August 2012, VOL 1, NO 3

The official publication of

August 2012 Volume 1 • Number 3 A Peer-Reviewed Journal

PM O

PERSONALIZED MEDICINE IN ONCOLOGY TM

INTERVIEW WITH THE INNOVATORS Incorporating Genomics Into Practice: An Interview With Kimberly J. Popovits ..........Page 18

CONTINUING MEDICAL EDUCATION Highlights From the 2012 World Cutaneous Malignancies Congress ................................Page 26

REGULATORY ISSUES Facilitating the Next Generation of Precision Medicine in Oncology ..................................Page 43

BREAST CANCER Which Breast Cancer Patients Should Receive Adjuvant Chemotherapy? ................Page 52

ALSO IN THIS ISSUE… • First-Line Afatinib in Advanced EGFR-Positive NSCLC ....................................................Page 11 • Potential Biomarkers for Response to Lenvatinib Identified ....................................................Page 12

IMPLEMENTING THE PROMISE OF PROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARE

TM

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

At diagnosis of metastatic colorectal cancer (mCRC)

Are you getting the full picture?

Name: Age: Cancer: Specialty: Biomarker Status:

George 58 mCRC Storyteller

Not an actual patient.

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1 Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2 Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4 Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3 The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7

Provides information on a patient’s likelihood of response or non-response to biomarker-directed treatment1

Approximately 2 out of every 3 patients are KRAS wild-type vs mutant5,7

May help define the patient’s overall prognosis irrespective of therapy1

Approximately 5%-9% of colorectal cancers are characterized by a specific mutation in the BRAF gene7

Testing of biomarkers at diagnosis of mCRC is important for treatment planning3,7*

Strongly recommends KRAS genotyping of CRC tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan for the treatment continuum.7

T E S T

BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7

T O

P L A N

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory.

References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/ documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/ pri/2011/932932/cta. Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

©2012 Bristol-Myers Squibb. All rights reserved. 693US12AB00106 04/12 Printed in USA.

T

he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.

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August 2012 Volume 1 • Number 3

PERSONALIZED MEDICINE IN ONCOLOGY ™

CONFERENCE NEWS New Targeted Therapies and New Biomarkers Explored at ASCO 2012

PAGE 10

First-Line Afatinib in Advanced EGFR-Positive NSCLC

Save the date for the Second Annual Conference, October 4-6, 2013 Visit www.globalbiomarkersconsortium.com to register

Potential Biomarkers for Response to Lenvatinib Identified

Prostate Cancer Roundup

PAGE 14

6-Gene Model Identifies Lower- Versus Higher-Risk CRPC Patients Gene Classifiers Predict Risk of Clinical Progression Following Prostatectomy

INTERVIEW WITH THE INNOVATORS

Who attends the GBC? 12.9% 29% 16.1%

12.9%

22.6% 6.4% Academic clinical practice Academic research only Community hospital Private practice Pharmaceutical industry Other

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Volume 1 • No 3

Incorporating Genomics Into Practice: An Interview With Kimberly J. Popovits

PAGE 18

PMO talks with the President and CEO of Genomic Health about their approach to personalized medicine, her inspiration to work in this field, and the future of cancer treatment.

CONTINUING MEDICAL EDUCATION Highlights From the 2012 World Cutaneous Malignancies Congress

PAGE 26

The WCMC focuses on advances in the fields of cutaneous malignancies and cutaneous T-cell lymphoma.

OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, 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, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

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The use of the Caris Target Now service, the use or interpretation of any information provided as part of su s ch servic vice, e, and and/or /or th the e sele selecti ct on of any dr drug ug age agents nts is so solel lelyy at a and within h n th the e disc discret retion ion of the treating physician’s independent medical judgment. The Caris Target Now services are performed by Cariss Li Life fe Sci Scienc ences, es, a CLI CLIA-c A-certifi fied ed lab labora orator toryy oper operati ating ng und under er the U. U.S. S. Cli Clinic nical al Laboratory Amendment Act of 1988 and in compliance with all relevant U.S. state and federal regulations. None off the Ca Caris ris Ta Targe rgett Now Now ser servic vices es hav have e been been re revie viewed wed by th the e Unit United ed Sta States tes Fo Food od and Drug Administration. Persons depicted are models and used for illustrative purposes only. ©2012 Caris Life Sciences an and d affi affilia liates tes.. All ri right ghtss rese reserve rved. d. CT CTN06 N06131 1312PM 2PMO O

PUBLISHING STAFF SENIOR VICE PRESIDENT, SALES AND MARKETING Philip Pawelko phil@greenhill.com PUBLISHERS John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com DIRECTOR, CLIENT SERVICES Lou Lesperance Jr lou@greenhillhc.com MANAGING DIRECTOR Pam Rattananont Ferris

Facilitating the Next Generation of Precision Medicine in Oncology

STRATEGIC EDITOR Robert E. Henry

Sheila D. Walcoff, JD

PAGE 43

Key stakeholders are increasingly considering new measures to protect and advance innovation and investment in diagnostics.

SENIOR COPY EDITOR BJ Hansen PRODUCTION MANAGER Marie RS Borrelli QUALITY CONTROL DIRECTOR Barbara Marino

BREAST CANCER Which Breast Cancer Patients Should Receive Adjuvant Chemotherapy?

BUSINESS MANAGER Blanche Marchitto CIRCULATION DEPARTMENT circulation@greenhillhc.com Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

Please convey any errors to the editorial director.

Volume 1 • No 3

PERSONALIZED MEDICINE IN ONCOLOGY ™

REGULATORY ISSUES

EDITORIAL DIRECTOR Kristin Siyahian kristin@greenhillhc.com

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A number of decision-making tools have become available to help clinicians and patients with early cancer discuss the risks and benefits of getting adjuvant therapy after surgery.

INTERVIEW WITH THE INNOVATORS An exclusive PMO series Personalized Medicine in Oncology™ is pleased to offer insightful interviews with leaders in oncology about their approach to personalized medicine.

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

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August 2012

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Editorial Board Editor in Chief AL B. BENSON III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer EDITH PEREZ, MD Mayo Clinic Jacksonville, Florida

Gastrointestinal Cancer EUNICE KWAK, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Drug Development IGOR PUZANOV, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies GAUTAM BORTHAKUR, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Lung Cancer VINCENT A. MILLER, MD Foundation Medicine Cambridge, Massachusetts

Pathology DAVID L. RIMM, MD, PHD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma DOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Predictive Modeling MICHAEL KATTAN, PHD Case Western Reserve University Cleveland, Ohio

Prostate Cancer OLIVER SARTOR, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD

TONY ALBINO, PHD Signal Genetics LLC New York, New York GREGORY D. AYERS, MS Vanderbilt University School of Medicine Nashville, Tennessee LYUDMILA BAZHENOVA, MD University of California, San Diego San Diego, California LEIF BERGSAGEL, MD Mayo Clinic Scottsdale, Arizona

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

K. PETER HIRTH, PHD Plexxikon, Inc. Berkeley, California

DANIELLE SCELFO, MHSA Genomic Health Redwood City, California

HOWARD L. KAUFMAN, MD Rush University Chicago, Illinois

LEE SCHWARTZBERG, MD The West Clinic Memphis, Tennessee

KATIE KELLEY, MD UCSF School of Medicine San Francisco, California

JOHN SHAUGHNESSY, PHD University of Arkansas for Medical Sciences Little Rock, Arkansas

MINETTA LIU, MD Georgetown University Hospital Washington, DC

KENNETH BLOOM, MD Clarient Inc. Aliso Viejo, California

KIM MARGOLIN, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

MARK S. BOGUSKI, MD, PHD Harvard Medical School Boston, Massachusetts GILBERTO CASTRO, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil MADELEINE DUVIC, MD The University of Texas MD Anderson Cancer Center Houston, Texas BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio STEPHEN GATELY, MD TGen Drug Development (TD2) Scottsdale, Arizona

STEVEN T. ROSEN, MD, FACP Northwestern University Chicago, Illinois

STEVEN D. GORE, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

SANJIV S. AGARWALA, MD St. Luke’s Hospital Bethlehem, Pennsylvania

GENE MORSE, PHARMD University at Buffalo Buffalo, New York AFSANEH MOTAMED-KHORASANI, PHD Radient Pharmaceuticals Tustin, California NIKHIL C. MUNSHI, MD Dana-Farber Cancer Institute Boston, Massachusetts

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STEVEN O’DAY, MD John Wayne Cancer Institute Santa Monica, California

DARREN SIGAL, MD Scripps Clinic Medical Group San Diego, California DAVID SPIGEL, MD Sarah Cannon Research Institute Nashville, Tennessee

SHEILA D. WALCOFF, JD Goldbug Strategies, LLC Rockville, Maryland

DAVID A. PROIA, PHD Synta Pharmaceuticals Lexington, Massachusetts

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JAMIE SHUTTER, MD South Beach Medical Consultants, LLC Miami Beach, Florida

MOSHE TALPAZ, MD University of Michigan Medical Center Ann Arbor, Michigan

ANAS YOUNES, MD The University of Texas MD Anderson Cancer Center Houston, Texas

RAFAEL ROSELL, MD, PHD Catalan Institute of Oncology Barcelona, Spain

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LAWRENCE N. SHULMAN, MD Dana-Farber Cancer Institute Boston, Massachusetts

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August 2012

Letter From the Board

Understanding Personalized Medicine Breeds Success Dear Reader, Welcome to this issue of Personalized Medicine in Oncology (PMO), the official publication of the Global Biomarkers Consortium (GBC). PMO and GBC are dedicated to bringing information to physicians that will support the adoption of personalized medicine into clinical practice.

Personalized medicine is more than just the pairing of biomarkers to biologics. It encompasses all personal patient conditions in engaging the entire cancer patient.

Understanding breeds success, and nothing succeeds in cancer like personalized Howard L. Kaufman, MD medicine. Thus, there is no turning back. What little we know scientifically or in terms of patient engagement drivers is continually undergoing expansion. PMO is identifying what can help the practicing oncologist now by means of personalized medicine techniques and research findings in the hope of offering patients their best chances for success.

For now, personalized medicine continues to overlap with conventional treatment. The explanation of personalized medicine techniques and findings comprise an essential stimulus to its expansion, and to that end we are identifying key applications to make this happen.

In addition to print and online media, we are pleased to host the annual GBC conference. Please save the date for the 2nd Annual Conference of the Global Biomarkers Consortium on October 4-6, 2013, in Boston, Massachusetts. The conference is designed to educate physicians specializing in hematology/ oncology, pathology, and genetics on the state-of-the-art advances in our understanding of tumor biomarkers and their use in the clinical management of a variety of solid tumors and hematologic malignancies.

Early bird registration is open for this important conference. To register, or for more information, please visit www.globalbiomarkersconsortium.com.

On behalf of the entire editorial board, thank you for being part of our PMO community.

Sincerely,

Howard L. Kaufman, MD Rush University PMO Editorial Board Member

Volume 1 • No 3

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New Targeted Therapies and New Biomarkers Explored at ASCO 2012 Alice Goodman

B

elow are some highlights of presentations at the 2012 ASCO Annual Meeting related to targeted therapies and personalized (precision) medicine.

T-DM1 The anti-body drug conjugate T-DM1 significantly prolonged progression-free survival (PFS) compared with standard capecitabine/lapatinib therapy for treatment of advanced HER2-positive breast cancer in the EMILIA trial (Abstract LBA1).

Median PFS was 9.6 months in the T-DM1 arm versus 6.4 months with capecitabine/lapatinib, representing a significant difference favoring the antibody conjugate (P<.0001). T-DM1 reduced the risk of progression by 35% compared with capecitabine/lapatinib.

For many patients with HER2-positive breast cancer, trastuzumab has been the mainstay of therapy, either alone or in combination with other chemotherapy.

For many patients with HER2-positive breast cancer, trastuzumab has been the mainstay of therapy, either alone or in combination with other chemotherapy.

T-DM1 goes one step better, linking trastuzumab with a potent cytotoxic agent that is a maytansine derivative using a stable linker. The novel compound delivers a potent cytotoxic agent to antigen-expressing tumor cells, sparing normal tissue.

“This antibody conjugate is significantly better than the current approved combination in keeping the cancer under control. T-DM1 demonstrated greater efficacy and safety compared with capecitabine/lapatinib and should offer an important therapeutic option for advanced HER2-positive breast cancer,” said Kimberly L. Blackwell, MD, Duke Cancer Institute, Durham, North Carolina.

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EMILIA was a 3-year, phase 3 trial randomizing 978 patients to receive either T-DM1 or capecitabine/ lapatinib. T-DM1 was better tolerated than capecitabine/ lapatinib. Subgroup analysis showed superiority of T-DM1 in all subgroups except those aged 65 years and older. Overall survival was improved in the T-DM1 group, but median overall survival had not been reached at the time of the ASCO meeting. At 2 years, 65.4% of the T-DM1 group was alive compared with 47.5% of the group on standard chemotherapy.

The incidence of grade 3 or higher adverse events was 40.8% with T-DM1 versus 57% for capecitabine/ lapatinib. The incidence of adverse events leading to treatment discontinuation was 5.9% versus 10.7%, respectively. Death due to toxicity was reported for 1 patient in the T-DM1 arm versus 5 in the capecitabine/ lapatinib arm. The most common adverse events grade 3 or higher in the T-DM1 arm were thrombocytopenia and increased hepatic enzymes; in the capecitabine/lapatinib arm, diarrhea, hand/foot syndrome, and vomiting.

Formal discussant of this trial, Louis M. Weiner, MD, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, said EMILIA’s results were convincing evidence in support of the potent antitumor activity of T-DM1, which he called a “magic bullet.”

PD-1 Targeted Immune Therapy The investigational anti–PD-1 antibody (BMS936558) achieved objective responses in 20% to 25% of patients with advanced non–small cell lung cancer (NSCLC), melanoma, and renal cell cancer with acceptable safety in a preliminary study reported at ASCO (Abstract CRA2509) and published simultaneously online in the New England Journal of Medicine. Preliminary data suggest that PD-L1 expression on tumor cells is related to response to the anti–PD-1 antibody.

“It’s exciting to see this degree of antitumor activity

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from a single agent among patients with a range of cancers that had progressed despite standard therapies. We were especially surprised to see activity in nearly 20% of NSCLC patients, who have been historically unresponsive to immune-based therapies. These findings mark what is probably the strongest anti–lung cancer activity observed to date with any immunotherapy,” commented lead author Suzanne L. Topalian, MD, Professor of Surgery and Oncology at The Johns Hopkins University School of Medicine, Baltimore, Maryland.

The PD-1 antibody targets a key pathway in T-cell activation that inhibits the body’s immune response to cancer. By blocking this pathway, BMS-936558 is thought to reactivate the immune system to attack cancer cells.

The phase 1 trial included 296 patients with disease progression despite standard therapies who received treatment through February 2012. Cancers included were melanoma (104 patients), NSCLC (122 patients), kidney cancer (34 patients), castrate-resistant prostate cancer (17 patients), and colorectal cancer (19 patients). The majority of patients were heavily pretreated; 47% received at least 3 prior regimens.

Response rates were as follows: melanoma, 28%; renal cancer, 27%; and NSCLC, 18%. Responses were observed in cancers with both squamous and nonsquamous histology. Some responses were quite durable; 20 of 31 responses lasted for at least 1 year, and several patients were still in response at the time of the ASCO meeting.

Safety was generally acceptable. Side effects were similar to those reported with other immunotherapies.

The most common treatment-related side effects were fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea. Serious (grades 3 and 4) adverse events were reported in 14% of patients. Drug-related serious adverse events occurred in 11%. Three deaths occurred due to pulmonary toxicity.

Another goal of the study was to find a biomarker for response. Subanalysis found that expression of a protein called PD-L1 on the tumor cell surface correlated with response. Response was seen in more than one-third of

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patients with PD-L1–positive tumors, while no response was seen in patients with PD-L1–negative tumors. Further studies are planned to evaluate this potential biomarker of response to BMS-936558.

“This drug has broken the ceiling of durable tumor response rates of 10% to 15%, which is the highest rate of many of the immunotherapy approaches used over the past 30 years,” wrote Antoni Ribas, MD, PhD, Jonsson Comprehensive Cancer Center at UCLA in Los Angeles, in his editorial in the New England Journal of Medicine.

