TAP Vol 5 Issue 7 by Harborside Press LLC

PD-L1 Expression

4, 5

| Smoldering Multiple Myeloma

| AURELIA Trial in Ovarian Cancer

VOLUME 5, ISSUE 7

MAY 1, 2014

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

American Association for Cancer Research Annual Meeting

PALOMA-1 Trial Finds Palbociclib/Letrozole Doubles Progression-Free Survival in Metastatic Breast Cancer

Maintenance Therapy in Multiple Myeloma By S. Vincent Rajkumar, MD

By Alice Goodman

irst-line treatment with the combination of palbociclib plus letrozole extended progression-free survival by approximately 50% in patients with metastatic estrogen receptor–positive, HER2-negative breast cancer, according to final results of the PALOMA-1 trial, a randomized phase II study presented at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego. Palbociclib plus letrozole achieved progression-free survival of 20.2 months vs 10.2 months with letrozole alone (P = .0004). Overall survival was trending in favor of the combination but was not statistically significant at the time of the progression-free survival analysis. “These data give us the confidence to move ahead with a phase III study. To put the data in perspective, no study of aromatase inhibitors alone in metastatic

breast cancer showed as dramatic a progression-free survival improvement as this study,” said presenting author Richard S. Finn, MD, Associate Professor of Medicine, Geffen School of Medicine at the University of California, Los Angeles. Richard S. Finn, MD Dennis Slamon, MD, PhD, Professor of Medicine and Director of the Revlon/ UCLA Women’s Cancer Program, was the senior author. Palbociclib, being developed by Pfizer, Inc, is a first-inclass cyclin-dependent kinase (CDK) 4/6 inhibitor that inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression. Other companies are also pursuing CDK4 and CDK6 inhibitors in breast cancontinued on page 3

Issues in Oncology

ASCO Speaks Out on Release of Medicare Physician Payment Data

Statement by the American Society of Clinical Oncology

he American Society of Clinical Oncology (ASCO) is deeply concerned about [the recent] release of Medicare physician payment data. ASCO is committed to the delivery of high-quality, high-value care for all people with cancer in the United States. This data release solely focuses attention on the dollars paid to practices for the medical care and treatment of patients on Medicare, rather than contributing to the ongoing national conversation about value and quality in health care. While ASCO strongly supports transparency in health care and sharing information with patients,

the data released by Medicare was issued with no context or explanation about the complexity of the payment system, the value of the services provided, and the needs of patients with cancer. The Medicare release makes health-care delivery less transparent than it initially may seem. Compounding this situation are the extensive inaccuracies in the data for many oncologists throughout the United States.

Unique Among Specialties

Cancer care is unique among specialties in the way it is reimbursed by Medicare. Oncology practices must purchase very expensive chemotherapy This data release solely focuses attention on the drugs for their patients dollars paid to practices for the medical care and prior to receiving reimbursement for those treatment of patients on Medicare, rather than drugs from Medicare. contributing to the ongoing national conversation Cancer patients also have life-threatening illnesses about value and quality in health care.

n 2012, three randomized placebo-controlled trials reported a significant prolongation of progression-free survival with lenalidomide (Revlimid) as maintenance therapy for multiple myeloma.1-3 Two of these trials tested lenalidomide maintenance after stem cell transplantation, and one investigated maintenance following conventional melphalan-based therapy. One of the three trials, a post-transplant study conducted in the United States, found an improvement in overall survival, while in the others, no survival benefit was seen. All three trials showed a significant increase in the incidence of second cancers. Following the publication of these trials, continued on page 58

Dr. Rajkumar is a hematologist at Mayo Clinic College of Medicine, Rochester, Minnesota. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage AACR Annual Meeting �� 3–5 Society of Surgical Oncology Annual Meeting �� 6, 12, 13 NCCN Annual Conference �� 14,15 Society of Gynecologic Oncology Annual Meeting �� 20, 22, 24, 26 FDA Update �� 17–19 Direct From ASCO �� 27–31

Teresa A. Gilewski, MD, on Palliative Care �� 41 Ongoing Clinical Trials ��45

continued on page 57

Visit The ASCO Post at ASCO’s Annual Meeting, booth 24092

A Harborside Press® Publication

The ASCO Post | MAY 1, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Paul F. Engstrom, MD Fox Chase Cancer Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

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

Samuel Silver, MD, PhD University of Michigan Health System

Associate Editors

Bishoy Morris Faltas, MD Weill Cornell Medical College

Jame Abraham, MD Cleveland Clinic Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

George W. Sledge, MD Indiana University

Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

John A. Fracchia, MD New York Urological Associates

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

Sarah McGullam, Web Editor Sarah@harborsidepress.com

Alison Freifeld, MD University of Nebraska Medical Center

Jamie Von Roenn, MD American Society of Clinical Oncology

Louis B. Harrison, MD Continuum Cancer Centers of New York

Lynn D. Wilson, MD Yale University School of Medicine

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

Stanley H. Winokur, MD Singer Island, Florida

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

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

Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center

International Editors

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

James L. Mulshine, MD Rush University Medical Center

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

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

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

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

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

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

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

hibited. For permission inquiries, contact permissions@ harborsidepress.com.

Canada: $397; Individual International: $523; Institutional Domestic: $335; Canada: $461; Institutional International: $587. Single Copy Domestic: $52; Canada: $59; International: $65. Contact subscriptions@harborsidepress.com.

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com.

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

Michael Buckley, Art Director Michael@harborsidepress.com Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com Anthony Cutrone, President Anthony@harborsidepress.com John A. Gentile, Jr., Chairman Jack@harborsidepress.com

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

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations. Disclosure information available at ASCOPost.com.

Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com.

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

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

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

Correspondence: Address general inquiries to Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com.

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

ASCOPost.com | MAY 1, 2014

PAGE 3

American Association for Cancer Research Annual Meeting Breast Cancer

LY2835219 Shows Strong Single-Agent Activity in Preliminary Study in Metastatic Breast Cancer By Alice Goodman

nhibitors of cyclin-dependent kinase (CDK) 4/6 are getting attention as a novel approach for the treatment of breast cancer. At the 2014 American Association for Cancer Research (AACR) Annual Meeting, two presentations focused on these new agents. One was a phase II study of Pfizer’s compound palbociclib as first-line therapy (see page 1) and the second was a preliminary study

of Lilly’s compound LY2835219 in heavily pretreated patients. The Pfizer study showed that the combination of palbociclib plus letrozole doubled progression-free survival as first-line treatment of metastatic breast cancer. In contrast, LY2835219 appears to have strong single-agent activity in this disease. Both studies identified hormone receptor positivity

PALOMA-1 Trial

was 26.1 months for the combination of palbociclib plus letrozole vs 5.7 months for letrozole alone (P < .0001). In part 2, progression-free survival was 18.1 vs 11 months, respectively (P = .0046). Dr. Finn called attention to progression-free survival in the control arms of part 1 and 2, noting that the population enriched for CCND1 amplification and loss of p16 “behaved differently” with letrozole alone. Overall, he continued, the take-away message from this study is that estrogen receptor positivity is the most sensitive predictor of response to the novel agent in combination with letrozole. Best overall response rate was 43% for the combination vs 33% for letrozole alone. Clinical benefit rate (complete and partial response plus stable disease) was 81% vs 58%, respectively.

continued from page 1

cer, including Lilly (with LY2835219) and Novartis (with LEE011).

Phase II Study The phase II study presented at the AACR Annual Meeting consisted of two parts. Part 1 randomly assigned 66 postmenopausal patients with estrogen receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer to the combination of palbociclib plus letrozole or letrozole alone. Part 2 randomly assigned an additional 99 patients to the same treatment arms with the same tumor characteristics as well as two additional potential biomarkers: CCND1 amplification and/or loss of p16. In part 1, progression-free survival

EXPERT POINT OF VIEW

resentation of the PALOMA-1 trial results represented “the culmination of a long journey from the discovery of cyclin-dependent kinase (CDK) 4/6 in the early 1990s,” said José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center, New York. Dr. Baselga was formal discussant of the trial presented by Finn et al at the American Association for Cancer Research Annual Meeting. “These strikingly positive results José Baselga, MD, PhD have a large potential to impact patients with breast cancer. If these results are confirmed, a CDK4/6 inhibitor plus endocrine therapy could be a new standard of care for metastatic breast cancer,” he said. “The elephant in the room,” Dr. Baselga continued, “is that highly positive randomized phase II studies that are open label and that have investigatorbased assessment of progression-free survival can be followed by negative phase III trials,” so the results need to be validated by further study. Palbociclib plus letrozole is going forward with phase III testing in the PALOMA-2 trial, and results of that study will be eagerly awaited. Breast cancer is a fertile area of research for CDK4/6 inhibitors, Dr. Baselga continued. Other CDK4/6 inhibitors are under study. Lilly’s compound LY2835219 had striking early results reported at this year’s AACR Annual Meeting and Novartis’ LEE011 is being evaluated in the phase III MONALEESA trial. n

Disclosure: Dr. Baselga is a consultant for Elli Lilly, Novartis, Genentech, Verastem, and Seragon.

as the major biomarker for selecting patients for treatment with these agents.

Phase I Trial “These results confirm single-agent activity of LY2835219. This compound appears to be very effective in heavily pretreated patients with metastatic breast cancer. Although our study was not designed to compare outcomes

based on hormone receptor status, results in the hormone receptor–positive patients were very encouraging,” said lead author Amita Patnaik, MD, Associate Director of Clinical Research at South Texas Accelerated Research Therapeutics in San Antonio. The phase I trial reported by Dr. Patnaik explored the effect of LY2835219 continued on page 4

Palbociclib/Letrozole in Metastatic Breast Cancer ■■ Palbociclib is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor. ■■ Palbociclib/letrozole achieved striking progression-free survival as first-line therapy for metastatic breast cancer.

Subgroup analysis showed that the progression-free survival benefit for the combination was consistent across all subgroups, including age, sites of metastatic disease, and previous adjuvant therapies or no adjuvant therapy. Overall survival at this early time point was 37.5 months for the combination vs 33.3 months with letrozole alone. This difference was not statistically significant.

Dr. LoRusso moderated the press conference where these results were presented. Dr. Slamon said “The potential impact of this study could be huge. We are doing further phase III work [PALOMA-2] with the drug, but the current data are as exciting as the initial studies we were involved

Acceptable Toxicity The toxicity of palbociclib in combination with letrozole was acceptable. Adverse events associated more frequently with the combination than with letrozole alone included neutropenia (grade 3, 48%, grade 4, 6%), leukopenia (grade 3, 19%), fatigue, and anemia. At the end of the trial, 23% of patients treated with palbociclib plus letrozole remained on therapy vs 10% on letrozole alone. The most common reason for treatment discontinuation was disease progression. “These data with palbociclib plus letrozole are impressive, and if confirmed in a larger phase III trial, will offer an additional alternative to breast cancer patients with receptor-positive metastatic disease similar to the excitement that resulted with early trials of everolimus and letrozole. If the palbociclib preliminary data are confirmed in phase III trials and remain as impressive, our patients will yet have another therapeutic alternative,” commented Patricia LoRusso, DO, Director of the Center for Experimental Therapeutics at the Barbara Ann Karmanos Center in Detroit.

Patricia LoRusso, DO

Dennis Slamon, MD, PhD

in when testing trastuzumab (Herceptin) for HER2-positive breast cancers.” Palbociclib has been granted Breakthrough Therapy designation by the FDA for firstline therapy of estrogen receptor–positive, HER2-negative advanced breast cancer. n

Disclosure: Drs. Finn and LoRusso reported no potential conflicts of interest. Dr. Slamon has received honoraria from Genentech and SanofiAventis.

Reference 1. Finn RS, et al: AACR Annual Meeting. Abstract CT101. Presented April 6, 2014.

The ASCO Post | MAY 1, 2014

PAGE 4

American Association for Cancer Research Annual Meeting Dermatologic Oncology

PD-L1 Studied as Biomarker for Anti–PD-1 Immunotherapy By Alice Goodman

he anti–PD-1 inhibitor MK-3475 (formerly lambrolizumab) is in late-stage trials for advanced melanoma and is also being studied in other malignancies, including non–small cell lung cancer (NSCLC). An important aspect of Merck’s development program for MK-3475, as well as for other anti–PD-1 agents being developed by other pharmaceutical companies, is identification of a biomarker for patient selection.

KEYNOTE-001 Trial As reported at the Annual Meeting of the American Association for Cancer Research (AACR), separate analyses of cohorts treated with MK-3475 in the KEYNOTE-001 phase I trial sought to correlate response to this agent with the biomarker PD-L1. A potent antibody that inhibits PD-1, MK-3475 is designed to restore the ability of the immune system to recognize and target cancer cells by selectively achieving dual blockade of two ligands of the PD-1 protein: PD-L1 and PD-L2. PD-L1 is expressed in some tumors both by tumor cells and by infiltrating

LY2835219 continued from page 3

in five different tumor types (n = 132). At the AACR meeting, Dr. Patnaik reported results in a cohort of 47 patients with metastatic breast cancer who received a median of seven prior therapies. Median age was 55 years. The majority had two or more metastatic sites; 74% had visceral metastases. Thirty-six patients (76%) were hormone receptor–positive. Among all patients, 11 (19%) had

immune cells within the stroma. Taken together, results of these analyses suggest that PD-L1 may be an important biomarker in patients receiving treatment with MK-3475, but further studies are needed for the protein to be established as clinically useful for patient selection. That said, the results were more promising for clinical utility of PD-L1 in NSCLC than in advanced melanoma, based on the differential response between patients with strong PD-L1 expression vs weak or negative expression. A major problem is the lack of standardization of PD-L1 testing. Different pharmaceutical companies developing anti–PD-1 immunotherapies use different assays, making it difficult to compare results, noted Mario Sznol, MD, of Yale Cancer Center, New Haven, Connecticut, who discussed both correlative trials at a Clinical Trials Symposium (see sidebar on page 5).

Melanoma Substudy KEYNOTE-001 had a complex design with many cohorts. The melanoma cohorts included 195 patients with ada partial response and 24 (29.8%) had stable disease. Progressive disease occurred in 11 patients (23.8%) who received LY2835219. Progression-free survival was estimated at 9.1 months. Among hormone receptor–positive patients, 9 (25%) had confirmed partial responses and 20 (56%) had stable disease, including 2 with unconfirmed partial responses; the clinical benefit rate was 61%, and disease control rate was 81%. Responses were durable, Dr. Patnaik said. All of the responders and 20 of 24 pa-

EXPERT POINT OF VIEW

ormal discussant of the LY2835219 trial reported at the American Association for Cancer Research Annual Meeting, Gary Schwartz, MD, of Columbia University School of Medicine, New York, said the drug had “dramatic effects” in estrogen receptor–positive patients. “This drug is highly active in luminal estrogen receptor–positive breast cancer. If we could identify a predictive biomarker [other than estrogen Gary Schwartz, MD receptor positivity], that would facilitate drug development. These [cyclin-dependent kinase–4/6 inhibitors] are new breakthrough drugs. It is an exciting time in oncology,” Dr. Schwartz said. n Disclosure: Dr. Schwartz reported no potential conflicts of interest.

PD-L1 and Anti–PD-1 Therapy ■■ Correlative studies of PD-L1 expression and outcomes showed the protein to be predictive of response to MK-3475 but failed to establish it as a clinically useful biomarker in patient selection for anti–PD-1 treatment. ■■ PD-L1 positivity was a more robust predictor of response and outcomes in lung cancer patients than in melanoma patients. ■■ Among the limitations of using PD-L1 as a biomarker, assays for its expression are not standardized and differ from one another.

vanced disease. After a mandatory biopsy, patients were treated with one of three doses of MK-3475 for 12 weeks; response was assessed and responders continued on treatment until disease progression, whereas nonresponders were dropped from the study. Lead author of the melanoma correlative study was Adil Daud, MD, of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. Previous treatment with ipilimumab (Yervoy) was allowed. Those who had received ipilimumab had no restriction on prior therapies; those who were ipilimumab-naive could have had up to two prior therapies.

Of 125 evaluable patients, 89 (71%) had PD-L1–positive tumors, and 36 (29%) were PD-L1–negative. The overall response rate was 40%. Among PDL1–positive patients, the response rate was 49% vs 13% among PD-L1–negative patients (P = .0007).3 Durable responses were observed in both PD-L1–positive and PD-L1– negative patients, Dr. Daud said. This limits the clinical utility of using PD-L1 expression as a biomarker in advanced melanoma, he noted. Progression-free survival curves revealed major differences between PLL1–positive and –negative patients. continued on page 5

Fatigue was the dose-limiting toxicity and 200 mg every 12 hours was identified as the maximum tolerated dose. The investigators determined that neutropenia did not correlate with clinical benefit. n

Disclosure: Dr. Patnaik has received research funding from and has been a consultant for Eli Lilly. Amita Patnaik, MD

tients with stable disease were hormone receptor–positive. Eighteen patients with hormone receptor–positive disease are still being treated with LY2835219. The drug will move forward for further evaluation in breast cancer.

Drug-Related Toxicity The most common side effects of LY2835219 were diarrhea, fatigue, nausea, vomiting, leukopenia, and neutropenia. “Side effects were tolerable, and no patient discontinued study due to drug-related toxicity,” Dr. Patnaik said.

References 1. Finn RS, Crown JP, Lang I, et al: Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)4/6 inhibitor, in combination with letrozole alone for first-line treatment of ER+/HER2advanced breast cancer (PALOMA-1/ TRIO-18). AACR Annual Meeting. Abstract CT101. Presented April 6, 2014. 2. Patnaik A, Rosen LS, Tolaney SM, et al: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. AACR Annual Meeting. Abstract CT232. Presented April 7, 2014.

LY2835219 in Metastatic Breast Cancer ■■ An investigational cyclin-dependent kinase (CDK) inhibitor of CDK4 and CDK6 showed promising activity in a cohort of heavily pretreated patients with metastatic breast cancer who failed to respond to standard therapies. ■■ Hormone receptor positivity is a biomarker for response to this agent.

ASCOPost.com | MAY 1, 2014

PAGE 5

American Association for Cancer Research Annual Meeting PD-L1 Studied as Biomarker continued from page 4

Median progression-free survival was 10.6 months in PD-L1–positive patients vs 2.9 months in PD-L1–negative patients (P = .0051). Overall survival data are not yet mature. Data from ongoing studies of MK3475 should provide additional information on the correlation between PDL1 expression and response in patients treated with MK-3475. Ongoing trials in advanced melanoma include the phase II KEYNOTE-002 trial and the phase III KEYNOTE-006 trial.

NSCLC Cohort A separate analysis of patients with NSCLC treated with MK-3475 showed that PD-L1 expression in at least 50% of tumor cells predicted response to MK-3475. These findings were based on analysis of a training set of 146 NSCLC patients from the ongoing KEYNOTE-001 phase I study and were reported by Leena Gandhi, MD, PhD,

of Dana-Farber Cancer Center, Boston. Using the 50% cutoff point, about 25% of patients were strongly positive for PD-L1 expression. The overall response rate for both PD-L1–positive and –negative groups was 19%. However, strong positivity clearly differentiated responders from nonresponders, Dr. Gandhi said. Median progression-free survival was 14.1 weeks in the PD-L1–positive patients vs 9.3 weeks in the weakly positive (1%–49% cutoff) and negative

patients. Overall survival was 9.3 vs 7.3 months, respectively, which was not statistically significant. “Progression-free survival was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect that the median and final progression-free survival may change over time because the data to date include only very few patients with long-term follow-up. As with melanoma, there is no statistically significant difference in survival at this point,

Progression-free survival was markedly improved in those with strong PD-L1 staining, and responses were durable…. As with melanoma, there is no statistically significant difference in survival at this point, but we do see a trend favoring PD-L1 positivity. —Leena Gandhi, MD, PhD

but we do see a trend favoring PD-L1 positivity,” Dr. Gandhi said. Additional analysis will be done on expanded patient groups in the phase I study, and an ongoing randomized study will compare MK-3475 at 2 mg/kg vs docetaxel at 10 mg in NSCLC. MK-3475 is also being evaluated in multiple trials across more than 30 types of cancer and hematologic malignancies. n

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

References 1. Daud AI, Hamid O, Ribas A, et al: Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma: Correlation of tumor PD-L1 expression with outcome. AACR Annual Meeting. Abstract CT104. Presented April 6, 2014. 2. Gandhi L, Balmanoukian A, Hui R, et al: MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression. AACR Annual Meeting. Abstract CT105. Presented April 6, 2014.

EXPERT POINT OF VIEW

ario Sznol, MD, of Yale Cancer Center, New Haven, Connecticut, was formal discussant of the MK-3475 presentations at the American Association for Cancer Research (AACR) Annual Meeting. He alluded to all the factors that complicate assays of PD-L1: the disparate nature of the assays themselves, the type of biopsy, the interval between biopsy and treatment, primary tumor vs metastatic tumor, antibody and staining conditions, automated vs manual readings, and the definition of a positive result with a cutoff point. “Several prior trials of PD-1/PDL1 pathway antibodies have shown correlations between PD-L1 expression and response in melanoma and also in combined cohorts of patients with various malignancies, mostly including renal cancer and non– small cell lung cancer, and several studies show that PD-L1 expression is also prognostic,” he continued.

Key Results The findings in melanoma, reported by Daud et al, showed a strong correlation between PD-L1 expression and response or disease control

rate, and PD-L1 expression with improved progression-free survival but

reported by Gandhi et al, Dr. Sznol said that using the 50% cutoff for PD-

At this point, I would not use these assays in the clinic to predict for response in individual patients. We need phase III trials to determine the potential benefit of anti–PD-1 therapy in the low [PD-L1]–negative group. —Mario Sznol, MD

no correlation with survival. “Survival was still better than expected in the PD-L1–negative melanoma patients. These data suggest that the drug may have an effect on survival in PD-L1–negative patients despite the apparent lack of impact on progression-free survival and response,” Dr. Sznol commented. Because of the drug’s effects on PD-L1–negative as well as –positive patients, “this study suggests that we should not be using [PD-L1] as a predictive assay in the clinic in melanoma,” Dr. Sznol stated. Regarding the data in lung cancer

L1 “loses 40% of potential responders.” As in the melanoma cohort, no major difference in overall survival was observed between PD-L1–positive and PD-L1–negative patients.

Better Biomarkers Needed “Multiple assays are in development for PD-L1 by drug companies. It is confusing to know which assay to use. There can be heterogeneity of PD-L1 expression within a single patient. Most of these patients don’t have good alternative therapies. MK3475 has clear treatment activity in a subset of low PD-L1 expressers, and

this is relevant in patients with no other alternatives,” he continued. An assay for PD-L1 expression might be useful in drug development, and it may be a way to stratify patients in clinical trials to target different response rates and expectations, Dr. Sznol said. It also may be useful in studying combinations of therapies. “Moving forward, we need better biomarkers. We don’t yet have the technology or capacity to decide whether an immune intervention is going to work or not at present. There are too many unanswered questions…. At this point, I would not use these assays to predict for response in the clinic for individual patients. We will also need phase III trials to determine benefit of anti– PD-1 therapy in the low [PD-L1–]– negative group,” he concluded. n Disclosure: Dr. Sznol served as an advisor or consultant for Bristol-Myers Squibb, Genesis Biopharma, Celgene, and Prometheus Labs. He received grants for clinical research from Bristol-Myers Squibb Company and owns stock, stock options, or bonds from Genesis Biopharma. Has research support from GlaxoSmithKline, LLC, and Merck.

