospectiverandomized Southwest Oncology Group(SWOG) 8814 study, which evaluated the riskof recurrence or death versus the RS result (bothprognosis and likelihood of chemotherapy bene-fit). In the SWOG 8814 study, 1477 women wererandomized to receive either tamoxifen alone for5 years (n=361), or 6 cycles of chemotherapywith cyclophosphamide, doxorubicin, and fluo-rouracil (CAF) with concurrent tamoxifen(n=550), or 6 cycles of CAF followed by tamox-ifen (CAF-T).60 In women in the low-risk or intermediate-risk groups, CAF-T offered no significant advantage over the 10-year disease-free or overall survival rates seen among thosewho received tamoxifen alone. In contrast,among the women in the high-risk group, the 10-year disease-free and overall survival rates weresignificantly greater with CAF-T than with ta-moxifen alone.

Prospective, Randomized Trials Under WayWhile the Oncotype DX is currently based

upon retrospective data from the aforementioned2 prospective randomized clinical trials, prospec-tive studies are ongoing. One prospective study,known as TAILORx (Trial Assigning Individual-ized Options for Treatment [Rx]) is examining

whether chemotherapy is required for the intermediate-risk group defined by the RS.61 Another prospective ran-domized trial, known as RxPONDER (Rx for PositiveNode, Endocrine Responsive Breast Cancer study, or


RelativeYear Discovery or Event Survival Rate1863 Cellular origin of cancer (Virchow)1889 Seed-and-soil hypothesis (Paget)1914 Chromosomal mutations in cancer (Boveri)1937 Founding of NCI1944 Transmission of cellular information by

DNA (Avery)1950 Availability of cancer drugs through

Cancer Chemotherapy National Service Center1953 Report on structure of DNA 35%1961 Breaking of the genetic code1970 Reverse transcriptase1971 Restriction enzymes

Passage of National Cancer Act1975 Hybridomas and monoclonal antibodies 50%

Tracking of cancer statistics by SEER program1976 Cellular origin of retroviral oncogenes1979 Epidermal growth factor and receptor1981 Suppression of tumor growth by p531984 G proteins and cell signaling1986 Retinoblastoma gene1990 First decrease in cancer incidence and mortality1991 Association between mutation in APC gene

and colorectal cancer1994 Genetic cancer syndromes

Association between BRCA1 and breast cancer2000 Sequencing of the human genome2002 Epigenetics in cancer

MicroRNAs in cancer2005 First decrease in total number of deaths 68%

from cancer2006 Tumor stromal interaction*Data are from the National Cancer Institute Surveillance, Epidemiology, and End Results program.From DeVita VT Jr, Rosenberg SA. Two hundred years of cancer research. N Engl J Med. 2012;366:2207-2214. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from MassachusettsMedical Society.

Table 2. Timeline of Pivotal Events in the Cancer Field andRelative Survival Rates for Patients With Cancer in theUnited States*


SWOG S1007), opened in January 2011 and will assesswhether chemotherapy benefits patients with node-pos-itive breast cancer who have a low to intermediate RS.The trial will also examine whether there is an optimalRS cutoff point for these patients, above whichchemotherapy should be recommended. This study in-cludes women with RS ≤25 who have early-stage, hor-mone receptor–positive, HER2-negative breast cancerthat has been found to involve 1 to 3 lymph nodes. Carey concluded her presentation by saying that ge-

nomic signatures have augmented clinical decision mak-ing in hormone receptor–positive/HER2-negative breastcancer. An emerging body of evidence indicates that ge-nomic signatures can be used to tailor (and reduce)chemotherapy use in early breast cancer. However, thereare no signatures in ER-negative or HER2-positive breastcancer yet.

Summary and Future DirectionsIn June 2012, the 200th anniversary issue of the New

England Journal of Medicine featured an article by DeVitaand Rosenberg that reviewed the history of cancer re-search and how these events affected patient outcomes(Table 2).62

Increased understanding of tumor heterogeneity, aswell as technical advances such as the identification ofmarkers, mutations, and genomic signatures, will con-tinue to improve clinical outcomes in patients with can-cer. Predictive markers identify groups of patients whoare likely to have increased sensitivity or resistance to agiven therapy; for example, recent findings in lung can-cer demonstrate that tumor-related molecular markers,such as EGFR mutations or mutations of the EML4-ALK fusion gene, can be used to define subsets of pa-tients who will benefit from particular treatments. Incolorectal cancer, one clinical or surrogate “biomarker”that is useful in predicting survival in patients receivingthe EGFR-targeted monoclonal antibodies cetuximaband panitumumab is the presence of a skin rash. TumorKRAS mutations have emerged as a predictive markerof resistance to these same treatments. In prostate can-cer, clinically useful biomarkers other than PSA have

been slow to develop. In breast cancer, genomic signa-tures have augmented clinical decision making in pa-tients with hormone receptor–positive/HER2-negativetumors. u

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41. CellSearch Circulating Tumor Cell Kit (Epithelial) [package insert].Raritan, NJ: Veridex LLC; 2009.42. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, dis-ease progression, and survival in metastatic breast cancer. N Engl J Med.2004;351:781-791.43. Cristofanilli M, Hayes DF, Budd GT, et al. Circulating tumor cells: anovel prognostic factor for newly diagnosed metastatic breast cancer. J ClinOncol. 2005;23:1420-1430.44. Shaffer DR, Leversha MA, Danila DC, et al. Circulating tumor cellanalysis in patients with progressive castration-resistant prostate cancer.Clin Cancer Res. 2007;13:2023-2029.45.Chen BT, Loberg RD, Neeley CK, et al. Preliminary study of immuno-magnetic quantification of circulating tumor cells in patients with ad-vanced disease. Urology. 2005;65:616-621.46.Malhotra GK, Zhao X, Band H, et al. Histological, molecular and func-tional subtypes of breast cancers. Cancer Biol Ther. 2010;10:955-960.47. Prat A, Perou CM. Deconstructing the molecular portraits of breastcancer. Mol Oncol. 2011;5:5-23.48. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of humanbreast tumours. Nature. 2000;406:747-752.49. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns ofbreast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci U S A. 2001;98:10869-10874.50. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breasttumor subtypes in independent gene expression data sets. Proc Natl AcadSci U S A. 2003;100:8418-8423.51. Herschkowitz JI, Simin K, Weigman VJ, et al. Identification of con-served gene expression features between murine mammary carcinoma mod-els and human breast tumors. Genome Biol. 2007;8:R76.52. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular char-acterization of the claudin-low intrinsic subtype of breast cancer. BreastCancer Res. 2010;12:R68.53. Harrell JC, Prat A, Parker JS, et al. Genomic analysis identifies uniquesignatures predictive of brain, lung, and liver relapse. Breast Cancer ResTreat. 2012;132:523-535.54. van ’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profil-ing predicts clinical outcome of breast cancer. Nature. 2002;415:530-536.55. van de Vijver MJ, He YD, van ’t Veer LJ, et al. A gene-expression sig-nature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999-2009.56. Buyse M, Loi S, van ’t Veer L, et al. Validation and clinical utility ofa 70-gene prognostic signature for women with node-negative breast can-cer. J Natl Cancer Inst. 2006;98:1183-1192.57. Rutgers E, Piccart-Gebhart MJ, Bogaerts J, et al. The EORTC10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase.Eur J Cancer. 2011;47:2742-2749.58. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrenceof tamoxifen-treated, node-negative breast cancer. N Engl J Med.2004;351:2817-2826.59. Paik S, Tang G, Shak S, et al. Gene expression and benefit ofchemotherapy in women with node-negative, estrogen receptor-positivebreast cancer. J Clin Oncol. 2006;24:3726-3734.60. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive valueof the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a ret-rospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65.61. Sparano JA, Paik S. Development of the 21-gene assay and its applica-tion in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-728.62. DeVita VT Jr, Rosenberg SA. Two hundred years of cancer research.N Engl J Med. 2012;366:2207-2214.