Afatinib improved PFS by about 4 months in this advanced disease population, and PFS benefits were almost doubled with afatinib in patients with 1 of the 2 most common EGFR mutations: del19 or L858R. First-Line Afatinib in Advanced EGFRPositive NSCLC First-line therapy with afatinib, a novel investigational oral epidermal growth factor receptor (EGFR) inhibitor, extended PFS compared with standard chemotherapy (pemetrexed/cisplatin) in EGFR-mutated advanced NSCLC, and PFS was prolonged even further in patients whose cancers harbored the 2 most common EGFR mutations (Abstract LBA7500). These were the results from the pivotal phase 3 international LUX-Lung 3 trial.

Afatinib improved PFS by about 4 months in this advanced disease population, and PFS benefits were almost doubled with afatinib in patients with 1 of the 2 most common EGFR mutations: del19 or L858R. Afatinib is an irreversible dual EGFR/HER2 inhibitor under development for NSCLC with EGFR mutations. Afatinib not only blocks EGFR but also blocks the ErbB family of receptors associated with the EGFR pathway, including HER2 and HER4. In the United States no therapy is approved by FDA specifically for EGFR mutation–positive lung cancer.

“Afatinib appears to be more potent than other

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EGFR-directed therapies because it blocks the molecular pathways that facilitate growth of these cancers more broadly and effectively. This new oral therapy may help patients live longer with no disease progression and requires fewer office visits than standard chemotherapy,” said principal investigator James Chih-Hsin Yang, MD, National University of Taiwan, Taipei, Taiwan.

Afatinib appears to be more potent than other EGFR-directed therapies because it blocks the molecular pathways that facilitate growth of these cancers more broadly and effectively.

The randomized, open-label, phase 3 LUX-Lung 3 trial was conducted at 133 sites in 25 countries, and it is the largest phase 3 trial in the first-line setting for EGFR mutation–positive, advanced, metastatic NSCLC; LUX-Lung 3 was also the first trial to use pemetrexed/cisplatin as the comparator arm. Patients (N=345) were randomized 2:1 to afatinib or standard chemotherapy with pemetrexed/cisplatin.

Median PFS in the afatinib arm was 11.1 months versus 6.9 months for standard chemotherapy, representing a 42% reduced risk of progression for those treated with afatinib (P=.0004). About 90% of patients enrolled in the trial had cancers that harbored del19 or L858R. In the subset of patients with these 2 common mutations, median PFS was 13.6 months with afatinib versus 6.9 months in the standard chemotherapy arm, representing a 51% reduced risk of progression with afatinib (P<.0001). Overall survival results will be available within the next 2 years.

The most common drug-related adverse events associated with afatinib included diarrhea (95%), rash (62%), and paronychia (57%). The most common drugrelated adverse events in the chemotherapy arm were nausea (66%), decreased appetite (53%), and vomiting (32%). Rates of discontinuation due to adverse events were 7.9% in the afatinib arm and 11.7% in the chemotherapy arm.

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Potential Biomarkers for Response to Lenvatinib Identified As part of the effort to identify biomarkers of response and outcomes in cancers, a phase 2 study of 58 patients with differentiated thyroid cancer treated with the investigational agent lenvatinib identified several potential predictive biomarkers of treatment response and outcomes (Abstract 5518). The study found that the combination of RAS and BRAF mutation with baseline vascular endothelial growth factor (VEGF) and ANG-2 or treatment-associated changes in FGF-2 and IL-2 level correlated with treatment response to lenvatinib.

Lenvatinib is an oral tyrosine multitargeted inhibitor that targets VEGFR-3, FGFR-4, RET, KIT, and PDGFRβ. In the study, patients received a starting dose of lenvatinib 24 mg once daily in 28-day cycles. Serum was collected at baseline, day 8, and day 36; multiple bead assays and enzyme-linked immunoabsorbent assay were used to measure serum concentrations of 47 cytokine and antigenic factors (CAFs). Thirty-three genes with a total of 443 mutations were examined in archival tumor samples (n=25).

The response rate was 50%. Longer PFS on lenvatinib was correlated with low baseline VEGF and ANG-2 (P=.02). Both baseline and changes in CAF levels showed an association with gene mutation status. High baseline levels of VEGF were seen in patients with wild-type RAS and BRAF, whereas high baseline sTIE-2 levels were associated with RAS mutation.

Increased levels of IL-10 and FGF-2 on day 8 posttreatment were associated with RAS and BRAF mutation. Combining gene mutation status with baseline CAF levels improved prediction of longer PFS on lenvatinib treatment than gene mutation status alone. Cluster modeling identified a set of CAFs that could predict longer PFS and greater tumor shrinkage or longer PFS without significant tumor shrinkage.

Lead author of this abstract was Douglas Wilmot Ball, MD, The Johns Hopkins University School of Medicine, Baltimore, Maryland. u

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Pancreatic Cancer: Progress and Challenges June 18-21, 2012 Lake Tahoe, NV An AACR Special Conference on: Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations June 27-30, 2012 Marriott Copley Place Boston, MA Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research October 16-19, 2012 Anaheim, CA Fifth Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved October 27-30, 2012 San Diego, CA EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 6-9, 2012 Dublin, Ireland

An AACR Special Conference on: Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment November 11-14, 2012 Hollywood, FL An AACR Special Conference on: Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances December 2-5, 2012 Miami, FL CTRC-AACR San Antonio Breast Cancer Symposium December 4-8, 2012 San Antonio, TX An AACR Special Conference on: Tumor Invasion and Metastasis January 20-23, 2013 San Diego, CA Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research February 21-25, 2013 Maui, HI AACR-Society of Nuclear Medicine Joint Conference on State-of-the-art Molecular Imaging in Cancer Biology and Therapy February 27-March 2, 2013 San Diego, CA

Please visit www.aacr.org/meetingscalendar for the complete calendar, as conferences are added and updated on a regular basis

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Prostate Cancer Roundup Alice Goodman

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early 3000 abstracts were selected for presentation at the recent ASCO 2012 Annual Meeting, many of them related to some aspect of personalized medicine. Below are some highlights selected from the meeting that focus on potential genomic predictors of aggressive versus indolent disease and on potential biomarkers.

6-Gene Model Identifies Lower- Versus Higher-Risk CRPC Patients A 6-gene model was found to discriminate between lower-risk patients and higher-risk patients with castration-resistant prostate cancer (CRPC) in both a training set and a validation study (Abstract 4516). Current models for risk assessment are based on clinical variables and only offer moderate predictive discrimination for men with CRPC who have a heterogeneous range of outcomes. Whole blood offers specific advantages as a biomarker – it is easy to collect, minimally invasive, can be standardized, and can be repeatedly collected over time.

The MSKCC validation set had a median survival of 18.5 months for lower-risk patients and 9.2 months for the higherrisk group.

“We demonstrated that the 6-gene model predicted survival,” stated presenting author William Oh, MD, professor at Mount Sinai School of Medicine in New York City.

Between August 2006 and June 2008, PAXgene Blood DNA Tubes were used to collect blood prospectively from 62 patients for a training set at Dana-Farber Cancer Institute, Oh told listeners. Subsequently, the researchers collaborated with the Memorial Sloan-Kettering Cancer Center (MSKCC), New York, for a validation set from 140 patients who had blood samples banked between August 2006 and February 2009. Two

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samples were eliminated because of poor-quality RNA. After an extensive review of studies in the literature, the researchers identified 6 candidate genes that would yield the best prediction of survival.

“When applied to the training set at Dana-Farber, we found that the lower-risk patients had a median survival of 34.9 months, while higher-risk patients had a median survival of 7.8 months (P=.0001),” Oh said. The gene model was superior to the Halabi nomogram variables based on data available for 6 of 7 of the variables, namely, alkaline phosphatase, ECOG performance status, hemoglobin, visceral metastases, prostate-specific antigen (PSA), and Gleason score. Area under the curve was 0.90 for the 6-gene model and 0.65 for the clinical model.

The MSKCC validation set had a median survival of 18.5 months for lower-risk patients and 9.2 months for the higher-risk group (P<.0001). As with the training set, the results were highly significant. The 6-gene model maintained its prognostic significance when clinical variables were added to it. The authors hope this study will provide models to help assist patient counseling and trial stratification.

Patient characteristics were typical for patients with CRPC. Metastatic disease was present in 87% and 90% of the training and validation cohorts, respectively.

The study was funded by Source MDx, which is no longer in business.

Gene Classifiers Predict Risk of Clinical Progression Following Prostatectomy The genomic classifier (GC) and the genomic-clinical classifier (GCC) were validated as predictors of clinical progression after radical prostatectomy in prostate cancer patients at high risk for disease progression (Abstract 4565). Both GC and the GCC were superior to a multivariable clinical classifier (CC) in this regard, supporting the promise of applying GCs in guiding decision making following radical prostatectomy.

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Christine Buerki, PhD, of GenomeDx Biosciences, Vancouver, Canada, reported these results, confirming that the GC is able to capture the majority of prognostic information.

The author believes that the lack of biomarkers, beyond clinical and pathologic factors, for predicting risk of clinically significant disease is a barrier to the efficient delivery of adjuvant therapy following prostatectomy.

The GC was developed from the Mayo Clinic radical prostatectomy registry of routine formalin-fixed, paraffin-embedded patient specimens.

In the case cohort study of 219 patients from the Mayo Clinic, clinical progression was defined as a positive bone or CT scan following prostatectomy. C-indices (measures of discrimination for model validation) of 0.79, 0.82, and 0.70 were found for GC, GCC, and CC, respectively.

Multivariable survival analysis revealed that most of the prognostic information of GCC was derived from the GC, with only a small contribution from Gleason score.

GCC, which is a combination of GC and established clinical and pathologic variables, had an overall higher net benefit compared with CC over a wide range of decision-to-treat thresholds for the risk of progression. GC emerged as an independent prognostic factor in this study.

The utility of GC and GCC in informing decision making in the adjuvant setting following radical prostatectomy will depend on the results of additional studies in other prostate cancer risk groups.

FDHT and FDG Potential Imaging Biomarkers Both 18F-16β-fluoro-5α-dihydrotestosterone (FDHT) and fludeoxyglucose (FDG) positive emission tomography (PET) are promising candidates for imaging biomarkers in men with metastatic castrate-resistant prostate cancer (mCRPC), as shown by a study designed to determine if FDHT and FDG PET scans are prognostic for survival (Abstract 4517). These findings suggest that more sophisticated imaging, such as FDHT and FDG, may be helpful in managing mCRPC. Current imaging modalities have limited ability to quan-

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tify disease burden and assess response to treatment.

Researchers at MSKCC in New York City prospectively scanned 170 patients in the FDG arm and 116 in the FDHT arm. All patients were diagnosed with mCRPC and had evidence of disease progression at time of the baseline scan.

Preliminary data from this study indicate that both FDG and FDHT are linked to clinical outcome and have potential utility as imaging biomarkers in building an evidence database.

Presenting author Karen A. Autio, MD, pointed out some important differences between the 2 imaging modalities used in the study. FDG images tumor metabolism but is not tumor specific and assumes that the lesions are glycolytic. FDHT, a structural analog of dihydrotestosterone, has a high affinity for the androgen receptor and captures its overexpression in bone, soft tissue, and viscera. FDHT measures androgen receptor expression and is prostate specific, but its utility requires a castrate state.

Each patient was assessed for standardized uptake values (SUV), specifically, SUVmax (ie, the hottest lesions) or SUVmaxavg (ie, average of the 5 hottest lesions).

“FDHTmaxavg and FDGmaxavg were significantly associated with survival (P=.049 and P=.0007, respectively),” Autio stated. “For FDHT, with a hazard ratio of 1.61, we can say that for every log 1 unit increase in SUV, the risk of death increased by 61%,” Autio said.

In comparison, the hazard ratio for FDG was 2.54. In a multivariate model, neither FDHT SUV or FDG SUV was prognostic of survival, and neither tracer was strongly associated with SUVmax.

FDHT was superior to PSA and Gleason score as a prognostic marker of survival.

Preliminary data from this study indicate that both FDG and FDHT are linked to clinical outcome and

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have potential utility as imaging biomarkers in building an evidence database.

RT-PCR–Based Technique Discriminates Between Indolent and Aggressive Prostate Cancer Reverse transcriptase-polymerase chain reaction (RT-PCR) provides a reliable measure of gene expression patterns and biological pathways associated with clinically aggressive prostate cancer in radical prostatectomy specimens obtained by needle biopsies, according to a study conducted at the Cleveland Clinic, which was confirmed by a study presented at a Poster Discussion

The study supports the potential value of a biopsy-based genomic assay to guide the decision between immediate treatment and active surveillance for patients with biopsy-diagnosed prostate cancer.

Session (Abstract 4560). The technique also discriminated between indolent and aggressive prostate cancer.

The study supports the potential value of a biopsybased genomic assay to guide the decision between immediate treatment and active surveillance for patients with biopsy-diagnosed prostate cancer. The study was presented by Eric A. Klein, MD, Glickman Urological and

We’re just a

Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

The study included 92 low-risk and 75 intermediaterisk patients who were biopsied and underwent radical prostatectomy between 1999 and 2010. The investigators used a novel design to assess gene expression in the context of tumor heterogeneity assessed by needle biopsy of tissue obtained from radical prostatectomy.

The researchers analyzed the expression of 81 prostate cancer–related genes, which were identified in a prior gene discovery study, and normalized to the average of 5 reference genes. Fifty-eight of the 81 discovery study genes (72%) also predicted adverse pathology and/or nonorgan-confined disease when assayed in biopsy tumor tissue. These included all stromal response and androgen genes and most (82%) cellular organization genes. Proportionately fewer proliferation (40%), stress response (29%), and basal epithelial (25%) genes were associated with an adverse path.

After covariate adjustment for clinical T stage, pretreatment PSA, and biopsy Gleason score, the researchers found that the predictive genes identified in biopsy specimens at diagnosis also predicted adverse pathology in biopsy tumor tissue.

An independent prospective study is currently under way to validate a clinical-grade multigene assay optimized for prostate needle core biopsy tissue. The assay is based on an algorithm incorporating the strongest genes and gene pathways. u

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PMPM O C

ERSONALIZED EDICINE IN ONCOLOGY

ALL FOR PAPERS

Personalized Medicine in Oncology’s mission is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies and each patient’s unique genetic blueprint.

Our vision is to transform the old medical model of stratified medicine into a new model of personalized care where all decisions and practices are tailored to the individual.

The goal of Personalized Medicine in Oncology is to sensitize practitioners to the performance realities of new diagnostic and treatment discoveries and to clarify molecular profiling technologies as they relate to diagnostic, prognostic, and predictive medicine. PMO will feature diagnostic and clinical treatment information concerning these 3 root aspects of personalized medicine in oncology.

Readers are invited to submit articles for consideration in the following categories:

Biologicals in Trial •

Exploring the challenges of clinical trial design and patient enrollment

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Presentation of emerging clinical data

Genetic Profiling Technologies •

What technologies are available to clinicians and consumers and their impact on diagnostic, prognostic, and predictive medicine

In Practice Predictive Models and Diagnostics •

Genetics and Biomarkers •

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A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalized medicine techniques into practice

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Development of treatment algorithms

A look at available diagnostic technologies and implementation in the community practice setting

Exploring genetic discoveries and impact on predictors of disease and therapeutic response

The Cost of Personalized Medicine •

Personalized medicine policy drivers

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Payer coverage of diagnostics and biologics

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Case studies, patient-reported outcomes, defining treatment goals, partnering with patients and caregivers

Submit the entire manuscript and a cover letter stating the objectives of the article to PMO@greenhillhc.com.

Manuscripts should follow the Author Guidelines available at www.PersonalizedMedOnc.com. "

Interview With the Innovators

Incorporating Genomics Into Practice: An Interview With Kimberly J. Popovits Kimberly J. Popovits Chairman of the Board, Chief Executive Officer, and President Genomic Health, Inc

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clinically validated assays that provide enomic Health, Inc, located the genomic profile of an individual’s in Redwood City, California, tumor, helping to understand whether is a global cancer company patients are likely to benefit from and founded in 2000. Genomic Health currespond to cancer therapies, or whether rently offers patients the Oncotype DX those patients are likely to experience a Breast Cancer Assay and the Oncotype recurrence of their cancer. Personalized DX Colon Cancer Assay. Genomic Health Medicine in Oncology recently had the maintains that the key to effectively pleasure of meeting with the President using clinical genomics to improve canand CEO of Genomic Health, Ms Kimcer treatment and outcomes lies in deberly J. Popovits, to discuss Genomic termining which sets of genes and gene Health’s approach to personalized medinteractions affect different subsets of Kimberly J. Popovits icine, her inspiration to work in this cancers. Genomic Health studies which field, and the future of cancer treatment. The following patterns of gene expression within a tumor are linked to a are excerpts from that interview. To view the interview response to cancer therapy, or to the likelihood that the in its entirety, please go to www.PersonalizedMed cancer will return or metastasize. The results of these geOnc.com/videolibrary. nomic studies and research can then be used to develop

PMO How do you define personalized medicine in oncology, particularly as it relates to the treatment of patients with breast or colon cancer?