The ASCO Post | MAY 1, 2014

PAGE 6

Society of Surgical Oncology Annual Cancer Symposium Dermatologic Oncology

Patients With Thin Melanoma Benefit From Sentinel Lymph Node Biopsy By Shalmali Pal

entinel node status is “the most powerful predictor” of melanomaspecific survival in patients with thin melanoma, according to a presentation at the 2014 Society of Surgical Oncology (SSO) Cancer Symposium in Phoenix.1 As a result, sentinel lymph node

Boland said. “It has become the standard of care for patients with tumors > 1 mm.”3 However, a large proportion of people who present in the clinic do so with thin melanoma, and this cohort of patients was not included in the MSLT1 trial, she said. “So the role of sentinel

There are likely some subsets of patients for whom the risk of a positive sentinel lymph node may be sufficient to offer them a sentinel lymph node biopsy, and we may be able to use clinicopathologic factors to stratify out the appropriate patients. —Genevieve Boland, MD, PhD, and colleagues

The removal of metastases in sentinel lymph nodes of patients with thin melanoma is associated with improved melanoma-specific survival compared with development of clinical nodal recurrence. —Mark Faries, MD

biopsy should be considered in patients with melanoma less than 0.70 mm, concluded Genevieve Boland, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues. In addition, the presence of mitotic activity and/or Clark level IV/V was associated with an increased risk of positive sentinel lymph node status. Dr. Boland’s research was one of two papers on the role of sentinel node biopsy in thin melanoma presented during an SSO Parallel Session on Melanoma. In the second, Mark Faries, MD, of the John Wayne Cancer Institute in Santa Monica, California, and colleagues compared outcomes among patients with thin melanoma who presented with sentinel node metastases and patients who developed clinical node recurrence.2

Predictors of Survival “We know from various studies, including the MSLT I [Multicenter Selective Lymphadenectomy Trial I], that sentinel lymph node biopsy is one of the most powerful predictors of recurrence and survival in patients with intermediate-thickness and thick melanoma,” Dr.

lymph node biopsy in thin melanoma is not well defined,” she added. Dr. Boland’s group examined clinicopathologic factors and sentinel lymph node status, along with melanoma-specific survival, in a contemporary clinical cohort (1999–2009). From a prospective database, they identified patients with clinically node-negative melanoma (≤ 1 mm) who also had wide excision and underwent sentinel node biopsy at MD Anderson Cancer Center. The study cohort consisted of 867 patients whose thin melanomas had a median Breslow thickness of 0.70 mm. Among those patients, 3% experienced ulceration, 45% had mitosis of ≥ 1 mm2, and the sentinel lymph node rate was 5%.

The authors identified the most dominant predictors of a positive sentinel lymph node as increasing Breslow thickness > 0.7 mm (vs < 0.7 mm, odds ratio [OR] = 5.6, P < .0001) and increasing mitosis ≥ 1 mm2 (vs < 1 mm2, OR = 4.0, P = .0001). They also noted that Clark level IV/V (vs II/III, OR = 3.1, P = .0002) was another statistically significant factor. “We chose to address these dominant factors a little more closely,” Dr. Boland said. “When we stratified the patient by a cutpoint of 0.7 mm … in the < 0.7-mm [group], there was a 2% incidence of positive sentinel lymph node vs 9% in the > 0.7-mm group. Among patients with the highest Breslow thickness, [there was] an increase in the incidence of positive sentinel lymph node rate to 12% when the mitotic rate was equal to or greater than 1 mm2.”

Melanoma-Specific Survival With regard to melanoma-specific survival, at a median follow-up of 6.8 years, the 5-year melanoma-specific survival was 98.5%. The following factors were associated with poorer melanoma-specific survival: • Breslow thickness: 0.7–1.0 mm (P = .0065) • presence of mitosis (P = .0017) • AJCC stage T1b (P = .0032) • age > 60 years at diagnosis (P = .0083) The 5-year melanoma-specific survival was 99% in patients with negative sentinel lymph nodes and 85% in those with positive nodes (P < .0001). In a multivariate analysis, the two independent factors predictive of melanoma-specific survival were positive vs negative sentinel lymph node status (hazard ratio [HR] = 36.57, 95% confidence interval [CI] = 14.84–90.3, P < .0001) and age at diagnosis (HR = 1.07, 95% CI = 1.03–1.10, P < .0001). There were 20 melanoma-specific deaths in the cohort, Dr. Boland reported. “The predictors that we found in our cohort of patients for sentinel lymph

Sentinel Node Biopsy in Melanoma ■■ Predictors for sentinel lymph node positivity in thin melanoma are a greater Breslow thickness, presence of mitosis, and Clark level ≥ IV. ■■ Sentinel lymph node biopsy should be considered in patients with melanoma < 0.70 mm. ■■ The removal of metastases in sentinel lymph nodes of patients with thin melanoma is associated with improved melanoma-specific survival compared with development of clinical nodal recurrence.

node positivity were a greater Breslow thickness, presence of mitosis, and Clark level greater than or equal to IV,” she said. “Stratifying patients according to this range, the sentinel lymph node– positive rate was 1% to 12%.” The authors concluded that sentinel lymph node status is a dominant predictor of melanoma survival. “There are likely some subsets of patients for whom the risk of a positive sentinel lymph node may be sufficient to offer them a sentinel lymph node biopsy, and we may be able to use clinicopathologic factors to stratify out the appropriate patients,” Dr. Boland stated.

Selection Bias Issues During the question-and-answer session, Dale Han, MD, of Yale University School of Medicine in New Haven, Connecticut, pointed out that “this is a very selective patient population. You show a 2% rate in your 0.7-mm population, but that’s probably even lower if you encompass all patients with 0.7 mm. Even when you substratify by mitotic rates, it’s still 4% at most.” Dr. Boland replied that “this is not the definitive guideline. We’ve selected out high-risk patients from the baseline, so this is not the average patient who is going to walk into the clinic…. There may be questions of biology; if our surveillance is good, we may catch bad biology early.” Daniel Coit, MD, of Memorial Sloan Kettering Cancer Center in New York, also brought up the issue of selection bias and suggested that the study authors were “making this way too complicated.” He continued, “I think you have a much simpler question to answer: What’s the threshold for doing a sentinel lymph

Daniel Coit, MD

node biopsy in an otherwise healthy, 40-year-old person—I’m going to pick an average age—and should that threshold be the same in America as it is in Australia; should it be the same around the world?” Dr. Boland’s coauthor Jeffrey Gershenwald, MD, also of MD Anderson, responded to Dr. Coit’s question. “On continued on page 11

STRENGTHEN HER DEFENSE

FDA-approved HER2* dimerization inhibitor (HDI) for the first-line treatment of HER2+ metastatic breast cancer (MBC)1,2

Indication

PERJETA速 (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin速 (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. *HER2 = human epidermal growth factor receptor.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly improve progression-free survival PERJETA-based regimen extended median progression-free survival (PFS) to 18.5 months (from 12.4 months)1 6.1-Month Improvement in Median IRF-assessed PFS1* Placebo + Herceptin + docetaxel

100

PERJETA + Herceptin + docetaxel

HR=0.62† 95% CI [0.51-0.75] P<0.0001

80 70

18.5 MONTHS

PFS (%)

60 50

12.4 MONTHS

40 30

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

20 10 0

P+H+D Pl+H+D

• At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk IRF = independent review facility; CI = confidence interval; HR = hazard ratio. *At the time of the final PFS analysis, OS was not mature and first interim OS analysis results did not meet the prespecified stopping boundary for statistical significance.1 Stratified by prior treatment status and geographic region.1 The CLEOPATRA trial was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of patients with HER2+ locally recurrent, unresectable or metastatic breast cancer (HER2+ status was defined as IHC 3+ or FISH amplification ratio ≥2.0 as determined at a central laboratory) (N=808); patients were randomized in a 1:1 ratio to either PERJETA + Herceptin + docetaxel (n=402) or placebo + Herceptin + docetaxel (n=406).1

†

Important Safety Information

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD) • In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETAtreated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions • PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

Significantly prolong overall survival 34% reduction in risk of death with PERJETA1 Second Interim Overall Survival (OS) Results1 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR=0.66 95% CI [0.52-0.84] P=0.0008‡

OS (%)

MEDIAN NOT YET REACHED

60 50

• More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at the time of the second interim analysis, thereby indicating that the median OS for this arm has not yet been reached1 • At the time of analysis, there were 113 (28.1%) and 154 (37.9%) deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin + docetaxel arm, respectively1

37.6 MONTHS

• Median follow-up was 30 months (1 year following the first interim analysis) for both the PERJETA-based regimen and the placebo + Herceptin + docetaxel arms (Kaplan-Meier estimate)1-3

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

20 10 0

P+H+D PI+H+D

402 406

387 383

371 350

342 324

317 285

25 30 MONTHS 230 143 198 128

84 67

33 22

9 4

0 0

Patients at risk OS = overall survival. ‡ The HR and P value for the second interim analysis of OS crossed the predefined efficacy stopping boundary (HR≤0.739, P≤0.0138).1

• Consistent PFS and OS benefit demonstrated across several HER2+ MBC patient subgroups1,3 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])1 • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI- CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

PER0001010504

Printed in USA.

10/13

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. September 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 3. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.

PERJETA®® (pertuzumab) PERJETA INJECTION,(pertuzumab) FOR INTRAVENOUS USE INJECTION, INTRAVENOUS INITIAL U.S. FOR APPROVAL: 2012 USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY EMBRYO-FETAL TOXICITY Cardiomyopathy Cardiomyopathy PERJETA administration can result in subclinical and PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6) contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Administration (2.1)]. Limitations of Use: Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. regimen has not been established. • The safety of PERJETA administered for greater than • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Information (17)]. Monitor patients who become pregnant during PERJETA therapy Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA hydration in the management of oligohydramnios due to PERJETA exposure is not known. exposure is not known. 5.2 Left Ventricular Dysfunction 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of radiotherapy to the chest area may be at higher risk of decreased LVEF. decreased LVEF. In patients receiving neoadjuvant treatment in Study 2, the In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. compared to the trastuzumab- and docetaxel-treated group. An increased incidence of LVEF declines was observed An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated TCH. Symptomatic LVSD occurred in 4.0% of patients treated

with PERJETA plus trastuzumab and docetaxel following FEC, with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to treatment or a cumulative prior anthracycline exposure to > 360 mg/m22 of doxorubicin or its equivalent. > 360 mg/m of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Related Reactions 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAfrequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2. (NCI - CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and in patients with severe infusion reactions [see Dosage and Administration (2.2)]. Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. placebo-treated group experienced anaphylaxis. In Study 2 and Study 3, hypersensitivity/anaphylaxis events In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCIplus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. CTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. of its excipients [see Contraindications (4)]. 5.5 HER2 Testing 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. overexpression by IHC. Assessment of HER2 status should be performed by Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater The following adverse reactions are discussed in greater detail in other sections of the label: detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] Precautions (5.4)] 6.1 Clinical Trials Experience 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical conditions, adverse reaction rates observed in the clinical

trials of a drug cannot be directly compared to rates in the trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates clinical trials of another drug and may not reflect the rates observed in clinical practice. observed in clinical practice. Metastatic Breast Cancer (MBC) Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 of Patients on the PERJETA Treatment Arm in Study 1 PERJETA Placebo PERJETA Placebo + trastuzumab + trastuzumab ++trastuzumab + trastuzumab docetaxel + docetaxel + docetaxel + docetaxel n=407 n=397 Body System/ n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades All % Grades All % Grades Grades, 3–4, % Grades, 3–4, % Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Infections and infestations Upper respiratory tract Upper respiratory tract infection 16.7 0.7 13.4 0.0 infection 16.7 0.7 13.4 0.0 Nasopharyngitis 11.8 0.0 12.8 0.3 Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome reported in association with a fatal outcome The following clinically relevant adverse reactions were reported The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo(5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo(1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) treated group) Immune system disorders: Hypersensitivity (10.1% in the Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). headache (11.4%), and fatigue (11.1%).

Cosmos Communications Cosmos Communications 26402a1_pi 26402a1_pi

K K

1 1

11.7.13 11.7.13

133 133

ej ej 2 2

Q1 Q1

Q2 Q2

Neoadjuvant Treatment of Breast Cancer (Study 2) Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2. treatment with PERJETA for breast cancer in Study 2. Table 2 Summary of Adverse Reactions Occurring in ≥ 10% Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2 in Study 2

Body System/ Body System/ Adverse Reactions Adverse Reactions

Trastuzumab Trastuzumab + docetaxel + docetaxel n=107 n=107 rate Frequency Frequency % rate All %Grades Grades 3–4 All Grades % % Grades 3–4 % %

PERJETA PERJETA + trastuzumab ++trastuzumab docetaxel + docetaxel n=107 n=107 rate Frequency Frequency % rate All %Grades Grades 3–4 All Grades % % Grades 3–4 % %

PERJETA PERJETA + trastuzumab + trastuzumab n=108 n=108 rate Frequency Frequency % rate All %Grades Grades 3–4 All Grades % % Grades 3–4 % %

General disorders and administration site conditions General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 10.3 0.0 2.8 0.0 0.9 0.0 Edema peripheral 10.3 0.0 2.8 0.0 0.9 0.0 Edema peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 Mucosal inflammation 21.5 0.0 26.2 1.9 2.8 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 Gastrointestinal disorders Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Peripheral Sensory 12.1 0.9 8.4 0.9 1.9 0.0 Sensory 12.1 0.9 8.4 0.9 1.9 0.0 Neuropathy Neuropathy Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0 Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

PERJETA +PERJETA docetaxel + docetaxel n=108 n=108 rate Frequency Frequency % rate All %Grades Grades 3–4 All Grades % % Grades 3–4 % %

25.5 25.5 16.0 16.0 5.3 5.3 25.5 25.5 8.5 8.5

1.1 1.1 2.1 2.1 0.0 0.0 0.0 0.0 0.0 0.0

67.0 67.0 28.7 28.7

0.0 0.0 1.1 1.1

54.3 54.3 36.2 36.2 16.0 16.0 9.6 9.6

4.3 4.3 1.1 1.1 2.1 2.1 0.0 0.0

64.9 64.9 13.8 13.8

57.4 57.4 8.5 8.5

12.8 12.8 7.4 7.4

0.0 0.0 0.0 0.0

10.6 0.0 10.6 0.0 21.3 21.3 9.6 9.6

0.0 0.0 0.0 0.0

14.9 0.0 14.9 0.0 8.5 8.5

0.0 0.0

The following adverse reactions were reported in < 10% The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast who received neoadjuvant treatment with PERJETA for breast cancer in Study 3 cancer in Study 3

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3 in Study 3 PERJETA

Body System/ Body System/ Adverse Reactions Adverse Reactions

PERJETA + trastuzumab trastuzumab ++FEC followed + by FECPERJETA followed PERJETA +by trastuzumab ++trastuzumab docetaxel + docetaxel n=72 n=72rate, % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

PERJETA PERJETA + trastuzumab ++trastuzumab docetaxel + docetaxel following FEC following n=75 FEC n=75rate, % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

PERJETA + TCH PERJETA n=76+ TCH n=76rate, % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

General disorders and administration site conditions General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3 Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3 Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Syndrome Gastrointestinal disorders Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Nervous system disorders Neuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0 Neuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0 Headache 22.2 0.0 14.7 0.0 17.1 0.0 Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0 Metabolism and nutrition disorders Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 0.0 Decreased appetite 20.8 0.0 10.7 0.0 21.1 0.0

observed incidence of a positive result in a test method may be observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. antibodies to other products may be misleading. 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.1 Pregnancy Pregnancy Category D Pregnancy Category D Risk Summary Risk Summary There are no adequate and well-controlled studies of PERJETA in There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard PERJETA, the patient should be apprised of the potential hazard to the fetus. to the fetus. If PERJETA is administered during pregnancy or if a patient becomes If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Patient Counseling Information (17)]. Animal Data Animal Data Reproductive toxicology studies have been conducted in Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20dose levels resulted in clinically relevant exposures of 2.5 to 20fold greater than the recommended human dose, based on Cmax. fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, human dose, based on C ). At Caesarean section on GD100, oligohydramnios, decreasedmaxrelative lung and kidney weights, and oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision adverse reactions in nursing infants from PERJETA, a decision

Table 3 Summary of Adverse Reactions ≥ 10% in Study 3 (Cont) Table 3 Summary of Adverse ReactionsPTZ ≥ 10% in Study 3 (Cont) +T+D Ptz + T + FEC Body System/ Body System/ Adverse Reactions Adverse Reactions

Ptz + T + FEC followed by followed Ptz + T + by D Ptz + T +rate, D % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

PTZ + T +FEC D following following n=75 FEC n=75rate, % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

PERJETA + TCH PERJETA n=76+ TCH n=76rate, % Frequency Frequency rate, % All Grades Grades 3–4 All Grades % Grades 3% –4 % %

Eye disorders Eye disorders Lacrimation increased 12.5 0.0 5.3 0.0 7.9 0.0 Lacrimation increased 12.5 0.0 5.3 0.0 7.9 0.0 Psychiatric disorders Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Investigations Investigations ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 FEC=5-fluorouracil, epirubicin, cyclophosphamide, FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/ 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/ Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/ Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/ Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm) in the Ptz+TCH arm) Respiratory, thoracic, and mediastinal disorders: Pleural effusion Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an As with all therapeutic proteins, there is the potential for an immune response to PERJETA. immune response to PERJETA. Patients in Study 1 were tested at multiple time-points for Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antihypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the and specificity of the test methods used. Additionally, the

ASCOPost.com | MAY 1, 2014

Thin Melanoma continued from page 6

a global level, for young, healthy patients, many people have considered a threshold of 5% as a starting point for discussion. Clearly, for someone with comorbidities, older age, etc, a threshold of 10% or more might just barely scratch the surface for offering someone the procedure,” he said. “There are lots of way we could do a lot more,” Dr. Gershenwald added. “This [current study] is one snapshot of one way to present data.”

Survival Advantage? Dr. Faries and colleagues sought to answer the question, is there a survival advantage to early treatment of lymph node metastases for patients with thin melanomas? They conducted a retrospective comparison of patients who had nodal disease, identified either by sentinel lymph node metastases or clinical node recurrence. They used data from two independent, prospectively maintained melanoma databases: one at John Wayne Cancer Institute (center 1) that tracked patients with positive sentinel lymph nodes from 1986 to 2010 and clinical node recurrence from 1971 to 2010, and one at the University of Pennsylvania in Philadelphia (center 2). The latter included sentinel lymph node– positive patients from 1996 to 2011 and a historic cohort with nodal recurrence from 1973 to 1989. From both centers,

should be made whether to discontinue nursing, or discontinue should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established The safety and effectiveness of PERJETA have not been established in pediatric patients. in pediatric patients. 8.5 Geriatric Use 8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800enroll in the MotHER Pregnancy Registry by contacting 1-800690-6720 [see Patient Counseling Information (17)]. 690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date. No drug overdoses have been reported with PERJETA to date.

PERJETA®® (pertuzumab) PERJETA (pertuzumab) Manufactured by: Manufactured by: Genentech, Inc. Genentech, Inc. A Member of the Roche Group A Member of the Roche Group 1 DNA Way 1 DNA Way South San Francisco, CA South San Francisco, CA 94080-4990 94080-4990 U.S. License No. 1048 U.S. License No. 1048

PERJETA is a registered PERJETA is a registered trademark of Genentech, trademark of Genentech, Inc. Inc. 09/13 PER0002094600 09/13 PER0002094600 © 2013 Genentech, Inc. © 2013 Genentech, Inc. 10139000 10139000

PAGE 11

“The removal of metastases in sentinel lymph nodes of patients with thin melanoma is associated with improved melanoma-specific survival compared with development of clinical nodal recurrence,” Dr. Faries concluded. “This may reflect tumor biology, … patient selection, or potential therapeutic efficacy of sentinel lymph node biopsy in thin melanoma.”

the authors looked at patient demographics, pathologic characteristics, and survival from primary melanoma diagnosis. They then compared survival between center 1 and center 2. When compared with nodal recurrence patients, sentinel lymph node patients at center 1 were older, had more ulcerated tumors, elevated Clark level (P < .0001 for all) and a trend toward increased Breslow thickness. At center 2, sentinel lymph node patients had increased Clark level and Breslow thickness, increased mitosis, and increased overall T stage, but a lower frequency of ulcerations.

Varied Reactions The study results elicited very different responses from the SSO attendees. Mary Sue Brady, MD, of Memorial Sloan Kettering Cancer Center, said that she thought this analysis was an oversimplification. “I’ve never believed that

Multivariate Analysis

In a multivariate analysis, the following were all prognostic variables for decreased melanoma-specific survival: • age > 50 (HR = 1.48, 95% CI = 1.15–1.89, P = .002) • ulceration (HR = 1.86, 95% CI = 1.19–2.93, P = .007) • truncal site (HR = 1.60, 95 CI = 1.17–2.20, P = .004) • method of nodal disease discovMary Sue Brady, MD ery, ie, clinical nodal recurrence vs positive sentinel lymph node (HR = people [for whom treatment fails] clini3.34, 95% CI = 1.86–6.02, P < .001) cally are the same as people with microThe 5-year survival rate for the sen- scopic disease,” she explained. “I think tinel lymph node–positive patients was it’s much more complex than that.” But Merrick Ross, MD, of MD An88% vs 72% for the nodal recurrence group. The 10-year survival was 84% vs derson Cancer Center, praised the study issue of differences 49%, respectively (P < .0001). Cosmos Communicationsresults. Addressing 1 Q1theQ2 Cosmos Communications 26402a1_pi 26402a1_pi

K K

11.7.13 11.7.13

133 133

ej ej 2 2

in patients, Dr. Ross stated, “maybe these are different patients; maybe they are different now because you’ve allowed them to have the metastasis grow in the lymph node for 5 years or 10 years, and they become different because the cells mutate.… Until we find a better way to identify these high-risk patients, this seems like a pretty good way.” He added, “In the absence of a prospective, randomized trial, which will never be done, … these data should not be dismissed.” n Disclosure: Dr. Boland reported no potential conflicts of interest. Dr. Faries has served as a consultant for Genentech and as an investigator/ proctor for Delcath Systems.

References 1. Boland G, Caudle A, Warneke C, et al: Predictors of survival in contemporary era patients with thin melanoma who underwent sentinel node biopsy. 2014 SSO Cancer Symposium. Abstract 53. Presented March 14, 2014. 2. Faries MB, Karakousis GC, Bartlett E, et al: Improved survival in patients with thin melanoma after positive sentinel node versus clinical nodal recurrence. 2014 SSO Cancer Symposium. Abstract 54. Presented March 14, 2014. 3. Howard JH, Thompson JF, Mozzillo N, et al: Metastasectomy for distant metastatic melanoma: Analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Ann Surg Oncol 19:2547-2555, 2012.

The ASCO Post | MAY 1, 2014

PAGE 12

Society of Surgical Oncology Annual Cancer Symposium Sarcoma

Surgery Plus Radiation Offers Mixed Results in Soft-Tissue Sarcoma By Shalmali Pal

djuvant radiation following surgery for soft-tissue sarcomas of the extremities did not lead to a survival benefit and seemed to be associated with some degree of long-term limb complications, according to a presentation at the 2014 Society of Surgical Oncology (SSO) Cancer Symposium in Phoenix.1 Follow-up data from a 146-patient trial that compared limb-sparing surgery alone vs surgery plus adjuvant external-beam radiation showed a 20-year survival rate of 64% (95% confidence interval [CI] = 52%–75%) for patients who received surgery alone and 71% (95 CI = 59%–81%) for patients who underwent the combination therapy (P = .22), reported Joal Beane, MD, of the National Cancer Institute in Bethesda, Maryland, and colleagues.

Uncertain Link “The ability of radiation therapy to improve local control following surgery has made it a cornerstone in the multimodality treatment of common cancers, like primary breast and rectal cancer. However, the link between improved local control and overall survival remains uncertain,” Dr. Beane said. Despite its widespread use in softtissue sarcoma of the extremity, the pairing of radiation and surgery has never turned in exceptional results for survival. For instance, in a 1982 prospective study that compared limb-sparing surgery plus external-beam radiation therapy to amputation, disease-free survival and overall survival were similar between the two study arms.2 Dr. Beane’s group evaluated longterm data from a 1983–1991 trial that reported better local control with limb-sparing surgery and externalbeam radiation therapy vs surgery alone, but still no differences in survival outcomes.3 The limited data available on long-term impact of radiation therapy on limb function may offset the modality’s benefit in local control, Dr. Beane explained.