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Certain chromosomal abnor-malities are associated withprognosis in multiple myeloma

(MM). The translocations t(4;14) andt(14;16), or deletion del(13), are poorprognostic factors in MM. Patientswith these abnormalities are consid-ered high risk.Genetic abnormalities are assessed

both by routine cytogenetic karyotyp-ing and by fluorescence in situ hy-bridization (FISH). FISH detectsgenetic abnormalities on both dividingand nondividing cells, while conventional cytogeneticsonly detects abnormalities in dividing cells. While FISH is more sensitive than conventional

karyotyping in detecting genetic aberrations, it is im-portant to note that not all laboratories perform FISHthe same way. Detection of genetic abnormalities byFISH can be limited by the percentage of plasma cellsin the specimen. If all the lab is doing is looking at 200random cells under a microscope and doing FISH, youmay receive false-negative FISH results in the case of lowmono clonal plasma cell tumor burden. A more reliableFISH test is one in which the lab uses a plasma cell en-richment technique, such as cytoplasmic immunoglob-ulin FISH (cIg-FISH), which uses light chain–specificimmunofluorescence, or by using CD138 magnetic mi-crobeads to sort the plasma cells.One way to do a quality control check on the lab

that’s doing your FISH tests is to request an analysis fordel(13). This marker is present in about 50% of allnewly diagnosed MM patients. If your lab does not re-turn a result showing 50% expression of del(13) in all

your newly diagnosed MM patients,then the lab is not using a plasma cellenrichment technique, and it is notgiving you reliable data.

Prognosis for Patients With t(4;14)The patient in our case was found by

cIg-FISH to have t(4;14), which indi-cates a poor prognosis. This genetic aber-ration occurs in about 15% of MMpatients.1 Results from a 2005 study byJaksic and colleagues2 showed that pa-

Multiple Myeloma

The Role of Personalized Therapy in the Managementof Multiple Myeloma: Case Study of a Patient With aCytogenetic AbnormalityAt the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando,Florida, Sagar Lonial, MD, from the Winship Cancer Institute and Emory University in Atlanta, Georgia,discussed the use of personalized therapy in the management of multiple myeloma.

Case• A 55-year-old woman presents with new-onset anemia (Hb 9.6 g/dL)

• Skeletal survey is normal• Chemistries are normal except for an elevated total protein(10.2 g/dL)

• Albumin is 3.9 g/dL; β2-microglobulin is 4.4 mg/L• Marrow shows 55% clonal plasma cells• Serum protein electrophoresis shows IgA kappa protein of3.6 g/dL

• Free light chain ratio is abnormal (20:1)• 24-hour urine protein electrophoresis shows 350 mg ofkappa light chains

• Conventional cytogenetic results are normal• FISH performed at outside laboratory was negative for cytogenetic abnormalities; however, FISH performed atEmory is positive for t(4;14)

FISH indicates fluorescence in situ hybridization; Hb, hemoglobin.

Sagar Lonial, MD


tients identified with t(4;14) by cIg-FISH who received in-duction followed by autologous stem cell transplantation(ASCT) had a median progression-free survival (PFS)

from the time of ASCT of only 14.1 months (Figure 1).2

This was significantly shorter than for t(4;14)-negative pa-tients, who had a median PFS of 25.8 months (P=.0003).

Multiple Myeloma

Figure 1. PFS and OS for Patients With t(4;14) Are Quite Poor

OS indicates overall survival; PFS, progression-free survival.Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agentresistance. J Clin Oncol. 2005;23:7069-7073. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

Figure 2. Left Panel: OS of Patients With Versus Without t(4;14). Right Panel: OS of Patients with t(4;14) According to Hb and β2-Microglobulin Values at Diagnosis

Hb indicates hemoglobin; OS, overall survival.Reprinted by permission from Macmillan Publishers Ltd: Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 casestreated with tandem transplantation in IFM99 trials. Leukemia. 2007;21:2020-2024. Copyright 2007.

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Overall survival according to t(4;14) positivity Overall survival of patients with t(4;14) according to hemoglobin and β2-microglobulin values at diagnosis

t(4;14) pos: 100 patients, t(4;14) neg: 616 patients; median 41.4 vs 65 months


The median overall survival (OS) for t(4;14)-positive pa-tients from the time of ASCT was only 24.2 months.2

Results from a study by Moreau and colleagues in2007 shows, however, that genetics alone does not tellthe whole story. In this study, researchers identified asubgroup of t(4;14) patients with both low β2-mi-croglobulin (<4 mg/L) and high hemoglobin (Hb; ≥10g/dL) who experienced prolonged survival (median OSof 54.6 months and median PFS of 26 months) after tan-dem transplant and benefited from high-dose therapy(Figure 2).3

Novel Therapies in the Treatment ofPatients With t(4;14)In the Intergroupe Francophone du Myélome 2005-

01 trial, newly diagnosed MM patients with t(4;14) whoreceived short-term induction with 4 cycles of bortez -omib-dexamethasone before high-dose melphalan ex-perienced significantly improved survival comparedwith those treated with vincristine, doxorubicin, anddexamethasone induction therapy (Figure 3).4

Cavo and colleagues from the GIMEMA Italian

Myeloma Network compared thalidomide plus dexa -methasone (TD) versus bortezomib plus TD (VTD) asinduction therapy before, and consolidation therapyafter, double ASCT in 480 patients with newly diag-nosed MM.5 Results showed that while TD failed toovercome the poor prognosis related to the presence oft(4;14), VTD completely overcame the poor prognosisrelated to the presence of t(4;14).