Ms Popovits I think one of the best ways to define personalized medicine is when disease happens to you or to somebody you love. Oftentimes we hear definitions of getting the right drug to the right patient in the right dose at the right time. I think specific to oncology and the areas that we’re in, breast, colon, and prostate cancer, it’s really about patients understanding their individual disease.

Cancer is many diseases. One tumor is not like another tumor, and it’s really important that patients understand the genomic makeup of their particular tumor.

We would actually refer to that as the molecular signature of your breast cancer. Knowing how that is different from somebody else’s breast cancer, and by understanding that biology, we’re able to better direct treatment.

PMO It appears that personalized medicine in oncology is a concept that is implemented mainly at academic centers or initiated by a small set of physicians

Ms Popovits has served as Chairman of the Board of Genomic Health since 2012, Chief Executive Officer and President since 2009, and President and Chief Operating Officer since 2002. Prior to joining Genomic Health, Ms Popovits served as Senior Vice President, Marketing and Sales, at Genentech, Inc. During her 15 years at Genentech, she led the commercialization of 14 new therapies, including Herceptin. She was named Woman of the Year in 2008 by the Women Health Care Executives and as one of the Most Influential Women in the Bay Area by the San Francisco Business Times from 2006-2012. Ms Popovits holds a bachelor of arts degree in business from Michigan State University.

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who understand the genetic principles behind molecular biomarkers and how to assess them appropriately. How can personalized medicine be made available to patients managed by community oncologists?

Ms Popovits I think one of the most important goals in oncology is to make sure that all patients have access to personalized medicine; that all patients have access to specific information about their own genome, about their own genetic makeup; and that their family history is incorporated into their treatment planning.

The dilemma we face is that 80% of patients actually present in the community and about 20% in the academic setting. We cannot assume that everybody is going to be sent to an academic center to get their cancer treatment.

There are a couple of barriers in our way right now, and a big one is education. We need to make sure that we are educating all physicians on the new information that’s before us right now. We’re in a world today where we have an unprecedented amount of data, and the key is going to be turning these data into really good actionable information for cancer patients. The tools are here, and folks are using the tools in a lot of places, but I don’t think it’s necessary that every community physician have a sequencer on their desktop. What’s important is that they have access to those tools through other resources, tools that they can present to their patients, so that the information then gets incorporated into treatment planning.

We have to work together. It’s going to be a collaborative effort, clearly driven by the academic institutions and the leading centers, but that information has to get to the community setting so that it’s available to all patients who present with cancer and need to have a personalized treatment plan.

PMO Most of us have been touched by cancer in some way. In fact, the inspiration for Genomic Health came from founder Randy Scott’s experience in watching a friend diagnosed with cancer in the late 1990s.

Can you tell us what brought you to Genomic Health and about your inspiration to work in this field?

Ms Popovits When I thought about whether to enter

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Oncotype DX testing is conducted in Genomic Health’s clinical laboratory in Redwood City, CA.

this whole realm of personalized medicine, and in particular Genomic Health, I was working at Genentech and had the wonderful experience of being involved in the development of very important cancer therapeutics.

What had occurred to me at that time was that we had a number of drugs in our pipeline at Genentech that might never see the light of day if we couldn’t figure out how to target them to the patients that would benefit.

We saw that first with Herceptin, a very important drug for the treatment of breast cancer, and it is a drug that I’m not sure we would have gotten to market if we hadn’t been able to develop a diagnostic test to find those patients who overexpress HER2.

So when the folks at Genomic Health called me in the very early days and said they had this idea of how we could better direct a lot of cancer treatment, and specifically chemotherapy, it really touched a cord with me in terms of the need for it in medicine, but also on a personal level. I think we are all touched by cancer in some way. It’s hard to run into somebody who doesn’t have a family member or a friend who’s had to make the really tough decision about whether to get chemotherapy treatment. I went through that with my mother about 19 years ago, and I am reluctant to say that she remains a survivor. My dad was less fortunate in that he died 4 years

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ago after a long battle with lung cancer. And I lost a very good friend to breast cancer just Mother’s Day weekend this year.

All of that is motivation to want to make this difference, and to really bring personalized medicine to a reality.

PMO Please describe how the gene panels for the breast and colon cancer assays were developed and validated.

Ms Popovits The colon cancer and breast cancer assays are different in the sense that they look at different genes. One of the things that’s really important to think about when we look at breast cancer or colon cancer, and now of course we’re looking at prostate cancer as well, is that all cancers are not driven by the same genetic or genomic profiles.

What we have shown is that...looking at a number of pathways is more powerful than just looking at 1 pathway or 1 gene alone.

Starting with the breast cancer assay, we asked ourselves a question, can we figure out who those good and bad actors are that come to the party? What are the good genes and what are the bad genes playing out in breast cancer? And so we started with a number of genes in breast cancer. It was several hundred genes that we started with, and then we pared that number down to what we thought were the most important genes.

We are measuring RNA expression with the Oncotype DX assays, looking at overexpression and underexpression of genes. With the breast cancer assay we ended up looking at 21 genes, an algorithm was developed, and a Recurrence Score produced.

It’s the same thing with colon cancer except it’s a different number of genes, and they’re different genes. One of the things that is at play here is that different pathways impact different cancers. What we have shown both in breast cancer and in colon cancer, and what we hope to show in prostate cancer as well, is that looking

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at a number of pathways is more powerful than just looking at 1 pathway or 1 gene alone.

PMO How does this differ from the DCIS Oncotype DX score?

Ms Popovits The DCIS score that we developed is based on the same set of 21 genes as the invasive breast cancer assay, but it’s looking at an earlier stage of breast cancer, using a specific algorithm to determine whether that disease is likely to recur over a period of time.

PMO How does the Recurrence Score correlate with the likelihood of distant recurrence?

Ms Popovits The Recurrence Score predicts the likelihood of disease aggressiveness, so what we were attempting to do when we did the test for invasive breast cancer was to figure out which women had disease that would be more aggressive and could potentially benefit from more aggressive treatment. And what we discovered when we developed that assay, the 21-gene assay, was that not only could we predict which patients had a likelihood of their disease recurring over a 10-year period, we did subsequent studies to show that we could also predict whether those women would benefit from chemotherapy.

We ended up in a situation where we had 50% of women in a low-risk group, 25% in an intermediate-risk group, and 25% in a high-risk group. Even better than that, we were able to give an individual score to each patient. When we designed the studies initially, we were hoping to be able to identify risk groups, and we were very pleased that not only could we identify certain risk groups, we could actually give women an individual score to show them their likelihood of recurrence. For example, if you get a Recurrence Score of 7, that correlates to a specific likelihood of recurrence over a 10-year period. We can also tell you if your cancer is likely to benefit from chemotherapy.

One fact that a lot of people are unaware of is that about 100,000 women are diagnosed each year with early-stage breast cancer, ie, estrogen receptor–positive, node-negative breast cancer. Most of those women, prior to Oncotype DX being available, would have been recommended chemotherapy based on cancer practice guidelines.

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What’s unfortunate there is that while most would have been recommended chemotherapy and most would have received it, most would not have benefited, because we know that only 3% to 4% of women with early-stage breast cancer actually benefit from chemotherapy. So we’re treating 100 women to find 3 or 4 who get some benefit, and that’s what we were trying to change.

The Oncotype DX assay allows us to tell 50% of these women that they have very low-risk disease. Their likelihood of recurrence is very low, and further, we can tell them that their disease isn’t likely to be impacted by chemotherapy. Conversely, we can tell those women who are in the high-risk group that they have a high risk for disease recurrence, and while that’s not necessarily good news, the good thing for these women is that chemotherapy actually will help them a good bit.

PMO How is the DCIS score result different from the Recurrence Score result?

Ms Popovits The DCIS score uses the same 21 genes from the invasive assay, with a distinct algorithm optimized for this earlier cancer, to predict which women with DCIS have more aggressive disease and which have less aggressive disease. And we were successful in doing that.

PMO Can you estimate how often the results of these assays change treatment decisions?

Ms Popovits One of the most important factors in personalized medicine, with the onset of the technology and the amount of data that are available to us today, is really making these data actionable. We knew that when we presented the breast cancer assay to physicians, and to payers specifically, some of the questions that we were going to get were, tell me that this is going to make a difference; tell me that patients are not going to get chemotherapy if they don’t need it.

One of the biggest fears was that we would introduce a diagnostic test into this treatment planning or pathway, and that no decisions would change.

We have embarked on over 15 decision impact studies across the United States, and now also outside the United States, to really look at what’s happening. So when patients get a Recurrence Score result and they

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are at high risk for recurrence or at low risk of recurrence, are they following that result?

The results of those studies have been amazingly consistent. Treatment decisions are changing on the order of 30% to 40% of the time when the patients have a Recurrence Score in front of them. That’s a significant change for a payer.

We were very pleased that not only could we identify certain risk groups, we could actually give women an individual score to show them their likelihood of recurrence.

The other thing that we’ve done is to monitor chemotherapy use across different payer systems and different clinical settings, and we are definitely seeing a decrease in the amount of chemotherapy being used as a direct result of the Recurrence Score being available for patients to consider in their treatment planning.

PMO What would you say to the breast cancer patient who has a low Recurrence Score but wants to initiate cytotoxic chemotherapy as “insurance”?

Ms Popovits Often we are asked if the Recurrence Score should be the final deciding factor in whether a patient gets chemotherapy. In personalized medicine, there are so many factors that have to be considered in making a treatment decision in any disease, but especially in cancer.

So you’ll factor in the patient history, patient preference, tumor size, tumor grade. What we do know is that the Recurrence Score is the most powerful predictor.

However, it has to be used in context with everything else that’s going on in a patient’s world at that given time.

People will ask us, well, if I have a high Recurrence Score, is it really terrible that I decide not to get chemotherapy? Or, I have a low Recurrence Score, but because my mom had breast cancer I am just not going to be comfortable not getting chemotherapy. And my personal feeling is that it’s a good decision if it’s made

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Genomic Health clinical laboratory scientists preparing patient samples.

with all of the relevant information in front of you.

So if you decide that you want chemo even though you have a low Recurrence Score, knowing that the low score means that you have a very low likelihood of your disease recurring, and further, are not going to get very

What we do know is that the Recurrence Score is the most powerful predictor.

However, it has to be used in context with everything else… much of a benefit from chemotherapy, if you understand that and you’ve been taken through the data and those facts, and you still decide that you want to proceed with

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chemotherapy, that’s a personal choice, and that to me is personalized medicine.

PMO Regarding the Genomic Health pipeline, you’re hoping to offer genomic assays in prostate cancer, as well as non–small cell lung cancer, renal cell carcinoma, and melanoma. Regarding an assay for prostate cancer, a test that could provide insight into the individual biology and behavior of newly diagnosed prostate cancers would be helpful in treatment planning for prostate cancer patients and their physicians, particularly to identify patients who are at low risk of disease progression and thus would be ideal candidates for close monitoring. Where are you in the process of bringing this assay to patients?

Ms Popovits We have a really exciting pipeline at Genomic Health; we started in breast cancer, and we moved into colon cancer. I’m happy to say that we have helped over 300,000 patients make really important treatment decisions, but each year over 1.6 million patients are diagnosed with cancer in the United States alone.

The other big cancer that we haven’t tackled yet is prostate cancer. We have a validation study under way.

We expect to be able to launch that test in 2013, should we be successful in this study, the results of which we hope to be able to announce toward the end of this year or early next year.

The need in prostate cancer is very similar to the need in breast cancer and colon cancer. Well over 200,000 men are diagnosed each year. Most are faced with a very important decision around how to handle their disease. Many opt for aggressive surgery, and that surgery has very significant lifelong side effects that include incontinence and impotence, which will dramatically impact their life.

We know prostate cancer is unlikely to present future problems for most men. Ninety percent of men should do fine with no treatment at all, yet we’re in a situation today where 90% of men are actually getting fairly aggressive treatment.

What we’re really hoping to answer in prostate cancer is whether we can tell men that they can be com-

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fortable that they have a very low-risk disease, and that they should be able to monitor that disease according to how they and their physician decide to monitor it, but there’s no need for them to go and get aggressive surgery or treatment at this point.

PMO Given the high incidence of breast, colon, prostate, and lung cancers, will it make sense for Genomic Health to develop assays that impact smaller patient populations, such as melanoma or other tumor types?

Ms Popovits There’s a number of things that we are really excited about getting into as we move forward.

Prostate cancer is the big focus right now as we extend our pipeline, but as you know, there are many cancers that we haven’t touched yet, including melanoma and ovarian and bladder cancer. Those are all cancers that we’re interested in.

What we have started with are the cancers that have a very low likelihood of presenting significant risks to patients, so it’s early-stage breast cancer, it’s early-stage colon cancer, it’s prostate cancer. In some of the other cancers that often get detected at a little later stage, our interest is to maybe look at therapeutic response, look at targeted therapies and try to determine if we can do a better job of helping patients choose a particular drug, given that we know that their cancers perhaps are a little bit more aggressive.

So, yes, we’re interested in moving toward other cancers, but right now the major ones that we have on our plate – breast, colon, and prostate cancer – will be our focus for the near term. We really hope to be able to say that we are with patients on their journey; to be able to be involved in looking at predisposition to cancer, looking at diagnosis of cancer, looking at drug monitoring through cancer, so that we stay with patients through their entire journey of cancer and cancer treatment.

PMO Genomic Health is transitioning from an RTPCR [reverse transcriptase-polymerase chain reaction] platform to next-generation sequencing as the basis for development of its future cancer diagnostic assays. Can you describe the opportunities and challenges associated with this transition?

Ms Popovits This is a really exciting time in the field

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of genomics because of how the technology has evolved, and we’re very interested in using next-generation sequencing, specifically to discover more about the biology of cancer. We have been using the next-generation sequencing platform in our research area for a number of years now, and what we’re finding is that we’re able to see the biology of disease even better than we ever have using RT-PCR as our platform.

Ninety percent of men should do fine with no treatment at all, yet we’re in a situation today where 90% of men are actually getting fairly aggressive treatment.

As we further our work with next-generation sequencing, we’re uncovering more and more genes that are these good and bad actors in cancer, and certainly we’re going to use this platform to develop more powerful assays in the future to help treatment decisions for patients with cancer.

PMO It seems that education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. What efforts is Genomic Health making in educating these stakeholders?

Ms Popovits Education is clearly going to be the cornerstone of personalized medicine being successful. Genomic Health has put a tremendous amount of resources into education – educating physicians, payers, and patients. We have worked very closely with the advocacy communities, and we knew going in that it was going to be very difficult to move a test like Oncotype DX into standard of care if we didn’t have payers on board, if we weren’t able to demonstrate that the test was making a difference in treatment planning. Getting payers on board, getting physicians to embrace the concept of personalized medicine, the understanding of genomics, and how to present genomics to their patients has been very, very important.

Again, we have worked closely with advocacy communities and done a number of educational programs.

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We’re very focused on working with the opinion leaders, both in the academic and in the community setting, to make sure that this information is available, and to

We’re very focused on working with the opinion leaders, both in the academic and in the community setting, to make sure that this information is available... make sure that we’re doing our job in promoting the education around genomics to make sure that personalized medicine is successful in the future.

PMO Can you describe the corporate culture of Genomic Health?

Ms Popovits Well, I’m probably a little biased as the

CEO, but Genomic Health is a pretty special place to work. We have nearly 600 employees now spread across the world, all drawn together with a single purpose. We really want to change the way cancer is treated. We want to change the way that patients are presented information. We want to change the way physicians use diagnostic tools. We want to change the way molecular pathology is incorporated into cancer treatment. You can feel that purpose here every day in our hallways, which makes this a very special place to work. It’s something that I personally guard very carefully.