Study Details In the original trial, the externalbeam radiation therapy protocol consisted of 4,500 cGy delivered to

a wide field, 1,800-cGy boost to the tumor bed, and 180-cGy fractions given 5 days a week for 6 to 7 weeks. Patients with high-grade soft-tissue sarcomas also received concurrent adjuvant chemotherapy with doxorubicin and cyclophosphamide. Dr. Beane’s group analyzed patient-reported quality of life using a phone-based questionnaire that included queries on severity of pain, need for pain medication more than three times a week, need for wound care, degree of limb edema, and impact of limb disability. Since the original publication of the trial results in 1998, 55 patients died, 76 were confirmed living, and 19 were lost to follow-up. The overall median follow-up time was 17.9 years for both study arms. The lack of a survival benefit with

Treating Soft-Tissue Sarcoma of the Extremities ■■ Adjuvant external-beam radiation therapy following surgery for soft-tissue sarcoma of the extremities did not lead to a survival benefit. ■■ Long-term complications seen in some patients who underwent surgery alone or surgery plus radiotherapy were pathologic fracture requiring surgical correction, hospitalization for limb edema, and amputation.

three orthopedic surgeries to correct the problem, while two patients in the combination treatment group required amputation. One amputation was secondary to nonunion of a pathologic fracture and the other was due to chronic wound complications and osteomyelitis, Dr. Beane stated. In terms of limb edema, most patients in the two study arms did not require treatment (63% and 50%), although two patients in the external-

The ability of radiation therapy to improve local control following surgery has made it a cornerstone in the multimodality treatment of common cancers, like primary breast and rectal cancer. However, the link between improved local control and overall survival remains uncertain. —Joal Beane, MD

radiation in the overall study was also true when patients with high-grade and low-grade lesions were considered separately (P = .59 and .14, respectively).

Quality of Life With regard to quality of life, among the 76 patients who were confirmed living, 54 completed the phone interviews. Results for variables related to pain favored limb-sparing surgery alone, but did not reach statistical significance when compared with dual-modality treatment. The majority of patients in either group did not require any wound care (79% for surgery alone and 73% for surgery plus radiotherapy). However, one patient in the surgery group had a pathologic fracture and required

beam radiation group did need to be hospitalized for treatment of limb edema (P = .21). Most patients in both groups had no deficits in their limbs from the treatment regimens (85% and 88%, P = .84). While the majority of patients did not suffer from long-term limb complications, Dr. Beane emphasized that “the use of adjuvant therapy should be selective in patients with a low risk of recurrence.”

Practicing-Changing? Dr. Beane noted that the study had many limitations including the small sample size and the fact that it was a retrospective analysis of limb function. In addition, the authors did not look at the effect of chemotherapy on

long-term complications. Finally, the study was done before the advent of three-dimensional radiation therapy and intensity-modulated radiation therapy. Both modalities require more complex planning, which could lead to improvements in outcomes. SSO Plenary Session moderator Ronald J. Weigel, MD, PhD, of the Unviersity of Iowa Carver College of Medicine, asked how the results would apply in clinical practice, given that radiation therapy in these patients is now standard. “I don’t think [radiation] treatment should be withheld,” Dr. Beane replied. “I think we need to be critical about when it’s administered, using some of the nonograms … that predict the 3and 5-year local recurrence in patients who don’t have external-beam radiation therapy. I think [with this study], we are trying to highlight that these [tools] should be used more frequently to better select patients who would benefit from radiation therapy.” n

Disclosure: Dr. Beane potential conflicts of interest.

reported

References 1. Beane JD, Yang JC, White D, et al: Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity: 20-year follow-up of a randomized prospective trial. 2014 SSO Cancer Symposium. Abstract 4. Presented March 14, 2014. 2. Rosenberg SA, Tepper J, Glatstein E, et al: The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196:305-315, 1982. 3. Yang JC, Chang AE, Baker AR, et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197203, 1998.

ASCOPost.com | MAY 1, 2014

PAGE 13

Society of Surgical Oncology Annual Cancer Symposium SSO Awarded ACCME’S Highest Accreditation Status

he Accreditation Council for Continuing Medical Education® (ACCME) recently awarded the Society of Surgical Oncology (SSO) the designation of Accreditation with Commendation. Accreditation with Commendation is ACCME’s highest accreditation award status and extends SSO’s reaccreditation period from 4 to 6 years. Out of 2,000 accredited providers in the United States, only 15% are granted this distinction. SSO demonstrated compliance across all 19 of ACCME’s accreditation criteria and was recognized as a “learning organization and a change agent for the physicians SSO serves.”

SSO’s Mission “This recognition emphasizes SSO’s mission of improving patient care by advancing the science and practice of surgical oncology worldwide through its excellent continuing medical education (CME) programs,” said SSO President Ronald J. Weigel, MD, PhD, MBA, Professor and Chairman, Department of Surgery, University of

sium, Surgical Oncology Self-Assessment Program (SOSAP), Maintenance of Certification (MOC) Part 2 Online Modules, Annals of Surgical Oncology journal CME/MOC, Virtual Meeting, and more. Visit surgonc.org to learn more about these opportunities.

About the Society of Surgical Oncology Founded in 1940 as the James Ewing Society, the Society of Surgical Oncology® is the premier organization for surgeons and health-care providers dedicated to advancing and promot-

ing the science and treatment of cancer worldwide. The 2,800-member Society’s focus on all solid-tumor disease sites is reflected in its Annual Cancer Symposium, monthly scientific journal (Annals of Surgical Oncology), educational initiatives, and committee structure. n

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MO DEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

Ronald J. Weigel, MD, PhD, MBA

Iowa Carver College of Medicine. “It is a significant achievement in CME and demonstrates the continued growth and success of SSO’s educational initiatives,” Dr. Weigel concluded. ACCME administers an extensive process for evaluating institutions’ CME programs according to the high accreditation standards adopted by all seven ACCME member organizations. These organizations include the American Board of Medical Specialties, American Hospital Association, American Medical Association, Association for Hospital Medical Education, Association of American Medical Colleges, Council of Medical Specialty Societies, and Federation of State Medical Boards. SSO provides a broad range of education opportunities for surgical oncologists, general surgeons, and other health-care professionals at all career levels. Among the programs offered include the SSO Annual Cancer Sympo-

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology. Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

The ASCO Post | MAY 1, 2014

PAGE 14

National Comprehensive Cancer Network Annual Conference Hematology

Promising Compounds in Development for Multiple Myeloma By Caroline Helwick

he term “novel agents” has been used for the past decade to describe proteasome inhibitors and immunomodulatory drugs that are now conventionally used for multiple myeloma. However, even newer agents in development will be considered truly novel when they hit the market, as they represent new classes of drugs that have not been used before in this cancer, according to Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston. At the National Comprehensive Cancer Network (NCCN) 2013 Annual Conference, Dr. Anderson described what he considers the most promising of these investigational agents. “We are excited about new proteasome inhibitors and [immunomodulatory drugs], but we are even more excited to have different classes of drugs. New proteasome inhibitors and [immunomodulatory drugs] are important, but their benefit is incremental. In multiple myeloma, we want a paradigm change,” he said. “My strong feeling is that we can incorporate these investigational therapies into all stages of disease, and likely in combination, and will further improve patient outcomes,” he predicted.

Monoclonal Antibodies

(ELOQUENT-1 and -2) are evaluating elotuzumab plus lenalidomide/dexamethasone in the relapsed/refractory and newly diagnosed populations. Among the antibodies targeting CD38 are SAR650984 and daratumumab. SAR650984 has multiple mechanisms of action: antibody-dependent cellular cytotoxicity and phagocytosis, complement-dependent cytotoxicity, direct apoptosis induction, and allosteric inhibition on CD38 enzymatic

Monoclonal antibodies are finally being developed for myeloma. The agents furthest along in development target CS1 and CD38 antigens. CS1 is present on all myeloma cells and on natural killer cells, and CD38 exists on myeloma cells but also on activated T cells, activated B cells, myeloid cells, monocytes, and endothelial cells. The CS1-targeting agent elotuzumab is well tolerated but as a single

In the new world of multiple myeloma, we will be using combinations of drugs, both up front and in relapse. New agents are going to have to be good team players. —Kenneth C. Anderson, MD

agent achieves only stable disease. When combined with lenalidomide (Revlimid), however, the effect is impressive. In phase I/II studies, response rates to this combination have been 80% to 90% and progression-free survival has approached 3 years; positive outcomes have been seen even in the context of 17p deletion or other adverse cytogenetics. Two clinical trials

activity. In a phase I/II trial reported at the American Society of Hematology (ASH) Annual Meeting last year, 5 of 13 patients with a median of five prior lines of therapy achieved a minor response or better, and two complete responses were observed; 69% had received carfilzomib (Kyprolis) and/or pomalidomide (Pomalyst).1 “It is very exciting to see complete

Should You Treat Smoldering Multiple Myeloma? By Caroline Helwick

recent article in The New England Journal of Medicine has provoked conversation about the management of smoldering multiple myeloma.1 At the recent National Comprehensive Cancer Network (NCCN) Annual Conference, Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston, shared his thoughts on the topic with The ASCO Post. He noted that smoldering myeloma was first described around 1980 as patients with plasmacytosis and monoclonal protein in lesser amounts, lacking clinical features. “These patients could go 8 to 10 years without treatment,” he pointed out. “Now, we can define a population who are more at risk and who progress to active myeloma more quickly.” These so-called “high risk” patients

are being enrolled in trials evaluating “high-risk protocols,” he said.

Redefining Smoldering Myeloma In the study by Mateos et al, lenalidomide/dexamethasone prolonged progression-free survival and overall survival in a “high-risk” population. However, Dr. Anderson and other experts have questioned whether the population was 100% “smoldering.” “If they truly had smoldering myeloma, why is there a survival advantage already, early on in the trial? It tells us that some of those patients who were thought to have smoldering myeloma actually had active myeloma, and their outcome was poorer than usual,” he suggested.

The International Myeloma Working Group is currently redefining smoldering myeloma. “The likelihood is that smoldering myeloma will become a smaller group of patients, and the active myeloma group will become larger,” he said. Meanwhile, Dr. Anderson’s opinion is that smoldering myeloma patients should be enrolled in clinical trials but should not receive treatment off-protocol. n

Disclosure: Dr. Anderson is on advisory boards for Celgene, Millennium, Onyx, Gilead, and Sanofi Aventis. He is Scientific Founder of Acetylon and Oncopep.

Reference 1. Mateos MV, Hernandez MT, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438447, 2013.

responses to this antibody alone,” Dr. Anderson commented. Daratumumab also showed strong activity in a phase I/II study of the drug as a single-agent, where 47% of patients derived benefit, and at doses of 4 mg/ kg, 66% had a minor response or better.2 The U.S. Food and Drug Administration has granted this agent breakthrough status. “It’s very exciting as a single agent, but as with elotuzumab, it may be better in combination with [lenalidomide/ dexamethasone],” he added. At doses of 4 mg or higher and in combination with lenalidomide/dexamethasone, almost all patients had a near-complete or complete drop in monoclonal protein.3

Antibody Conjugates Also new to myeloma is the introduction of new immune-based strategies—specifically, a potent antibodydrug conjugate that targets CD138, an antigen that is highly expressed on myeloma cells. Indatuximab ravtansine (BT062) is designed to deliver the maytansinoid cytotoxic agent DM4 specifically to these CD138-expressing cells. In a phase I trial of 21 patients, stable disease or better was observed in 100% of 15 evaluable patients, including two complete responses, four very good partial responses, and five partial responses, for an overall response rate of 73%.4

HDAC Inhibitors Dr. Anderson said he is particularly interested in the histone deacetylase (HDAC) inhibitors, due to their rational biology in myeloma and impressive preclinical activity. HDACs are implicated in bringing the proteasome protein into the alternative aggresomal autophagy system, and HDAC inhibitors block the aggresomal pathway. In preclinical studies, inhibition of both the proteasome (ie, with a proteasome inhibitor) and the aggresome (with HDAC inhibition) “has produced the most potent cytotoxicity we have ever observed,” he noted, “and if we put the HDAC inhibitor together with an [immunomodulatory drug] we block an important oncogene—c-Myc.” However, with the current broadacting HDAC inhibitors—especially vorinostat (Zolinza) and to some degree panobinostat—toxicity has been an issue. In the international VANTAGE 088 trial, vorinostat led to

ASCOPost.com | MAY 1, 2014

PAGE 15

National Comprehensive Cancer Network Annual Conference only a 1-month benefit in progressionfree survival, because side effects limited the drug’s tolerability.5 Vorinostat, therefore, is not moving forward in myeloma, but results with panobinostat are more promising, with phase III clinical trial results coming soon, he said. Probably the best bet will be the more selective HDAC inhibitors, which are capable of overcoming toxicity presented by the broad-acting drugs, he said. The current focus is on ricolinostat (ACY-1215), which was studied in combination with lenalidomide and dexamethasone in a phase Ib study reported at the 2013 ASH Annual Meeting.6 Of 16 patients evaluable for response, 100% experienced clinical benefit and 11 (69%) had a partial response or better, including one complete response, three very good partial responses, and seven partial responses. “Almost all these patients with relapsed/refractory disease benefited, and most importantly, ricolinostat was well tolerated,” Dr. Anderson reported. “Both broad-acting inhibitors have not been able to be combined with [immunomodulatory drugs] because of low blood counts, but this drug seems well tolerated, and so, it is excellent in combination.” Ricolinostat is moving forward in development in combination with lenalidomide/dexamethasone.

Kinesin Spindle Protein Inhibitors Another novel class in myeloma is the kinesin spindle protein inhibitors. Inhibition of kinesin spindle protein induces ab-

errant mitotic arrest and rapid cell death. The kinesin spindle protein inhibitor filanesib (ARRY-520) was studied in a phase II trial as a single agent and combined with dexamethasone, where the overall response rates were 16% and 15%, respectively.7 Better responses (24%) were observed, however, in patients who had low levels of the carrier protein α-1 acid glycoprotein (AAG), which binds the drug; duration of response in this subset was 8.6 months. According to Dr. Anderson, “This drug is going forward in combination with bortezomib [Velcade] in the population of patients selected for low levels of AAG.”

Akt Inhibitors The Akt inhibitor afuresertib (PKB115125) is also an interesting compound, he said, “because when we treat with a proteasome inhibitor, we activate Akt, so the principle is to block the activation and get synergistic cytotoxicity with this combination.” In a phase I/II trial by Voorhees et al, the Akt inhibitor plus bortezomib produced impressive falls in M protein.8

Novel Combinations “In the new world of multiple myeloma, we will be using combinations of drugs, both up front and in relapse,” Dr. Anderson predicted. “New agents are going to have to be good team players.” Gene-sequencing studies have not revealed a predominant mutation; rather, multiple clones of cells are present from the start. When patients are fol-

lowed over time, “the already-complicated genetic analysis becomes much more so,” he observed. This means that myeloma might best be treated the way that some cancers, such as leukemia and Hodgkin lymphoma, and some infectious diseases, such as tuberculosis and human immunodeficiency virus, are already managed, he said. That is, the optimal approach might include “using combinations of effective and well tolerated agents upfront and early in the disease, treating the pathways that mediate growth and survival, attacking the marked clonal abnormalities, and anticipating mechanisms of acquired resistance.” n

Disclosure: Dr. Anderson is on advisory boards for Celgene, Millennium, Onyx, Gilead, and Sanofi Aventis. He is Scientific Founder of Acetylon and Oncopep.

References 1. Martin TG, Strickland S, Glenn M, et al: SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies—data from a dose-escalation phase I study. 2013 ASH Annual Meeting. Abstract 284. Presented December 9, 2013. 2. Plesner T, Lokhorst H, Gimsing P, et al: Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma—data from a dose-escalation phase I/II study. 2012 ASH Annual Meeting. Abstract 73. Presented December 9, 2012. 3. Plesner T, Arkenau T, Lokhorst H, et al: Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. 2013 ASH

Annual Meeting. Abstract 1986. Presented December 7, 2013. 4. Kelly KR, Chanan-Khan A, Somlo G, et al: Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: Clinical activity in len/dex-refractory patients. 2013 ASH Annual Meeting. Abstract 758. Presented December 9, 2013. 5. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicenter, randomized, double-blind study. Lancet Oncol 14:1129-1140, 2013. 6. Yee A, Vorhees P, Bensinger W, et al: ACY-1215, a selective histone deacetylase 6 inhibitor, in combination with lenalidomide and dexamethasone, is well tolerated without dose limiting toxicity in patients with multiple myeloma at doses demonstrating biolgic activity: Interim results of a phase 1b trial. 2013 ASH Annual Meeting. Abstract 3190. Presented December 8, 2013. 7. Lonial S, Shah J, Zonder J, et al: Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma patients with low α-1 acid glycoprotein levels: Results from a phase 2 study. 2013 ASH Annual Meeting. Abstract 285. Presented December 9, 2013. 8. Voorhees PM, Spencer A, Sutherland H, et al: Novel AKT inhibitor afuresertib in combination with bortezomib and dexamethasone demonstrates favorable safety profile and significant clinical activity in patients with relapsed/refractory multiple myeloma. 2013 ASH Annual Meeting. Abstract 283. Presented December 9, 2013.

Special Supplement to The ASCO Post

Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment

Supplement • Volume 5, Issue 7 • May 1, 2014

Methotrexate and Fluorouracil Toxicities: A Collaborative Practice Approach to Prevention and Treatment Proceedings From a Roundtable Discussion, January 26, 2014, St. Petersburg, Florida

Proceedings From a Roundtable Discussion, January 26, 2014, St. Petersburg, Florida

Featuring Lee S. Schwartzberg, MD, FACP The West Clinic, Memphis, Tennessee

Wendy H. Vogel, MSN, FNP, AOCNP®

Wellmont Cancer Institute, Kingsport, Tennessee

Lee S. Schwartzberg, MD, FACP

Wendy H. Vogel, MSN, FNP, AOCNP®

Christopher J. Campen, PharmD, BCPS, BCOP

Medical Director, The West Clinic, Memphis, Tennessee

Oncology Nurse Practitioner, Wellmont Cancer Institute, Kingsport, Tennessee

Clinical Oncology Pharmacist, University of Arizona Cancer Center, Tucson, Arizona

EARN CE CREDIT: Continuing education credit is provided through the Meniscus Educational Institute, a triple accredited provider for CME/CE/CEU credits and contact hours, upon successful completion of the supplement and evaluation.

Christopher J. Campen, PharmD, BCPS, BCOP

The University of Arizona Cancer Center, Tucson, Arizona

Editor-in-Chief, James O. Armitage, MD

Making a world of diﬀerence in cancer care

ASCOPost.com

A Harborside Press® Publication

Look for your copy, mailing with this issue of The ASCO Post.

The ASCO Post | MAY 1, 2014

PAGE 16

Announcements

NCCN Receives $2 Million in Research Funding to Study Nintedanib in Colorectal and Lung Cancers

he National Comprehensive Cancer Network® (NCCN®) Oncology Research Program (ORP) has announced it has been awarded a $2 million grant from Boehringer Ingelheim Pharmaceuticals, Inc. to develop a program to scientifically evaluate and define the safety and clinical effectiveness of the investigational compound nintedanib* (BIBF 1120) in the treatment of colorectal and non-small cell lung cancers. Nintedanib is an investigational orally administered triple angiokinase inhibitor that targets three of the receptor tyrosine kinases shown to aid in the regulation of angiogenesis: fibroblast growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. All three receptors are associated with tumor angiogenesis, and their blockade may lead to the inhibition of tumor growth and spread. “We are grateful to collaborate with Boehringer Ingelheim on this groundbreaking research initiative,” said Diane E. Paul, MS, RN, Vice President, NCCN ORP. “The research supported by this grant gives investigators from NCCN Member Institutions the opportunity to advance the field of oncology by evaluating the use of nintedanib in multiple tumor types.”

Proposals Development Team The first phase of the program will involve the establishment of an NCCN Nintedanib Request for Proposals Development Team to evaluate existing data and to discuss and define the data and type of studies necessary to further characterize the safety and clinical effectiveness of nintedanib in colorectal and non-small cell lung cancers. The NCCN ORP draws on the expertise of investigators at NCCN Member Institutions and the NCCN Affiliate Research Consortium to facilitate all phases of clinical research. This research is made possible by collaborations with pharmaceutical and biotechnology companies in order to advance therapeutic options for patients with cancer. The NCCN ORP * This compound [nintedanib] is investigational and not approved by the U.S. Food and Drug Administration. Its safety and efficacy have not been established.

will utilize the grant from Boehringer Ingelheim Pharmaceuticals, Inc. to support investigator-initiated clinical and correlative studies at NCCN Member Institutions and their af-

filiate community hospitals for nintedanib. To date, this successful research model has S:6.75” received approximately $44 million in research grants and supported 116 studies that have

produced a number of publications in peer-reviewed journals. To learn more about the NCCN ORP and ongoing clinical trials, visit NCCN.org. n

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

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

B:1

T:1

FDA Update

FDA Grants Orphan Drug Designation for Anti-CD19 T-Cell Cancer Immunotherapy Product therapy, an autologous engineered T-cell product that targets CD19 expression on B-cell malignancies, S:6.75” for the treatment of diffuse large B-cell lymphoma. Orphan drug designation is granted

by the FDA Office of Orphan Products Development to novel drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/

disorders that affect fewer than 200,000 people in the United States. The orphan drug designation also would entitle Kite Pharma to a 7-year period of marketing exclusivity in the United States. n

PROD

ite Pharma, Inc, announced that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted orphan drug designation for the company’s lead investigational

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

months

11.2

ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

Please see brief summary of full Prescribing Information on next page.

COMETRIQ.com

DATE

SIGNOFF

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

Disk release

Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

T:10.25”

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

PharmaGraphics

15”

PAGE 17

S&H

17.5”

ASCOPost.com | MAY 1, 2014

Cosmos Commu

The ASCO Post | MAY 1, 2014

PAGE 18

FDA Update

FDA Approves Ofatumumab for Previously Untreated Chronic Lymphocytic Leukemia

he U.S. Food and Drug Administration (FDA) has approved ofatumumab (Arzerra) injection in combination with chlorambucil (Leukeran) for the treatment of previ-

ously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate. The approval was based on the

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

results of a multicenter, randomized, open-label trial comparing ofatumumab in combination with chlorambucil to single-agent chlorambucil.

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 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 safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

Trial Details The trial enrolled 447 patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that in-

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

ASCOPost.com | MAY 1, 2014

PAGE 19

FDA Update

cluded advanced age or presence of comorbidities. In the overall trial population, the median age was 69 years (range, 35–92 years), 72% of patients had two or more comorbidities, and 48% of patients had a creatinine clearance < 70 mL/min. Patients received ofatumumab as an intravenous infusion according to the fol-

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

lowing schedule: 300 mg administered on cycle 1 on day 1, 1,000 mg administered on cycle 1 on day 8, and 1,000 mg administered on day 1 of all subsequent 28-day cycles. In both arms, chlorambucil was given at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glu-

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

cocorticoid. The primary endpoint of the trial was progression free survival.

Outcomes Median progression-free survival was 22.4 months (95% confidence interval [CI] = 19.0–25.2 months) for patients receiving ofatumumab in combination with chlorambucil vs 13.1

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

months (95% CI = 10.6–13.8 months) for patients receiving single-agent chlorambucil (hazard ratio = 0.57, 95% CI =

0.45–0.72, stratified log-rank P < .001). The most common adverse reactions (≥ 5%) with ofatumumab in combination with chlorambucil (≥ 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Overall, 67% of patients who received ofatumumab experienced one or more symptoms of infusion reaction, and 10% of patients experienced a grade 3 or greater infusion reaction.