In the area of personalized medicine for myeloma, itmay be different from other solid tumors. In myeloma,with good induction therapy, most patients will respond,and thus the challenge remains how to keep them in amajor response. Because combinations of agents are sosuccessful for newly diagnosed patients, the real person-

Multiple Myeloma

Figure 3. EFS and OS in Patients With and Without t(4;14) Treated With Bortezomib-Dexamethasone Induction Therapy

EFS indicates event-free survival; OS, overall survival.Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients withdel(17p). J Clin Oncol. 2010;28:4630-4634. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

Specific targeted maintenance holds thepromise for better long-term diseasecontrol while still taking advantage of thecombination effect when patients areinitially diagnosed.


alization occurs in the maintenance setting, where wecan use novel methods of keeping disease in control,such as stratified maintenance. This appears to be thefuture, as specific targeted maintenance holds the prom-ise for better long-term disease control while still takingadvantage of the combination effect when patients areinitially diagnosed. u

References1. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities andsurvival in multiple myeloma: the experience of the Intergroupe Franco -

p hone du Myélome. Blood. 2007;109:3489-3495.2. Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4;14) multiplemyeloma: a chemotherapy-sensitive disease characterized by rapid relapseand alkylating agent resistance. J Clin Oncol. 2005;23:7069-7073.3.Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiplemyeloma. Long-term follow-up of 100 cases treated with tandem trans-plantation in IFM99 trials. Leukemia. 2007;21:2020-2024.4.Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexametha-sone induction improves outcome of patients with t(4;14) myeloma butnot outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634.5. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomideplus dexamethasone compared with thalidomide plus dexamethasone asinduction therapy before, and consolidation therapy after, double autolo-gous stem-cell transplantation in newly diagnosed multiple myeloma: arandomised phase 3 study. Lancet. 2010;376:2075-2085.

Multiple Myeloma

Deborah Dunsire, MDPresident and Chief Executive OfficerMillennium: The Takeda Oncology Company

Kathy GiustiFounder and Chief Executive OfficerMultiple Myeloma Research FoundationMultiple Myeloma Research Consortium

K. Peter Hirth, PhDChief Executive OfficerPlexxikon, Inc.

Currently featuring:

Kimberly J. PopovitsPresident, Chief Executive OfficerGenomic Health, Inc.

Thomas C.Reynolds, MD, PhDChief Medical OfficerSeattle Genetics

Edith Perez, MDDeputy DirectorMayo Clinic Cancer Center Florida

INTERVIEW WITH THE INNOVATORSAn exclusive PMO series

Personalized Medicine in Oncology™ is pleased to offer insightful interviewswith leaders in oncology about their approach to personalized medicine.

To watch our interviews, visit www.PersonalizedMedOnc.com/videolibrary

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Pushing Your Limits

COEKsize71112CE©iStockphoto.com/altaykaya


Tumor immunotherapy is a modality of cancertherapy that utilizes the immune system to rec-ognize and eradicate cancer.1-5 The potential for

tumor immunotherapy has been recognized for over acentury after William Coley’s initial observation, “at theend of two weeks [since vaccination with erysipelas] thetumor in the neck had disappeared.”1 The work of Bur-net and Thomas in the 1950s further established thatthe immune system was capable of immune surveillanceand provided the foundation for understanding the na-ture of tumor rejection antigens. In the 1980s such re-jection antigens were indeed identified in cancer cells,

most notably in melanoma. These discoveries paved theway for vaccine development and provided a basic foun-dation for understanding how the immune system canbe used for therapeutic purposes in cancer.The clinical development of immunotherapy has

lagged behind the theoretical and preclinical models,but the potential for durable therapeutic responses hasbeen recognized for many years. The first major successwas the use of allogeneic hematopoietic cell transplan-tation for leukemia, which was first performed in 1956.6

The use of nonspecific agents followed, including ap-proval of Bacillus Calmette-Guérin for superficial blad-

Immunotherapy

The Cancer Immunotherapy Trials Network: A NationalStrategy for the Development and Implementation ofImmunotherapy for the Treatment of CancerHolbrook E. Kohrt, MD, PhDStanford Cancer Institute, Stanford, California

Howard L. Kaufman, MDRush University Cancer Center, Chicago, Illinois

Mary L. Disis, MDUniversity of Washington, Seattle, Washington

Dr Kohrt is an Assistant Professor of Oncology at the Stanford Cancer Institute. His research focuses on models of tumor immunology, including vaccine therapy for patients undergoing bone marrow transplantation.Dr Kaufman is Director of the Rush University Cancer Center, Associate Dean of the Rush Medical College, and Professorof Surgery and Immunology & Microbiology at the Rush University Medical Center. His primary research interests are inmelanoma and tumor immunotherapy.Dr Disis is Associate Member at the Fred Hutchinson Cancer Research Center, Professor in the Division of Medical Oncology,and Associate Dean of Translational Science at the University of Washington School of Medicine. She is involved in researchingvaccines and immunotherapy for cancer.

Key Points

• The clinical development of immunotherapy has lagged behind the theoretical and preclinical models, but thepotential for durable therapeutic responses has been recognized for many years

• The lack of widespread clinical expertise with immunotherapy presents a challenge for fully realizing the ther-apeutic opportunities of emerging immunotherapeutic strategies

• The Cancer Immunotherapy Trials Network was established to address these concerns and promote the rapiddevelopment of new immunotherapy agents and combination therapy using an integrated national network


der cancer, the cytokine interferon-alpha for treatmentof hairy cell leukemia and adjuvant therapy of stage IIImelanoma, and interleukin-2 for treatment of metastaticrenal cell carcinoma and melanoma.Monoclonal antibodies targeting sur-face molecules on tumor cells mediateantitumor activity, at least in part,through immune mechanisms, and sev-eral approved agents are current stan-dard of care, most notably rituximab,which targets CD20 and is approvedfor the treatment of patients with non-Hodgkin lymphoma,7 and trastuzumab,which targets HER2/neu and is ap-proved for the treatment of HER2-expressing metastatic breast cancer.1

The development of antigen-spe-cific immunotherapy remained a more elusive goal, andcaution was warranted based on significant toxicity re-ported with an anti-CD28 monoclonal antibody.2,8-12

Despite these challenges, the field has been re-energizedwith the approval of sipuleucel-T, an antigen-specificvaccine for prostate cancer in 2010, and ipilimumab, an anticytotoxic T-lymphocyte antigen 4 (CTLA-4)mono clonal antibody for metastatic melanoma in2011.4,5 These agents, while first in class, have usheredin a new era of tumor immunotherapy and have high-lighted the potential of such treatment in patients withadvanced cancer. The unique toxicity profiles of theseagents, the need for more appropriate clinical end pointsbased on the mechanism of action of immunotherapyagents, and the lack of widespread clinical expertisewith immunotherapy presents a challenge for fully real-izing the therapeutic opportunities of emerging im-munotherapeutic strategies. Most importantly, the majorbarrier to the development of effective immunotherapyis the lack of broad availability of already invented im-munotherapy agents with known and profound abilityto augment immune responses. Agents from the inter-leukin (IL) family, such as IL-15 and IL-7, have high po-tential to benefit cancer patients but are not broadlyavailable for testing. The Cancer Immunotherapy Trials

Network (CITN) was established to address these con-cerns and promote the rapid development of new im-munotherapy agents and combination therapy using an

integrated national network.