You’ll see pictures of patients in our hallways, you’ll hear stories of patients at our all-employee meetings because patients are at the center of all we do.

Every test result that goes out of our door makes a significant impact in the life of somebody, and I don’t ever want people to forget that. u

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The Next Generation in Oncologic Care

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Highlights From the 2012 World Cutaneous Malignancies Congress Teresa Petrella, BSc, MD, MSc, FRCPC University of Toronto, Toronto, Ontario, Canada Kim A. Margolin, MD, FACP University of Washington, Seattle, Washington

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he World Cutaneous Malignancies Congress, which took place in April 2012 in Montreal, Canada, focused on advances in the fields of cutaneous malignancies (ie, malignant melanoma, basal cell carcinoma) and cutaneous T-cell lymphoma, including biology, pathology, staging, personalized therapy, maintenance therapy, novel agents, and ongoing research.

Melanoma Epidemiology: Hereditary Plus Environmental Risk Factors Julia Newton-Bishop, MD, from the University of

Leeds in the United Kingdom, presented a talk called, “Cutaneous Malignancies: at the Intersection of Genes and the Environment,” in which she discussed what genetic epidemiology tells us about the molecular biology of melanoma and thus about prevention.

Melanoma is predominantly genetic; it’s essentially a cancer of fair-skinned people. Within those groups with a fair complexion, hereditary factors (eg, red hair, numerous moles, and the propensity to sunburn) contribute to risk. However, environmental factors are important because when people with these phenotypes have immigrated to sunny countries, like Australia and

CME/CE Information Sponsors This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation The University of Cincinnati designates this enduring material activity for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

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

Registered Pharmacy Designation Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of con-

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Volume 1 • No 3

tinuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-12-025-H01-P. Commercial Support Acknowledgment This activity is supported by an educational grant from Amgen Inc.

Target Audience This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, nurse practitioners, nurses, physician assistants, pharmacists, and other healthcare professionals involved in the treatment of patients with cutaneous malignancies.

Educational Objectives After completing this activity, the participants should be better able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

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To receive credit, complete the posttest at www.mlicme.org/P11080.html.

New Zealand, the risk is greatest. So both ultraviolet exposure and genes are important determinants of melanoma risk.

The first progress in understanding the molecular biology of melanoma came from genetic studies of familial melanoma, which showed that members of a family in the United Kingdom with many cases of melanoma have an inherited germline mutation in the CDKN2A gene,1 which encodes the tumor suppressor protein p16 and also a second tumor suppressor protein – p14ARF. Additional mutations that provide more information about the biology of melanoma are slowly being discovered. For example, in very rare families, the susceptibility to melanoma is due to mutations in the CDK4 gene,2 and recently a mutation in BAP1 has been reported in families with ocular and cutaneous melanoma.3 These are genes with high penetrance and a lower environmental contribution to risk, but they provide information about the biology.

CME/CE Information (continued) Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/P11080.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by University of Cincinnati and Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Planners and Managers Disclosures Rick Ricer, MD, UC CME Content Reviewer, has nothing to disclose.

Kathyrn Gada, MSN, MLI Peer Reviewer, has nothing to disclose.

Teresa Haile, RPh, MBA, MLI Peer Reviewer, has nothing to disclose.

Volume 1 • No 3

FACULTY CHAIRS

Teresa Petrella, BSc, MD, MSc, FRCPC

Kim A. Margolin, MD, FACP

Familial mutations explain only a small proportion of melanoma cases. In routine clinical practice, only 2% of melanoma patients will have a CDKN2A mutation (M Harland, unpublished data, 2012). Even when nonFaculty Disclosures Kim A. Margolin, MD, FACP, is on the advisory board for Genentech and Roche.

Teresa Petrella, BSc, MD, MSc, FRCPC, is on the advisory board for Bristol-Myers Squibb, GlaxoSmithKline, Merck, and Roche; is a consultant for GlaxoSmithKline, Merck, and Roche; and is on the speakers bureau for Merck and Roche.

The associates of University of Cincinnati, Medical Learning Institute, Inc., the accredited providers for this activity, Center of Excellence Media, LLC, and Core Principle Solutions, LLC, do not have any financial relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months.

Disclaimer The information provided at this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred.

Estimated time to complete this activity: 1.25 hours Initial Release Date: August 17, 2012 Expiration Date: August 17, 2013

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Table 1. Associations Between Sun Exposure and Melanoma Risk7 Controls

Cases

OR (95% CI) (adjusted age/sex)

Never

315 (68%)

511 (58%)

1

At least once

147 (27%)

365 (42%)

1.56 (1.23-1.99)

Factor Sunburn ≥20

Average holiday exposure (hours/year) ≤46.2

167 (34%)

345 (38%)

1

46.2-71.3

161 (33%)

259 (28%)

0.75 (0.57-0.98)

>71.3

163 (33%)

312 (34%)

0.87 (0.66-1.15)

Average weekend exposure warm months (hours/day) ≤4

168 (34%)

377 (42%)

1

4.0-5.0

164 (33%)

262 (29%)

0.72 (0.55-0.94)

>5.0

161 (33%)

262 (29%)

0.67 (0.50-0.89)

OR indicates odds ratio.

selected patients present with a family history of 2 or more additional cases, the majority (88%) will not have CDKN2A mutations. Mutations are most likely to confer susceptibility if the patient has 3 or more primary melanomas or has more than 1 primary and a family history (M Harland, unpublished data, 2012). The genetic basis of susceptibility to melanoma remains unknown in 30% to 40% of families featuring 4 or more cases!4

What underlies susceptibility in the rest of the melanoma cases? Is it due to a clustering of lower-risk genes and environmental exposures?

The questions remain: What underlies susceptibility in the rest of the melanoma cases? Is it due to a clustering of lower-risk genes and environmental exposures?

Mutations in high-risk genes have yet to be identified.

Recently, however, a major international study identified a novel “boutique” mutation that appears to increase the risk of both inherited and sporadic cases of

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melanoma.5 This germline mutation occurs in the gene encoding MITF, a transcription factor that controls the expression of several important proteins – some related to pigmentation – in melanocytes, the melanoma precursor cells.

One puzzling statistic for those studying the epidemiology of melanoma is that outdoor workers do not have an increased risk of melanoma over otherwise similar individuals who do not work in the sun. Also, a relationship between solar exposure and the risk of melanoma has not been demonstrated. In an effort to better understand the contribution of the sun to risk of melanoma, Newton-Bishop and colleagues performed a pooled analysis of 15 case-control studies correlating patterns of sun exposure, sunburn, and solar keratoses (3 studies) with melanoma risk.6 They found that melanoma is essentially a cancer of intermittent sun exposure rather than of chronic sun exposure. Data from a more recent case-control study by the same investigators indicate that paradoxically, sun exposure may be protective under selected circumstances (Table 1).7 For example, individuals who had moderate weekend sun exposure (ie, over 5 hours outdoors on Saturdays and Sundays) actually had a lower risk of melanoma. Another conundrum is the relationship between sun exposure and the presence of a large number of nevi (moles). In another study, Chang and colleagues found that nevi are strongly related to sunny holidays, but not to sunburn history.8 The researchers concluded that while sunburn history is a robust risk factor for melanoma in all studies, the relationship between sun exposure (and ultraviolet A vs ultraviolet B wavelength exposure) and risk may be different for “the nevus route” to melanoma.

To investigate genes that explain melanoma risk in individuals who do not have a family history of melanoma, genome-wide association studies have been conducted by the Melanoma Genetics Consortium, and 15 genes (including pigment genes, nevus genes, and some genes related to DNA repair pathways but not associated with at-risk phenotype) have now been identified as low- to medium-penetrance susceptibility genes.9-11

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Molecular Alterations in Melanoma Boris C. Bastian, MD, from the University of California San Francisco School of Medicine, explained that melanoma is not a single disease entity; there are different genetically distinct types of melanoma (Table 2) that differ in their anatomic distribution, age of onset, relationship to ultraviolet radiation, and patterns of somatic mutations.12 In fact, Bastian pointed out that the statement “melanoma is primarily a disease of lightskinned people” is only partially true, because although 2 genetically distinct forms of melanoma are very common in light-skinned individuals, other types of melanoma unrelated to sun exposure occur in darkskinned individuals. The anatomic distribution of primary melanoma differs between light- and dark-skinned individuals. While melanomas manifest on the intermittently or chronically sun-exposed skin in lightskinned individuals, dark-skinned people typically get their melanomas on acral sites that are not exposed to ultraviolet light, ie, the palms, soles, nails, mucosa, and occasionally, the eye, where it is known as uveal melanoma.13 The appearance of a lesion on a patient’s skin or under the microscope is linked to the genetic alterations found in its cells. For example, a mutation in the BRAF gene is very common in melanomas originating on skin that is intermittently exposed to the sun but without pathologic evidence of chronic sun damage. Mutations in KIT occur in a subset of patients with melanoma originating on the hands, the soles of the feet, and the nails (about 10% with c-KIT mutations). Around 25% of patients with melanoma originating in the mucous membranes of the oral and nasal cavities or the urogenital tract have a c-KIT mutation, and a small percentage of patients with chronically sun-damaged skin, usually older individuals, also have 1 of several c-KIT mutations acting as “drivers” in their melanoma pathogenesis and possible therapeutic targets.14 NRAS is another oncogene that is mutated in ~15% of melanomas, although almost never in the same melanomas that harbor a BRAF mutation. For almost half of the cases of melanomas, a specific oncogenic “driver” mutation

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Table 2. World Health Organization Classification of Melanoma12 • Superficial spreading melanoma • Nodular melanoma • Lentigo maligna melanoma • Desmoplastic melanoma • Nevoid melanoma • Acral lentiginous melanoma • Mucosal melanoma • Uveal melanoma • Melanoma of childhood • Melanoma arising from giant congenital nevus • Melanoma arising from a blue nevus • Persistent melanoma

or genetic aberrancy has not yet been identified.

Another type of melanoma is uveal melanoma, which is the most common intraocular cancer. It is estimated that 40% of uveal melanomas contain mutations in GNAQ, which encodes an alpha subunit of heterotrimeric G proteins that act downstream of G protein–coupled receptors. A recent study found that 83% of uveal melanomas had somatic mutations in GNAQ or GNA11, a closely related gene, concluding that the 2 genes appear to be major contributors to uveal melanoma.15

Around 25% of patients with melanoma originating in the mucous membranes of the oral and nasal cavities or the urogenital tract have a c-KIT mutation...

Thus, mutually exclusive oncogenic mutations in melanomas involving NRAS, BRAF, KIT, and GNAQ/GNA11 have been identified that provide a new way to molecularly classify melanoma. In this new classification method, the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion, and require similar clinical management.

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of each of the mutations seen in each of the melanoma subtypes (Table 3).

Melanoma Subtype Davies and colleagues recently pubCutaneous Cutaneous lished their current recommendations for Mutations Without Chronic With Chronic molecular testing in patients who present Sun Damage Acral Mucosal Sun Damage Uveal with advanced melanoma (Table 4).17 BRAF mutations 50% 20% 3% 5% 0 However, in the future, multipanel testing NRAS will become available, and it will no longer mutations 20% 10% 5% 10% 0 be necessary to select individual tests.

KIT Finally, Davies discussed the implicaMutations ~1% 20%-40% 20%-40% 20%-40% 0 tions of this molecular information on GNAQ mutations 0 0 0 0 45% targeted therapies for melanoma. The GNA11 discovery of BRAF, NRAS, PTEN, and mutations 0 0 0 0 35% c-KIT mutations in melanoma has supported the development of a variety of targeted therapies against these proteins and related Table 4. Molecular Testing in Melanoma Clinical pathways, but approximately 30% of melanoma patients Subtypes17 have no detectable abnormality in these genes. In order Testing Recommendations to develop therapeutic approaches for these patients, it Subtype of will be necessary to determine if their tumors are actiMelanoma First Step Second Step vating similar pathways, or if they are dependent on Cutaneous completely different signaling cascades.17 (without chronic

Table 3. MAPK Pathway Mutations: Prevalence by Site16

sun damage)

BRAF ± NRAS

KIT

Cutaneous (with chronic sun damage)

BRAF ± NRAS

KIT

Acral

BRAF, KIT ± NRAS

–

Mucosal

BRAF, KIT ± NRAS

–

Uveal

Gene expression profiling or monosomy 3 determination*

–

Melanoma from an unknown primary

BRAF, NRAS

KIT, GNAQ, GNA11, monosomy 3

*Tests for metastatic risk.

Implications for Testing and Therapy Michael Davies, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, Texas, then discussed, among other topics, the implications of the molecular heterogeneity of melanoma on testing and therapy. He began by summarizing the frequencies

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Update on Pegylated Interferon in Adjuvant Melanoma Therapy Alexander Eggermont, MD, PhD, Directeur Général at the Institut de Cancérologie Gustave Roussy in Paris, France, discussed the results of a post hoc meta-analysis of 2 phase 3 adjuvant trials: European Organisation for Research and Treatment of Cancer (EORTC) trial 18952 (intermediate doses of interferon α-2b [IFN] vs observation in stage IIb/III patients) and EORTC 18991 (pegylated [PEG]-IFN vs observation in stage III patients) in melanoma.18 Both trials were stratified for stage (microscopic nonpalpable nodal involvement vs palpable nodal relapse) as well as for the presence of ulceration in the primary melanoma.

The results of the meta-analysis showed that patients with stage IIb/III N1 melanoma benefited significantly from IFN or PEG-IFN treatment, while patients with stage III N2 disease did not. Also, patients with an ulcerated primary tumor benefited significantly from ad-

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Continuing Medical Education

Figure 1. Overall Survival in Pretreated Patients Receiving Ipilimumab 3 mg/kg With or Without gp10019

,' ,(0. &, $*.+-$#

Volume 1 â&#x20AC;˘ No 3

&, $*.+-$#

-

-

$#( ' gp indicates glycoprotein; Ipi, ipilimumab.

- -

Table 5. Severe to Fatal Immune-Mediated Adverse -Reactions Reported With Ipilimumab19 -

-

Study Group -

Adverse Reaction Enterocolitis Endocrinopathy Hypopituitarism Adrenal Insufficiency Dermatitis Hepatotoxicity Hepatitis Neuropathy Nephritis - Eosinophilia Pneumonitis Meningitis - Pericarditis

Ipilimumab Alone (n=131) 7%

Ipilimumab Plus gp100 (n=380) 7%

4% â&#x20AC;&#x201C; 2% â&#x20AC;&#x201C; 1% 1% 1% 1% â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

1% 1% 3% 2% â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; <1% <1% <1%

-

-

-

Cytotoxic T-Lymphocyteâ&#x20AC;&#x201C;Associated Antigen 4 Blockade Caroline Robert, MD, PhD, from the Service de Dermatologie et INSERM at the Institut Gustave Roussy in Villejuif, France, discussed ipilimumab, a fully human monoclonal antibody (IgG1) that blocks the activity of cytotoxic T-lymphocyteâ&#x20AC;&#x201C;associated antigen 4. Ipilimumab has been approved by the FDA for the treatment of unresectable or metastatic melanoma. Ipilimumab was studied in 2 phase 3 trials â&#x20AC;&#x201C; 1 in previously treated patients19 and 1 in treatment-naive patients.20 In the first study, ipilimumab, administered with or without a glycoprotein 100 (gp100) peptide vaccine, was compared with gp100 alone in 676 HLA-A*0201â&#x20AC;&#x201C;positive patients with previously treated unresectable stage III or IV metastatic melanoma whose disease had progressed while they were receiving therapy.19 Patients were randomly assigned in a 3:1:1 ratio to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg/kg body weight, was administered with or without gp100 every 3 weeks for up to 4 treatments (induction). The median overall survival (Figure 1) was 10.0 months among patients receiving ipilimumab plus gp100, compared with 6.4 months among patients receiving gp100 alone (HR for death, 0.68; P<.001). The median overall survival with ipilimumab alone was 10.1 months (HR for death in the comparison with gp100 alone, 0.66; P=.003). No difference in overall survival was detected between the ipilimumab groups (HR with ipilimumab plus gp100, 1.04; P=.76).

,' $*.+-$#

-

* & ""- )&* * "-

juvant IFN or PEG-IFN therapy, while patients with a nonulcerated primary tumor did not. Patients with both favorable stage (IIb and III N1) and ulcerated primary tumor benefited greatly (hazard ratios [HRs] 0.56-0.69) with regard to relapse-free survival, distant metastasisfree survival, and overall survival. Patients with stage III N2 disease did not derive significant benefit for any end point, even when they had an ulcerated primary tumor.