Regular Approval The results of this randomized trial were adequate to fulfill the postmarketing requirement for GlaxoSmithKline to verify the clinical benefit of ofatumumab and, therefore, the approval of ofatumumab was converted from accelerated approval to regular approval. The recommended dose and schedule for the approved regimen for ofatumumab in previously untreated CLL is 300 mg on day 1 followed 1 week later by 1,000 mg on day 8 (cycle 1) followed by 1,000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles. n

Ethiodized Oil Approved for Imaging of Hepatocellular Carcinoma Tumors

he U.S. Food and Drug Administration has approved ethiodized oil injection (Lipiodol) for selective hepatic intra-arterial use for imaging tumors in adults with known hepatocellular carcinoma. The agent received orphan drug designation for management of patients with known hepatocellular carcinoma in October 2013. Ethiodized oil, an oil-based radiopaque contrast agent, is also indicated for hysterosalpingography in adults and lymphography in adult and pediatric patients. The agent is contraindicated in patients with hypersensitivity to ethiodized oil, hyperthyroidism, traumatic injuries, recent hemorrhage, or bleeding. n

The ASCO Post | MAY 1, 2014

PAGE 20

Gastrointestinal Society of Gynecologic Cancers Oncology Symposium Annual Meeting Gynecologic Oncology

Gynecologic Cancer Treatment at High-Volume Centers May Be Lifesaving By Alice Goodman

omen with gynecologic cancers who are treated at hospitals that frequently manage these conditions appear to live significantly longer than those who receive their care at lower-volume centers, according to a large study presented at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held March 22–25 in Tampa, Florida. Improved survival was observed at highvolume centers independent of prognostic factors. In fact, life was extended by about 1 year for women with cervical, ovarian, uterine, vaginal, and vulvar cancers cared for at high-volume centers compared with those at low-volume centers. The study also showed an increasing trend over time in the number of wom-

More efforts should be directed at helping patients with gynecologic cancers seek care at high-volume hospitals. —Jeff F. Lin, MD

en with gynecologic cancers who seek treatment at a high-volume center.

Increasingly Complex Care “This trend is good news for women. Although these data don’t tell us exactly why more women are being treated at high-volume centers, gynecologic cancer

care is becoming increasingly complex, and doctors may feel more comfortable referring patients to specialized high-volume centers that can better coordinate such care,” suggested lead author Jeff F. Lin, MD, Magee-Womens Hospital of University of Pittsburgh Medical Center. “Studies have already shown that spe-

cialty care for some cancers improves the quality of care and survival. The relative rarity and diversity of gynecologic cancers suggest that they require complex management and would benefit from regionalization of care. In addition, the current environment of health-care reform encourages regionalization of cancer care into specialized centers. Based on this study and others, more efforts should be directed at helping patients with gynecologic cancers seek care at high-volume hospitals,” Dr. Lin said. Potential reasons Dr. Lin cited for superior survival at high-volume centers include improved coordination of care, better access to clinical trials and/or cutting-edge therapy, and greater likelihood of being treated for cancers of female continued on page 22

EXPERT POINT OF VIEW

hen asked to comment on the study presented by Lin et al at the Annual Meeting on Women’s Cancer, William Cliby, MD, Chair, Division of Surgery, The Mayo Clinic, Rochester, Minnesota, said, “This study is important because of its size and the utilization of the National Cancer Data

William Cliby, MD

logic Oncology, explained that his committee seeks to understand problems and identify deficiencies in the care of women with gynecologic malignancies. Addressing these issues should improve patient outcomes, he noted. “Outcomes based on research such as that presented by Dr. Lin are vital for

Matthew A. Powell, MD

Base—the largest, national resource designed specifically to look at trends in national cancer care, create benchmarks, and serve as a basis for quality improvement. The results confirm findings from earlier, smaller studies: facility case volume of cancer affects survival. This effect was seen across gynecologic cancers. The challenge for providers, patients, and payors is to develop improved systems that facilitate getting these complex patients to regional highvolume centers.” Matthew A. Powell, MD, Associate Professor, Washington University School of Medicine, St. Louis, and Chair of the Quality and Outcomes Committee for the Society of Gyneco-

David M. O’Malley, MD

us to help meet our goals,” Dr. Powell said. He noted that for nearly all aspects of complex medical care in the United States, increased volume of the provider and facility have been associated with improved results.

Centralization of Care “Solid organ transplant is a great example where better results were seen at higher-volume centers, and this has led to centralization of care to high-volume centers. Several European countries have evaluated their outcomes for patients with cancer and have mandated centralized care due to superior results. The Norwegian health system has been the most successful in formalizing its

management of patients with ovarian cancer and mandating centralization of care,” Dr. Powell continued. Dr. Lin’s study utilizes the National Cancer Data Base, which was established in 1989 and captures data on approximately 26 million patients from more than 1,500 participating hospitals, including nearly 70% of newly diagnosed cancers each year. “The study showed that treatment of gynecologic cancer at high-volume centers is associated with improved outcomes independent of significant prognostic factors. Patients treated at high-volume centers lived on average over 1 year longer. Elderly and advanced-stage patients are more likely to be treated at low-volume centers. These data support regionalization of gynecologic cancer care and identify areas for improvement,” Dr. Powell stated.

Multidisciplinary Teamwork A third expert commenting on this paper, David M. O’Malley, MD, Assistant Professor at The James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University College of Medicine, Columbus, emphasized the importance of multidisciplinary teamwork at high-volume centers. “One of the greatest impacts on overall survival in women who have been diagnosed with a gynecologic cancer is treatment at a center that not only offers specialty care but also offers care

to a large number of patients. Dr Lin’s report is not able to identify the factors responsible for these findings. Most likely, this highly significant improvement in overall survival is related to offering comprehensive care by teams that are specialty-trained.” Dr. O’Malley said. “The teams at high-volume institutions are often led by a specialty-trained gynecologic oncologist working with other physicians trained in the treatment of gynecologic cancers to include medical oncologists, radiation oncologists, and pain and palliative care specialists. The physicians are just a part of the team that are involved in improving care of women at these high-volume institutions; pharmacists, nurse practitioners, physician assistants, nurses, and other important team members who have been trained in the treatment of women diagnosed with gynecologic cancers are very important to the care of these women,” Dr. O’Malley stated. He noted that it is important to identify barriers to being treated at the high-volume institutions. “The report by Dr. Lin and colleagues further provides evidence that it may be time to establish a system that deems specialty programs as centers of excellence, such as those established in other diseases in the treatment of gynecologic cancers,” he said. n Disclosure: Drs. Cliby, Powell, and O’Malley reported no potential conflicts of interest.

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

The ASCO Post | MAY 1, 2014

PAGE 22

Gastrointestinal Society of Gynecologic Cancers Oncology Symposium Annual Meeting Gynecologic Oncology

High-Risk Uterine Cancers Found in BRCA1 Mutation Carriers Who Had Preventive Oophorectomy but Not Hysterectomy By Alice Goodman

rophylactic surgery to remove the ovaries and fallopian tubes is advised for women who carry BRCA mutations to reduce the risk of breast and ovarian cancer. This procedure, referred to as risk-reducing salpingo-oo-

over the following 10 years. No increased risk was observed for the more common types of uterine cancer in women who had salpingo-oophorectomy and no hysterectomy, and women who were BRCA2 carriers had no increased risk of these rare aggressive cancers.

Key Risk Findings The study enrolled 525 women with BRCA1 (n = 296) or BRCA2 mutations (n = 226) who underwent salpingooophorectomy without a hysterectomy. An aggressive form of uterine cancer (serous Noah D. Kauff, MD Catherine Shu, MD carcinoma, carcinosarcoma, phorectomy, typically does not require leiomyosarcoma) developed in 4 of the a hysterectomy. However, a new study 296 women with a BRCA1 mutation, presented at the Society of Gynecologic translating to a 2.1% risk of developing Oncology (SGO) Annual Meeting on this type of cancer over 10 years. This risk is approximately 26-fold Women’s Cancer suggests that including a hysterectomy as part of prophylactic higher than what one would expect in the surgery may be advisable in women with general population, said senior author BRCA1 mutations. The meeting was Noah D. Kauff, MD, Director of Ovarian Cancer Screening and Prevention on the held March 22–25 in Tampa, Florida. In the study, women with BRCA1 Gynecology Service at Memorial Sloan mutations who underwent risk-reducing Kettering Cancer Center, New York. salpingo-oophorectomy (but not a hys- Catherine Shu, MD, a fellow at Memoterectomy) were at increased risk of de- rial Sloan Kettering, was lead author. The current National Comprehensive veloping rare, aggressive uterine cancers

Gynecologic Cancer Treatment continued from page 20

reproductive organs by gynecologic oncologists and allied specialists.

Study Details The study was based on data from the National Cancer Database, which is maintained by the American College of Surgeons Commission on Cancer and the American Cancer Society. The study population included 863,156 patients with female reproductive cancers treated at 1,666 centers between January 1998 and December 2011. The centers were categorized according to quartiles representing the highest-volume

centers that care for nearly 300 gynecologic cancer patients per year to the lowest-volume centers caring for fewer than 20 such patients annually. For all gynecologic cancer patients, median overall survival was 122.7 months at the highest-volume hospitals and 110 months at the lowest-volume hospitals. “This difference represents 12.7 months,” Dr. Lin stated. “A difference in survival of 12-plus months can mean that a patient can see her newborn grandchild, travel the world, or make a difference in others’ lives—all of this resting on a decision made before she even walks into the hospital.” The difference in favor of high-volume hospitals was even greater for rare

Trends in Gynecologic Oncology ■■ Gynecologic cancers are relatively rare and often require complex management by multidisciplinary teams. ■■ Women with gynecologic cancers treated at high-volume hospitals enjoy longer survival than those treated at centers where such diseases are treated less frequently.

Cancer Network (NCCN) recommendation is that women with a BRCA1 mutation undergo risk-reducing salpingo-oophorectomy between the ages of 35 and 40 after childbearing is complete. Hysterectomy is not included in the current recommendations, because this procedure carries both short- and long-term risks. Also, it has been assumed that uterine cancers that develop following risk-reducing salpingo-oophorectomy were likely to be low risk, but the new study throws that assumption into question. “While the absolute risk of aggressive uterine cancer is still relatively low in BRCA1 carriers who did not have a hysterectomy, it is much higher than we would have expected. Doctors should discuss these findings with their pa-

tients with BRCA1 mutations who are considering risk-reducing salpingo- oophorectomy. They may decide to opt for a hysterectomy as well. However, the decision to undertake a hysterectomy in addition to salpingo-oophorectomy depends on several factors, including the woman’s age, prior history of cancer, and childbearing status,” Dr. Kauff said.

Study Data The prospective cohort study was conducted from June 1, 1995, to December 31, 2011. After undergoing risk-reducing salpingo-oophorectomy with the uterus left in situ, 525 women were followed prospectively via annual questionnaires and medical record review for a median of 5.8 years (range, 0.1–16.9 years).

BRCA1 and Uterine Cancer Risk ■■ A prospective cohort study at a single center found a higher-than-expected rate of aggressive uterine cancers (serous carcinoma, carcinosarcoma, leiomyosarcoma) in women who were BRCA1 mutation carriers and had undergone risk-reducing salpingo-oophorectomy (but not hysterectomy). ■■ Further study is needed to confirm this finding. ■■ Oncologists should discuss this information with their patients who carry BRCA1 mutations, and—depending on the patient’s age, childbearing status, and other factors—present the option of hysterectomy.

cancers and those that require complex management. For ovarian cancer, median survival was 49.4 months at the highest-volume centers vs 32.5 months at the lowest-volume centers. For vaginal cancers, median overall survival was 72.2 vs 38.1 months, respectively—a difference of nearly 3 years favoring highest-volume centers. The number of women treated for gynecologic cancers each year remained steady at the lowest-volume centers—about 18. However, a steady increase was observed in the number of women treated at high-volume centers, particularly among the hospitals that treated the most women. At the start of the study in 1998, the highest-volume hospital treated 188 patients per year; this number rose to 291 in 2011 at the end of the study.

Multivariable Analysis According to a multivariable analysis performed to identify factors associated with treatment at high-volume centers, the highest-volume centers were more

likely to be more than 5 miles away from where patients lived, more likely to treat insured patients, and more likely to treat traditionally underserved populations. Elderly patients (ie, over age 71), with higher-stage cancer and more medical issues, were significantly more likely to be treated at the lowest-quartile centers. Dr. Lin noted that this study did not address what specific components of care at high-volume centers might confer a survival advantage, whether certain best practices can be adapted in lowervolume centers, and whether regionalization of care improves efficiency and care delivery. He looks forward to studies that address these questions. n

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

Reference 1. Lin JF, Alexander AL, Beriwal S, et al: Characteristics of high-volume gynecologic cancer centers—framework toward centers of excellence: A National Cancer Data Base (NCDB) study. SGO Annual Meeting on Women’s Cancer. Abstract 89. Presented March 24, 2014.

ASCOPost.com | MAY 1, 2014

PAGE 23

Gastrointestinal Society of Gynecologic Cancers Oncology Symposium Annual Meeting During 3,292 woman-years of follow-up, four high-risk uterine cancers were diagnosed (two serous carcinomas, one carcinosarcoma, and one leiomyosarcoma) at 1.4 to 12.9 years following salpingo-oophorectomy, and no woman developed a low-risk uterine cancer. Of the four cancers, one developed in 168 women with no prior history of breast cancer, and three developed in 357 women with prior breast cancer; two developed in women with a history of tamoxifen use, and two developed in women who had not taken tamoxifen. “While both a previous history of breast cancer and tamoxifen use have been associated with an increased risk of aggressive uterine cancer, the risk of magnitude that has been reported for these exposures is unlikely to fully explain our findings,” Dr. Kauff stated.

hypothesis-generating but not confirmatory of an increased risk of uterine cancer for these gene carriers.” Dr. Herzog said that a larger validation trial is required prior to making hysterectomy a standard recommendation for women who are BRCA mutation carriers. “These data should be considered in

counseling, but they must be weighed against the increased morbidity, cost, and inconvenience of a hysterectomy vs outpatient management, especially considering the low absolute risk of developing uterine cancer for these patients,” Dr. Herzog emphasized. n Disclosure: Dr. Kauff has consulted and provided expert testimony for Pfizer.

Reference 1. Shu CA, Pike M, Jotwani AR, et al: Risk of developing uterine corpus cancer following risk-reducing salpingooophorectomy in women with BRCA mutations. SGO Annual Meeting on Women’s Cancer. Late-Breaking Abstract 5. Presented March 24, 2014.

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

Hypothesis-Generating According to Thomas Herzog, MD, Director of Gynecologic Oncology at Columbia University Medical Center in

Thomas Herzog, MD

New York, this abstract presents important information, but the findings are “not ready for prime-time” application. “This late-breaking abstract was very interesting in that the type of surgery required when a patient is diagnosed with a BRCA mutation requires careful consideration. Kauff et al have raised an important consideration regarding the role of uterine removal. The data are

The ASCO Post Follow us on

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1 • Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today. Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

@ASCOPost

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy. Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

Proceed with confidence

The ASCO Post | MAY 1, 2014

PAGE 24

Gastrointestinal Society of Gynecologic Cancers Oncology Symposium Annual Meeting Gynecologic Oncology

Bariatric Surgery Reduces Risk of Uterine Cancer in Obese Women By Alice Goodman

ariatric surgery for weight loss appears to protect obese women from developing uterine cancer, according to a large retrospective study presented at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held March 22–25

an option for appropriately selected patients,” Dr. Ward said. Guidelines for referral to bariatric surgery include a well-informed, motivated patient who is severely obese (body mass index ≥ 40 kg/mg2), has acceptable surgical risk, and has failed to achieve ad-

This research adds to the growing evidence that reducing obesity reduces cancer risk. —Kristy Ward, MD

in Tampa, Florida. The study found that obese women who underwent bariatric surgery had a 71% lower risk of developing uterine cancer than obese women who did not, and the risk was reduced by 81% if the weight loss was maintained postsurgery.

Modifiable Risk Factor Approximately 95% of all uterine cancers are endometrial, and roughly half of cases of endometrial cancer are thought to be due to obesity; obese women are two to four times more likely to develop endometrial cancer than their normal-weight counterparts. “Obesity is the second leading cause of preventable death in the United States, and it appears to be a modifiable risk factor for uterine cancer,” said Kristy Ward, MD, senior gynecologic oncology fellow in the Department of Reproductive Medicine at the University of California, San Diego, School of Medicine and Moores Cancer Center. “We found that the risk of uterine cancer decreased after bariatric surgery. This research adds to the growing evidence that reducing obesity reduces cancer risk. We need to emphasize the importance of helping women lose weight, and bariatric surgery may be

equate weight loss by other means. Bariatric surgery is also suitable for people with body mass index ≥ 35 kg/m2 who have either diabetes, obstructive sleep apnea, obesity-related cardiomyopathy, or severe joint disease. About 200,000 people undergo bariatric surgery annually. The study did not analyze different types of bariatric surgery, she said.

Study Findings The retrospective study was based on the University Health System Consortium database of more than 7.4 million women aged 18 and older and admitted to any of 392 academic medical center hospitals or affiliated hospitals between January 1, 2009, and June 1, 2013. Mean age was 52.6 years; 56.6% were white, 21.3% were black, 8.5% were Hispanic, and 2.7% were Asian or South Pacific Islander. The study controlled for two variables: a history of bariatric surgery

EXPERT POINT OF VIEW

avid M. O’Malley, MD, Assistant Professor at The James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University College of Medicine, Columbus, commented on the abstract presented by Ward et al at the Annual Meeting on Women’s Cancer. “Dr. Ward and colleagues report further convincing evidence that bariatric surgery reduces the rate of endometrial/uterine cancer from a large hospital-based database. The report highlights the fact that oncologists have a unique opportunity to initiate the discussion about obesity-related issues with patients. This is especially true when they are diagnosed with an obesity-related cancer (eg, endometrial, breast, colon).” Dr. O’Malley said that several organizations have published documents to aid oncologists in counseling patients about weight loss, including the National Institutes of Health (www.nhlbi.nih.gov/health/prof/heart/obesity/ aim_kit/steps.pdf), and the Society of Gynecologic Oncology (https:// www.sgo.org/obesity). He emphasized the importance of educating patients and medical providers about the relationship between obesity and cancer. “The reality of an obesity-associated cancer diagnosis should be an opportunity to emphasize how obesity is impacting the patient’s health. Patients will respond to their oncologist, who should be a leader in education for preventive health strategies. Obviously, weight loss interventions could have a high impact on overall health and decrease cancer occurrences,” Dr. O’Malley stated. n Disclosure: Dr. O’Malley reported no potential conflicts of interest.

and presence of obesity. Among all admissions, 103,797 had undergone bariatric surgery and 44,345 had a history of uterine cancer. Among women who did not have a history of bariatric surgery, the rate of uterine malignancy was 599 per 100,000, and the rate was 2.8 times higher among obese than nonobese women: 1,409 per 100,000 vs 496 per 100,000, respectively. Looking at patients with a history of bariatric surgery, the risk of uterine malignancy was 408 per 100,000. The rate remained high among women who had persistent obesity, while it was much

Reducing Uterine Cancer Risk ■■ A large retrospective study shows that bariatric surgery reduces the risk of uterine cancer by 71% in obese women, and even more in women who have the surgery and maintain the weight loss. ■■ These findings suggest that bariatric surgery is a valid option for weight loss and reducing the risk of uterine cancer.

lower in women who were no longer obese: 682 per 100,000 vs 270 per 100,000, respectively. Among all obese patients, bariatric surgery conferred a 71% risk reduction in uterine cancer compared with no bariatric surgery. Women who had the surgery and were not currently obese had an 81% risk reduction in uterine cancer compared with those who did not have bariatric surgery. Women who had the surgery but were obese had a 52% reduced risk of ovarian cancer compared with those who did not have the surgery. n

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

Reference 1. Ward KK, Ronancio AM, Shah NR, et al: Bariatric surgery decreases the risk of uterine malignancy. SGO Annual Meeting on Women’s Cancer. Abstract 4. Presented March 22, 2014.

Visit The ASCO Post website at ASCOPost.com

Because your patients have different needs… …Amgen supports a broad range of access programs INDEPENDENT CO-PAY FOUNDATIONS Amgen Assist can check the current funding status at different independent foundations for your office

MEDICARE

UNINSURED

COMMERCIALLY INSURED

THE SAFETY NET FOUNDATION The Safety Net Foundation provides products at no cost to eligible uninsured and underinsured patients THE NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM The NEULASTA/NEUPOGEN FIRST STEP™ Program helps reduce out-of-pocket (OOP) costs for all eligible commercially insured patients. Go to www.amgenfirststep.com for program eligibility and limitations

NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM For more information regarding these programs, please call 1-888-4ASSIST or visit AmgenAssistOnline.com To enroll your patient into the Amgen FIRST STEP™ Co-pay Coupon Program call 1-888-65-STEP1 (1-888-657-8371) or visit amgenfirststep.com. The NEULASTA/NEUPOGEN FIRST STEP™ Program MasterCard is issued by The Bancorp Bank pursuant to license by MasterCard International and this card may not be used everywhere Debit MasterCard is accepted. No cash or ATM access. MasterCard is a registered trademark of MasterCard International Incorporated. The Bancorp Bank; Member FDIC.

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

The ASCO Post | MAY 1, 2014

PAGE 26

Gastrointestinal Society of Gynecologic Cancers Oncology Symposium Annual Meeting Gynecologic Oncology

Preliminary Study Suggests Veliparib May Be Effective in Resistant, BRCA-Mutated Ovarian Cancers By Alice Goodman

eliparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, appears to be of value in treating women with BRCA-mutated gynecologic cancers that are resistant to other therapies. These preliminary findings of a phase II

num-resistant patients with recurrent or persistent disease,” said Dr. Coleman. “The findings of our study demonstrate promising clinical activity and tolerance warranting further investigation of veliparib in this setting. Most of

The findings of our study demonstrate promising clinical activity and tolerance warranting further investigation of veliparib in this setting. Most of these patients have few other treatment options, and it is encouraging to think we have another potential therapy to offer them. —Robert L. Coleman, MD

study support the concept that BRCAassociated ovarian cancers are sensitive to veliparib.

PARP Inhibitor Therapy Veliparib targets the PARP enzyme, an important factor in repairing single-strand DNA injury, resulting in cell death in situations where higherfidelity repair mechansims are lacking. This situation is called “synthetic lethality,” explained lead author Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center, Houston, at the Society of Gynecologic Oncology (SGO) Annual Meeting.1 Previous studies have suggested that veliparib was effective in combination with chemotherapy for gynecologic cancers. The multicenter phase II trial presented at the SGO meeting offers the first phase II evidence suggesting that single-agent veliparib has activity in treating resistant cancers in BRCA mutation carriers. “PARP inhibitors have had limited efficacy evaluation in patients with documented resistance to platinum and other therapies. We found that veliparib appears to be effective in some plati-

these patients have few other treatment options, and it is encouraging to think we have another potential therapy to offer them,” he added.

Study Data The study enrolled 52 patients (50 of them evaluable for efficacy and toxicity) with recurrent or persistent measurable epithelial ovarian, peritoneal, or fallopian tube cancer and germline mutations in BRCA1 (78%) or BRCA2 (22%). The majority of cancers (82%) were high-grade serous cell carcinomas. Patients had received up to three prior therapies (with the exception of a prior PARP inhibitor). Thirty patients were platinum-resistant and 20 were platinum-sensitive. Veliparib was initiated at 400 mg

EXPERT POINT OF VIEW

“P

ARP inhibitors are a very promising strategy that moves the treatment of ovarian cancer into the era of personalized medicine,” said Thomas J. Herzog, MD, Director of Gynecologic Oncology at Columbia University Medical Center, New York. “We now have a biomarker for identifying who will benefit from these agents. Certainly we know those who will most likely benefit are patients Thomas J. Herzog, MD with a germline mutation in BRCA1 or BRCA2 genes. This strategy was leveraged in the GOG 280 trial, as all patients were required to have a mutation for trial eligibility,” Dr. Herzog said. Other patients may also benefit from PARP inhibitors, he continued, “such as those with somatic BRCA mutations and those with other defects in the homologous recombination genes.” Dr. Herzog said that the responses to veliparib in platinum-resistant patients are very encouraging and warrant further study. n Disclosure: Dr. Herzog reported no potential conflicts of interest.

twice daily for 28 days (one cycle), and dose reductions were allowed for toxicity. The median number of cycles given was six (range, 1–22). Overall response rate was 26%, with 2 complete responses and 11 partial responses. The response rate was 20% in platinum-resistant patients, 35% in platinum-sensitive patients, 26% in BRCA1 carriers, and 27% in BRCA2 carriers. At the end of the study, 8 patients remained on treatment and 42 were off study (27 due to progression, 11 due to toxicity, and 4 who refused further treatment). At the time of the SGO meeting, median progression-free survival was 8.11 months. At 6 months, 60% of patients were event-free. Overall survival was estimated at 19.7 months.