Sipuleucel-T andIpilimumab as ParadigmsSipuleucel-T and ipilimumab high-

light several important features ofmodern tumor immunotherapy. Sipu -leucel-T is an antigen-specific vaccinewith limited side effects, both attrac-tive pharmacologic features, but it isassociated with limited clinical effi-cacy. In contrast, ipilimumab is notantigen specific and has significanttoxicity requiring close clinical moni-

toring, but it may be associated with significant clinicalbenefit. The characteristics of these agents will be brieflydiscussed.Sipuleucel-T is composed of autologous peripheral

blood mononuclear cells, including dendritic cells, animmune-stimulating cytokine (granulocyte-macrophagecolony-stimulating factor, GM-CSF), and prostatic acidphosphatase (PAP), a prostate-associated tumor anti-

gen.4 The cells are extracted from patients throughleukapheresis and require ex vivo loading of the PAPand GM-CSF, transport back to the clinic, and IV infu-sion into patients. In the pivotal randomized phase 3trial, vaccination improved median survival by 4.1months in patients with asymptomatic or mildly symp-tomatic metastatic castration-resistant prostate cancer.4

This was the first vaccine to be approved in the UnitedStates for the treatment of established cancer utilizing

Immunotherapy

Howard L. Kaufman, MD

Agents from the interleukin family, such asIL-15 and IL-7, have high potential tobenefit cancer patients but are notbroadly available for testing.


an antigen-specific target. Vaccination is generally welltolerated, but challenges with autologous cell collectionand viability, ex vivo manipulation and regulatory re-quirements, and the lack of a clear correlation betweensurvival and induction of PAP-specific T-cell immunitysuggest that further studies are needed to optimize thisform of immunotherapy. Because clinical developmentof sipuleucel-T for FDA approval began in 1997, the for-mulation and regimen of sipuleucel-T have remained un-changed for almost 15 years. Given the advances madein immunology and immunotherapy in the past decadeand a half, it is axiomatic that regimens based on currentimmunologic science would provide higher and longer-lasting immune responses (ie, greater areas under thecurve) and, in the case of sipuleucel-T, enhanced patientbenefit. The question remains, “Which strategies aremost likely to be effective and the most ripe for testing?”Agents such as IL-15, IL-7, anti–CTLA-4, and anti–PD-1 (programmed death 1) are among the priorityagents being tested by the CITN and others that arelikely to increase the efficacy of sipuleucel-T.

CTLA-4 is an inhibitory checkpoint receptor ex-pressed on the surface of T cells, where it serves to in-hibit T-cell activation and helps regulate the balancebetween immune activation and tolerance.13-15 T-cellfunction is regulated by a series of signals typically pro-vided by antigen-presenting cells.16,17 In preclinical stud-ies, the addition of an antagonist CTLA-4 monoclonalantibody with a specific vaccine was shown to induceantigen-specific T-cell activation and mediate rejectionof B16 melanoma in mice.18 Ipilimumab is a humanizedanti–CTLA-4 monoclonal antibody and has demon-strated therapeutic benefit in patients with metastaticmelanoma.19-21 In a dose-finding trial, objective re-

sponses were seen in 11.1% of patients at the 10-mg/kgdose and in 4.2% at the 3-mg/kg dose, with no responsesat the lower dose.19 The early studies of ipilimumab alsoidentified a unique toxicity profile characterized by au-toimmune events, including dermatitis, colitis, hepatitis,endocrinopathies, and neuritis.22-24 Mortality related tobowel perforation was reported in less than 2% of pa-tients in early studies before the development of auto -immune toxicity was recognized. The autoimmune sideeffects are manageable with early use of low-dosesteroids and, rarely, more intensive immunosuppressivetreatment.24 The pivotal phase 3 clinical trial was aprospective, randomized, double-blind study of 676HLA-A2 patients with previously treated metastaticmelanoma.25 Patients treated with ipilimumab demon-strated an overall survival benefit of 10 months com-pared with 6.4 months in the vaccine-alone arm.25 Asubsequent trial in treatment-naive metastaticmelanoma patients demonstrated that overall survivalwas significantly prolonged to 11.2 months in the ipi -limumab-treated patients compared with 9.1 months indacarbazine-treated patients. A survival effect persistedat 3 years, with 20.8% alive in the ipilimumab/dacar-bazine-treated arm compared with 12.2% in the dacar-bazine-alone arm (hazard ratio for death, 0.72;P<.001).26

An interesting finding in both phase 3 ipilimumabstudies was the lack of improvement in progression-freesurvival, suggesting that the immune response is slow todevelop and can result in a delayed therapeutic re-sponse. Indeed, studies have shown that responses maybe delayed for several months, and this has led to a newset of clinical immune response guidelines for clinicalmonitoring of patients on immunotherapy studies.27,28

These guidelines require further validation, and this maybe possible through the CITN.PD-1 is another T-cell coinhibitory receptor that

binds to the PD-1 and PD-2 ligands (PD-L1, PD-L2) onantigen-presenting cells and suppresses T-cell activa-tion. PD-1 is highly expressed on both activated and ex-hausted T cells following exposure to chronic antigen,while PD-L1 is expressed directly on cancer cells in a

Immunotherapy

Ipilimumab is a humanized anti–CTLA-4monoclonal antibody and hasdemonstrated therapeutic benefit inpatients with metastatic melanoma.


number of different tumors, including melanoma, renalcell, colorectal, ovarian, and non–small cell lung cancer(NSCLC).29-39 A humanized antibody to PD-1 has beenevaluated in patients with previously treated solid tu-mors, with objective responses reported in patients withcolorectal cancer, melanoma, and NSCLC.40,41 Morerecently, a phase 1 clinical trial using an anti–PD-L1mono clonal antibody in a dose-escalation design rang-ing from 0.3 mg/kg to 10 mg/kg was conducted in pa-tients with metastatic cancer, with objective clinicalresponses observed in 9 of 52 evaluable melanoma, 2 of17 renal cell carcinoma, 5 of 49 NSCLC, and 1 of 17ovarian cancer patients.42

These clinical data are encouraging, and there arenumerous other agents that have shown preclinical potential or early-stage clinical evidence of therapeuticeffectiveness. For example, novel cytokines in development include IL-15, IL-18, IL-21, and new im-mune checkpoint-targeted monoclonal antibodiesagainst OX40, 4-1BB, GITR, and CD27 are in develop-ment. Further, there is evidence that blockade ofCTLA-4 and PD-1 can act synergistically against themurine B16 melanoma, providing evidence that combi-nation immunotherapy should be pursued in the clinic.43

Because of the availability of these new agents, coupledwith the cost of drug development and the need formore appropriate clinical trial designs that can bettercapture the impact of immunotherapy drugs, a model forprioritization of agents and trial design is needed to en-sure that the full impact of tumor immunotherapy canbe realized for patients with cancer.