The authors concluded that both tumor stage and ulceration were predictive factors for the efficacy of adjuvant IFN/PEG-IFN therapy.

gp indicates glycoprotein.

In the second study, ipilimumab (10 mg/kg) plus dacarbazine versus dacarbazine plus placebo was studied in 502 patients with previously - untreated metastatic - 2) -was -significantly melanoma. Overall survival (Figure longer in the group receiving ipilimumab plus dacarbazine than in the group receiving- dacarbazine plus - - placebo (11.2 vs 9.1 months), with higher - survival rates

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Figure 2. Overall Survival in Previously Untreated Patients Receiving Ipilimumab 10 mg/kg With Dacarbazine20 100

Censored Censored

Patients Surviving (%)

90 80 70 60 50 40

Ipilimumab窶電acarbazine

30 20

Placebo窶電acarbazine

10 0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

42

44

46

48

Months

Table 6. Most Common Adverse Reactions Reported With Ipilimumab19 Study Group Ipilimumab Alone (n=131) 41% 32% 31% 29% 8%

Adverse Reaction Fatigue Diarrhea Pruritus Rash Colitis

Ipilimumab Plus gp100 (n=380) 34% 37% 21% 25% 5%

gp100 Alone (n=132) 31% 20% 11% 8% 2%

P

gp indicates glycoprotein.

in the ipilimumab-dacarbazine group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%) (HR for death, 0.72; P<.001).20 Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab was also studied in an open-label phase 2 trial in 72 patients with melanoma and brain metastases.21 Results showed that ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic.

Toxicity, including severe to fatal immune-mediated adverse reactions, was a serious problem in the ipilim-

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umab studies (Table 5).19 The most common adverse reactions seen with ipilimumab are listed in Table 6.

Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.19 The benefit/risk ratio associated with ipilimumab can be optimized either by increasing the efficacy or by the selection of the patients for their likelihood of benefit from this treatment. It may be possible to enhance antitumor activity by modifying the dosing regimen or by combining therapies (such as ipilimumab plus vemurafenib), but none of these approaches can be recommended until clinical trials have shown a safe and effective improvement over what is currently approved.

Selection of patients involves increasing the understanding of tumor/host/therapy interactions, which are under active investigation and likely to yield insights over the next few years.

Basal Cell Carcinoma Epidemiology and Etiology Dirk Schadendorf, MD, PhD, Director and Chair of the Department of Dermatology Skin Cancer Center at the University Hospital Essen, Essen, Germany, began his presentation by reviewing the epidemiology of basal cell carcinoma. The annual global incidence of non-

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Table 7. Subtypes of Basal Cell Carcinoma27,28,31 Percentage of Cases Description

Nodular 60% • Occurs frequently on sun-exposed areas of the head • Often presents as a papule or nodule

melanoma skin cancer is 2 to 3 million cases,22 and approximately 80% of these are basal cell carcinomas.23,24 Epidemiologic data suggest that the overall incidence of basal cell carcinoma is increasing significantly and show marked geographical variation.23-26 Australia has the highest incidence rate of basal cell carcinoma in the world, reporting a rate of 1% to 2% per year.23,24 Basal cell carcinoma develops in the basal layer of the epidermis and is the most commonly diagnosed malignancy worldwide.24,27-29 The average lifetime risk for Caucasians to develop basal cell carcinoma is in the range of 5% to 30%, depending in large part on skin type and patterns of sun exposure.24,27 A major cause of basal cell carcinoma is exposure to ultraviolet radiation, leading to cumulative DNA damage and acquired gene mutations.24,27-30 Most sporadic cases of basal cell carcinoma arise from chronic sun exposure; 80% occur on the head and neck, 15% on the trunk, and 5% on the arms, legs, or other sites.24,27 Basal cell carcinoma is classified into 3 subtypes (Table 7).27,28,31 Surgical excision is the most common treatment for basal cell carcinoma and has a high success rate, particularly in uncomplicated cases (Table 8).27,31 However, surgery can be both debilitating and disfiguring.31 Tumors that are not appropriate for surgery, or for which surgery would result in substantial deformity (ie, in difficult-to-treat locations) require treatment with nonsurgical approaches, such as radiotherapy,27 photodynamic therapy,32 chemotherapy,33 and topical therapy.34,35

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Superficial 30% • Occurs most frequently on the trunk • Characterized by small buds of basaloid tumor cells extending from the epidermis

Other 10% • For example, morphoeic cases, also called sclerosing or fibrosing basal cell carcinomas, are aggressive infiltrating subtypes • Often have ill-defined borders, making complete excision a challenge

Table 8. Cure Rates for Various Surgical Techniques in Basal Cell Carcinoma27,31 Surgical Technique

5-Year Cure Rate

Surgical excision

≥95%

Curettage and cautery

≥95%

Cryosurgery

≥95%

Mohs micrographic surgery

~99%

National Comprehensive Cancer Network Guidelines Mark Pittelkow, MD, from the Mayo Clinic College of Medicine in Rochester, Minnesota, reviewed the National Comprehensive Cancer Network (NCCN) guidelines for treating basal cell carcinomas, in which treatment is stratified by risk status.36 According to the NCCN guidelines, high-risk basal cell carcinomas include the following36: • Recurrent or incompletely excised basal cell carcinoma • Primary basal cell carcinoma with clinically indistinct borders • Lesion in high-risk (known as the “H,” or “mask”) areas, mainly the embryonic fusion planes (eg, eyelids, nose, ear, nasolabial folds, upper lip, vermillion border, columella, periorbital region, temples, preauricular and postauricular areas, and scalp) • Lesions that develop in cosmetically and functionally important areas (eg, face, genitals, anal and perianal regions, hands and feet, and the nail unit areas) • Tumors with aggressive clinical behavior (ie, growing rapidly or >2 cm)

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Figure 3. Classification of Patients With Basal Cell Carcinoma25,27,40,41 Locally advanced basal cell carcinoma • Patients whose lesions are not appropriate for surgery, or who have medical contraindications to surgery • Patients for whom surgery would result in substantial morbidity and/or deformity (eg, invasion into skull, limb amputation, or enucleation)

Basal Cell Carcinoma

Locally advanced basal cell carcinoma Metastatic basal cell carcinoma

Advanced Basal Cell Carcinoma

Metastatic basal cell carcinoma • Sometimes occurs in patients with long-standing primary lesions that are large or recurrent • Rare but serious form of basal cell carcinoma (0.0028%0.55% of tumors progress to metastatic disease) • Includes distant metastases (eg, bone, lung, and liver) or lymph node involvement • Poor prognosis (median survival: 8-14 months; 5-year survival rate: 10%) Advanced basal cell carcinoma • Locally advanced disease • Metastatic disease

• Tumors with aggressive histologic subtype, including sclerosing (morpheaform), basosquamous (metatypical or keratinizing), perineural, periappendageal, or perivascular invasion, infiltrating, adenoidal, or multicentric • Tumors that develop in sites with previous radiation therapy • Tumors that develop in immunosuppressed patients Treatment Challenges for Advanced Basal Cell Carcinoma Nicole Basset-Seguin, MD, PhD, from the Hôpital Saint-Louis in Paris, France, discussed treatment challenges for patients with various types of basal cell carcinoma, especially advanced disease (Figure 3). She pointed out that, at present, patients with inoperable, advanced basal cell carcinoma, or those in whom surgical resection would result in substantial deformity, have very few therapeutic options. There is no standard ther-

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apy for advanced basal cell carcinoma.37 Once basal cell carcinoma has metastasized, it is highly malignant and has a poor prognosis.38,39 Therefore, new treatment options are needed for advanced basal cell carcinoma.

The Hedgehog Signaling Pathway Joel Claveau, MD, CSPQ, FRCPC, Associate Professor of Medicine in the Dermatology Division at Laval University in Quebec, Canada, discussed the molecular pathogenesis of basal cell carcinoma. He provided an overview of the hedgehog signaling pathway, which plays a fundamental role in normal embryonic development. The hedgehog pathway was discovered in the fruit fly (Drosophila) and is conserved in vertebrates (including humans).42,43 It is involved in cell growth and differentiation to control organ formation during embryonic development. Hedgehog signaling regulates embryonic development, ensuring that tissues reach correct size and location, maintaining tissue polarity and cellu-

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lar content.43 In the skin, the hedgehog pathway is critical for regulating hair follicle and sebaceous gland development.44 Germline mutations in components of the hedgehog signaling pathway result in a number of developmental abnormalities.45,46 Hedgehog signaling normally remains inactive in most adult tissues.

Key components involved in hedgehog signaling include the hedgehog ligand, hedgehog (Hh), which initiates signal transduction of the hedgehog pathway; the hedgehog signal transducer, smoothened (SMO), which is normally suppressed by the hedgehog ligand receptor, patched (PTCH), preventing its activation of the hedgehog signaling cascade; the hedgehog ligand receptor, PTCH, which normally suppresses the activity of SMO; and the hedgehog effectors, which are a cytosolic complex of proteins including suppressor of fused and the Gli family of transcription factors. Activation leads to expression of specific genes that promote cell proliferation and differentiation.43 When the hedgehog pathway is inactive, PTCH inhibits SMO activity, and the intracellular signaling cascade is suppressed.30,47,48 Activation of the pathway is initiated by the Hh ligand binding to PTCH, releasing its inhibitory effect on SMO, which results in target gene expression.30,47-49 Abnormal hedgehog pathway signaling plays an important role in the pathogenesis of certain types of cancer. Different mechanisms drive abnormal hedgehog pathway signaling in different types of cancer43,50,51: • Ligand-independent signaling driven by mutations (eg, basal cell carcinoma and medulloblastoma) • Mutations in key pathway regulators (eg, PTCH or SMO) that cause SMO to be in a constitutively active state • Ligand-dependent signaling driven by overexpression of Hh ligand by tumor cells (eg, ovarian, colorectal, and pancreatic cancer) As a result of inactivating PTCH mutations or activating SMO mutations, SMO moves to the cell surface leading to activation of the Gli family of transcription factors. Activated Gli then moves to the nucleus and initiates the transcription of target genes.30,43,49,51-56 Ab-

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Table 9. New and Investigational SMO Inhibitors57 Drug

Status

Trials

Erivedge (vismodegib) FDA approved for locally advanced and metastatic basal cell carcinoma Investigational LDE225 LEQ506 Investigational BMS-833823 Investigational (XL139) TAK-441 Investigational IPI926 Investigational (saridegib) PF-04449913 Investigational

Phase 2 Phase 1 Phase 1 Phase 2 Phase 1 Phase 1 Phase 2 Phase 1

SMO indicates smoothened.

normal activation of the hedgehog signaling pathway is thought to play a critical role in the pathogenesis and progression of basal cell carcinoma, either by inactivating PTCH mutations or by activating SMO mutations.

Hedgehog pathway inhibitors may provide a new treatment option for patients with advanced basal cell carcinoma.49

Abnormal activation of the hedgehog signaling pathway is thought to play a critical role in the pathogenesis and progression of basal cell carcinoma.

In basal cell carcinoma, abnormal hedgehog pathway signaling is the key molecular driver of the disease. More than 90% of basal cell carcinomas have abnormal activation of hedgehog pathway signaling. Most basal cell carcinoma tumors have either inactivating mutations in PTCH or, less commonly, activating mutations in SMO. Targeted Hedgehog Inhibition Aleksandar Sekulic, MD, PhD, from the Mayo Clinic and the Translational Genomics Institute in Scottsdale, Arizona, presented a keynote lecture on targeted hedgehog pathway inhibition in basal cell carcinoma. He pointed out that the hedgehog pathway is aberrantly activated in virtually all basal cell carcinomas, so there is no need to screen. A number of hedgehog pathway in-

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Table 10. Adverse Reactions Occurring in ≥10% of Advanced Basal Cell Carcinoma Patients With Vismodegib in Clinical Trials58 MedDRA Preferred Term

All aBCC Patients (N=138) All Grades* (%) Grade 3 (%) Grade 4 (%)

Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) – –

– – – –

General disorders and administration-site conditions Fatigue

55 (39.9%)

7 (5.1%)

1 (0.7%)

Investigations Weight loss

62 (44.9%)

10 (7.2%)

–

Metabolism and nutrition disorders Decreased appetite

35 (25.4%)

3 (2.2%)

–

Musculoskeletal and connective tissue disorders Muscle spasms 99 (71.7%) Arthralgias 22 (15.9%)

5 (3.6%) 1 (0.7%)

– –

these adverse reactions were frequent but mostly mild to moderate. They may be acceptable in advanced and metastatic basal cell carcinoma, but the question remains whether they would be acceptable in patients who have operable disease. Preliminary data suggest that these adverse effects are reversible. Selection of patients and adverse effect management are key to the use of this agent.

Cutaneous T-Cell Lymphomas

Nervous system disorders Dysgeusia Ageusia

76 (55.1%) 15 (10.9%)

– –

– –

Skin and subcutaneous tissue disorders Alopecia

88 (63.8%)

–

–

Joan Guitart, MD, Professor of Dermatology and Pathology at the Feinberg Medical School in Chicago, Illinois, began her talk by pointing out that normal human skin is populated by 20 billion T cells, and that cutaneous T-cell lymphoma is a malignancy of T cells that reside in the skin.59 Guitart then provided a “world tour” of photographs of cutaneous T-cell lymphomas. She organized her presentation based on the World Health Organization and European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphomas (Table 11).60

aBCC indicates advanced basal cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities. *Grading according to NCI-CTCAE v3.0.

hibiting agents, mainly SMO inhibitors, are under development (Table 9).

Currently, 1 hedgehog pathway inhibitor, vismodegib, has been approved by the FDA for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. The most common adverse reactions (≥10%) with vismodegib were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 10).58 Overall,

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Host Immune Response Alain Rook, MD, from the Abramson Cancer Center and the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, discussed the importance of host immune response in the treatment of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma is highly responsive to immune modulation. The malignant CD4+ T cells observed in most cases of mycosis fungoides and Sézary syndrome appear to exhibit a T helper cell type 2 (Th2) phenotype (Figure 4). In mycosis fungoides and Sézary syndrome, the malignant T cell (CD4+/ CLA+/CCR4+) produces the cytokines IL-4, IL-5, and IL-10 that result in a Th2 predominance and subse-

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quent multiple abnormalities in cellular immunity.61 Numerous arms of the immune system must cooperate to generate a sufficient host antitumor response such that the proliferation of the malignant T-cell population in mycosis fungoides and Sézary syndrome can be controlled.

Elimination of the malignant T-cell clone during immunotherapy leads to restoration of a normal immune response. Studies of numerous patients with Sézary syndrome have demonstrated that induction of complete remission with clearing of the malignant T-cell clone during multimodality immunotherapy leads to a restoration of normal host immune function (Table 12).

Management of Early-Stage Cutaneous T-Cell Lymphomas (Mycosis Fungoides) Larisa Geskin, MD, from the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania, reviewed treatments for early-stage cutaneous T-cell lymphomas.

She explained that skin-directed therapies, including topical corticosteroids,62 topical chemotherapy (eg, nitrogen mustard63,64 or carmustine65), topical retinoids, and phototherapy66,67 are used for early-stage (stage Ia, Ib, IIa) disease. Radiation, both localized and total-skin electron beam radiation,68 as well as photopheresis,69 are used for stage IIb and III, and systemic treatments, such as bexarotene,70-73 interferon-alpha, romidepsin,74 vorinostat,75,76 alemtuzumab, and chemotherapy, are used for stage IVa and IVb disease (Table 13).

Staging/Classification and End Points/ Response Criteria Elise A. Olsen, MD, Professor of Dermatology and Oncology and Director of the Duke Cutaneous Lymphoma Research and Treatment Center in Durham, North Carolina, discussed staging and classification, as well as new end points and response criteria.