Veliparib in Ovarian Cancer ■■ A phase II study shows that veliparib, an oral PARP inhibitor, may have promise in treating women carrying a BRCA mutation who have recurrent, previously treated ovarian cancer. ■■ This is the first phase II efficacy data for single-agent veliparib. ■■ Responses in platinum-sensitive and platinum-resistant disease settings suggest further study is warranted.

Download The ASCO Post iPad App Free From iTunes Today!

Adverse Events Toxicity was acceptable in these heavily pretreated patients. The only grade 4 toxicity was thrombocytopenia, reported in one patient. Grade 3 adverse events included fatigue (n = 2), nausea (n = 2), leukopenia (n = 1), neutropenia (n = 1), dehydration (n = 1), and elevated alanine transaminase level (n = 1). Grade 2 adverse events that were reported in more than 10% of patients included nausea (46%), fatigue (26%), vomiting (16%), and anemia (14%). Dose reductions for toxicity were needed in 24 patients (48%). n

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

Reference 1. Coleman RL, Sill M, Aghajanian C, et al: A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation. SGO Annual Meeting. Abstract 136. Presented March 25, 2014.

ASCOPost.com | MAY 1, 2014

PAGE 27

Direct From ASCO

Conquering Colorectal Cancer With Sanjay Goel, MD, the 2010 Advanced Clinical Research Award in Colorectal Cancer Recipient

olorectal cancer is the third most common cancer diagnosed in both men and women in the United States, and about 1 in 20 individuals will develop colorectal cancer in

Professor at the Albert Einstein College of Medicine, received a 2010 Conquer Cancer Foundation of ASCO Advanced Clinical Research Award (ACRA) in Colorectal Cancer

While taking care of each individual has its own satisfaction, the thought that one is involved in something that has the potential to have long-lasting implications on an entire generation of future patients is unparalleled. —Sanjay Goel, MD

their lifetime. The good news is that improvements in screening, earlier detection, and treatments are all leading to improved outcomes for patients with colorectal cancer. Approximately 40% of colorectal cancers have a mutation in the KRAS gene. When KRAS is mutated, certain targeted therapies for colorectal cancer will not work, leaving fewer effective treatment options for those patients.

to help patients with colorectal cancer for whom certain targeted therapies will not be effective because of mutations in the KRAS gene. Dr. Goel’s approach focused on

developing a reovirus (RNA virus) that could be used to treat patients with KRAS mutation in their tumors. In the lab, Dr. Goel and his team found synergy between the reovirus and irinotecan, which is currently used in chemotherapy to treat colorectal cancer. The two agents interacted in such a way that magnified the effects of the irinotecan. The second step is an ongoing clinical trial of the reovirus in combination with the standard chemotherapy protocol. Results from this study have the potential to make a big impact for patients. “If the combination is superior to current standards, it clearly could offer a new paradigm of treatment for [patients with KRAS-mutant colorectal cancer],” said Dr. Goel. “While taking care of each individual has its own satisfaction, the

Potential New Treatment Option for Patients Research has shown that not all tumors have the same targets, which means that the same targeted treatments do not work for every person. Sanjay Goel, MD, Associate

thought that one is involved in something that has the potential to have long-lasting implications on an entire generation of future patients is unparalleled,” he reflected.

Impact of Conquer Cancer Foundation Grant Dr. Goel’s first message to Conquer Cancer Foundation donors is “a very warm and heartfelt thank you.” His Conquer Cancer Foundation grant “had a deep and lasting impact on my career,” he says, an impact that is especially important in a funding landscape for researchers that is so challenging that even the most promising and passionate young researchers have a hard time pursuing their lifesaving work. “The Conquer Cancer Foundation truly is a major player in ensuring that future research-oriented physicians stay put and help mature into future leaders,” said Dr. Goel. Created in 2004, the ACRA program now has 15 grant recipients conducting research in multiple cancer types including breast, lung, hematologic malignancies, sarcoma, glioma, and colorectal cancer. Visit ConquerCancerFoundation.org/ACRA to learn more about the ACRA program, and please consider making a donation to support researchers like Dr. Goel. n © 2014. American Society of Clinical Oncology. All rights reserved.

We Need Your Vote: History’s Top 5 Cancer Research Achievements

hroughout the year, we are celebrating not only ASCO’s 50th anniversary, but also the tremendous progress achieved against cancer in the last 50 years. Thanks to the dedication and contributions of patients and researchers, and our nation’s long-standing commitment to funding clinical research, patients have access to more powerful cancer screening, prevention, and treatment options, and are living longer and better lives than ever before. In fact, ASCO wants your help to identify and recognize the five most pivotal research discoveries that made this progress possible. Make your voice heard by going to www.CancerProgress.Net and clicking on “Vote: Top Advances.” Here you can cast your ballot for the “Top 5” cancer advances since 1964, the year ASCO was

founded. Not only that, you can also tell us why you made your choices. There are more than 30 landmark research achievements to choose from, all

drawn from the Major Milestones section of CancerProgress.Net’s interactive timeline of cancer advances. This interactive timeline, and CancerProgress.Net as a whole, was developed under the guidance of a 21-member editorial board to provide an easily accessible, visual journey through the history of cancer research and to demonstrate the payoff of sustained U.S. investment in research. The site features news and commentary on cancer research achievements, as well as videos and other multimedia content.

Vote Now—Before It’s Too Late Vote on your laptop, mobile phone, or tablet device. Then, tweet one or more of your “Top 5” to your colleagues and friends, or share via other social media platforms, such as LinkedIn or Facebook, to encourage others to get involved.

Time is running out to cast a ballot. Voting will close soon after the Annual Meeting, and your vote is important. It will not only help ASCO spread the word about how federal investment in clinical research has paid off for the past 50 years, but it will help us advocate for continued funding that will help sustain the next 50 years of discovery. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | MAY 1, 2014

PAGE 28

Direct From ASCO

Enhance Your ASCO Annual Meeting Experience With Attendee Resources

t the end of the month, more than 25,000 oncology professionals from around the world will meet in Chicago for the 2014 ASCO Annual Meeting. Will you be joining this global community? As you’re beginning to consider what to pack for your trip,

keep in mind that you have a host of electronic resources at your fingertips that will help you plan your meeting and enhance your onsite experience. The mobile-friendly Attendee Resource Center (am.asco.org/arc) serves as your one-stop shop for all Annual

Meeting resources. Through this portal, you have access to everything you need before, during, and after the meeting.

Build Your Itinerary and Browse Abstracts Beforehand Build your meeting itinerary on your

computer or mobile device with the iPlanner, a scheduling tool that allows you to search presentations and add them to your schedule and lineup of selected recordings. Search by session, speaker, or abstract, and narrow down sessions of interest with this helpful tool. A new way to connect: visit the networking and messaging center, part of the Attendee Resource Center (am.asco.org/arc).

What is BiTE ? ®

BiTE (bispecific T cell engager) is an innovative area of research that uses a technology designed to help activate the potential of T cells to target malignant cells.1,2 ®

Amgen is committed to investigating this area of research. Please visit www.BiteAntibodies.com References: 1. Nagorsen D, Baeuerle PA. Exp Cell Res. 2011;317:1255-1260. 2. Baeuerle PA, Kufer P, Bargou R. Curr Opin Mol Ther. 2009;11:22-30. Statements are based on the company’s current beliefs and Amgen disclaims any duty to update. For more information about Amgen and its business, including risks and uncertainties, please refer to Amgen’s filings with the US Securities and Exchange Commission.

The iPlanner is available as a mobile app (available for Apple and Android devices) and as an online version. Conveniently, both versions automatically sync, so an itinerary you build on your computer will be available to you onsite at the meeting via your mobile device. The iPlanner also offers an additional exciting feature, new this year: the ability to claim continuing medical education (CME) credit while in a session. Browse and download abstracts of interest from the Annual Meeting Proceedings Part I, available in several digital formats. This publication will be available after the May 14 abstract launch at 5:00 PM (EDT) via abstracts.asco.org. It can be downloaded as a PDF (with a by track or full download option) or as an ePub file (for iPads and Nooks). Review articles written by Annual

Help Your Patients Learn About Collecting Family Cancer History

ased on ASCO’s recent recommendations, Cancer.Net has provided your patients with an article and an infographic on the importance of collecting family cancer history, what information to collect, what it can mean, and when and with whom to share this information. Direct your patients to www.cancer.net/familyhistory for these materials and ASCO’s Cancer Family History questionnaire. n

ASCOPost.com | MAY 1, 2014

PAGE 29

Direct From ASCO Meeting faculty in the ASCO Educational Book. This peer-reviewed publication highlights standards of care and offers insight into future therapeutic possibilities in oncology. It is searchable by author, topic, title, track, or keyword. Download the ASCO Educational Book as a PDF (with a by track or full download option), ePub file (for iPads and Nooks), or mobi file (for Kindles).

Stay Up to Date During the Annual Meeting The online Attendee Resource Center also offers a host of resources that will streamline and enhance your Annual Meeting experience once you arrive in Chicago. Access videos and podcasts, find shuttle schedules, easily locate exhibitors, and read editions of the ASCO Daily News—all on the go. Virtual Meeting resources are also available through the Attendee ReClaim CME credit and submit MOC requests through the Annual Meeting iPlanner.

source Center, equipping you with the ability to revisit favorite sessions or those you missed. While in a session, log in to the Attendee Resource Center to request Certificates of Attendance and submit Continuing Medical Education (CME) and Maintenance of Certification (MOC) requests.

nation. After successful completion of the postexamination, participants will be eligible to claim 10 MOC points in SelfAssessment of Medical Knowledge. The Maintenance of Certification and Lifelong Learning Workshop is a The registration deadline for the Core Session MOC Self-Assessment Activity is May 16, 2014.

Earn MOC Credit at the Annual Meeting With the recent changes to the American Board of Internal Medicine (ABIM) MOC requirements, ASCO recognizes it is more important than ever to provide opportunities to earn points more frequently. The 2014 Annual Meeting will feature two activities to help attendees earn MOC points while onsite at the meeting. The Annual Meeting Core Session MOC Self-Assessment Activity is designed for attendees who want to refresh their knowledge, update their skills, or prepare for their board certification or MOC examination. Registrants will complete a pre-examination to identify areas of educational need, receive a list of suggested Core Education Sessions to attend to fill knowledge gaps, and assess their improvement with an online postexami-

3.5-hour interactive session that will use audience response technology to review one ABIM medical oncology self-evaluation program module. Each of the module’s 30 multiple-choice questions will be reviewed through detailed group discussion led by expert faculty. At the completion of the session, diplomates will be able to submit their answers to the ABIM for MOC credit. Registration for this session is open to all meeting attendees; however, those enrolled in the ABIM Maintenance of Certification process will receive first priority. The Maintenance of Certification and Lifelong Learning session will

take place on Friday, May 30, from 1:00 to 4:30 PM and will utilize the ABIM 2013 Update in Medical Oncology module. Visit am.asco.org, select “Registration and Hotel Information,” then “Maintenance of Certification” in the left navigation bar to learn more about these opportunities. And don’t forget that you can claim CME credit and submit MOC requests during and after the meeting via the mobile or online versions of the iPlanner.

Review Supplementary Products at the ASCO University Bookstore Plan to stop by the ASCO University Bookstore during the meeting to try new ASCO products, find the latest titles, and receive technical help from ASCO staff. The bookstore, which will be located in both the Oncology Professionals Hall and Concierge Services, features product demonstrations by expert staff, who will showcase ASCO University’s suite of products, including the Oncology Slide Library and the newest edition of ASCO-SEP®, featuring all-new self-assessment questions, an Online continued on page 31

ASCO Urges CMS to Require Medicare Advantage Coverage for Clinical Trials

ASCO Releases Quality Assessment Tool for Community-Based Research Sites

SCO and 20 other organizations representing people impacted by serious or life-threatening diseases, specialty providers, and research professionals are urging the Centers for Medicare & Medicaid Services (CMS) to correct a long-standing inequity in Medicare coverage by requiring that Medicare Advantage plans provide coverage for clinical trials. CMS policy currently requires individuals in Medicare Advantage plans to relinquish their Medicare Advantage coverage and revert to standard fee-forservice Medicare if they wish to participate in a clinical trial. The policy is confusing and may deter Medicare Advantage enrollees from participating in a clinical trial, according to the letter. Medicare Advantage enrollees typically chose these plans because they involve lower costs than fee-for-service coverage and provide more comprehensive coverage. Medicare Advantage

enrollees, while participating in a clinical trial under the fee-for-service reimbursement, are required to cover all deductibles, copays, and the 20% coinsurance for all charges associated with clinical trial care. “Without the cost-saving potential of [Medicare Advantage] coverage, the current policy could not only discourage [Medicare Advantage] enrollees from choosing clinical trials but also exacerbate health care disparities,” the organizations wrote. “This issue is of particular concern to us because of our eagerness to ensure access and participation of underserved populations in clinical trials,” which is also of concern to the National Institutes of Health, the National Cancer Institute, and the Food and Drug Administration. n © 2014. American Society of Clinical Oncology. All rights reserved.

SCO’s Community Research Forum has released the ASCO Research Program Quality Assessment Tool, designed to help communitybased practices to assess their research programs.

Quality Components The new tool provides an overview of important components of an internal quality assessment program as well as a checklist to help sites conduct an assessment of whether their program includes these components. These quality components are largely based on the 2008 ASCO Statement on Minimum Standards and Exemplary Attributes of Clinical Trial Sites, reported by Zon et al in the Journal of Clinical Oncology. “Community-based practices that do clinical research sites are responsible for assuring that research is conducted with

a high level of quality,” said Nicholas J. Robert, MD, Chair of ASCO’s Community Research Forum. “This new tool will help community-based investigators establish and conduct an internal process for assessing the quality of their research programs.” To access the Quality Assessment Tool, please go to: www.asco.org/practiceresearch/asco-research-program-qualityassessment-tool-contact-information. n © 2014. American Society of Clinical Oncology. All rights reserved. Questions or comments about the tool should be sent to: ASCO Community Research Forum c/o Patricia Hurley American Society of Clinical Oncology 2318 Mill Road, Suite 800 Alexandria, VA 22314

The ASCO Post | MAY 1, 2014

PAGE 30

Direct From ASCO

ASCO Rolls Out Support for Changes in Maintenance of Certification Requirements

ig changes came to the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program requirements in 2014. As of January 1, all diplomates, including “grandfathers” (or those certified before 1990 who are “board-certified for life”), must actively participate in MOC activities in order to be listed as “Meeting MOC Requirements” on the ABIM website. According to ABIM, the new requirements were designed to increase the relevancy of the credential in an environment where there is growing recognition that the field of medicine is rapidly evolv-

To earn practice assessment points, members who are currently participating in ASCO’s Quality Oncology Practice Initiative (QOPI®) program can refer

to the practice’s QOPI data report and select three measures to report to the ABIM using the ABIM’s Self-Directed Performance Improvement Module. The

ABIM site will prompt the oncologist to select one measure for improvement, and request specific information regarding planned improvement efforts.

Jamie H. Von Roenn, MD

ing and assessment of medical knowledge every 10 years is not sufficient. “For grandfathers, their ABIM certification persists, but on the ABIM webpage it will say that they are not participating in MOC requirements,” said Jamie H. Von Roenn, MD, Senior Director of Education, Science, and Professional Development at ASCO. “In the future, this Meeting MOC Requirements status will likely be tied to academic status, appointments at hospitals, and insurance payments.” Some of the specific milestones among the new requirements are participation in some MOC activity every 2 years, earning 100 MOC points every 5 years, including 20 in practice assessment and 20 in medical knowledge, and passing a secure MOC exam every 10 years.

New MOC Resources ASCO is rolling out a series of new MOC-approved, oncology-focused products to assist its members as they begin to tackle these new requirements. Members can visit ASCO University to earn medical knowledge points by completing any of a series of ASCOdeveloped medical knowledge courses worth 10 MOC points each, including courses on Palliative Care, Geriatric Oncology, Ethics, and Comprehensive Oncology. Nine additional courses on a variety of cancer topics are scheduled for release later in 2014.

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | MAY 1, 2014

PAGE 31

Direct From ASCO New Sessions at the Annual Meeting Members can also earn MOC points by participating in two sessions at the 2014 ASCO Annual Meeting (registration required). The Maintenance of Certification and Lifelong Learning Workshop is a 3.5-hour interactive ses-

sion that will use audience-response technology to review an ABIM medical oncology SEP module. After the session, ABIM diplomates can submit their answers for MOC credit. Members can also participate in the Core Session MOC Self-Assessment Activity. Members will complete a premeet-

ing test, and based on their responses to the questions, ASCO will recommend sessions to attend to fill in any knowledge gaps. Members then complete a post-test to document that the knowledge gaps have been filled in order to claim MOC credit. According to Dr. Von Roenn,

ASCO plans to make MOC points available in the future for attending its other specialty specific meetings such as the Breast Cancer Symposium, Quality Care Symposium, Genitourinary Cancers Symposium, and the Gastrointestinal Cancers Symposium. “ASCO is going to be developing more and more innovative ways to help members meet MOC credit requirements through activities that they already participate in,” said Dr. Von Roenn. “We want these to be time efficient so that members can earn credits, for example, answering daily education questions while standing at the elevator or on hold for a phone call. We want to streamline this process so that people can stay up to date.” For full information on the ABIM MOC changes, visit moc2014.abim.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

Attendee Resources continued from page 29

Question Bank, an eBook component, and ASCO Flashcards—a new app to help you test your knowledge.

View Videos and Podcasts of Presentations via Virtual Meeting

Advertisement not displayed in digital edition at advertiser’s request

Onsite or at your computer, you have access to the Virtual Meeting. The Virtual Meeting and its companion product, the ASCO iMeeting app, provide video and podcast access to completed meeting presentations. You’re able to access meeting presentations in a variety of convenient ways: • Personal computer. View presentations via streaming video. Search presentations by session title, author, or track. • Podcast. Download audio from your selected presentations to your handheld device. Pick and choose the presentations you want to hear at your convenience. • Mobile devices. A mobile-friendly site (meetinglibrary.asco.org/vm) is available for accessing Virtual Meeting on smartphones or other webenabled devices. • ASCO iMeeting app for iPad. Stream meeting presentations and save videos for offline viewing on this iPad app. The app will be available to iPad users later this month. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | MAY 1, 2014

PAGE 32

JCO Spotlight Gynecologic Oncology

AURELIA Trial: Adding Bevacizumab to Chemotherapy Improves Outcomes in Platinum-Resistant Recurrent Ovarian Cancer By Matthew Stenger

ingle-agent chemotherapy is standard in platinum-resistant ovarian cancer. In the open-label phase III AURELIA trial reported in the Journal of Clinical Oncology, Eric PujadeLauraine, MD, PhD, of Université Paris Descartes, and colleagues found that the addition of bevacizumab (Avastin) to chemotherapy resulted in signifi-

Patients were stratified according to selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. Crossover to single-agent bevacizumab was permitted after disease progression in patients in the chemotherapy-alone group. The bevacizumab/chemotherapy and chemotherapy-alone groups were

On the basis of the statistically significantly improved [progressionfree survival], together with response rate and safety results, bevacizumab combined with chemotherapy should be considered a standard option in platinum-resistant ovarian cancer. —Eric Pujade-Lauraine, MD, PhD, and colleagues

cant improvement in progression-free survival, the primary study endpoint, and objective response rate in patients with platinum-resistant ovarian cancer.1 However, no significant difference in overall survival was observed.

Study Details In the trial, investigators selected chemotherapy consisting of pegylated liposomal doxorubicin at 40 mg/m2 on day 1 every 4 weeks (n = 126), paclitaxel at 80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (n = 115), or topotecan at 4 mg/m2 on days 1, 8, and 15 every 4 weeks or 1.25 mg/m2 on days 1 to 5 every 3 weeks (n = 120) for women with measurable/assessable ovarian cancer that had progressed within 6 months of completing platinum-based therapy. Recruitment was capped for each chemotherapy cohort, with the doxorubicin cohort being the first to be fully recruited, in October 2010, and recruitment to the paclitaxel and topotecan cohorts being completed in April 2011. Once chemotherapy was selected, patients were randomly assigned to receive chemotherapy alone (n = 182) or with bevacizumab (n = 179) at 10 mg/ kg every 2 weeks or at 15 mg/kg every 3 weeks in patients receiving topotecan on the every-3-week schedule. Patients with refractory disease or a history of bowel obstruction as well as those who had received more than two prior anticancer regimens were ineligible.

generally balanced for age (median, 62 and 61 years), ovary as origin of cancer (93% and 86%), histology (serous/adenocarcinoma in 87% and 84%, endometrioid in 5% in both, clear cell in 2% and 7%), histologic grade (1 in 6% and 5%, 2 in 30% and 26%, 3 in 53% and 58%), prior antiangiogenic therapy (7% and 8%), receipt of two prior chemotherapy regimens (40% and 43%), platinumfree interval less than 3 months (28% and 25%), Eastern Cooperative Oncology Group performance status (0 in 60% and 54%, 1 in 32% and 38%, 2 in 7% and 6%), measurable disease (80% and 79%), and presence of ascites (33% and 30%).

Improved Progression-Free Survival Median follow-up was 13.0 months in the bevacizumab/chemotherapy group and 13.9 months in the chemotherapy-alone group. Median progression-free survival by RECIST criteria was 6.7 vs 3.4 months (hazard ratio [HR] = 0.48, P < .001, on unstratified log-rank test; HR = 0.42, P < .001, on stratified log-rank test). The progression-free survival benefit was consistent across all subgroups evaluated.

Response Rate and Overall Survival Response was evaluable by RECIST or Gynecologic Cancer Intergroup cancer antigen (GCIC CA)-125 criteria in

350 patients. Objective response rates were 30.9% in the combination group and 12.6% in the chemotherapy-alone group (P < .001), including 27.3% vs 11.8% on RECIST (n = 287; P = .001) and 31.8% vs 11.6% on GCIG CA-125 criteria (n = 297; P < .001). At the time of data cutoff for the final overall survival analysis, 40% of patients in the chemotherapy-alone group had received single-agent bevacizumab after progression. Median overall survival was 16.6 months in the bevacizumab/chemotherapy group and 13.3 months in the chemotherapy-alone group (HR = 0.85, P = .174). Among patients with ascites at baseline, paracentesis was performed in 17% of those in the chemotherapy-alone group and in 2% of those in the bevacizumab/chemotherapy group (one patient, who received paracentesis on the first day of bevacizumab treatment).

Adverse Events Adverse events of special interest with regard to bevacizumab occurred in 57.0% of the bevacizumab/chemotherapy group vs 40.3% of the chemotherapy-alone group, including grade ≥ 2 hypertension (20% vs 7%), gastrointestinal (GI) perforation (2% vs 0%), and fistula/abscess (2% vs 0%). Grade ≥ 3 adverse events included hypertension (7% vs 1%), proteinuria (2% vs 0%), GI perforation (2% vs 0%), thromboembolic events (5% vs 4%), fistula/abscess (1% vs 0%), and reversible posterior leukoencephalopathy syndrome (1% vs 0%). Rates of grade ≥ 3 bleeding (1% in both) and congestive heart failure (1% in both) were identical in the two groups, and no cases of wound healing complications or other cardiac disorders were ob-

served in either group. Among other grade ≥ 3 adverse events, the frequency of neutropenia was similar in both groups, and leukopenia and events potentially related to tumor burden, such as fatigue, abdominal pain, vomiting and dyspnea, were more common in the chemotherapy-alone group. Hand-foot syndrome and peripheral sensory neuropathy were more common in the bevacizumab/chemotherapy group, likely reflecting the longer exposure to chemotherapy in this group associated with prolonged time to progression. Five deaths (2.8% of patients) in each group were considered to be not primarily due to progressive disease, including death due to infection with neutropenia, GI hemorrhage, GI perforation, cardiac arrest, and shock in the bevacizumab/ chemotherapy group and to infection with neutropenia, cardiac failure, septic shock, peritonitis, and GI hemorrhage in the chemotherapy-alone group. Dr. Pujade-Lauraine and colleagues concluded: Adding bevacizumab to chemotherapy statistically significantly improved [progression-free survival] and [objective response rate]; the [overall survival] trend was not significant. No new safety signals were observed…. AURELIA is the first trial to our knowledge demonstrating a significant [progression-free survival] benefit of either a combination regimen or a biologic agent in platinum-resistant ovarian cancer. On the basis of the statistically significantly improved [progression-free survival], together with response rate and safety results, bevacizumab combined with chemotherapy should be considered a standard option in platinum-resistant ovarian cancer.