Mission of the CITNThe goal of the CITN is to facilitate broad availabil-

ity of multiple immunotherapy agents with defined bio-logic function for cancer therapy. The CITN isselecting, designing, and conducting early-phase trialswith highly promising immunotherapy agents and pro-vides a platform for high-quality immune monitoringand biomarker studies essential to inform subsequent de-velopment pathways leading to the commercializationof these agents for treating patients with cancer. The

work performed through the network is expediting reg-ulatory approval of cancer immunotherapy.CITN members help design novel early-phase trials

developing strategies and biomarkers that inform phase3 pivotal trials. The CITN will implement and completecomplex multicomponent trials that facilitate subse-quent development pathways, particularly of agents incombination. The CITN will also provide high-qualityimmune response and biomarker data that elucidatemechanism of response and inform design of subsequenttrials.

The CITN is a collaborative research project estab-lished by and operating under a grant from the NationalCancer Institute (NCI) and awarded to the Central Op-erating and Statistical Center (COSC) at the FredHutchinson Cancer Research Center (FHCRC). TheCOSC provides overall leadership, organizational infra-structure, and statistical and protocol coordination sup-port. A competitive grant process was used by the NCIto select 28 participating sites across the United Statesand Canada. Input from NCI and industry partners is alsoutilized to foster the identification of promising agentsand integration to promote combination strategies.

Organizational Structure of the CITNThe organization model of the CITN is an interac-

tive, inclusive organization whose members and collab-orators strive toward common goals. The overallorganizational structure and governance of the CITN isoutlined in the Figure. The CITN, collaborating withthe NCI, industry, and various disease-oriented andnonprofit foundations, uses the collective experienceand wisdom in the field to prioritize and develop optimaltrials in a synergistic fashion that will be more informa-tive than those performed by scientists and companies

Immunotherapy

The goal of the CITN is to facilitate broadavailability of multiple immunotherapyagents with defined biologic function forcancer therapy.


working in isolation. The NCI, FHCRC, and memberinstitutions each contributes resources to the CITN.Within the NCI, the Biological Resources Branch, Bio-metrics Research Branch, and Cancer Therapy Evalua-tion Program (CTEP) provide support to CITN trials.CTEP plays an important role in study regulatory anddata management through the Cancer Trials SupportUnit, site monitoring and auditing through the ClinicalTrials Monitoring Branch, and application for investi-gational new drugs through the Regulatory AffairsBranch. Three core facilities are provided by FHCRC,specifically in collaboration with the HIV Vaccine TrialsNetwork (regulatory and trial operations support), theStatistical Center for HIV/AIDS Research & Preven-tion (supporting statistical design and analysis), and a

joint collaboration with FHCRC and the University ofWashington (scientific leadership and laboratory man-agement). Each member site provides guidance in trialdesign, patient enrollment, safety reporting, protocolcompliance, as well as biospecimen collection and lab-oratory analysis. To foster new cancer immunotherapyclinical trials, the CITN works closely withcorporate/pharmaceutical entities to identify and selectagents for investigation and to obtain access to thesetherapeutics. Given the complexity of trial implemen-tation, the CITN partners with foundations and non-profit organizations with expertise in a specific diseaseor therapeutic area.Leadership of the CITN comprises the Executive

Committee including the COSC principal investigator(PI), 3 PIs from member sites, an administrative direc-tor, laboratory director, and NCI program officer (Fig-ure). At the level of an identified drug and selected

protocol, the CITN organizes Concept WorkingGroups, which have the responsibility of determiningthe study design and final clinical trial protocol. TheWorking Group includes a chair and cochairs frommember sites, consultants familiar with the disease areaor the therapeutic, a statistician, patient advocate, pro-tocol development manager, immune monitoring corerepresentative, CTEP/NCI member, and an industryrepresentative, depending on the agent and industry in-terest in contributing.

Processes of the CITNThe list of priority agents to be investigated by the

CITN resulted from 3 prior NCI workshops and feed-back from over 80 leaders providing clinical and scien-tific expertise. The first workshop, ImmunotherapyAgent Workshop, ranked the top 20 agents from 126suggestions with known substantial immunologic activ-ity that have not been adequately tested in cancer patients.44

Shortly thereafter, the Cancer Antigen PrioritizationProject ranked 75 target cancer antigens according topredetermined and predefined characteristics to focuson the 6 most promising.45 Finally, given the potentialfor combining agents, an Immune Response ModifierPathway Working Group developed criteria to structurethe combination of immunopotentiating agents withvaccines in clinical trials.46 The final list of top agentsto bring to patients in clinical trials is shown in Table 1and includes T-cell growth factors (IL-7 and IL-15),dendritic cell activators (anti-CD40), inhibitors of T-cell checkpoint blockade (anti–PD-1), dendritic cellgrowth factors (Flt3L), vaccine adjuvants (IL-12), andT-cell stimulators (4-1BB).Clinical trials entering the CITN are selected by a

peer review process. Trials can be submitted from bothacademia and industry. A Letter of Intent is reviewedby the CITN Executive Committee and either rejectedor forwarded to the CITN Steering Committee for fur-ther review. The Steering Committee is composed of asubgroup of CITN site investigators. Members of theSteering Committee serve for 3-year terms. The com-

Immunotherapy

Each member site provides guidance intrial design, patient enrollment, safetyreporting, protocol compliance, as well as biospecimen collection and laboratory analysis.


mittee will approve or disapprove the proposal and as-sign the concept a priority. High-priority concepts moveforward in the system, while approved but lower-priorityconcepts may be held while an alternate funding strat-egy is developed. Once a concept is deemed high prior-ity, a lead investigator is identified and a Working Groupis formed. This Working Group fully develops the pro-tocol. Simultaneously, the Correlative Sciences Com-mittee works with the protocol group to develop thelaboratory analysis to support the study. Once com-pleted, the protocol moves forward for institutional andCTEP approval.