The Mycosis Fungoides Cooperative Group staging system for cutaneous T-cell lymphoma published in 1979 was revised in 2007 by the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the EORTC.81 The highlights of the revised system are:

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Table 11. WHO-EORTC Classification of Cutaneous T-Cell and Natural Killer (NK) Cell Lymphomas60 • Mycosis fungoides (MF) – Folliculotropic MF – Pagetoid reticulosis – Granulomatous slack skin • Sézary syndrome • Adult T-cell leukemia/lymphoma • Primary cutaneous CD30+ lymphoproliferative disorders – Primary cutaneous anaplastic large cell lymphoma – Lymphomatoid papulosis • Subcutaneous panniculitis-like T-cell lymphoma • Extranodal NK/T-cell lymphoma, nasal type • Primary cutaneous peripheral T-cell lymphoma, unspecified • Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) • Cutaneous γ/δ T-cell lymphoma • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) EORTC indicates European Organisation for Research and Treatment of Cancer; WHO, World Health Organization.

Figure 4. Consequences of Malignant T-Cell Cytokine Production61

IgE indicates immunoglobulin E; Th1, T helper cell type 1; Th2, T helper cell type 2.

• Include technological those of

advances,

including

molecular biology and immunohistochemistry

variables

• Incorporate new data on prognostic in my

cosis

fungoides

and Sézary

syndrome

• Exclude other non–mycosis fungoides/non–Sézary

variants

syndrome from the staging system

• Identify potential prognostic variables for the purpose

of tracking and validation

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Table 12. Immunological Phenotype in Sézary Syndrome Increased

Decreased

• CD4+/CLA+/CCR4+ T cells

• CD8 T cells

• Th2 cytokines; IL-4, IL-5, IL-10

• Loss of normal T-cell repertoire

• Regulatory T cells (Tregs)

• NK cells; Th1 cytokines; IFN-g

• Programmed Death 1 (PD-1)

• Dendritic cells (CD123 and CD11c), IL-12, IFN-α • CD40 ligand expression

IFN indicates interferon; IL, interleukin; NK cells, natural killer cells; Th1, T helper cell type 1; Th2, T helper cell type 2.

Table 13. Treatment Options for Patients With Mycosis Fungoides and Sézary Syndrome77-80 • Topical corticosteroids • Topical chemotherapy with mechlorethamine (nitrogen mustard) or carmustine • Psoralen and ultraviolet A radiation • Ultraviolet B radiation • Total-skin electron beam radiation • Radiation of symptomatic skin lesions • Interferon-α or interferon-γ alone or in combination with topical therapy • Single-agent and multiagent chemotherapy • Bexarotene (topical gel or oral); retinoids • Denileukin diftitox (recombinant fusion protein of diphtheria toxin fragments and interleukin-2 sequences) • Vorinostat or romidepsin (oral histone deacetylase inhibitors) • Alemtuzumab (a humanized monoclonal antibody targeting the CD52 antigen) • Combined modality treatment

A comparison of the original and revised staging systems is shown in Table 14.

In 2011, the ISCL, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC published consensus recommendations for the general conduct of clinical trials of patients with mycosis fungoides and Sézary syndrome, as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood,

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and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with mycosis fungoides or Sézary syndrome.82 New staging for mycosis fungoides and Sézary syndrome and non–mycosis fungoides/non–Sézary syndrome primary cutaneous lymphomas allows for incorporation of new molecular data into diagnostic criteria as well as standardization of clinical trial inclusion/exclusion criteria. New end points and response criteria for all types of primary cutaneous lymphoma allow for comparison of data from clinical trials of different medications conducted at different time points and facilitation of multicenter clinical trials, whether pharma supported or investigator initiated.

CD30+ Skin Lymphomas Lauren Pinter-Brown, MD, Clinical Professor of Medicine in the Division of Hematology-Oncology at the UCLA Medical Center in Los Angeles, California, discussed new approaches in the management of CD30+ skin lymphomas, which include: • Primary cutaneous anaplastic large cell lymphoma • Lymphomatoid papulosis • Mycosis fungoides (transformed) • Secondary cutaneous anaplastic large cell lymphoma • Peripheral T-cell lymphoma (unspecified), adult Tcell leukemia/lymphoma • Hodgkin lymphoma SGN-30 is a chimeric monoclonal antibody against the cluster C epitope of CD30. Brentuximab vedotin (formerly known as SGN-35) is an antibody-drug conjugate of SGN30 with an auristatin derivative (tubulin inhibitor).

Treatment with single-agent brentuximab vedotin resulted in unprecedented objective response rates and complete response rates of 75% and 34%, respectively, in relapsed or refractory Hodgkin lymphoma, and of 86% and 57%, respectively, in relapsed or refractory systemic anaplastic large cell lymphoma patients. Peripheral sensory neuropathy and neutropenia were observed

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Table 14. Comparison Between the 1979 Staging System for Cutaneous T-Cell Lymphomas and the 2007 Revised Staging System for Mycosis Fungoides and Sézary Syndrome81 1979 Staging System for Cutaneous T-Cell Lymphomas

2007 Revised Staging System for Mycosis Fungoides and Sézary Syndrome

Stage IA IB IIA IIB III

T 1 2 1-2 3 4

N 0 0 1 0, 1 0, 1

M 0 0 0 0 0

IVA IVB

1-4 1-4

2-3 0-3

0 1

Stage IA IB IIA IIB IIIA IIIB IVA1 IVA2 IVB

with brentuximab vedotin but were generally grade 1 and 2 in severity and manageable.83 In 2011, the FDA granted accelerated approval for brentuximab vedotin for the following indications84: • Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) • Hodgkin lymphoma in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens • Systemic anaplastic large cell lymphoma after failure of at least 1 multiagent chemotherapy regimen Brentuximab vedotin is currently being investigated in a number of clinical trials: • Phase 3 trial for patients at high risk of residual Hodgkin lymphoma following ASCT • Phase 3 trial for patients with relapsed CD30+ cutaneous T-cell lymphoma • Phase 2 trial for patients with relapsed or refractory CD30+ non-Hodgkin lymphomas • Phase 2 trial for patients with CD30+ nonlymphoma malignancies • Phase 2 trial for retreatment of patients who previously participated in a brentuximab vedotin study • Phase 1 trial in combination with chemotherapy for frontline treatment of Hodgkin lymphoma • Phase 1 trial in combination with chemotherapy for frontline treatment of CD30+ mature T-cell malignancies

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T 1 2 1-2 3 4 4 1-4 1-4 1-4

N 0 0 1-2 0-2 0-2 0-2 0-2 3 0-3

M 0 0 0 0 0 0 0 0 1

B 0, 1 0, 1 0, 1 0, 1 0 1 2 0-2 0-2

Conclusion The 2012 World Cutaneous Malignancies Congress covered the biology, pathology, staging, personalized therapy, maintenance therapy, novel agents, and ongoing research of a wide range of cutaneous malignancies.

Molecular biology and pathogenesis were reviewed as they relate to treatment of these cutaneous malignancies. Risk stratification of patients was discussed, along with how to tailor treatment based on patient and tumor characteristics. At this global forum, experts from around the world gathered to discuss personalized treatment strategies that incorporate current standards of care and emerging treatment options for the optimal treatment of patients with cutaneous malignancies into oncologists’ practice. u

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INTERVIEW WITH THE INNOVATORS An exclusive PMO series Personalized Medicine in Oncology™ is pleased to offer insightful interviews with leaders in oncology about their approach to personalized medicine.

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

Currently featuring:

Volume 1 • No 3

Deborah Dunsire, MD President and Chief Executive Officer Millennium: The Takeda Oncology Company

Kathy Giusti Founder and Chief Executive Officer Multiple Myeloma Research Foundation Multiple Myeloma Research Consortium

K. Peter Hirth, PhD Chief Executive Officer Plexxikon, Inc.

Kimberly J. Popovits President, Chief Executive Officer Genomic Health, Inc.

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MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

For more information please visit

www.AVBCConline.org

Regulatory Issues

Facilitating the Next Generation of Precision Medicine in Oncology The collision of regulatory paradigms in clinical genomic pathology Sheila D. Walcoff, JD Founding Principal, Goldbug Strategies, LLC Rockville, Maryland

Key Points • Key stakeholders are increasingly considering new measures to protect and advance innovation and investment in diagnostics • Efforts are under way to establish more appropriate and least burdensome regulatory policies to address stakeholder concerns specific to in vitro diagnostic tests • FDA is concerned with the risk of false-positive and false-negative test results that would be incorporated into clinical treatment decisions • FDA has struggled to find the most appropriate way to address regulatory oversight where gaps between CLIA and FDA are perceived • FDA’s move toward greater oversight of the clinical validity of genomic-based tests has, thus far, not resulted in a path to personalized medicine paved with greater clarity, certainty, and confidence

Value of Diagnostics in Healthcare – Foundation of Personalized Medicine in Oncology

ingly considering new measures to protect and advance innovation and investment in diagnostics. There is particular interest in so-called advanced linical laboratory testing has personalized diagnostics (APDx), a tremendous impact on pawhich drive greater “precision” in tient outcomes and health medical diagnosis and targeted treateconomics. Over 7 billion ment. APDx has been defined in draft laboratory tests are performed annually in federal legislation as in vitro diagnos1 the United States, and clinical tests contic products that provide “an analysis of deoxyribonucleic acid (DNA), ritribute to an estimated 70% or more of all 2 bonucleic acid (RNA), a chromodecision making in medical practice. Yet, the total cost of laboratory services acsome, a protein, or a metabolite… intended principally for use in detectcounts for merely 1.8% of all Medicare ing genotypes, mutations, patterns, or spending annually and only 2.3% of nachromosomal changes for the purpose tional healthcare spending.3 Sheila D. Walcoff, JD Key stakeholders, including industry, of diagnosis, prevention, cure, mitigapatient advocates, regulators, and legislators, are increastion, or treatment of any disease or impairment, includ-

C

Sheila D. Walcoff, JD, is a health and science attorney and the founding principal of Goldbug Strategies, LLC, a consulting and law practice offering business strategy, federal legislative and regulatory advocacy, and legal counsel related to personalized medicine and FDA-regulated medical products.

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ing prognosis or prediction of the outcome of a treatment or the assessment of the health of humans” and “…excluding methods of analysis principally comprising routine chemistry or routine immunology.”4 The important healthcare and economic benefits of APDx include, for example, more accurate and timely diagnoses (eg, fewer hospital bed days, longer survival, etc); surgery avoidance (eg, organ resection and resulting lifelong pharmacotherapy); appropriate therapy selection (eg, pharmacogenomics to optimize therapy selection and treatment response monitoring); and better avoidance of ineffective therapies (eg, toxic and costly side effects of chemotherapy). Despite regulatory and reimbursement uncertainty, these tests promise to be even more widespread in the very near term as physicians across specialties overwhelmingly believe genetic testing will improve patient care and anticipate testing to impact 14% of patients in their own practice within 5 years.5

Evolving Regulation of Diagnostic Tests, Including APDx: CLIA Versus FDA Molecular diagnostic tests performed in clinical laboratories have long been regulated by multiple federal and state agencies. Since the enactment of the federal Clinical Laboratory Improvement Amendments of 1988 (CLIA), tests developed and performed in clinical lab-

Molecular diagnostic tests performed in clinical laboratories have long been regulated by multiple federal and state agencies. oratories have been regulated chiefly by the Centers for Medicare & Medicaid Services (CMS) and various states pursuant to state-by-state laboratory licensure laws. But certain test components and reagents, whether a single analyte-specific reagent or combinations of components and reagents packaged together as a “kit,” general-purpose reagents, laboratory equipment, and software offered by manufacturers for sale or distribution to clinical laboratories for research, investigational, or

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clinical uses remained regulated by the FDA under the authority of the Federal Food, Drug and Cosmetic Act (FFDCA) as amended.6 Pursuant to its authority under section 201(h) of the FFDCA, FDA defines in vitro diagnostic tests and components as “medical devices.”

Specifically, “...reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae.” Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.7 Importantly, state authorities (rather than the federal government) regulate the practice of medicine, including laboratory medicine.

For tests performed in clinical laboratories, CLIA requires that each clinical laboratory that introduces a test system not subject to FDA clearance or approval, or uses a test system for which performance specifications are not provided by the test kit manufacturer, must establish for each test system the performance specifications for certain performance characteristics, including accuracy, precision, analytical sensitivity and specificity, reference intervals, and reportable ranges for results.8 Additionally, clinical laboratories often are accredited by other independent organizations, such as the College of American Pathologists (CAP).9 Clinical test systems are subject to rigorous certification by state entities as well, for example, the New York State Clinical Laboratory Evaluation Program (CLEP). Laboratories located in and holding clinical laboratory permits from several state programs, including the New York CLEP program, have been granted exempt status by CMS from additional accreditation under CLIA.10 The New York CLEP program is a well-known example of a very rigorous state licensure program designed to ensure the accuracy and reliability of results of laboratory tests on specimens obtained within the state. For clinical laboratories and blood banks holding New York state permits, CLEP also performs laboratory inspections, proficiency testing, and evaluation of laboratory personnel.10 In vitro diagnostic tests that are manufactured outside the clinical laboratory and then distributed to 1 or

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more clinical laboratories must be cleared or approved by the FDA prior to such distribution, although these tests may be modified later by clinical laboratories under the CLIA bridge testing and other validation requirements. FDA also has authority over reagents and instrumentation labeled for research use or investigational use, defined in regulations as in vitro diagnostic products. Specifically, the FDA considers products labeled Research Use Only (RUO) “…to be products that are in the laboratory research phase of development, that is, either basic research or the initial search for potential clinical utility, and not represented as an effective in vitro diagnostic product.” During this phase, the focus of manufacturer-initiated studies is typically to evaluate limited-scale performance and potential clinical or informational usefulness of the test. These products must be labeled “For Research Use Only. Not for use in diagnostic procedures.”11 FDA does not require RUO products to be cleared or approved by FDA since such products are not “intended” to be used for clinical purposes. Likewise, no premarket review or notification is required by FDA for products labeled for Investigational Use Only (IUO) that are intended only for controlled investigations to gather performance data on products with informed consent/Institutional Review Board approval. However, such products have long been used in practice by CLIA-accredited laboratories in tests offered by such clinical laboratories and validated pursuant to CLIA standards and requirements in each laboratory.

This practice of laboratory validation is widely accepted and subject to the regulatory rigors of both state and federal laboratory regulations.

With regard to tests developed and performed by clinical laboratories, known as laboratory-developed tests (LDTs), the FDA has long asserted that it has the authority to require premarket review of LDTs under the legal definition of “medical device” but has historically deferred to CMS to regulate LDTs at the federal level under CLIA. FDA’s policy of not requiring CLIA-accredited laboratories, including hospital and academic medical center laboratories, to submit LDTs to FDA prior to offering such tests for clinical purposes is called

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“enforcement discretion.” Importantly, FDA has applied enforcement discretion only to those clinical diagnostic tests it defines as LDTs, meaning “…for use in the diagnosis of disease or other conditions that was developed by [CLIA] certified clinical laboratory for use in that laboratory” and are “neither an analyte-specific reagent nor are the components for research use only.”12 Notably, FDA has taken enforcement action against laboratories performing tests as LDTs that have not been entirely developed and validated in a single facility.13 FDA has asserted that even the provision of customized reagents with instructions for clinical use or the transfer of data alone, such as instructions for use, performance

FDA does not require RUO products to be cleared or approved by FDA since such products are not “intended” to be used for clinical purposes. characteristics, or protocols, between a manufacturer, research entity, CLIA laboratory, or other entity and CLIA laboratory, disqualifies the test as an LDT with enforcement discretion protection and subjects it to the FDA premarket review or notification requirements.13 FDA’s assertion of the existing framework for review and approval of traditional medical devices (like heart valves) is not well suited for both LDTs and distributed in vitro diagnostic kits. Consequently, efforts are under way to establish more appropriate and least burdensome regulatory policies, including evidentiary requirements and review standards, to address stakeholder concerns specific to in vitro diagnostic tests. These proposals range from creating a new category of regulated product for risk-based review of all in vitro diagnostic products under FDA while retaining CLIA oversight of laboratory operations and the actual performance of the test (the premise of the draft legislation contemplated by US Senator Orrin Hatch), to expanding the regulatory role of CMS under CLIA and excluding FDA entirely from LDT oversight (the premise of US House of Representatives Bill 3207 introduced by Representative Michael

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Burgess), to creating a “transitional” class of novel or “emerging” in vitro diagnostic kits for which manufacturers could obtain conditional clearance as part of the existing medical device framework (identified as a potential approach in the most recent FDA agreement on reauthorization of medical device user fees).4,14,15

FDA Steps Into the Clinical Laboratory As the field of genomic testing began to evolve and move increasingly into clinical practice, the FDA became concerned about the analytical and clinical validity standards for genomic tests. In particular, the FDA is concerned with the risk of false-positive and false-negative test results that would be incorporated into clinical treatment decisions for serious and life-threatening diseases such as cancer. Although FDA has long limited its premarket oversight of in vitro diagnostic tests to those that constitute “kits” manufactured and sold or distributed to clinical laboratories, in recent years the regula-

Still, the FDA has moved forward with the publication of a plethora of other Draft Guidance related to in vitro diagnostics... tory paradigms have begun to shift dramatically as more multianalyte assays using algorithmic analysis and new faster sequencing technologies, such as next-generation sequencing (NGS), have entered the field. The FDA has struggled to find the most appropriate way to address regulatory oversight where gaps between CLIA and FDA are perceived, yet, at the same time, avoid erecting further barriers to innovation.