Bevacizumab/Chemotherapy in Ovarian Cancer ■■ The addition of bevacizumab significantly improved progression-free survival and objective response rate in patients with platinum-resistant ovarian cancer. ■■ At the time of overall survival analysis, 40% of patients in the chemotherapy group had crossed over to single-agent bevacizumab; no difference in overall survival was observed between groups. ■■ Bevacizumab/chemotherapy was associated with significant improvements in abdominal/gastrointestinal symptoms, overall symptoms, and general health/quality-of-life measures. ■■ Bevacizumab/chemotherapy may constitute an option in selected patients with platinum-resistant disease.

ASCOPost.com | MAY 1, 2014

PAGE 33

JCO Spotlight Patient-Reported Outcomes A patient-reported outcomes analysis in the trial, reported separately in the Journal of Clinical Oncology by Martin R. Stockler, MD, of The University of Sydney, and colleagues, showed significant improvement in abdominal/ GI symptoms with the bevacizumab/ chemotherapy regimen, as well as significant improvement in other symptoms and global health/quality-of-life measures.2 A prespecified secondary endpoint in AURELIA, patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Core Quality of Life Ques-

tionnaire C30 (EORTC QLQ-C30), EORTC QLQ-Ovarian Cancer Module 28 (EORTC QLQ-OV28), and the Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index (FOSI) at baseline and every two to three cycles (8/9 weeks) until disease progression. The primary hypothesis was that a greater proportion of patients in the bevacizumab/chemotherapy group would achieve absolute improvement of ≥ 15% (≥ 15 points) on the QLQOV28 abdominal/GI symptom subscale (items 31–36) at week 8/9. Patients with missing week 8/9 questionnaires were included as unimproved. Questionnaires from all as-

sessments through disease progression were analyzed using a linear mixedmodel repeated-measures analysis of patient-reported outcomes as continuous variables. Baseline questionnaires were completed by 155 patients in the bevacizumab/chemotherapy group and 162 in the chemotherapy-alone group (87.8% of all patients). Questionnaires were completed at week 8/9 by 122 patients (78.8%) and 84 patients (51.9%), respectively. There were no marked differences in baseline characteristics between patients evaluable for patient-reported outcomes and the intent-to-treat population, and mean scores for each

patient-reported outcome scale were similar in the two treatment groups.

Abdominal/GI Symptoms At week 8/9, a ≥ 15% improvement in abdominal/GI symptoms on the EORTC QLQ-OV28 was reported by 21.9% of patients in the bevacizumab/ chemotherapy group vs 9.3% patients in the chemotherapy-alone group (difference = 12.7%, P = .002). Sensitivity analyses, including analysis with improvement defined as a ≥ 10% increase, yielded similar results. Analysis excluding all patients with questionnaires missing at week 8/9, to continued on page 37

EXPERT POINT OF VIEW

n an editorial accompanying publication of the AURELIA study results, Joyce F. Liu, MD, MPH, of Dana-Farber Cancer Institute, and Stephen A. Cannistra, MD, of Beth Israel Deaconess Medical Center, Boston, considered the implications of the benefits observed in the trial and limitations in interpretation of the findings.1 These authors voiced support for consideration of the bevacizumab/chemotherapy regimen in selected patients with platinumresistant disease. Drs. Liu and Cannistra pointed out that AURELIA is the fourth randomized phase III study of bevacizumab (Avastin) in ovarian cancer; the GOG 218 and ICON7 trials assessed bevacizumab/chemotherapy followed by bevacizumab maintenance in newly diagnosed ovarian cancer, and the OCEANS trial evaluated bevacizumab plus carboplatin/ gemcitabine followed by bevacizumab maintenance in platinum-sensitive recurrent disease.

Consistent Improvement in Progression-Free Survival All four studies have shown a significant improvement in progressionfree survival with the addition of bevacizumab, with the magnitude of improvement being remarkably consistent, given the different settings in which the combination has been evaluated. The OCEANS trial also showed a significant improvement in objective response rate. However, none of the studies has shown an overall survival benefit. AURELIA raised no new safety issues for bevacizumab/chemotherapy combinations.

The commentators noted that AURELIA is the first of the bevacizumab combination studies to show an improvement in abdominal/gastrointestinal symptoms and other patient-reported outcomes. The GOG 218 and ICON7 studies incorporating bevacizumab into first-line treatment and maintenance showed either no improvement (GOG 218) or a slight worsening (ICON 7) of patient-reported outcomes, and patient-reported outcomes were not examined in OCEANS. As stated by Drs. Liu and Can-

Interpreting Findings Potential problems in interpreting the findings of AURELIA, according to the commentators, include the possibility of bias in the progression-free survival endpoint due to the open-label design of the trial and the absence of a placebo control, particularly since the study allowed for crossover to bevacizumab in progressing chemotherapy patients. Crossover also likely affected the ability to detect any overall survival difference, with 40% of the chemotherapy-alone group receiv-

AURELIA raises the possibility that an improvement in [patientreported outcomes], taken together with an improvement in both [progression-free survival] and [objective response rate], might be sufficient to justify the acceptance of a new regimen in a disease setting in which palliation is an important goal. —Joyce F. Liu, MD, MPH, and Stephen A. Cannistra, MD

nistra, “In the setting of platinumresistant ovarian cancer, in which therapy is palliative, improvement in [patient-reported outcomes] is of potential importance even in the absence of an [overall survival] benefit.”

ing subsequent bevacizumab at the time of overall survival analysis. The commentators noted that the overall survival findings in the trial raise the possibility that using bevacizumab sequentially as monotherapy after progression on chemotherapy alone

might yield equivalent overall survival compared with concomitant combined therapy in this disease setting. The open-label design may have also influenced the patient-reported outcome endpoints, since patients were aware of whether or not they were receiving bevacizumab and may have unintentionally reported better patient-reported outcomes consistent with an expectation that the bevacizumab/chemotherapy regimen was a more effective treatment.

Progression and PatientReported Outcomes Finally, an important difficulty in interpreting patient-reported outcomes derives from the imbalance in the proportions of patients in the two groups who completed assessments at week 8/9. A greater proportion of patients in the bevacizumab group completed assessments, reflecting the lower rate of progression in this group. In the trial, patients with missing patient-reported outcomes data were scored as patient-reported outcome nonresponders, on the assumption that patients with disease progression did not experience improvements in patient-reported outcomes. As noted by the commentators, this assumption may not have been valid for some patients, who might have experienced improvement in patient-reported outcomes related to such factors as corticosteroid antiemetic treatment during chemotherapy or more effective pain management. The editorialists stated: Taking this into account, it is possible continued on page 38

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

ASCOPost.com | MAY 1, 2014

PAGE 37

JCO Spotlight AURELIA Trial continued from page 33

a large degree reflecting patients with early progressive disease, showed a smaller, nonsignificant effect size for bevacizumab/chemotherapy vs chemotherapy alone (27.9% vs 17.9%, difference = 10.0%, P = .13). Subgroup analyses among 233 patients with sufficient symptoms at baseline (score ≥ 15) to al-

of-life subscales (24.4% vs 13.0%, P = .011), with a nonsignificantly greater proportion having improvement on the emotional function subscale (23.8% vs 15.5%, P = .072). When patients with missing questionnaires at week 8/9 were excluded from analysis, only the difference on the physical function subscale remained significant (P = .006). The mixed-mod-

The results of these prespecified [quality-of-life] analyses indicate that the benefits of bevacizumab in AURELIA extended beyond the prolongation of [progression-free survival] to include greater improvements in abdominal/GI symptoms and other aspects of [quality of life]… —Martin R. Stockler, MD, and colleagues

Advertisement not displayed in digital edition at advertiser’s request

low detectable improvement (29.6% vs 12.7%, P = .002) and among 99 patients with ascites at baseline (44.0% vs 4.1%, P < .001) also showed improved outcome with bevacizumab/chemotherapy, as did analysis at week 16/18 among all patients (15.5% vs 5.6%, P = .005). The mixed-model repeated-measures analysis of score as a continuous variable showed a difference of 6.4 points favoring the bevacizumab/chemotherapy group (P = .015).

Overall Symptoms and Quality of Life With regard to secondary endpoints, significantly greater proportions of bevacizumab/chemotherapy patients had ≥ 15% improvement in FOSI score (≥ 5 point increase) at week 8/9 among all patients (12.2% vs 3.1%, P = .003), among a subgroup of 267 with sufficient symptoms at baseline (score < 27) to allow detectable improvement (14.6% vs 3.6%, P = .002), among the subgroup of 99 with ascites at baseline (21.6% vs 2.1%, P = .004), as well as at week 16/18 among all patients (9.0% vs 1.3%, P = .002). Mixedmodel repeated-measures analysis did not show important treatment effects either overall or at week 8/9 (betweengroup difference = 0.7, P = .21). For the QLQ-C30 findings at week 8/9, significantly greater proportions of bevacizumab/chemotherapy patients had ≥ 15% improvement on the physical function (12.0% vs 1.8%, P < .001), role function (22.2% vs 10.0%, P = .003), social function (22.7% vs 12.6%, P = .020), and global health status/quality-

el repeated-measures analysis of the global health/quality-of-life subscale showed no significant difference between treatment groups. Dr. Stockler and colleagues concluded: Bevacizumab increased the proportion of patients achieving a 15% improvement in patient-reported abdominal/ gastrointestinal symptoms during chemotherapy for platinum-resistant ovarian cancer…. The results of these prespecified [quality-of-life] analyses indicate that the benefits of bevacizumab in AURELIA extended beyond the prolongation of [progression-free survival] to include greater improvements in abdominal/GI symptoms and other aspects of [quality of life], supporting a role for bevacizumab with chemotherapy in the treatment of women with platinum-resistant ovarian cancer. n Disclosure: The AURELIA study was sponsored by F. Hoffmann-La Roche. For full disclosures of the study authors, visit jco. ascopubs.org.

References 1. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. March 17, 2014 (early release online). 2. Stockler MR, Hilpert F, Friedlander M, et al: Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol. March 31, 2014 (early release online).

The ASCO Post | MAY 1, 2014

PAGE 38

JCO Spotlight

Joyce F. Liu, MD, MPH Stephen A. Cannistra, MD continued from page 33

that the greater percentage of patients with missing data in the control arm might bias the [patient-reported outcome] results in favor of the bevacizumab group, essentially rendering [patient-reported outcome] assessment a surrogate of disease progression as opposed to a pure metric of symptom improvement. In this regard, it is interesting that by excluding missing data from the [patient-reported outcome] analysis, the effect size in [patient-reported outcome] benefit between the bevacizumabcontaining arm and the chemotherapy-alone arm decreased and became nonstatistically significant.

They also noted, however, that differences in patient-reported outcomes still favored bevacizumab/ chemotherapy, albeit nonsignificantly, when patients with missing patient-reported outcomes data were

excluded from the analysis. This finding suggests that improvement in patient-reported outcomes can be expected with the addition of bevacizumab to chemotherapy in the platinum-resistant setting.

Option in Selected Patients As to whether the findings in AURELIA support use of bevacizumab/ chemotherapy as a new standard of care in the platinum-resistant setting, the commentators observed that the combined improvements in patientreported outcome, progression-free survival, and objective response rate make it hard to ignore the possibility that such treatment could benefit appropriately selected patients. They noted, however, that patient selection would have to reflect the eligibility criteria of the trial, which excluded patients with more than two prior lines of chemotherapy and those with platinum-refractory disease. Given the risk of bowel perforation with bevacizumab observed in

other trials, it also excluded patients with history of bowel obstruction, clinical signs of bowel obstruction, or evidence of bowel involvement on computed tomography. With regard to this latter consideration, they stated, “Thus, those patients with the greatest need for symptom improvement and response, and who therefore might derive the greatest benefit from a bevacizumab-containing combination, might also be the ones who are at greatest risk for serious toxicity.” Treatment options for patients with platinum-resistant disease are suboptimal. In acknowledgment of this situation—and notwithstanding the limitations in use and absence of evidence of overall survival improvement with the regimen—the commentators concluded that there is potentially a role for bevacizumab/chemotherapy in this setting. They stated: …AURELIA raises the possibility that an improvement in [patientreported outcomes], taken together

with an improvement in both [progression-free survival] and [objective response rate], might be sufficient to justify the acceptance of a new regimen in a disease setting in which palliation is an important goal. In our view, it is not unreasonable to consider such evidence supportive of a role for the chemotherapy plus bevacizumab combination in carefully selected patients with symptomatic, platinum-resistant disease, at the same time recognizing that the data to support a [patient-reported outcomes] benefit are suggestive rather than definitive.” n Disclosure: Dr. Liu has received research funding from Genentech. Dr. Cannistra reported no potential conflicts of interest.

Reference 1. Liu JF, Cannistra SA: Emerging role for bevacizumab in combination with chemotherapy for patients with platinum-resistant ovarian cancer [editorial]. J Clin Oncol. March 24, 2014 (early release online).

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

José Baselga, MD, PhD, on the PALOMA-1 Trial in Metastatic Breast Cancer see page 3

Kenneth C. Anderson, MD, on Drugs in Development for Multiple Myeloma see page 14

Mario Sznol, MD, on PD-L1 as a Biomarker see page 5

Thomas J. Herzog, MD, on Velaparib in Resistant Ovarian Cancers see page 26

William Cliby, MD, Matthew A. Powell, MD, and David M. O’Malley, MD, on Gynecologic Cancer Treatment at High-Volume Centers see page 20

Joyce F. Liu, MD, MPH, and Stephen A. Cannistra, MD, on the AURELIA Trial in Ovarian Cancer see page 33

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MAY 1, 2014

PAGE 39

Psychosocial Oncology

American Psychosocial Oncology Society Launches Psychosocial Distress Program By Jo Cavallo

n February, the American Psychosocial Oncology Society (APOS) held its 11th Annual Conference in Tampa, Florida, and it marked a number of firsts. With over 500 registrants and more than 300 abstracts presented over the 3-day program, this was the largest APOS event to date. The theme of this year’s conference was Implementing Quality Care Standards for Psychosocial Oncology and Supportive Care. Highlighting the conference was the keynote address by Carolyn D. Runowicz, MD, Executive Associate Dean for Academic Affairs and Professor of Obstetrics and Gynecology at the Herbert Wertheim College of Medicine at Florida International University, University Park, and a

Carolyn D. Runowicz, MD

Mark Lazenby, PhD, APRN, FAPOS

member of ASCO’s Board of Directors. Dr. Runowicz addressed ASCO’s proposed response to the Institute of Medicine’s report, The Learning Health Care System in America, and presented details on CancerLinQ™, ASCO’s rapid-learning health information technology initiative, which will provide oncologists with the tools necessary to achieve high-quality, high-value can-

cer care with better outcomes for their patients. She also told the audience about how CancerLinQ can be used to screen patients with cancer for psychological stress. “Dr. Runowicz talked about how CancerLinQ can be a tool that APOS and psycho-oncologists can use to implement our quality care standards, particularly in screening patients for psychosocial distress, as well as a resource for real-time quality improvement research,” said Mark Lazenby, PhD, APRN, FAPOS, APOS Conference Chair and Assistant Professor of Nursing at Yale University School of Nursing, Orange, Connecticut. “That information was really exciting for us to hear.”

with a 1-day workshop held at the APOS Annual Conference and continues with videoconferences with experts in psycho-oncology every 3 months. The second year of the program includes an advanced 1-day workshop at

Screening Program Launch

the APOS conference and two videoconferences throughout the year. The NCI grant covers the full tuition of the program for each participant, which includes the 1-day workshop held the day before the APOS Annual Conference, the registration fee to attend the APOS Annual Conference, and a $400 stipend to help defray costs for attending the workshop and conference. “We had been trying to get the NCI grant for over 5 years, and we are so pleased to finally have the funding to launch this program,” said Ruth McCorkle, PhD, FAAN, FAPOS, Florence Schorske Wald Professor of

This year’s conference also marked the launch of the Screening for Psychosocial Distress Program, a joint venture between APOS and the Yale University School of Nursing. Funded for 5 years by a grant from the National Cancer Institute (NCI), the 2-year educational program aims to prepare cancer care professionals in the development and implementation of a comprehensive distress-screening instrument to help determine patients’ levels of distress or depression. The program includes assessment of patients for the sources of their distress, linking of patients and family members to psychosocial services, follow-up on referrals to psychosocial health-care resources, and use of ASCO’s Quality Oncology Practice Initiative (QOPI®) to measure the program’s effectiveness. Two people from a cancer care facility or private practice in any discipline—including oncologists, nurses, chaplains, psychiatrists, psychologists, and social workers— can receive the training.

How the Program Works The first year of the Screening for Psychosocial Distress Program begins

Nursing and Professor of Epidemiology at Yale University. At the inaugural workshop, the 39 oncology professionals accepted into the program represented cancer care facilities nationwide that serve a di-

We had been trying to get the NCI grant for over 5 years, and we are so pleased to finally have the funding to launch this program. —Ruth McCorkle, PhD, FAAN, FAPOS

Save the Date

The American Psychosocial Oncology Society’s 12 Annual Conference will be held jointly with the International Psycho-Oncology Society’s 17th World Congress of PsychoOncology in Washington, DC, from July 28 through August 1, 2015. The theme of the conference is From National to Global: Implementing the Standard of Psychosocial Care in Oncology.

verse population. “What is really interesting to me is that the facilities we accepted serve 13% of black or African Americans and 73% of Caucasian patients, and that mirrors the racial breakdown in the general population of the United States, so we were very pleased with that demographic,” said Dr. Lazenby. “Program participants came from urban, suburban, and rural parts of the country, and that was important, too, because we need to see how the program will work in different contexts and geographic locations.”

Applying for the Program The next workshop of the Screening for Psychosocial Distress Program will be held in Washington, DC, on July 29, 2015, prior to the start of the joint APOS 12th Annual Conference and the International Psycho-Oncology Society’s 17th World Congress. Applications for the 2015 workshop will be accepted in September 2014. To learn more about the program and receive notification when applications become available, go to http://apossociety.org/screening. n Disclosure: Drs. Runowicz, Lazenby, and McCorkle reported no potential conflicts of interest.

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

NOW ENROLLING – A RANDOMIZED PHASE III STUDY

A phase III study of the CDK4/6 inhibitor LEE011 in combination with letrozole for the treatment of postmenopausal women with advanced breast cancer Screening assessments

Postmenopausal women with HR+/HER2– advanced breast cancer No prior systemic anticancer therapy for advanced disease

Randomization (1:1)

ECOG performance status 0 or 1 Additional inclusion/exclusion criteria apply.

Letrozole 2.5 mg QD + LEE011 600 mg QD

For more information • Contact your local Novartis medical representative • Call Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (US only)

Letrozole 2.5 mg QD + placebo QD

Primary end point: Progression-free survival Key secondary end point: Overall survival

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; QD, once daily.

• Visit www.clinicaltrials.gov (NCT01958021)

LEE011 is an investigational drug. Efficacy and safety have not been established. There is no guarantee that LEE011 will become commercially available. MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.

Novartis Pharma AG CH-4002 Basel, Switzerland

March 2014

G-PIP-1084431

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

ASCOPost.com | MAY 1, 2014

PAGE 41

Palliative Care in Oncology Bringing the Humanistic Approach to Palliative Care: From Diagnosis and Throughout Disease Course A Conversation With Teresa A. Gilewski, MD By Jo Cavallo

or much of her career in oncology, Teresa A. Gilewski, MD, has sought to bridge the science of medicine with the humanistic aspect of care. She has created the Art of Medicine lecture series at Memorial Sloan Kettering Cancer Center in New York, where she is a medical oncologist on the Breast Cancer Service in the Department of Medicine. Dr. Gilewski has also written, produced, and directed four films focusing on humanistic care, including The Physician as the Patient, which was shown at ASCO’s Annual Meeting in 2007. At this year’s ASCO Annual Meeting, Dr. Gilewski will convene the event’s first Humanism in Medicine book club. The book featured for dis-

treatment or their cancer at any stage of their disease, physicians will palliate these symptoms. So palliative care is really a continuous approach to care throughout a patient’s illness. Palliative care includes not only the use of drugs, but also interactions with patients that may focus more on the humanistic side of care. For example, one of my colleagues who has been ill noted that he searched for a physician who was “in it for him.” He wanted a physician who would go the extra mile for him—not only someone who would try to find the best treatment for his disease, but one who would convey that he really cared about him. I think that the optimal approach to patient care is real-

If we can integrate the humanistic aspects of care into the scientific aspects of care, it is likely that both patients and physicians will benefit. Both of these components of medicine are part of a lifelong learning curve. —Teresa A. Gilewski, MD

cussion is Mountains Beyond Mountains: The Quest of Dr. Paul Farmer, A Man Who Would Cure the World by Tracy Kidder (Random House, 2003). The ASCO Post talked with Dr. Gilewski about the importance of practicing humanism in palliative care.

Integrating Science With Humanism Please describe the humanistic aspect of palliative care. I view the humanistic aspect of palliative care—and oncology care in general—as the practice of medicine that highlights the interactions between human beings. It encompasses the personal interactions between the physician and the patient, the physician and the family members, and other professional caregivers and the patient. Please explain the importance of initiating palliative care soon after a cancer diagnosis. Palliative care has historically been viewed as end-of-life care. However, if patients are experiencing symptoms such as nausea, vomiting, or pain from

ly the integration of science with these humanistic components. Part of our responsibility in the practice of medicine is to alleviate suffering—not just physical suffering, but also, at times, a broader level of suffering that may include emotional, psychological, and existential suffering. Caring for the whole patient should ideally be second nature to us, but that is often a challenge for oncologists. In addition to developing the best drug regimen, we need to identify strategies that may alleviate patients’ emotional and physical pain.

Barriers to Humanism What are some of the barriers to practicing humanism in oncology? There are many. First, there is the perception that being humanistic requires a lot of time. While on occasion that may be true, for some patients it may only take a few minutes to convey a sincere interest in their well-being. A patient’s daughter once told me that when her mother visits the doctor, the usual initial question is, “How are you feeling?” But it is the next couple of questions the doctor asks, “How was

your weekend? How are your grandchildren?” that actually mean the most to her mother. Those few inquiries about a patient’s life express a concern about the patient as a human being and are viewed very positively. Also, the business of medicine today does not really encourage physicians to focus on the humanistic aspects of care. It’s relatively easy to submit a bill for reimbursement of chemotherapy or for a procedure. It’s much more difficult to get reimbursed for the humanistic aspects of care. Another major challenge is overcoming a level of professional discomfort, because the humanistic approach to medicine thus far is often not evidenced-based or easily measureable. There is also discomfort on a personal level, because some oncologists may feel that this humanistic component of medicine chips away at the protective mechanism they’ve put in place and could result in a huge emotional toll. Moreover, sometimes physicians just might be having a “bad day,” and they may fall short of their best intentions. It is challenging to achieve a balance between these humanistic elements and the day-to-day practice of medicine, but we can’t view humanism as an all-or-nothing approach to care. We learn such a tremendous amount from patients—and not just about science. There are so many profound moments in our interactions with patients that may really impact on how we perceive life in general and how we face our own mortality. As physicians, we are so privileged to have the opportunity to experience these interactions with patients. If we don’t allow ourselves to take advantage of these opportunities, I think we miss out on what it means to be a physician. While the science is incredibly important in determining treatment and evaluating potential outcome, these other parts of patient care, while harder to quantify, are equally important. I would even go so far as to say that at certain points in a patient’s illness, the humanistic aspects of cancer care supersede the scientific.

Greater Focus on Humanism What has to happen to make humanism a more integral part of palliative care and oncology care overall?