During the review process, the CITN ExecutiveCommittee determines the source of and obtains theproposed immunotherapy agent(s), discusses with mem-ber sites and determines the financial expense of thetrial, and reviews the trial implementation/start-up stepsneeded at participating institutions. Given the limitedper patient budget of the CITN, depending on the ex-pense of the particular trial, secondary sources of fund-ing are obtained. Prior to finalization and CTEPapproval, pharmaceutical/industrial agreements arereached in order to guarantee drug supply.A key component of the CITN is a central immuno-

Immunotherapy

Figure. Organizational Structure of the Cancer Immunotherapy Trials Network

FHCRC: Fred Hutchinson Cancer Research CenterUW: University of WashingtonHVTN: HIV Vaccine Trials NetworkSCHARP: Statistical Center forHIV/AIDS Research & PreventionCTSU: Cancer Trials Support UnitCTMB: Clinical Trials MonitoringBranchRAB: Regulatory Affairs BranchIND: Investigational new drugs

FHCRC/UWScientificleadership

Lab management

HVTNCore, Fiscal,

Trial Operations Regulatory

SCHARPStatistical

design andanalysis

Trial DesignsCommitteeLeadership

Biospecimencollection

Lab analysis contract

Patient EnrollmentSafety reporting

Protocol compliance

Concept and Trial

Collaboration

Define strategiesfor agent

approval, accessto agents

Biometrics Research

Branch Reviewdata

Biological ResourcesBranch

Cancer TherapyEvaluation

Program (CTEP)

RABINDs

CTMBSite audits/monitoring

CTSU Trial/regulatorysupport, EDC/data mgmt

Fred HutchinsonCancer Research

CenterMember Sites

Corporate Entities

Foundations or Nonprofit Entities

National Cancer Institute

Cancer ImmunotherapyTrials Network


logic monitoring laboratory and a CITN member labo-ratory network. The central laboratory assures adequateshipping and processing of samples from the studies andmanages the assays that will be performed by the central

laboratory or other laboratories in the network. Withinthe network lies significant expertise in basic immuno-logic monitoring, flow cytometry, analysis of the tumormicroenvironment, assessment of circulating tumor

Immunotherapy

Agent(rank)* Function Trial(s)

IL-15 (#1) T-cell and natural killer Trial with NCI E coli rhIL-15 in solid tumors to develop a subcutaneous cell growth factor regimen with a safety profile appropriate for combining with vaccines,

standard antibody therapy, and other agents; protocol submitted to CTEP (PIs: Miller [U Minnesota] and Kohrt [Stanford U])Trial with Altor mammalian-derived IL-15/IL-15αSu/Fc Fusion Complex, an IL-15 agent with theoretically improved pharmacokinetics; to be cofunded by approved Melanoma Research Alliance grant to Dr Margolin (PI: Margolin [U Washington])

IL-7 (#5) T-cell growth factor Trial of sipuleucel-T (Provenge; Dendreon) + IL-7 (Cytheris) modulate first FDA-approved cancer vaccine; LOI submitted to CTEP; grant submitted to Prostate Cancer Foundation for cofunding (PIs: Fong [UC San Francisco] and Ferrari [New York U])Trial of MAGE-A3 + AS15 ASCI (GSK) + IL-7 (Cytheris); commitment for agents and partial funding by GSK and Cytheris (PI: Gajewski [U Chicago])

Anti-CD40 (#4) Dendritic cell activator Trial of neoadjuvant CP-870,893 (Pfizer) in resectable pancreas cancer; initiated and led by Dr Vonderheide at U Penn as single institution with commitment for expansion to other CITN sites; cofunded by U Penn and CITN; protocol approved by Institutional Review Board and FDA

Flt3 Ligand (#11) Dendritic cell Trial of Flt3 ligand to expand DC followed by poly ICLC (#15*) and growth factor Resiquimod (#18*) to activate DC and NY-ESO-1-DEC-205 fusion

protein vaccine to target DC; Celldex committed to provide agents; in collaboration with CVC/CRI investigators (PIs: Wolchok [MSKCC], Odunsi [Roswell Park CC], Bhardwaj [New York U]; all three are CITN and CVC/CRI investigators)

IDO Inhibitors IDO inhibition Trials in development with Incyte (INCB24360) and/or NewLink (#7) Genetics (1-MT), most likely in ovarian cancer and melanoma

(Evaluating concepts by Odunsi [Roswell Park CC], Slingluff [U Virginia])

Anti–PD-1 (#2) Anti-checkpoint Active discussions with Merck for trials in lymphoma, ovarian, and head & neck cancers (Evaluating concepts by Kohrt, Levy [Stanford U], Coukos, Adams [U Penn], Pai [Johns Hopkins U])

Anti–IL-10 (#10) Inhibitor of suppression Active discussions with Merck for trials in ovarian and breast cancer (Evaluating concepts by Coukos [U Penn] and Salazar [U Washington])

*Numbers represent ranking from the NCI Immunotherapy Agent Workshop; https://dcb.nci.nih.gov/Reports/Pages/immunotherapyagentworkshop.aspx.

CITN indicates Cancer Immunotherapy Trials Network; CTEP, Cancer Therapy Evaluation Program; CVC/CRI, CancerVaccine Collaborative/Cancer Research Institute; DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; GSK, Glaxo-SmithKline; IL-7, interleukin-7; IL-10, interleukin-10; IL-15, interleukin-15; LOI, Letter of Intent; MSKCC, MemorialSloan-Kettering Cancer Center; NCI, National Cancer Institute; PD-1, programmed death 1; PI, principal investigator;rhIL-15, recombinant human IL-15.

Table 1. CITN Trials in Development as of August 2012


cells, and other specialized assays. The laboratory analy-ses are prioritized into primary and secondary assays. Pri-mary assays are those that are performed during thecourse of the study, and secondary assays are those thatmay be performed once the study has been completed.Prioritization of the analysis maximizes the collectionof useful information in the most efficient manner possible.

Member Sites of the CITNThe CITN selected member sites through a compet-

itive National Institutes of Health grant process and se-

lection criteria, including basic tumor immunotherapyexperience at the site, willingness to participate in pro-posed clinical trials, availability of clinical trial infra-structure, and ability to participate in establishingvalidation standards or collect biospecimen data for in-clusion in immune monitoring and biomarker correla-tive studies. Member sites were asked to select a PI forcoordinating the activities at each site and to participatein the executive committee. The member sites are lo-cated throughout the continental United States andCanada, assuring patient access for pivotal clinical trials.The member sites and PI contact information is listed

Immunotherapy

State/Province Study Site Principal Investigator Site Contact

California Stanford University Ronald Levy, MD (650) 498-7061UC San Diego Thomas Kipps, MD, PhD (858) 657-7000UC San Francisco Lawrence Fong, MD (877) 827-3222

Connecticut Yale University Mario Sznol, MD (203) 785-5702Florida Moffitt Cancer Center Scott Antonia, MD, PhD (888) 663-3488

University of Miami Joseph Rosenblatt, MD (866) 574-5124Georgia Emory University Edmund Waller, MD, PhD (888) 946-7447Illinois Rush University Howard Kaufman, MD (312) 942-0600

University of Chicago Thomas Gajewski, MD, PhD (855) 702-8222Maryland National Cancer Institute Jeff Schlom, PhD (301) 496-4164Massachusetts Dana-Farber Cancer Institute F. Stephen Hodi, MD (866) 408-3324Minnesota University of Minnesota Jeffrey Miller, MD (888) 226-2376New Hampshire Dartmouth University Marc Ernstoff, MD (800) 639-6918New York Memorial Sloan-Kettering Jedd Wolchok, MD, PhD (800) 525-2225

Cancer CenterNew York University Nina Bhardwaj, MD, PhD (212) 263-6485Roswell Park Kunle Odunsi, MD, PhD (877) 275-7724