After failed attempts to target additional premarket regulation to a more limited class of multianalyte LDTs, FDA announced in 2010 its intent instead to regulate LDTs broadly.16-18 However, the now years-long process FDA has undertaken to develop and publish Draft Guidance on LDT regulation has been stalled, first due to substantial concerns expressed by both stakeholders and government policy makers regarding the awkward and

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ill-defined approach taken by FDA to determine LDTs potentially subject to dual oversight by CLIA and FDA, and later due to broader-based concerns regarding the potential negative impact the proposed policies would have on the advancement of personalized medicine in general. Nonetheless, the FDA remains committed and has indicated that the Draft Guidance on LDT policy remains a priority for 2012 publication.19 In the meantime, top FDA officials continue to be vocal in expressing the agency’s distrust of the CLIA regulations to appropriately establish analytical and clinical validity of LDTs, whether single analyte, multianalyte, or NGS based.20 And although stakeholders and legal scholars alike have challenged the FDA’s assertion of authority over LDTs and the agency’s proposal to require FDA premarket oversight of LDTs absent formal rule making by the FDA [guidance documents cannot, as a matter of law, “create or confer any rights for or on any person.” See 21 U.S.C. Sec. 371(h)(1)(A)], the agency has proceeded to develop policies impacting LDTs through “draft” guidance documents, which lack transparency of process and predictably of policy compared with regulations established through formal rule making.21 Still, the FDA has moved forward with the publication of a plethora of other Draft Guidance related to in vitro diagnostics, 2 of which could have immediate impact on clinical laboratories and LDTs: Draft Guidance for Industry and FDA Staff – Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions, June 1, 2011 (Draft RUO/IUO Guidance); and Draft Guidance for Industry and Food and Drug Administration Staff – In Vitro Companion Diagnostic Devices, July 14, 2011 (Draft Companion Diagnostic Guidance).22,23

Clinical Laboratory Use of Products Labeled Research or Investigation Use Only The Draft RUO/IUO Guidance suggests that if a manufacturer of products labeled RUO or IUO sells or distributes those products to a clinical laboratory, and

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the manufacturer or distributor knows or should have known that a CLIA laboratory is using the products in clinical tests beyond research or investigational purposes, the manufacturer should “cease sales” to such CLIA laboratory.23 This proposed requirement has been widely viewed as a departure from historic FDA enforcement policy, which requires a manufacturer to advertise or promote the product as validated for clinical use, not merely sell to a clinical laboratory. Moreover, the suggestion that the burden is on manufacturers to understand the ultimate use of products sold to third parties and to cease sales if such “known” use is inconsistent with the manufacturer’s label, absent unlawful promotion or advertising of the product, has caused widespread concern among laboratories and other stakeholders.23 Many reagents and components are available to clinical laboratories only as RUO products, but the FDA has announced its intent to step up enforcement against manufacturers that sell products to clinical laboratories with an RUO label rather than seeking separate clearance or approval for such RUO diagnostic “kits” under the FDA’s medical device regulations.22 Contrary to widely accepted laboratory practice under CLIA, the FDA has asserted in this Draft Guidance that validation of the performance specifications of such products as part of a test legally offered to patients by the laboratory under CLIA regulations (or state licensure laws for those states exempt from CLIA, like New York) does not extinguish the responsibility of the manufacturer to properly label its products based on the use of the product by the laboratory. However, the agency specifically exempted CLIA laboratories from enforcement action by FDA for using RUO- or IUOlabeled products in clinical tests. This was an important public health decision given the necessity of many of these products in widely used clinical tests. Moreover, the FDA made it clear in the guidance that it was not intended to be a mechanism to modify or limit the policy of “enforcement discretion” for LDTs generally.22 Nevertheless, the widespread and accepted use of products labeled RUO or IUO by clinical laboratories as components of tests developed and validated in those

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Figure 1. FDA Perspective on Companion LDTs Without Additional FDA Regulatory Oversight “Health care practitioners rely on information from companion diagnostic [tests] to help make critical treatment decisions…if companion [test] results are incorrect, it is worse than if there had not been a test at all.” As to enforcement [for companion diagnostic tests], “FDA expects to require compliance with the device regulations, whether the test is lab-developed or distributed as a kit.”27

CLIA laboratories, uncertainty about the trigger for the manufacturer “awareness” of purchaser use of its products, and the related requirement to “cease sales” to laboratories when such “knowledge” is achieved, has created regulatory uncertainty and confusion. The potential disruption of physician orders for thousands of clinical laboratory tests and the resulting detrimental

The agency exempted CLIA laboratories from enforcement action by FDA for using RUO- or IUO-labeled products in clinical tests. impact on public health, as described in public comments on this Draft Guidance, has prompted criticism and a congressional inquiry into this FDA policy in particular, and use of Draft Guidance, more generally to establish or modify its enforcement policy.24,25 Consistent with previous public comments from agency officials, FDA responded to the congressional inquiry by citing its established regulations on labeling requirements for medical devices and suggesting that products labeled RUO/IUO are generally not manufactured under Good Manufacturing Practice guidelines and may lack important design controls.26 These are important public health concerns and of particular importance to the FDA in the context of driving treatment or clinical trial selection decisions in serious or life-threatening diseases like cancer, but it fails to recognize the important role of CLIA to ensure clinical tests are properly validated for use in patient treatment and management (Figure 1).

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“Companion Diagnostics” as Essential Drivers of Precision Oncology Genomic-based assays have become critical tools and are more frequently becoming accepted standard of care in clinical guidelines for oncology.28-30 For tests that FDA has deemed “essential” for the safe and effective use of a novel therapeutic product, its new Draft Companion Diagnostics Guidance will require the companion test to be approved by FDA before the drug product can be approved and labeled, whether developed by a clinical laboratory and offered as an LDT or manufac-

Figure 2. Recent FDA Companion Diagnostics Approvals • Pfizer’s Xalkori (crizotinib) for the treatment of locally advanced or metastatic NSCLC in EML4-ALK fusion gene–positive patients — Companion Dx: Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit for tumor testing to select which patients will respond to this drug31 • Roche’s melanoma drug Zelboraf for BRAF gene mutation– positive patients — Companion Dx: Roche’s BRAF V600E mutation to select which patients will respond to this drug32

tured and distributed as a “kit” to clinical laboratories.23 Following the publication of this Draft Guidance, FDA quickly approved 2 such companion diagnostics and novel drugs, illustrating how the FDA considers these types of dual product approvals (Figure 2).

Like the Draft Guidance for products labeled RUO or IUO, the FDA has continued to maintain the policy of “enforcement discretion” under the Companion Diagnostics Draft Guidance for LDTs pending the publication of the long-anticipated LDT Draft Guidance.

While a companion diagnostic cleared or approved by FDA may be developed as an LDT by a clinical laboratory or by a manufacturer as a test “kit,” FDA at this time is only requiring a single test be approved with the therapeutic.23 This means that all other LDTs offered for the same purpose by CLIA-accredited laboratories be-

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fore, or even after, the FDA approves a companion diagnostic for the same purpose may remain on the market and will not be required to seek additional FDA approval as long as the test meets the FDA’s definition of LDT.23 Additionally, in the practice of medicine, physicians are not bound by federal regulatory authorities to choose a particular test or therapy for any given patient.

FDA has complicated the marketplace for companion diagnostics further by using only a test description in the drug product labeling rather than the proprietary name of the FDA-approved test (eg, the drug label requires testing using an “FDA-approved” BRAF V600E test).23,33 Given the substantial investment necessary to meet the FDA standards for a Class III Premarket Application for a medical device coupled with the lack of requirements for CLIA laboratories performing LDT companion diagnostic testing to seek additional FDA approval, it is unlikely FDA will be flooded with applications for approval of LDTs offered in clinical oncology that are offered as a “companion” to an approved drug.

FDA has announced it hopes to publish “final” Companion Diagnostics Guidance this year,20 but unless the agency establishes a new framework for LDTs that is not overly burdensome, duplicative of, or contradictory to CLIA, and physicians find greater medical value in tests approved by FDA than those offered by trusted laboratories accredited by CLIA or accredited state programs, it will be difficult to discern meaningful impact from the FDA review of companion diagnostics on the practice of medicine.

Implications of New Technologies on Companion Diagnostics in Oncology The rapid advances of NGS and other medical information processing technologies have created incredible excitement in the field of oncology, in particular. At the same time, FDA remains deeply concerned about the lack of tools to evaluate the accuracy, reliability, and clinical validity of test results based on these rapidly advancing technologies. A senior FDA official described the view of the agency as deep concern about “…the rapid ability to transfer from research to clinical use.”27

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FDA has held a public meeting on novel sequencing issues and, in addition to companion diagnostics, also published Draft Guidance on Mobile Apps in 2011.34,35 The FDA already regulates certain standalone software as a “medical device,” and the agency is working to update its policy with respect to regulatory requirements for clinical decision support tools that process information intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.

With respect to use of these technological advances in clinical laboratories, while manufacturers and clinical laboratories continue to await new regulatory requirements and standards from the FDA, third-party accreditation entities and professional societies continue to press forward to advance personalized medicine. For example, CAP published guidelines in 2009 for validating molecular tests in clinical laboratories, and the American College of Medical Genetics and Genomics published a policy statement, “Points to Consider in the Clinical Application of Genomic Sequencing,” in early 2012. These recommendations, in the absence of more definitive statements by the FDA on LDTs, in particular tests using NGS and other advanced information technology platforms, will continue to drive best practices and standards for both analytical and clinical validity that will usher in the new era of precision media in oncology.36,37

Achieving the Next Generation – the Outlook for Personalized Medicine in Oncology The FDA’s move toward greater oversight of the clinical validity of genomic-based tests has, thus far, not resulted in a path to personalized medicine paved with greater clarity, certainty, and confidence. Regardless, physicians and patients alike continue to seek increasingly individualized genomic-based treatment options.

Given the accelerated pace of new discoveries in sequencing and information technologies as well as clinical applications, the promise of continued advancement in genomic pathology that will drive greater precision in medical and clinical oncology likely will continue to

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be measured by new regulatory hurdles. The challenge for federal policy makers at both CMS and FDA, Congress and, to some extent, the federal courts, will be to

FDA has complicated the marketplace for companion diagnostics further by using only a test description in the drug product labeling... balance new regulatory paradigms to support continued investment in innovative technologies and diagnostic test capabilities without creating overly burdensome barriers or duplicative and overlapping requirements that in practice fail to support public health.

Disclosure Statement S. Walcoff is a consultant to various stakeholders in genomics and personalized medicine, including clinical laboratories, biotechnology and pharmaceutical companies, investors, coalitions, and diagnostic device manufacturers. She has received no financial compensation or other content contribution for this work, and the paper has not been shared with her clients prior to publication. u

References 1. Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention. Laboratory Medicine: A National Status Report. www.fu turelabmedicine.org/pdfs/2007%20status%20report%20laboratory_medi cine_-_a_national_status_report_from_the_lewin_group.pdf. May 2008.

Accessed April 2012.

2. Faulkner E. Clinical utility or impossibility? Addressing the molecular diagnostics health technology assessment and reimbursement conundrum.

Journal of Managed Care Medicine. 2009;12:42-55.

3. Simon CJ, Wolcott J, Hogan P. Can We Reduce Health Care Spending?

Searching for Low-Hanging Fruit in the Garden of Health System Reform. www.optuminsight.com/~/media/Ingenix/Resources/Articles/LewinReport CostDrivers.pdf. October 26, 2009. Accessed April 2012.

4. Ray T. Latest draft of Hatch IVD bill contains new regulatory proposals; pricing reforms under discussion. Pharmacogenomics Reporter. www.genomeweb.com/dxpgx/latest-draft-hatch-ivd-bill-contains-new-reg ulatory-proposals-pricing-reforms-un. July 6, 2011. Accessed April 2012.

5. UnitedHealth Group. Personalized Medicine: Trends and prospects for the new science of genetic testing and molecular diagnostics.www.unitedhealthgroup. com/hrm/UNH_WorkingPaper7.pdf. March 2012. Accessed April 2012.

6. 21 U.S.C. § 301 et seq.

7. 21 U.S.C. 321(h); see 21 CFR 809.3(a).

8. 42 CFR 493.1253(b)(2).

9. College of American Pathologists. Accreditation and laboratory improvement. www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accred

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itation. Accessed April 2012.

10. Wadsworth Center. New York State Department of Health. Clinical Laboratory Evaluation Program Web site. www.wadsworth.org/labcert/clep/ clep.html. Accessed April 2012.

11. 21 CFR 809.10 (c)(2)(i).

12. US Food and Drug Administration. Product Classification. www.ac cessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/PCDSimpleSearch.cfm?db=PC D&id=OQS. Accessed April 2012.

13. US Food and Drug Administration. Inspections, Compliance, Enforcement, and Criminal Investigation. FDA warning letter on OvaSure. www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm10481 14.htm. Accessed April 2012.

14. H.R. 2307: Modernizing Laboratory Test Standards for Patients Act of 2011. www.govtrack.us/congress/bills/112/hr3207.

15. US Food and Drug Administration. FDA commitment letter on the Medical Device and User Fee Modernization Act (MDUFMA). www.fda. gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDe viceUserFeeandModernizationActMDUFMA/ucm293728.htmletter. Accessed April 2012.

16. Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363:301-304.

17. Notice of Public Meeting on FDA Oversight of Laboratory Developed Tests. Federal Register. June 17, 2010:34463-34464.

18. FDA to drop IVDMIA policy. BioCentury Today. www.biocentury. com/dailynews/politics/2010-06-16/fda-to-drop-ivdmia-policy. June 16, 2010. Accessed April 2012.

19. Documents the Center for Devices and Radiological Health is considering for development (FY12). www.fda.gov/MedicalDevices/DeviceReg ulationandGuidance/Overview/MedicalDeviceUserFeeandModernization ActMDUFMA/ucm109196.htm. Accessed April 2012.

20. Bureau of National Affairs, Inc. Personalized medicine: co-approval said necessary to market companion diagnostic test, therapeutic. Regulatory News. 2012;6:180-181.

21. Javitt GH, Garnder KS. Must FDA engage in rulemaking to regulate laboratory-developed tests? Food and Drug Law Institute Policy Forum. www.sidley.com/files/Publication/d83df2d8-e7a8-4159-8cff57bc99413ebe/Presentation/PublicationAttachment/9ab25938-f024-4f9d9535-58be237fd31f/FDLI%20Policy%20Forum%2017.pdf. September 14, 2011. Accessed April 2012.

22. US Food and Drug Administration. Draft Guidance for Industry and FDA Staff – Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions. www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocu ments/ucm253307.htm. June 1, 2011. Accessed April 2012.

23. US Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff – In Vitro Companion Diagnostic Devices. www.fda.gov/medicaldevices/deviceregulationandguidance/guidan cedocuments/ucm262292.htm. July 14, 2011. Accessed April 2012.

24. Public comments to FDA Draft Guidance for Industry and FDA Staff: Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions; Availability. www.regulations.gov/#!docketDetail;dct=FR%252BPR%252

BN%252BO%252BSR%252BPS;rpp=25;po=0;D=FDA-2011-D-0305.

Accessed April 2012.

25. One Hundred Twelfth Congress. Congress of the United States. House of Representatives. Committee on Energy and Commerce. Letter to the FDA regarding June 1 draft guidance document. http://Republicans.Ener gyCommerce.house.gov/Media/file/Letters/112th/031912FDA.pdf. Accessed April 2012.

26. One Hundred Twelfth Congress. Congress of the United States. House of Representatives. Committee on Energy and Commerce. FDA response letter to Energy and Commerce Committee inquiry regarding June 1 draft guidance document. http://republicans.energycommerce.house.gov/news/ letters.aspx. Accessed April 2012.