GUEST EDITOR

Jamie H. Von Roenn, MD

Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department. One suggestion is to include these other aspects of care in the programs for our scientific meetings. When we don’t spend time focusing on these humanistic parts of care, there is an implication that they are not as important as the scientific parts of care. One of the things we can do as a community in ASCO is to include sessions on the humanistic approach to oncology care as part of the routine agenda at the ASCO Annual Meeting. This would acknowledge that while advances in science to improve patient outcome are critical, these humanistic issues are also of significant value. If we have regular sessions on this topic, emphasis on the humanistic components of patient care may become more commonplace. Articles in the Art of Oncology section in the Journal of Clinical Oncology (jco.ascopubs.org/cgi/collection/ a007) and the Piece of My Mind section in JAMA (jama.jamanetwork.com/ collection.aspx?categoryid=5766) also provide a venue for thought-provoking insights into the challenges and experiences of patient care with an emphasis on these humanistic issues. If we can integrate the humanistic aspects of care into the scientific aspects of care, it is likely that both patients and physicians will benefit. Both of these components of medicine are part of a lifelong learning curve. n Disclosure: Dr. Gilewski reported no potential conflicts of interest.

K E Y DAT E S F O R T H E INAUGURAL

PALLIATIVE CARE IN ONCOLOGY SYMPOSIUM P a t i e n t - C e n t e re d C a re A c ro s s t h e C a n c e r C o n t i n u u m

OCTOBER 24-25, 2014 The Westin Boston Waterfront Boston, MA Early May Early May July 1 September 17

Registration and Hotel Reservations Open Abstract Submitter Opens Abstract Submission Deadline Hotel Reservation and Early Registration Deadline

PALLONC.ORG TARG E T I NG

C A NC E R

C A RE

ASCOPost.com | MAY 1, 2014

PAGE 43

Announcements

American Association for Cancer Research Inaugurates 2014 Class of Fellows

he American Association for Cancer Research (AACR) inducted the 2014 class of elected Fellows of the AACR Academy at the Association’s Annual Meeting, held recently in San Diego. The AACR Academy is an entity within the AACR that recognizes those individuals who have made exceptional contributions to cancer research and/or cancer-related biomedical science. “Our 2014 class of fellows includes a number of the most prestigious laboratory researchers and physician-scientists who have contributed enormously to the cancer field,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR.

2014 Class of Fellows of the AACR Academy • Jerry Adams, PhD, Joint Head of the Molecular Genetics of Cancer Division and Director of the Leukemia and Lymphoma Society Specialized Center of Research, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia • James P. Allison, PhD, Professor and Chair of the Department of Immunology, Director of the Immunology Platform, and Deputy Director of the David H. Koch Center for Applied Research in Genitourinary Cancers, Department of Genitourinary Research, The University of Texas MD Anderson Cancer Center, Houston, Texas • Mariano Barbacid, PhD, Professor of Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain • José Baselga, MD, PhD, Physicianin-Chief, Memorial Sloan Kettering Cancer Center, New York, N.Y. • Stephen B. Baylin, MD, Deputy Director and Associate Director for Research, Sidney Kimmel Comprehensive Cancer Center; Virginia and D.K. Ludwig Professor for Cancer Research and Medicine and Chief of the Cancer Biology Division, Johns Hopkins University School of Medicine, Baltimore. • Günter Blobel, MD, PhD, John D. Rockefeller Jr. Professor, Laboratory of Cell Biology, The Rockefeller University, New York; Investigator, Howard Hughes Medical Institute • David Botstein, PhD, Anthony B. Evnin Professor of Genomics, Princeton University, Princeton; Chief Scientific Officer, Calico, San Francisco

• Joan S. Brugge, PhD, Louise Foote Pfeiffer professor of cell biology and chair of the Department of Cell Biology, Harvard Medical School, Boston • Lewis C. Cantley, PhD, Margaret and Herman Sokol Professor and Director of the Meyer Cancer Center, Weill Cornell Medical College, affiliated with New York-Presbyterian Hospital, New York • Pierre Chambon, MD, Honorary Professor, Collège-de-France; Professor of Molecular Biology and Genetics, Institute for Advanced Study, University of Strasbourg; Group Leader, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Graffenstaden, Strasburg, France • Hans Clevers, MD, PhD, Professor in Medical Genetics, University of Utrecht; President of the Royal Netherlands Academy of Arts and Sciences, Hubrecht Institute, Utrecht, Netherlands • James E. Darnell Jr., MD, Vincent Astor Professor Emeritus and Head, Laboratory of Molecular Cell Biology, The Rockefeller University, New York • Titia de Lange, PhD, Leon Hess Professor, American Cancer Society Research Professor, and Director of the Anderson Center for Cancer Research, The Rockefeller University, New York • Vincent T. DeVita Jr., MD, Amy and Joseph Perella Professor of Medicine, Yale Cancer Center; Pprofessor of Epidemiology and Public Health, Yale Medical School, New Haven • Lawrence H. Einhorn, MD, Distinguished Professor of Medicine and Lance Armstrong Foundation Professor of Medicine, Indiana University School of Medicine, Indianapolis • Stephen J. Elledge, PhD, Gregor Mendel Professor of Genetics and Medicine, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston • Ronald M. Evans, PhD, Professor and Director of the Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology, The Salk Institute for Biological Studies, La Jolla; Investigator, Howard Hughes Medical Institute • Andrew Z. Fire, PhD, Departments of Pathology and Genetics, George

D. Smith Professor in Molecular and Genetic Medicine, Stanford University School of Medicine • Emil J. Freireich, MD, Ruth Harriet Ainsworth Chair, Distinguished Teaching Professor, Director of the Adult Leukemia Research Program, and Director of the Special Medical Education Programs, The University of Texas MD Anderson Cancer Center, Houston, Texas • Robert C. Gallo, MD, Homer and Martha Gudelsky Distinguished Professor of Medicine, Professor of Medicine and of Microbiology and Immunology, and Director of the Institute of Human Virology, University of Maryland School of Medicine, College Park, Maryland • Douglas Hanahan, PhD, Director of the Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology Department of Life Sciences, Lausanne, Switzerland • Richard O. Hynes, PhD, Daniel K. Ludwig Professor for Cancer Research, Massachusetts Institute of Technology; Investigator, Howard Hughes Medical Institute • William G. Kaelin Jr., MD, Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston; Investigator, Howard Hughes Medical Institute • Kenneth W. Kinzler, PhD, Professor of Oncology and Director of the Ludwig Center, Johns Hopkins University, Johns Hopkins Kimmel Cancer Center, Baltimore • Richard D. Kolodner, PhD, Member and Head of the Laboratory of Cancer Genetics, Ludwig Institute for Cancer Research; Distinguished Professor in the Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego School of Medicine, San Diego • Ronald Levy, MD, Robert K. and Helen K. Summy Professor of Medicine, Stanford University School of Medicine, Palo Alto • Frederick P. Li, MD, Professor of Clinical Cancer Epidemiology Emeritus, Harvard School of Public Health; Professor of Medicine Emeritus, Dana-Farber Cancer Institute, Boston • David M. Livingston, MD, Deputy Director of the Dana-Farber Cancer Institute, Chief of the Charles A.

Dana Division of Human Cancer Genetics, and Emil Frei Professor of Genetics and Medicine, Harvard Medical School, Boston • Paul A. Marks, MD, President Emeritus, Memorial Sloan Kettering Cancer Center, New York • Peter C. Nowell, MD, Gaylord P. and Mary Louise Harnwell Professor Emeritus in the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia • Christiane Nüsslein-Volhard, PhD, Director of the Department of Genetics, Max Planck Institute for Developmental Biology, Tübingen, Germany • Sir Richard Peto, FRS, Professor of Medical Statistics and Epidemiology, University of Oxford, Oxford, United Kingdom • Charles L. Sawyers, MD, Chairperson of the Human Oncology and Pathogenesis Program and member at Memorial Sloan Kettering Cancer Center; Professor, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York; Investigator, Howard Hughes Medical Institute • Sir Michael R. Stratton, MBBS, PhD, Director, Wellcome Trust Sanger Institute, Cambridge, United Kingdom • Axel Ullrich, PhD, Director of the Department of Molecular Biology, Max Planck Institute of Biochemistry, Munich, Germany • Inder M. Verma, PhD, Irwin and Joan Jacobs Chair in Exemplary Life Science and American Cancer Society Professor of Molecular Biology, The Salk Institute for Biological Sciences, La Jolla • Irving L. Weissman, MD, Director of the Institute for Stem Cell Biology and Regenerative Medicine, Director of the Stanford Ludwig Center for Cancer Stem Cell Research and Medicine, and Professor of Pathology and Developmental Biology, Stanford University School of Medicine, Palo Alto • Owen N. Witte, MD, Director of the Broad Stem Cell Research Center and Distinguished Professor of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Investigator at Howard Hughes Medical Institute n

Amgen is exploring thePostâ&#x20AC;&#x201A; expanded of biomarker | â&#x20AC;&#x201A; MAY 1,potential The ASCO 2014 analysis in metastatic colorectal cancer (mCRC)

PAGE 44

When is your RAS analysis complete?

Expanding the potential of biomarker analysis means helping physicians not only determine what options are appropriate for patients but, equally as important, understanding what options are not appropriate for patients. Amgen is investigating extended RAS testing to further biomarker analysis in mCRC.

Learn more at www.amgenoncology.com

77929-R1-V1

11-13

ASCOPost.com | MAY 1, 2014

PAGE 45

Clinical Trials Resource Guide Hematology

Ongoing Clinical Trials Actively Recruiting Patients With Hodgkin Lymphomas Compiled by Jo Cavallo

he information in this Clinical Trials Resource Guide includes details of actively recruiting clinical studies of patients with Hodgkin lymphomas, including patients with human immunodeficiency virus–associated and Epstein-Barr virus–positive Hodgkin lymphoma. Two of the studies are also recruiting patients with mature T-cell lymphoma, multiple myeloma, and diffuse large B-cell lymphoma. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov. The studies are all phase I and II clinical trials.

HODGKIN LYMPHOMAS Study Type: Phase II/interventional/single group assignment Study Title: Phase II Trial of Response-Adapted Therapy Based on Positron Emission Tomography (PET) for Bulky Stage I and Stage II Classical Hodgkin Lymphoma. Study Sponsor and Collaborators: Cancer and Leukemia Group B; National Cancer Institute Purpose: Diagnostic procedures, such as PET scan, done before, during, and after chemotherapy may help doctors plan the best treatment for their patients. This phase II clinical trial is studying how well response-based therapy assessed by PET scan works in treating patients with bulky stage I and stage II Hodgkin lymphoma. Ages Eligible for Study: 18 to 60 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival at 36 months from enrollment (time frame: up to 8 weeks) Principal Investigator: Ann S. LaCasce, MD, Dana-Farber Cancer Institute; 617-632-5959 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01118026 Study Type: Phase I/II/interven-

tional/single group assignment Study Title: A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma Study Sponsor and Collaborators: National Cancer Institute Purpose: This pilot phase I/II trial is studying the side effects and the best dose of brentuximab vedotin and combination chemotherapy in treating patients with stage II-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Giving brentuximab vedotin together with combination chemotherapy may be more effective in killing more cancer cells. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximal tolerated doses of brentuximab vedotin when combined with AVD (doxorubicin hydrochloride, vinblastine, and dacarbazine) chemotherapy regimen in HIV patients with advanced stage Hodgkin lymphoma (time frame: 28 days); progression-free survival for patients using brentuximab vedotin plus AVD regimen with HIVassociated advanced stage Hodgkin lymphoma (time frame: 2 years) Principal Investigator: Paul G. Rubinstein, MD, AIDS Associated Malignancies Clinical Trials Consortium; 312-864-7277; prubinstein@cookcountyhhs.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01771107 Study Type: Phase II/interventional/single group assignment Study Title: A Phase II Study of Brentuximab Vedotin as Salvage Therapy for Hodgkin Lymphoma Prior to Autologous Hematapoietic Stem Cell Transplantation Study Sponsor and Collaborators: City of Hope Medical Center; National Cancer Institute Purpose: To study how well giving brentuximab vedotin before autologous stem cell transplant works in treating patients with Hodgkin lymphoma. Ages Eligible for Study: 11 years and older Genders Eligible for Study: Both

Accepts Health Volunteers: No Primary Outcome Measures: Overall response rate of salvage brentuximab vedotin treatment for Hodgkin lymphoma before autologous hematopoietic stem cell transplantation (time frame: 21 days after completion of last course of study treatment) Principal Investigator: Robert W. Chen, MD, City of Hope Medical Center; 800-826-4673; rchen@coh.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01393717 Study Type: Phase II/interventional/single group assignment Study Title: A Multicenter Pilot Study of Reduced Intensity Allogeneic Stem Cell Transplantation Followed by Adoptive Cellular Immunotherapy With Donor Derived Latent Membrane Protein (LMP) Specific-CTLs in Patients With Epstein-Bar Virus (EBV) Positive Refractory or Recurrent Hodgkin Lymphoma Study Sponsor and Collaborators: New York Medical College; Children’s Research Institute, Baylor College of Medicine, MD Anderson Cancer Center, Beckman Research Institute, Johns Hopkins University, Ohio State University, University of Utah, and the University of Michigan Purpose: To utilize reduced intensity conditioning and allogeneic stem cell transplantation (AlloSCT) from EBV-positive HLA-matched sibling or unrelated adult donor combined with post-AlloSCT allogeneic donor-derived latent membrane protein (LMP)specific cytotoxic T-lymphocyte infusions in EBV-positive patients with poor-risk Hodgkin lymphoma. One of three reduced intensity conditioning regimens predetermined at each institutional center of the Childhood, Adolescent and Young Adult Lymphoma Cell Therapy Consortium (LCTC) will be utilized for related or matched unrelated adult donor allogeneic transplant followed by donor LMP-specific cytotoxic T-lymphocyte infusion for three doses post-AlloSCT. The investigators hypothesize that the addition of donorderived LMP-specific cytotoxic T-lymphocytes will be safe and feasible. Ages Eligible for Study: Up to 45 years

Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Safety and toxicity: The number of serious adverse events associated with administering allogeneic HLAmatched donor derived LMP-specific CTSs in CAYA with EBV-associated refractory/relapsed Hodgkin lymphoma following reduced intensity and allogeneic stem cell transplant (time frame: 1 year) Principal Investigator: Mitchell S. Cairo, MD, New York Medical College; 914-594-3650; mitchell_cairo@nymc. edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01636388 Study Type: Phase II/Nonrandomized/interventional/single group assignment Study Title: Phase II Trial of Alemtuzumab (Campath) and Dose-Adjusted EPOCH-Rituximab (DA-EPOCHR) in Relapsed or Refractory Diffuse Large B-Cell and Hodgkin Lymphomas Study Sponsor and Collaborators: National Cancer Institute Purpose: To test whether giving alemtuzumab (Campath) in combination with continuous infusion EPOCH-R (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, and rituximab) chemotherapy will improve the outcome of lymphoma treatment. This protocol is specifically for people with diffuse large B-cell or Hodgkin lymphoma who have not responded to standard treatments. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To assess response, progression-free survival, and overall survival in relapsed/ refractory DLBCL and Hodgkin lymphoma (time frame: 5 years) Principal Investigator: Wyndham H. Wilson, MD, National Cancer Institute; 301-435-2415; wilsonw@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01030900 n

At Amgen, biologic medicines are rooted in

quality

and nurtured by

reliability.

Robust quality control and a reliable supply are every bit as important as scientific innovation. For more than 30 years, Amgen has poured commitment, passion, and a drive for perfection into every medicine we make. So you can turn to Amgen for the biologic medicines that matter so much to your patients’ treatment…for generations to come. To learn more about Amgen’s commitment to consistent quality and reliable supply, visit biotechnologybyamgen.com ©2013 Amgen Inc. All rights reserved. 73979-R1-V1

ASCOPost.com | MAY 1, 2014

PAGE 47

Journal Spotlight Screening

Lack of Insurance Coverage a Barrier to Lung Cancer Screening

he majority of current and former smokers would welcome screenings for lung cancer if their insurance covered the spiral computed tomography (CT) scans, according to research

cancer screening using spiral CT scans. Current smokers (78.5%) and former smokers (81.4%) said they would be willing to be tested, if advised to do so by their physician.

The results are consistent with previous studies that have shown high enthusiasm from patients to undergo cancer screening if the procedure is recommended by their doctors and covered by their insurance. —K. Michael Cummings, PhD

from Roswell Park Cancer Institute and the Medical University of South Carolina. The study by Jennifer Delmerico, MPH, and colleagues was published online ahead of print in the journal Lung Cancer.1

Study Details More than 1,200 adult current smokers and former smokers were surveyed about their attitudes toward lung

Reasons why smokers are not willing to be screened included a lack of insurance coverage (33% for smokers, 25% for former smokers) and a fear of being diagnosed with lung cancer (33% for smokers, 12.5% for former smokers). Among former smokers, the most commonly cited reason for not having the screening was a belief that they did not have lung cancer. “This study provides valuable in-

formation regarding the barriers to lung cancer screening, including a lack of insurance coverage,” said Andrew Hyland, PhD, Chair of the Department of Health Behavior at Roswell Park Cancer Institute. “These data speak to the need of insurance companies to pay for this lifesaving test.”

High Patient Interest in Screening The recent National Lung Screening Trial, a major study involving 53,454 current or former heavy smokers, reported a 20% reduction in mortality rate when lung cancer was diagnosed using spiral CT, compared to annual chest x-rays. Currently, only 17% of patients treated for lung cancer survive beyond 5 years. A number of professional organizations have recommended lung cancer screening with spiral CT, including the U.S. Preventive Services Task Force, American Association of Thoracic Surgery, and American Cancer Society. These recommendations can influence health insurance coverage for the procedure. K. Michael Cummings, PhD, of

Andrew Hyland, PhD

the Department of Psychiatry & Behavioral Sciences at the Medical University of South Carolina, added, “The results are consistent with previous studies that have shown high enthusiasm from patients to undergo cancer screening if the procedure is recommended by their doctors and covered by their insurance.” n Disclosure: The study was funded by Roswell Park Cancer Institute. For disclosures of the study authors, visit www.lungcancerjournal. info.

Reference 1. Delmerico J, Hyland A, Celestino P, et al: Patient willingness and barriers to receiving a CT scan for lung cancer screening. Lung Cancer. March 27, 2014 (early release online).

Delivered to your inbox every weekday evening. Visit ASCOPost.com to learn more.

NCCN 9th Annual Congress:

Hematologic Malignancies

™

September 19 – 20, 2014

Reserve Your Seat Today at NCCN.org/hem

New York Marriott Marquis 1535 Broadway • New York, New York Moderator: Andrew D. Zelenetz, MD, PhD Memorial Sloan-Kettering Cancer Center

Scan QR code to go to NCCN.org/hem

Sponsorship and exhibit opportunities available! For more information, contact Jennifer Tredwell at tredwell@nccn.org. This activity will be approved for AMA PRA Category 1 Credit(s)™ for physicians and will also be accredited for nurses, pharmacists, and other health care professionals. Please refer to the complete accreditation details for more information.

Online Anytime!

Visit education.nccn.org/hem2013 for online CME opportunities from the NCCN 8th Annual Congress!

JNCCN-N-0192-0414

ASCOPost.com | MAY 1, 2014

PAGE 49

2014-2015 Oncology Meetings May Association for Value-Based Cancer Care – 4th Annual Conference May 6-9 • Los Angeles, California For more information: http://avbcconline.org/ Accelerating Anticancer Agent Development and Validation

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/ Current Issues in Palliative Care 2014 May 8-9 • London, United Kingdom For more information: http://www.mahealthcareevents.co.uk REV 2014 Forum: Navigating Cancer Care in the Era of Personalized Medicine May 8-9 • Washington, DC For more information: www.rev-forum.com/ ASPHO’s 27th Annual Meeting May 14-17 • Chicago, Illinois For more information: www.aspho.org Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information:

June

2014-2015

The 12th Annual Scientific Meeting of Japanese Society of Medical Oncology July 17-19 • Fukuoka, Japan For more information: www.congre.co.jp/jsmo2014/en/

ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/

2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org/

2nd Annual Prostate Symposium: Challenges and Solutions June 6-7 • Winston-Salem, North Carolina For more information: http:// northwestahec.wfubmc.edu Targeting VEGF-mediated Tumor Angiogenesis in Cancer Therapy June 19-20 • New York, New York For more information: http://www.nyas.org/Events 6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/ 16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606 5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org

July Best of ASCO in Japan July 5-6 • Kobe, Japan For more information: www.jsmo.or.jp/en/

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org

www.mdanderson.org/conferences 2014 State of the Art Radiation

Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org/

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/

Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: http://aonnonline.org continued on page 50

July 21-25, 2014

The Kohala Coast, Hawaii

Abstract Submission Deadline: Early Registartion Deadline:

April 11, 2014 May 20, 2014

u n m c . e d u/p a np a c i fi c l y m p h o m a

The ASCO Post | MAY 1, 2014

PAGE 50

2014-2015 Oncology Meetings continued from page 49

NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/meetings/ hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr. org/home/scientists/meetings-workshops/special-conferences/ advances-in-melanoma-frombiology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29 - October 2 • Cambridge, Massachusetts For more information: http://steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org

18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: http://www2. kenes.com/sis/Pages/Home.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco. org 16th World Congress of PsychoOncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com/ ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ ce/home/programs/physicians

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

RSNA 2014 Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November

11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org

Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747 Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: http://www .mayo.edu/cme/surgical-specialties2014s306

11th Meeting of the Eurpean Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: http://www. eano.eu/mee_welcome.php 2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ breastcancer/pages/index.aspx

2014-2015

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: http://www.cutaneousmalignancies .com

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org 37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

ASCOPost.com | MAY 1, 2014

PAGE 51

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Exemestane to Reduce Invasive Breast Cancer Risk Has Small Negative Impact on Quality of Life Detailed quality-of-life data from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Mammary Prevention 3 (MAP.3) trial showed that exemestane given for the prevention of breast cancer “has limited negative impact on menopause-specific and health-related [quality of life] in healthy postmenopausal women at risk for breast cancer.” Previously reported results from the placebo-controlled randomized MAP.3 trial showed that the steroidal aromastase inhibitor exemestane reduced invasive breast cancer incidence by 65%. “Exemestane had small negative effects on women’s self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of [quality of life] at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed,” Elizabeth Maunsell, PhD, of Hôpital du SaintSacrement, Research Centre, in Quebec and colleagues stated in the Journal of Clinical Oncology. “Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment.” MAP.3 trial randomized 4,560 postmenopausal women to exemestane at 25 mg or placebo orally daily for up to 5 years. The trial’s primary endpoint was invasive breast cancer incidence, with menopause-specific and general quality of life among the secondary endpoints. At baseline, 4,468 women (98%) completed both the Menopause-Specific Quality of Life Questionnaire (MENQOL) and the Medical Outcomes Study 36-item Short Form Health Survey (SF-36). “By trial design, MAP.3 intervention ended once the required number of invasive breast cancers had occurred and the main trial objective had been analyzed,” the investigators explained.

Consequently, the percentages of participants that had accumulated sufficient follow-up time at trial closure to complete quality-of-life questionnaires were only 39.9% at 3 years, 21.7% at 4 years, and 5.2% at 5 years after random assignment. Quality-oflife questionnaire compliance “was excellent; between 88% and 98% of participants still taking study medication continued to complete these forms at 6 months and years 1, 2, 3, 4, and 5,” the researchers noted. The negative influence on vasomotor symptoms, which included hot flashes, night sweats, and sweating, were more common in women younger than 60 years old. “The overall prevalence of bothersome sexual symptoms was higher in women younger than age 60, and negative differences attributable to exemestane were seen only in this age group. For the physical domain, the main negative effects of exemestane were for ‘aching muscles and joints’ and ‘difficulty sleeping,’ and this did not differ by age group,” according to the study report. “No clear effects of exemestane on bothersome symptoms in the psychosocial domain were observed in either age group. Although being severely bothered by ‘poor memory’ was the second most frequently reported symptom in this domain, there were no between-group differences attributable to exemestane at either time or by age group,” the investigators noted. Maunsell E, et al: J Clin Oncol April 7, 2014 (early release online).