North Carolina Duke University H. Kim Lyerly, MD (888) 275-3853Ohio Case Western Reserve Pierre Triozzi, MD (800) 641-2422

Ohio State University William Carson, MD (800) 293-5123Oregon Providence Medical Center Walter Urba, MD, PhD (800) 833-8899

x56014Pennsylvania University of Pennsylvania Carl June, MD (855) 216-0098

University of Pittsburgh Robert Ferris, MD, PhDHassane Zarour, MD (877) 470-7241

Texas Baylor University Karolina Palucka, MD, PhD (214) 820-7451MD Anderson Cancer Center Laurence Cooper, MD, PhD (877) 632-6789

Virginia University of Virginia Craig Slingluff, MD (434) 924-5022Washington University of Washington John Thompson, MD (855) 557-0555Wisconsin University of Wisconsin Paul Sondel, MD, PhD (800) 622-8922Ontario University of Toronto Pamela Ohashi, PhD (416) 946-2000

Table 2. Participating CITN Study Sites in the United States and Canada


in Table 2. Further information and updates are avail-able on the CITN Web site at www.CITNinfo.org.

How to Refer to the CITNClinical trials initiated through the CITN will be

listed on www.clinicaltrials.gov, at member institutions’trial registries, and at www.CITNinfo.org. Study con-tacts, including study PI or trial coordinator will belisted for each participating institution in a CITN or-ganized clinical trial. Patients are encouraged to speakwith their primary oncologist to discuss their interest inclinical trials, including CITN and non-CITN devel-oped trials. Risks and benefits of a clinical trial and al-ternative treatment options should be discussed whenconsidering a patient’s next therapy. Referring physi-cians should contact a local PI or co-PI based on thespecific trial of interest. Contact information, similarly,can be obtained at the sites listed above.Pharmaceutical and industry representatives with in-

terest in collaboration should contact Martin A. “Mac”Cheever, MD, the principal investigator of the CITNbased at the FHCRC.

ConclusionCancer immunotherapy has come of age, and the

promise of improved survival by targeting the immuneresponse against cancer has been demonstrated withseveral agents, including sipuleucel-T and ipilimumab.However, this marks only the beginning of an era of im-munotherapy that faces significant challenges in selec-tion of agents, design of clinical trials, ensuringavailability of novel therapies, and developing processesfor working through the complex regulatory, intellectualproperty, and financial challenges for combining im-

munotherapy agents. The NCI has established theCITN as a means to prioritize immunotherapy agentsand combinations, gain access to high-priority agents,develop clinical trial designs that are appropriate for de-tecting therapeutic effectiveness, validating and incor-porating correlative immune monitoring and biomarkerassays into clinical trials, and implementing a nationalnetwork for patient participation in pivotal tumor im-munotherapy trials. The CITN provides a uniquely or-ganized effort to conduct early-phase trials, with a focuson trials likely to achieve the quickest route to proof ofconcept, demonstration of patient benefit, and providea pathway to regulatory approval.By accelerating ongoing interactions between CITN

investigators, industry, foundations, and nonprofit enti-ties, the CITN strives to have many immunotherapyagents with defined biologic function broadly availablefor rapid clinical trial evaluation. The CITN will play asignificant role in firmly establishing the effectivenessof tumor immunotherapy and defining the clinical ap-plication of immunotherapy as a standard treatment forpatients with cancer. u

AcknowledgmentsThe authors would like to acknowledge Dr “Mac”

Cheever for useful discussions and guidance in the man-uscript preparation, and Judith Kaiser for providing in-vestigator contact information.

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Immunotherapy

Patients are encouraged to speak withtheir primary oncologist to discuss theirinterest in clinical trials, including CITN andnon-CITN developed trials.


10. Peled N, Oton AB, Hirsch FR, et al. MAGE A3 antigen-specific can-cer immunotherapeutic. Immunotherapy. 2009;1:19-25.11. Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer im-munotherapy. Adv Immunol. 2006;90:297-339.12. Stebbings R, Findlay L, Edwards C, et al. “Cytokine storm” in thephase I trial of monoclonal antibody TGN1412: better understanding thecauses to improve preclinical testing of immunotherapeutics. J Immunol.2007;179:3325-3331.13. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science.1995;270:985-988.14. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads tomassive lymphoproliferation and fatal multiorgan tissue destruction, re-vealing a critical negative regulatory role of CTLA-4. Immunity.1995;3:541-547.15. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation ofCD4+ T cells. Immunity. 1997;7:885-895.16. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited.Annu Rev Immunol. 2005;23:515-548.17. Salama AK, Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4.Clin Cancer Res. 2011;17:4622-4628.18. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapyof B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4(CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatictumors accompanied by autoimmune depigmentation. J Exp Med.1999;190:355-366.19. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy inpatients with pretreated advanced melanoma: a randomised, double-blind,multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.20. O’Day SJ, Maio M, Chiarion-Seleni V, et al. Efficacy and safety of ipi -limumab monotherapy in patients with pretreated advanced melanoma: amulticenter single-arm phase II study. Ann Oncol. 2010;21:1712-1717.21. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind,placebo-controlled, phase II study comparing the tolerability and efficacyof ipilimumab administered with or without prophylactic budesonide inpatients with unresectable stage III or IV melanoma. Clin Cancer Res.2009;15:5591-5598.22. Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27:478-479.23. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associ-ated antigen-4 blockage can induce autoimmune hypophysitis in patientswith metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.24. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoim-munity induced by cytotoxic T lymphocyte-associated antigen 4 blockadein patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-8377.25. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipi -limumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.26. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazinefor previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.27. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation ofimmune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009;15:7412-7420.

28. Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for can-cer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388-1397.29. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 im-munoinhibitory receptor by a novel B7 family member leads to negativeregulation of lymphocyte activation. J Exp Med. 2000;192:1027-1034.30. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhaustedCD8 T cells during chronic viral infection. Nature. 2006;439:682-687.31. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 bymonoclonal antibodies potentiates cancer therapeutic immunity. CancerRes. 2005;65:1089-1096.32. Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor in-duced phosphorylation of the ZAP70/CD3zeta signalosome and down-stream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.33. Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor in-hibits B cell receptor-mediated signaling by recruiting src homology 2-do-main-containing tyrosine phosphatase 2 to phosphotyrosine. Proc NatlAcad Sci U S A. 2001;98:13866-13871.34. Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death1 ligands by murine T cells and APC. J Immunol. 2002;169:5538-5545.35. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumorcells in the escape from host immune system and tumor immunotherapyby PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293-12297.36. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of pro-grammed cell death-1 ligand 1 is a prognostic factor for malignantmelanoma. Cancer. 2010;116:1757-1766.37. He YF, Zhang GM, Wang XH, et al. Blocking programmed death-1ligand-PD-1 interactions by local gene therapy results in enhancement ofantitumor effect of secondary lymphoid tissue chemokine. J Immunol.2004;173:4919-4928.38. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adop-tive T-cell immunotherapy for squamous cell carcinoma. Cancer Res.2003;63:6501-6505.39. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinicalapplication. Int Immunol. 2007;19:813-824.40. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agentanti-programmed death-1 (MDX-1106) in refractory solid tumors: safety,clinical activity, pharmacodynamics, and immunologic correlates. J ClinOncol. 2010;28:3167-3175.41. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immunecorrelates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.42. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.43. Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combi-nation blockade expands infiltrating T cells and reduces regulatory T andmyeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A.2010;107:4275-4280.44. National Cancer Institute Immunotherapy Agent Workshop.https://dcb.nci.nih.gov/Reports/Pages/immunotherapyagentworkshop.aspx.Accessed September 20, 2012.45. Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancerantigens: a National Cancer Institute pilot project for the acceleration oftranslational research. Clin Cancer Res. 2009;15:5323-5337.46. Cheever MA, Matrisian LM. Report of the Immune Response ModifierPathway Prioritization Working Group (IRMP WG), November 2009.http://deainfo.nci.nih.gov/advisory/ctac/workgroup/ctacsupmat.htm. Ac-cessed September 20, 2012.