27. Mansfield E. Development of the companion diagnostic draft guidance.

Presented at: 4th Annual Forum for Payers on Personalized Medicine; March 12-13, 2012; Washington, DC. www.cbinet.com/compendiums/FC12020/Pre sentations/Mansfield_Elizabeth_pres.pdf. Accessed April 2012.

28. National Comprehensive Cancer Network. NCCN updates guidelines for colorectal cancer. www.nccn.org/about/news/newsinfo.asp?NewsID= 194. Accessed April 2012.

29. National Comprehensive Cancer Network. NCCN updates breast cancer guidelines. www.nccn.org/about/news/newsinfo.asp?NewsID=127. Accessed April 2012.

30. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287-5312.

31. US Food and Drug Administration. News & Events. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.ht m. August 17, 2011. Accessed April 2012.

32. US Food and Drug Administration. News & Events. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.ht m. August 17, 2011. Accessed April 2012.

33. Zelboraf [package insert]. South San Francisco, CA: Roche; 2011.

Highlights of prescribing information. www.gene.com/gene/products/infor mation/zelboraf/pdf/pi.pdf. Accessed April 2012.

34. US Food and Drug Administration. Medical Devices. Ultra high throughput sequencing for clinical diagnostic applications – approaches to assess analytical validity, June 23, 2011.www.fda.gov/MedicalDevices/New sEvents/WorkshopsConferences/ucm255327.htm. Accessed April 2012.

35. US Food and Drug Administration. Medical Devices. Draft guidance for industry and food and drug administration staff – mobile medical applications. www.fda.gov/medicaldevices/deviceregulationandguidance/guid ancedocuments/ucm263280.htm. July 21, 2011. Accessed April 2012.

36. Jennings L, Van Deerlin VM, Gulley ML; College of American Pathologists Molecular Pathology Resource Committee. Recommended principles and practices for validating clinical molecular pathology tests. Arch Pathol Lab Med. 2009;133:743-755.

37. American College of Medical Genetics and Genomics. Policy statement on clinical application of whole genomic sequencing. www.acmg.net/A M/Template.cfm?Section=Home3&Template=/CM/HTMLDisplay.cfm& ContentID=6980. March 28, 2012. Accessed April 2012.

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Breast Cancer

Which Breast Cancer Patients Should Receive Adjuvant Chemotherapy?

Tools to Aid Decision Making At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Alvaro Moreno-Aspitia, MD, from the Mayo Clinic in Jacksonville, Florida, discussed the use of personalized therapy in the management of breast cancer.

Key Points • A number of decision-making tools have become available to help clinicians and patients with early cancer discuss the risks and benefits of getting adjuvant therapy after surgery • Adjuvant! Online 8.0 estimates the risk of negative outcome (cancer-related mortality or relapse) without systemic adjuvant therapy, the reduction of these risks afforded by therapy, and the risks of side effects of the therapy • Gene-profiling assays, such as Oncotype DX and MammaPrint, are commercially available to help identify patients at high risk of recurrence

P

rognostication in breast cancer is an inexact science, with tumor (and patient) heterogeneity likely contributing to this lack of prognostic precision. For example, even in patients traditionally considered at low risk for recurrence (ie, those who are T1, N0, ER+), about 15% will have a recurrence within 10 years with tamoxifen treatment alone.1 Therefore, much interest surrounds the field of personalized medicine, which aims to identify patients at high risk of recurrence and to tailor therapy specifically for those patients. It is hoped that personalized medicine will bring to the clinic newer drugs that target this high-risk population and

Case • A 52-year-old woman recently underwent surgery for a stage IA, 1.5-cm, right breast tumor (grade 2 invasive ductile carcinoma, estrogen receptor [ER]-positive, progesterone receptor [PR]-positive, and HER2-negative) • Her biopsy showed no vascular invasion, negative surgical margins, and 2 negative lymph nodes • You feel she should receive adjuvant radiation therapy and endocrine therapy, but how do you decide whether she should receive adjuvant chemotherapy?

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avoid overtreating patients who have an overall good prognosis, and avoid costly side effects as well.

Prognostic Indexes Over the past decade, a number of decision-making tools have become available to help healthcare professionals and patients with early cancer discuss the risks and benefits of getting adjuvant therapy after surgery.

One of these tools is Adjuvant! Online 8.0,2 a Webbased validated tool that predicts 10-year outcomes with and without adjuvant systemic therapy for patients with early breast cancer.3,4 Adjuvant! Online incorporates the updated St. Gallen consensus guidelines,5 the National Comprehensive Cancer Network guidelines,6 the Update of the Oxford Overview,7 the Early Breast Cancer Trialists’ Collaborative Group meta-analysis,8 as well as clinical trial information in the literature and reported at major breast cancer meetings, including information on the 7 major aromatase inhibitor trials, the 5 major adjuvant trastuzumab trials, and the new trials that incorporate taxanes into adjuvant therapy.

When a patient’s data (eg, patient age, tumor size, nodal involvement, histologic grade, etc) are entered into Adjuvant! Online, the program estimates the risk of negative outcome (cancer-related mortality or

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Table 1. Commercially Available Genomic Assays Assay

Company

Description

Oncotype DX Breast Cancer Assay

Genomic Health

A 21-gene assay that provides an individualized prediction of adjuvant chemotherapy benefit and 10-year distant recurrence.

MammaPrint

Agendia

Analyzes 70 critical genes that comprise a definitive gene expression signature and stratifies patients into 2 distinct groups – those with low risk or high risk of distant recurrence.

BluePrint

Agendia

An 80-gene expression signature that classifies breast cancer into basal-type, luminal-type, and ERBB2-type cancers.

TargetPrint

Agendia

A microarray-based gene expression test that quantitatively assesses the level of ER, PR and HER2/neu overexpression within the tumor.

TheraPrint

Agendia

A microarray-based gene expression panel of 56 genes that have been identified as potential targets for prognosis and therapeutic response to a variety of therapies.

PAM50 Breast Cancer Intrinsic Classifier

ARUP Laboratories

A real-time quantitative polymerase chain reaction assay that measures the expression of 50 classifier genes and 5 control genes to identify the intrinsic subtypes known as luminal A, luminal B, HER2-enriched, and basal-like.

OncoVue Breast Cancer Risk Test

InterGenetics

A genetic-based breast cancer risk test that incorporates both individualized genetic-based single-nucleotide polymorphisms and personal history measures to estimate a woman’s breast cancer risk.

Pathwork Tissue of Origin Test

Pathwork Diagnostics

A gene expression–based test that uses a tumor’s own genomic information to aid in identifying challenging tumors, including metastatic, poorly differentiated, and undifferentiated tumors.

Pathwork Mutation Tests

Pathwork Diagnostics

KRAS, BRAF, and EGFR mutation testing to help determine whether patients will respond to targeted therapies.

ER indicates estrogen receptor; PR, progesterone receptor.

relapse) without systemic adjuvant therapy, the reduction of these risks afforded by therapy, and the risks of side effects of the therapy. These estimates are then provided on printed sheets in simple graphic and text formats to be used in consultations with patients and may be useful in supporting decision making.

Gene Profiling of Tumor Because the patient’s father had a rough time with chemotherapy for lung cancer, the patient still wasn’t convinced, and asked, “Is there anything else that you can provide to help me make a decision?” Indeed, sev-

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eral genomic assays are commercially available (Table 1). Among these gene-profiling assays, Oncotype DX and MammaPrint are the most mature.

Indeed, several genomic assays are commercially available. Among these gene-profiling assays, Oncotype DX and MammaPrint are the most mature.

Oncotype DX The Oncotype DX assay analyzes the expression of 21 genes by reverse transcriptase-polymerase chain reaction

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to provide an individualized Recurrence Score (RS; from 0 to 100) for each patient.9,10 In addition to quantifying breast cancer recurrence risk, the Oncotype DX assay also assesses the benefit from chemotherapy.

Node-Negative, ER-Positive Breast Cancer The data from which the assay was developed were retrospectively analyzed from a prospective randomized trial known as the National Surgical Adjuvant Breast and Bowel Project Study B-20, which compared the combination of chemotherapy (ie, 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil) plus hormonal therapy (ie, tamoxifen) with hormonal therapy alone in 651 women with lymph node–negative, ERpositive breast cancer. Patients with an RS lower than

While the Oncotype DX is currently based on retrospective data from the 2 aforementioned prospective randomized clinical trials, prospective studies are ongoing.

18 are categorized as low risk. These patients do well, with over 90% of patients alive at 10 years. Patients with an RS of 31 or higher are considered as high risk of recurrence. Those with scores in the middle (18 to <31) are classified as intermediate risk (Figure 1).9 When the Oncotype DX assay was used for the patient in this case, an RS of 27 was obtained, which put her in the intermediate-risk group (Figure 2). In that case, her risk of distant recurrence is about 17%, which is actually similar to the estimated recurrence rate found with Adjuvant! Online.

Node-Positive, ER-Positive Postmenopausal Breast Cancer For lymph node–positive, ER-positive postmenopausal patients treated with tamoxifen, the Oncotype DX report form now includes data retrospectively analyzed from the prospective randomized Southwest On-

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Case (cont) • What if the patient in our case has 2 macroscopically (0.5 cm each without extracapsular extension) involved sentinel lymph nodes?

cology Group (SWOG) 8814 study, which evaluated the risk of recurrence or death versus the RS result (both prognosis and likelihood of chemotherapy benefit). In the SWOG 8814 study, 1477 women were randomized to receive either tamoxifen alone for 5 years (n=361), or 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) with concurrent tamoxifen (n=550), or 6 cycles of CAF followed by tamoxifen (CAF-T).11 Among the groups of women with RS <18 (the low-risk group) or 18 to 30 (intermediaterisk group), CAF-T offered no significant advantage over the 10-year disease-free or overall survival rates seen among those who received tamoxifen alone. In contrast, among the women who had RS ≥31, the 10year disease-free and overall survival rates were significantly greater with CAF-T than with tamoxifen alone.

Prospective, Randomized Trials Under Way While the Oncotype DX is currently based on retrospective data from the 2 aforementioned prospective randomized clinical trials, prospective studies are ongoing. One prospective study, known as the Trial Assigning Individualized Options for Treatment (Rx) (TAILORx), is examining whether chemotherapy is required for the intermediate-risk group defined by the RS.12 Another prospective randomized trial, known as the Rx for Positive Node, Endocrine Responsive Breast Cancer (RxPONDER, or SWOG S1007) study, opened in January 2011 and will assess whether chemotherapy benefits patients with node-positive breast cancer who have low to intermediate RS. The trial will also examine whether there is an optimal RS cutoff point for these patients, above which chemotherapy should be recommended. This study includes women with RS ≤25 who have early-stage, hormone receptor–positive, HER2-

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Figure 1. 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 (RS <18); C, intermediate risk (RS 18-30); D, high risk (RS ≥31).

RS indicates Recurrence Score.

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.

negative breast cancer that has been found to involve 1 to 3 lymph nodes.

MammaPrint MammaPrint analyzes 70 genes that comprise a definitive gene expression signature and stratifies patients to 1 of 2 groups: those with low risk of distant recurrence (good signature group) and those with high risk of

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distant recurrence (poor signature group).13 With MammaPrint, there are no intermediate results. Patients who have a good signature do quite well, with less than 20% experiencing a relapse 10 years after their diagnosis, while patients with a poor signature do poorly overall, with about 50% to 60% experiencing relapse.14 Key differences between MammaPrint and Oncotype DX are listed in Table 2.

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Figure 2. Case Example: Patient With Oncotype DX Recurrence Score of 27 Recurrence Score as Continuous Predictor Rate of Distant Recurrence at 10 Years

40% Low Risk

High Risk

Intermediate Risk

35% 30% 25% 20% 15% 10%

Rate 95% Confidence Interval

5% 0% 0

5

10

15

20

25

30

35

40

45

50

Recurrence Score 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 Š 2004 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Table 2. Key Differences Between MammaPrint and Oncotype DX MammaPrint

Oncotype DX

Analyzes messenger RNA signals for 70 genes

Measures the expression of 21 genes using PCR

Can be used to test patients with any ER status

Approved only for ER-positive patients

Predictive (ie, it can be used to predict treatment benefit)

Prognostic (ie, it can be used to estimate recurrence risk) and predictive (ie, it can be used to predict treatment benefit)

ER indicates estrogen receptor; PCR, polymerase chain reaction.

MammaPrint is being evaluated in a clinical trial known as Microarray In Node-negative and 1-3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT), which is a randomized European study comparing MammaPrint with clinical assessment.15 MINDACT has enrolled over 6000 patients, who have been classified into high or low genomic risk by MammaPrint and clinicopathologic risk through Adjuvant! Online. Patients with both genomic and clinical high risks are offered adjuvant chemotherapy; those with both genomic and clinical low risks do not receive chemotherapy; patients with discordant risk are randomized for the decision of adjuvant chemotherapy

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based on genomic or clinical risk.15 MINDACT is due to complete data collection in 2019. u

References 1. Fisher B, Redmond C. Systemic therapy in node-negative patients: updated findings from NSABP clinical trials. National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst Monogr. 1992;(11):105-116.

2. Adjuvant Inc. Adjuvant! Online 8.0. www.adjuvantonline.com/index. jsp. Accessed July 23, 2012.

3. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol.

2005;23:2716-2725.

4. Mook S, Schmidt MK, Rutgers EJ, et al. Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study. Lancet Oncol.

2009;10:1070-1076.

5. Gnant M, Harbeck N, Thomssen C. St. Gallen Consensus Discussion.

Breast Care (Basel). 2011;6:136-141.

6. National Comprehensive Cancer Network guidelines. www.nccn.org/ professionals/physician_gls/pdf/breast.pdf.

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

7. Pritchard KI, Bergh J, Burstein HJ. Update of the Oxford Overview. www.asco.org/ASCOv2/Home/Education%20&%20Training/Educa tional%20Book/PDF%20Files/2012/zds00112000071.PDF. 8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444.

9. 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.

10. 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.

11. Albain K, Barlow W, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-negative ERpositive breast cancer. Presented at: 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. 2007. Abstract LBA10.

12. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721728.

13. van ’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530-536.

14. van de Vijver MJ, He YD, van ’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999-2009.

15. Rutgers E, Piccart-Gebhart MJ, Bogaerts J, et al. The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase.

Eur J Cancer. 2011;47:2742-2749.

SECOND ANNUAL CONFERENCE

Gastrointestinal Perforations The 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 Complications The 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).]

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

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil– based chemotherapy.

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

1.3 Glioblastoma Avastin 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 CONTRAINDICATIONS None.

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5.2 Surgery and Wound Healing Complications Avastin 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).]

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5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious 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 fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 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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AVASTIN ® (bevacizumab)

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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).]

Warnings and Precautions (5.3).]

L Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

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

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

L Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

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

L 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.

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%.

Proteinuria Grade 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 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 congestive heart failure (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.

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

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula 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 first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, 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 Hypertension The 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 confirm 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 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. 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 Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

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

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: L Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

L Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

L Hemorrhage [See Boxed Warning, Dosage and Administration (2.4),

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 3795 patients with CRC, non-squamous NSCLC, MBC, 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).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18-88 years (median 59), 43.2% male and 85.3% white. The population included 1783 firstand second-line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The 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 fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The 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 Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and Infection The 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 first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound

NCI-CTC Grade 3-4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL ++ Placebo (n = 396) 74%

Arm 2 IFL ++ Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

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

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

AVASTIN® (bevacizumab) Table 2 (cont’d) 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) Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only 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 infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All 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 (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9% a

Adverse events were encoded using MedDRA, Version 10.1.

IFN-α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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

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).]

6.2 Immunogenicity As 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 specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin 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 OVERDOSAGE The 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.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 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 POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested.

Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It 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 Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In 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.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

01/12 AVA0000759202 10127309 Initial U.S.Approval: February 2004 Code Revision Date: December 2011 Avastin® is a registered trademark of Genentech, Inc. ©2012 Genentech, Inc.

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models.

Its clinical significance is unknown.

Indications

Most common adverse events

Avastin 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 first-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 first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil– based chemotherapy.

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 infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-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%)

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastintreated 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 fistula 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 first 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 †

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.

©2012 Genentech USA, Inc.

All rights reserved.

AVA0000488301

Printed in USA.

(01/12)

www.avastin.com