OVARIAN CANCER Desensitization Protocols May Allow Reintroduction of Chemotherapeutic Agents After Hypersensitivity Reactions Hypersensitivity reactions to chemotherapeutic agents used to treat ovarian cancer are “increasingly common and can greatly limit their use,” according to an article published in the Journal of the National Comprehensive Cancer Network. “Drug desensitization has emerged as a safe and effective way of reintroducing a chemotherapeutic agent or monoclonal antibody responsible for [a hypersensitivity reaction] in a patient who is expected to benefit from its contin-

ued use and for whom alternatives are considered less effective and/or more toxic,” reported Matthieu Picard, MD, and colleagues from Brigham and Women’s Hospital, Harvard Medical School, and Dana-Farber Cancer Institute in Boston. “[Hypersensitivity reactions] to chemotherapy are unpredictable, can occur suddenly, and may deteriorate quickly,” the researchers stated. “[Hypersensitivity reactions] may manifest with a variety of symptoms and may vary in severity from isolated flushing to anaphylaxis. In any case, the drug infusion should be immediately stopped.” Further management of hypersensitivity reactions depends on the drug and the severity of the initial reaction “in accordance with the [National Comprehensive Cancer Network] Clinical Practice Guidelines in Oncology for Ovarian Cancer,” the authors advised. The most common type of hypersensitivity reactions are type I reactions, also referred to as allergic or infusion reactions, and the article focuses mainly on type I–compatible hypersensitivity reactions to taxanes and platinum drugs, which the researchers noted are key to improving survival in patients with newly diagnosed ovarian cancer and recurrent disease that remains sensitive to platinum. Management options range from drug reintroduction to discontinuation. “Several tools can assist the clinician in this difficult decision-making process,” the researchers noted. “For instance, an elevated serum tryptase level following an acute reaction can confirm mast cell involvement in the [hypersensitivity reaction], emphasizing the need for prudence if reintroduction is attempted. And in evaluating a patient after [a hypersensitivity reaction], skin testing can accurately identify patients with an allergy to platinum drugs, in whom reintroduction should only be considered through a desensitization protocol.” The authors added that skin testing to other drugs, including taxanes, may also prove useful in the future. “Recently, the development of desensitization protocols with remarkable safety records has allowed patients with ovarian cancer who experienced mast cell–mediated chemotherapy [hypersensitivity reactions] of any severity to be re-treated with

these life-saving molecules. Experience with these protocols is increasing rapidly, because their usefulness in the management of chemotherapy [hypersensitivity reactions] is being increasingly recognized. Efforts are now needed to increase awareness about desensitization procedures so that more patients may benefit. This is a challenge that will require the close collaboration of patients, nurses, oncologists, and allergists,” the investigators concluded. Picard M, et al: J Natl Compr Canc Netw 12:389-402, 2014.

LYMPHOMA Brentuximab Vedotin Shows Antitumor Activity in Patients With Relapsed Peripheral T-Cell Lymphoma In a phase II study, the 34 evaluable patients with peripheral T-cell lymphomas who received brentuximab vedotin (Adcetris) had an overall response rate of 41%, including an overall response rate of 54% among the 13 patients with angioimmunoblastic T-cell lymphoma. The median progression-free survival at the time the study was reported in Blood was 6.7 months. Brentuximab vedotin was generally well tolerated. “Based on the activity and safety observed in patients on this investigational phase 2 trial, single-agent brentuximab vedotin has the potential to be a therapeutic option in treating relapsed and refractory [peripheral T-cell lymphomas],” Steven M. Horowitz, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues concluded. Study participants were enrolled at 13 sites in the United States and 1 in Canada. Eligibility criteria included histologically confirmed mature Tcell lymphoma with any detectable CD30 expression, the investigators explained. Patients with anaplastic large cell lymphoma, Sezary syndrome, and mycosis fungoides were excluded. The median age of patients was 64 years; 77% were male, and 71% were white. Most patients (77%) had stage III or IV disease, and 63% were refractory to most recent therapy. Patients were treated with brentuximab vedotin, a CD30-directed antibody-drug conjugate, at 1.8 mg/ kg continued on page 56

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (mPAC), in combination with gemcitabine.

ignite survival in first-line mPAC Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to

patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may

substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months

0.4

(95% CI: 6.0-7.2)

0.3

HR: 0.72 (95% CI: 0.62-0.83) a

0.2

P<0.0001b

0.1 0.0 0

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

Patients at risk A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

STUDY DESIGN The multinational, randomized, phase III MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with mPAC. The primary end point was OS.

T:14”

B:14.25”

S:13”

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%),

headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages. For more information, please visit www.abraxane.com. ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 01/14 US-ABR130068a(1)

Geriatric • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary for metastatic adenocarcinoma of the pancreas; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels Bilirubin Levels ABRAXANE Dosea Pancreatic c Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 75 600 2nd dose reduction If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Cycle Day Day 1 Day 8

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to ≤ Grade 1; No dose reduction Grade 3 or 4 resume at next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis or diarrhea lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS 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. In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabinetreated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm Gemcitabine ABRAXANE(125 mg/m2)/Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421)

Gemcitabine (N=402)

System Organ Class

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

General disorders and administration site conditions

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Gastrointestinal disorders

Skin and subcutaneous tissue disorders Nervous system disorders

Metabolism and nutrition disorders Respiratory, thoracic and mediastinal disorders

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Alopecia

212 (50%)

6 (1%)

21 (5%)

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%) 3 (1%)

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

Dysgeusia

68 (16%)

33 (8%)

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%)

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

6 (1%)

Cough

72 (17%)

30 (7%)

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%) 1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

Psychiatric disorders

Depression

51 (12%)

1 (<1%)

24 (6%)

T:14”

B:14.25”

S:13”

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal. Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site

10 16

reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_PANC_HCP_BSv007 10_2013

The ASCO Post | MAY 1, 2014

PAGE 56

In the Literature Emerging Clinical Data continued from page 51

intravenously on day 1 of each 3-week cycle. “Patients who achieved at least stable disease … were eligible to receive continued brentuximab vedotin treatment until disease progression, unacceptable toxicity, or study closure. Patients who received at least one dose of brentuximab vedotin were followed for disease status and survival,” the investigators explained.

Key Results Among the 14 patients achieving an objective response, 8 had complete responses, including 5 patients with angioimmunoblastic T-cell lymphoma. At the time of the study report, the median duration of response for all patients was 7.6 months, with five responding patients remaining in follow-up and five on therapy. “Safety data were generally consistent with the known profile of brentuximab vedotin,” the researchers reported. “The most frequently occurring ≥ Grade 3 events were neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each).” Serious adverse events occurred in four patients, including grade 3 pyrexi, rash, and pneumonia, and grade 5 acute respiratory distress syndrome. Three patients died within 30 days of receiving the last dose, one due to acute respiratory distress syndrome and two related to disease progression, and another patient died after 30 days with severe complications including sepsis unrelated to treatment. “The response rates in this trial and the lack of correlation with

CD30 expression suggest potentially broad activity of brentuximab vedotin among various subtypes of T-cell lymphomas,” the authors stated. They also pointed out that the overall response rate achieved was “comparable to that in similar populations studied with other recently approved agents,” such as pralatrexate (Folotyn) and romidepsin (Istodax). “The results from the current phase 2 trial in [peripheral T-cell lymphomas] coupled with the ability to combine brentuximab vedotin with standard induction chemotherapy has led to the initiation of a phase 3, double-blinded randomized study,” the authors added. That study will compare brentuximab vedotin plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) vs CHP (CHOP minus vincristine) for untreated patients with CD30-expressing mature T-cell lymphomas. The current study was registered at ClinicalTrials.gov with the identifier NCT01421667. Horwitz SM, et al: Blood. March 20, 2014 (early release online).

FOLLOW-UP CARE Identifying One Main Provider and Involving Oncology Specialist Are Key to High-Quality Rating for Follow-up Care Long-term cancer survivors are more likely to rate their follow-up care as high-quality when one main provider is identified and an oncology specialist is involved, according

to results of a population-based crosssectional study among adult survivors of breast, prostate, colorectal, endometrial, and ovarian cancer. Among 1,490 survivors responding to questionnaires 4 to 14 years after diagnosis, 68.7% reported recent follow-up care, 47.4% from oncology specialists only, and 27.6% shared care from oncology and primary care providers. “Most survivors perceived their recent follow-up care as high quality (excellent or very good, 77.3%),” the researchers reported in the Journal of Oncology Practice.

Role of Primary Care Provider “Survivors who identified a [primary care provider] as their main follow-up care physician were as likely as those identifying an oncology specialist to rate their care as high quality (odds ratio [OR], 2.56; 95% CI, 0.98 to 6.74); however, survivors who could not identify a main followup care provider were less likely to report high-quality care (OR, 0.20; 95% CI, 0.08 to 0.50),” the investigators stated. “Compared with follow-up care by an oncology specialist only, care by a [primary care provider] only was associated with a lower quality-of-care rating (OR, 0.34; 95% CI, 0.13 to 0.91), but there was no significant difference in quality rating by survivors when care was shared by an oncology specialist and [primary care provider] compared with an oncology specialist only.” The Follow-Up Care Use Among Survivors (FOCUS) study was sponsored by the National Cancer Institute and sampled patient cases from the Surveillance, Epidemiology, and End Results (SEER) cancer registries in California. The researchers represented the University of Southern California, Los Angeles, and the Cancer Prevention Institute of California, Fremont, as well as other facilities.

Study Data

Among those completing the questionnaire, 66.5% were ≥ 65 years and 64% had early stage cancer (stages 0– II). Slightly more than half (50.6%) identified themselves as from ethnic minorities. Most (79.9%) survivors reported that they were told they needed cancer-related follow-up care, but only 41.7% reported that a physician had discussed late and long-term effects of treatment and only 19.9% said they had received written treatment summaries. “Endometrial cancer survivors re-

ported the lowest rates of advice regarding follow-up care and late and long-term effects. Prostate cancer survivors had the highest reports of longterm effects advice and treatment summaries,” the researchers noted. A majority of survivors (82.9%) reported receiving cancer-related follow-up care and almost 40% had three follow-up care visits in the past 2 years. “Follow-up care was most common among ovarian cancer survivors and least common among endometrial cancer survivors,” the investigators reported. Reasons cited for follow-up care were similar across cancer sites. The most common reason, reported by 71.1%, was checking for recurrence of primary cancer, followed by being screened for other cancers, cited by 66.1%. “Only 27.8% reported that screening for late effects was a reason for recent care; however, survivors who reported advice about late effects also rated that care as higher quality. Given the critical importance of late effects among long-term survivors, better survivor and provider education regarding the reasons for and content of survivorship care should be a focus of future research and practice,” the investigators commented.

Impact of IOM Report “Survivors in this study were diagnosed and treated before the 2006 Institute of Medicine report highlighting the importance of cancer-related follow-up care and implementation of formal survivorship care programs at many cancer centers,” the authors stated. “Thus, the rates in our study are lower than those from a 2006 to 2010 national study reporting that 38% of survivors received treatment summaries, and we expect future cohorts to report higher levels.” The investigators pointed out that the finding that 75% of survivors continued to receive follow-up care from an oncologist or cancer-related specialist “has implications for health care systems looking to constrain cost and meet a growing demand for oncology services. Shared care models have emerged as a way to meet survivors’ complex care needs.” But including multiple providers, the researchers noted, “suggests challenges for care coordination.” n Weaver KE, et al: J Oncol Pract. April 1, 2014 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | MAY 1, 2014

PAGE 57

Issues in Oncology Medicare Payment Data continued from page 1

that require extensive patient services, many of which are under-reimbursed or not reimbursed at all by Medicare. Most of the amounts shown in the Medicare database for oncologists are not, in fact, revenue to oncology practices. Instead, these Medicare payments merely cover the upfront costs of purchasing drugs for patients. Also, the data reflect the high cost of some chemotherapy drugs that further distort the actual practice revenue. A substantial proportion of Medicare reimbursement also goes to providing the highly skilled professional staff necessary to care for seriously ill patients, such as oncologycertified nurses and pharmacists. We urge the Centers for Medicare &

Statement From ASH President Linda J. Burns, MD, on Release of Medicare Physician Payment Data

he Centers for Medicare & Medicaid Services has released a large and complex set of data about the number and type

Medicaid Services (CMS) to work with ASCO and the oncology community to identify and correct data mistakes and to refrain from releasing more information until a more helpful process can be established that provides reimbursement information in the appropriate clinical context. We further ask CMS to allow physicians to review their personal information for accu-

racy—something not currently permitted. ASCO is actively engaged in helping physicians make the best clinical decisions with and for their patients by disseminating clinical guidelines, establishing quality measurement and improvement programs, and fostering open discussions about cost and value. We look forward to working with CMS

to advance our common goals by ensuring that this information is useful and meaningful to physicians and patients. n For more information and additional resources about this developing situation, please visit http://www.asco.org/advocacy/ medicare-physician-database-informationresource-center.

ASCO Makes Earning MOC Points Easy

ANNUAL MEETING CORE SESSION MOC SELF-ASSESSMENT ACTIVITY STEP 1: TAKE A PRE-EXAM This 30-question online test is designed to identify knowledge gaps within a variety of cancer topics.

STEP 2: GET SESSIONS TO ATTEND Linda J. Burns, MD

of health-care services that individual physicians and certain other health-care professionals delivered in 2012, and the amount Medicare paid them for those services. The data, which cover $77 billion of Medicare Part B Fee-for-Service program payments to 880,000 providers, are intended to allow the public to identify outliers and patterns in payment. The American Society of Hematology (ASH), the world’s largest professional society concerned with the causes and treatment of blood disorders, is committed to improving the quality of care delivcontinued on page 59

Based on how you score on the pre-exam, ASCO provides a personalized list of core sessions to attend while you are at the meeting to help fill your knowledge gaps.

STEP 3: TAKE A POST-EXAM Once the Annual Meetings ends, you will receive an email linking you to the post test, which is designed to demonstrate knowledge gained during the meeting. Upon passing the test, you will be eligible to claim 10 MOC points by submitting your data directly to ABIM.

am.asco.org

Questions? Email: moc@asco.org Phone: 888-273-3508

The ASCO Post | MAY 1, 2014

PAGE 58

Perspective S. Vincent Rajkumar, MD continued from page 1

there has been some controversy on the implications of these findings. Some experts have endorsed routine maintenance, at least in the post-transplant setting, while others have argued that additional data are needed before such therapy might be recommended. Frequent updates of these study results at subsequent meetings have not clarified the issues, but rather, have given rise to new misconceptions. In this column, I will focus on those findings that apply to the post-transplant setting.

Why the Reservations? When these studies were first published, I had pointed out reasons why caution is needed, and stated that we need more data to determine whether all patients should receive post-transplant maintenance with lenalidomide.4 I still feel that way. But why would someone like me who has worked with lenalidomide from the outset not recommend routine maintenance? What is it that I am worried about?

Let us first examine the setting: post-transplant maintenance therapy. Autologous stem cell transplantation is not curative in myeloma but prolongs overall survival. Subsequently, three randomized trials found that the timing of stem cell transplantation (early vs transplant at first relapse) does not affect overall survival, but we generally favor early stem cell transplant since it provides a longer time without therapy or toxicity. Routine maintenance, even with an orally administered, well-tolerated drug, threatens the concept of “time without therapy,” which in fact is the major allure of early autologous stem cell transplantation. In fact, indefinite maintenance until disease progression virtually ensures continuous lifelong drug therapy for myeloma patients, at a time when median survival for younger standard-risk patients is approaching > 10 years. A clear overall survival benefit will still justify this approach, particularly if therapy is reasonably well tolerated. Chronic myelogenous leukemia is a good example in this situation. Howev-

er, we simply do not have data that survival is convincingly prolonged, at least as of now. Even in the U.S. study that found a survival benefit, we know that not all subgroups derived an improvement in survival. And we do know that some patients can be harmed.

Major Misconception Next, let us examine a major misconception. We have two fairly similar trials, one done in the United States and one in France by the Intergroupe Francophone du Myélome (IFM), but a survival improvement was seen only in the U.S. trial. Why? A common explanation is that the French trial stopped maintenance after 2 years, whereas the U.S. trial continued maintenance until progression. This is an incorrect interpretation. The U.S. trial found a survival benefit at a time when the median duration of maintenance in the study was several months short of 2 years, and much less than the median duration of therapy that had already been administered in the French trial!

While it is true that the IFM trial decided to cap maintenance after a median duration of 2 years once a risk of second cancers was identified, that was not the reason for the lack of survival benefit. Patients in the IFM trial, which accrued and closed faster than the U.S. trial, at that point had already received almost an extra year of therapy (lenalidomide or placebo) but were simply not seeing the survival difference that the U.S. trial observed. In fact, since the U.S. trial recommended a crossover when the median duration of maintenance was approximately 12 months—a point from which comparisons between the two arms becomes difficult to interpret—it is impossible to determine the specific benefit gained by prolonging the maintenance duration beyond that point other than to confirm that differences persist despite crossover. At this point, the 4-year overall survival is 80% to 82% in both arms of the IFM trial and the lenalidomide arm of the U.S. trial; it is approximately 10% lower in the placebo arm of the U.S. trial.

MEDICAL DIRECTOR, QUALITY DEPARTMENT The American Society of Clinical Oncology (ASCO) is recruiting the Medical Director for its critically important and growing Quality Department. Headquartered in Alexandria, VA, the non-for-profit ASCO (www.asco.org) currently has more than 280 dedicated full-time staff to manage its growing number of programs, services, and interests in cancer public health issues. ASCO’s Quality Department was formed in 2011 and is one of 12 ASCO Departments. A total of 75 individuals are being assembled to staff the Quality Department under the leadership of Robert Hauser, PharmD, Ph.D. The Medical Director will lead a team of 35-40 individuals to advance the following programs: • The Quality Oncology Practice Initiative (QOPI) • QOPI Practice Certification (QCO) • Practice Guidelines • Performance Measures and Practice Improvements • CancerLinQ, ASCO’s learning healthcare system for oncology The ideal candidate will be a board-certified physician with a good working knowledge of electronic health records and knowledge of current trends in health IT, familiarity with data collection and analytics, and a solid background in performance measurement and practice improvement activities.

Spencer Stuart has been retained to assist with this important recruitment. Spencer Stuart and ASCO respect the importance of maintaining confidentiality. Letters of application, with resumes, and letters of nominations should be submitted by e-mail to: Lmedoff@spencerstuart.com

ASCOPost.com | MAY 1, 2014

PAGE 59

Perspective Possible Explanations What could possibly be the reason for the differences in survival between the two trials? There are many possible reasons,4 but at least two are worth discussing in detail. One is that 35% of patients in the U.S. trial had received lenalidomide as induction, and these were the patients who contributed to the significant survival benefit. No significant survival differences were seen in patients not receiving lenalidomide induction. How does this affect interpretation? Since the response to and toxicity from lenalidomide use was known a priori in a substantial subset of patients screened for enrollment in the U.S. trial, patients who did not respond and those with undue toxicity with lenalidomide induction were naturally less likely to have been enrolled. On the other hand, patients in whom a clear survival benefit was observed were those who received prior lenalidomide, and were most likely already known to be responsive and tolerating such therapy well at the time of randomization. A second stated reason for the lack of survival benefit in the IFM trial is that 2 months of consolidation with lenalidomide was given to all patients following autologous stem cell transplantation. While some may view this as a problem in the French trial, I do not. A more reasonable interpretation is that if 2 months of consolidation can provide all of the improved survival that comes with 4 years of maintenance, why not go with that? After all, 2 months’ consolidation is less toxic, carries little risk of second cancers, and is much less expensive!

Risk of Second Cancers A major concern is the increased risk of second cancers in all three trials of lenalidomide maintenance—approximate-

ASH President on Medicare Data continued from page 57

ered to patients with hematologic diseases and eliminating waste and overuse in the field.

Incredibly Complex Data While ASH supports greater transparency about Medicare physician payment and its potential to enhance the quality of the U.S. health-care system, the Society strongly believes that this incredibly complex data must be released with appropriate disclosures and explanatory statements that will encourage and facilitate value-based

ly 7% in the lenalidomide group vs 3% in the placebo group (P < .01). This risk is related to the fact that lenalidomide is given shortly after high-dose melphalan– based therapy in the transplant setting, as it is not seen in the front-line settting, where lenalidomide can be given until progression without an apparent increase in the risk of second cancers.5 The risk of second cancers can be negated by a clear survival benefit, but not by merely showing a delay in time to progression.6 Although the risk of progression of myeloma is much higher than the risk of second cancers, this is not a relevant comparison in this set-

plete data. At the Mayo Clinic, after a careful assessment of risks and benefits, we have the following recommendations (www.msmart.org).7 For standard-risk patients, we recommend 2 months of lenalidomide consolidation following autologous stem cell transplantation. The French results show that with this strategy, overall survival is similar with and without lenalidomide maintenance. After 2 months of consolidation, if patients are known to be lenalidomide-responsive and are not in very good partial response or complete response, we recommend lenalidomide maintenance.

Frequent updates of these study results have not clarified the issues, but rather, have given rise to new misconceptions. —S. Vincent Rajkumar, MD

ting since “progression” is largely a biochemical definition in myeloma that can be treated upon detection, while a lethal second cancer is far more serious.

Recommendations It is likely that many remaining questions will be resolved by longer followup of these trials, and also by final results of a separate Italian trial that tested this question. We will also gain insight from an ongoing randomized trial by the Eastern Cooperative Oncology Group that is testing duration of maintenance: for 2 years vs until progression. Meanwhile, we have to make some judgments based on available incom-

consumer decision-making. Specifically, the numbers alone will not explain quality of care or account for specific drivers of cost such as specialty, location, supply costs, and support staff. The release of data without placing these aspects of care and others into context may result in inaccurate and misleading information for consumers. Greater transparency of Medicare provider payment has the potential to improve the quality of care nationwide for patients with hematologic diseases; however, data must be presented in the proper context to be valuable to the overall improvement of the U.S. health-care system. n

These are the specific subsets where the U.S. trial found a survival benefit. As far as duration of therapy, we recommend capping maintenance at approximately 2 years. Beyond this point, we do not have randomized comparative data on the value of prolonged maintenance, but we do know risks of second cancers increase in the French trial where the integrity of the random assignment has been preserved. For intermediate- and high-risk patients, we prefer bortezomib (Velcade)based maintenance based on the results of several recent trials. Myeloma is a cytogenetically heterogeneous complex entity, and we should try to indivualize

therapy to maximize benefit and limit harm to patients. n Disclosure: Dr. Rajkumar reported no potential conflicts of interest.

Editor’s note: For more on management of multiple myeloma, see pages 14 and 15 in this issue of The ASCO Post.

References 1. McCarthy PL, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012. 2. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stemcell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012. 3. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012. 4. Rajkumar SV: Haematological cancer: Lenalidomide maintenance—perils of a premature denouement. Nat Rev Clin Oncol 9:372-374, 2012. 5. Facon T, Dimopoulos MA, Dispenzieri A, et al: Initial phase 3 results of the FIRST (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). 2013 ASH Annual Meeting. Abstract 2. Presented December 8, 2013. 6. Rajkumar SV, Gahrton G, Bergsagel PL: Approach to the treatment of multiple myeloma: A clash of philosophies. Blood 118:3205-3211, 2011. 7. Mikhael JR, Dingli D, Roy V, et al: Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and RiskAdapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 88:360376, 2013.

ASCO CEO Allen S. Lichter, MD, on Data Issue Excerpted From a Letter to the Editor, Boston Globe Metro, April 14, 2014

“W

hile there is no question that transparency about health-care costs is a good thing, the new database is already doing more to disrupt good care than shed light on bad care. “The Centers for Medicare and Medicaid Services has a responsibility to educate the public about the data they are releasing. As doctors, we are deeply concerned about the wedge this will drive between doctors and patients, and about the aggressive marketing and unfounded

fraud allegations that are likely to ensue. We urge Medicare to identify and correct data mistakes, refrain from releasing more information until a more helpful process can be established that provides information in the appropriate clinical context, and allow physicians to review their personal information for accuracy.” n

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request