Immunotherapy

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Welcome to our new column, The Last Word.At the outset, let me comment on theirony of the title, for this is not a forum that

presumes to have the “last word” on any aspects of per-sonalized medicine. The column willserve as the concluding editorial ineach issue of Personalized Medicine inOncology, where I am given the chanceto explore the extraordinary opportu-nities personalized medicine offers patients. Permit me to acquaint you with me

as you join my journey through theinner workings of our healthcare sys-tem. I am a veteran of nearly 40 yearsin the healthcare industry, whichbegan with pre-med studies motivatedby an enduring desire to heal. How-ever, a nagging desire to understand human nature ledme to graduate with a major in the humanities. Buthealthcare beckoned again, and leaving graduate studiesin history to join a pharmaceutical company, I soonforged a career in medical education programs and pub-lishing that fuses humanities with medical and managedcare best practices. Convinced that medical care is at heart a cultural pursuit and not merely scientific, Iwill discuss the balance between healthcare discoveryand value.The Last Word will position healthcare as the crown

of a civilized culture, with personalized medicine fulfill-ing medicine’s cultural pursuit to serve individual pa-tient’s needs, not grouping patients together in adepersonalized population-based manner. I hope that you will find The Last Word every bit as

fascinating as my own exploration of uncharted watersof healthcare has been. I will take you into the inner

realms of the healthcare process and fire your imagina-tion by opening up new vistas of this still nascentprocess of care whose implications and downstream ef-fects are so plentiful. This model of care is facilitated by

new technologies, but its mission istimeless: the ancient pursuit to bringhealth to those who have lost it andstand to lose their lives without stop-ping the process of destruction thatcancer is posing to them.Along the way, The Last Word will

stop to explore the very matter ofchange, how disruptive innovation in-herently repels all but a small groupknown to pharmaceutical marketers asinnovators, who take their place on aclassic bell-shaped curve for new prod-uct adoption. It will examine how clin-

ical oncologists operating within the population-basedmodel of care must overcome their comfort level withit and find how to live with the uncertainties of a newparadigm that eradicates old fixed boundaries that de-fined expectations. It will explore healthcare delivery asa matter of overall resource allocation. So sit back and get ready to enjoy the ride. I can even

promise to share a most apt quote from a very old JoanBaez folk song. These are all part of The Last Word – it’sthe last word in enjoyment of the learning process thatgoes with an initiative as splendid as the personalizedmedicine model for oncologic care. u

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Robert E. Henry


Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to �ve-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the �rst- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-�uorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the �rst-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

1.4 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and �stula formation. The majority of cases occurred within the �rst 50 days of initiation of Avastin.Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to �ve-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin

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were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula FormationSerious and sometimes fatal non-gastrointestinal �stula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the �rst 6 months of Avastin therapy.Discontinue Avastin in patients with �stula formation involving an internal organ. [See Dosage and Administration (2.4).]

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

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

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. 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 (MRI) is necessary to con�rm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed �ndings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

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

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

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications [See Boxed Warning,

Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

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

6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not re�ect the rates observed in practice.The data below re�ect exposure to Avastin in 4198 patients with CRC, non-squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18-88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 �rst- and second-line mCRC patients who received a median of 10 doses of Avastin, 480 �rst-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also re�ect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

Surgery and Wound Healing ComplicationsThe incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone.In Study 5, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal �uid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic EventsThe overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of �rst VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients

receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the �rst 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

ProteinuriaGrade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).]

Congestive Heart Failure (CHF)The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were sign�cantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, de�ned as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

Ovarian FailureThe incidence of new cases of ovarian failure (de�ned as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identi�ed in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is de�ned as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

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

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

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

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

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

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected

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

(

was no difference in the mean exposure of interferon alfa

a

for the �rst approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

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

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

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

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

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

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

Avastin in Combination with FOLFOX4 in Second-line mCRCOnly Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary in�ltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 3.

Table 3 NCI-CTC Grades 1−5 Adverse Events in Study 7

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

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

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal re�ux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and speci�city of the assay. Additionally, the observed incidence of antibody positivity in an assay may be in�uenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing ExperienceThe following adverse reactions have been identi�ed during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular in�ammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous �oaters; Ocular hyperemia; Ocular pain or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaHepatobiliary disorders: Gallbladder perforationMusculoskeletal: Osteonecrosis of the jawRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphoniaSystemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

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

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of speci�c gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential bene�t to the pregnant woman justi�es the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic pro�le of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insuf�cient information to determine the safety and ef�cacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in �ve randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive PotentialAvastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

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

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

06/12 AVA000075920310127309

Initial U.S.Approval: February 2004Code Revision Date: May 2012

Avastin® is a registered trademark of Genentech, Inc.

©2012 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080-4990

Think Avastin Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis mattersAvastin is designed to directly inhibit the VEGF ligand to speci�cally inhibit angiogenesis1*

To confront a common threat across approved indications...

VEGF=vascular endothelial growth factor. * The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical signi�cance is unknown.

IndicationsAvastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.Avastin is indicated for the �rst-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.Avastin is indicated for the �rst- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-�uorouracil– based chemotherapy.

Boxed WARNINGS Gastrointestinal (GI) perforation

— Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls

— The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation

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

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

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

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

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

central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%

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

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

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the

Avastin-treated arm vs control included — Non-GI �stula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included

— Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

Infusion reactions with the �rst dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events Most common adverse reactions observed in Avastin patients at a rate >10% and at least

twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

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

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need

to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance

of Avastin to the mother In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2%

higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection

In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary in�ltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

In �rst-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

†Avastin is not approved for use in combination with irinotecan.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.

www.avastin.com©2012 Genentech USA, Inc. All rights reserved. AVA0000488301 Printed in USA. (01/12)

november 2012, vol 1, no 5

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