TAP Vol 5 Issue 6

Canadian Breast Screening Trial

21–26

| Complications After Prostatectomy

34–41

| Thyroid Cancer

VOLUME 5, ISSUE 6

50

APRIL 15, 2014

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

The Outlook on Cancer Research in This Era of Leaner Federal Funding

Journal Spotlight

SSO-ASTRO Consensus Guideline on Margins for Breast-Conserving Surgery in Stage I/II Invasive Breast Cancer

A Conversation With Douglas R. Lowy, MD

Margins wider than ‘no ink on tumor’ do not further reduce risk of ipsilateral recurrence.

I

By Matthew Stenger

T

he Society of Surgical Oncology (SSO) and American Society for Radiation Oncology (ASTRO) formed a multidisciplinary expert panel in 2013 to examine the relationship between surgical margin width and ipsilateral breast tumor recurrence and develop guidelines on margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer. The panel used a meta-analysis of margin width and ipsilateral recurrence from a systematic review of 33 studies published between 1965 and January 2013 including 28,162 patients as the primary evidence base for consensus.

The SSO-ASTRO guideline was published in Annals of Sur-

gical Oncology, International Journal of Radiation Oncology*Biology*Physics, and Journal of Clinical Oncology1 and is available at www.surgonc.org/marginsstudy, www.redjournal.org, and jco.ascopubs.org.

Primary Clinical Question The primary clinical question the panel sought to answer was: What margin width minimizes the risk of ipsilateral breast tumor recurrence? Review of the evidence did not support routine removal of larger amounts of healthy breast tissue beyond having no cancerous cells touching the edge of the lumpectomy specimen, with this finding being true irrespective of patient age or presence of more aggressive, triple-negcontinued on page 58

Issues in Oncology

ASCO Releases Its First-Ever Report on the State of Cancer Care in America

continued on page 136

Dr. Lowy is Deputy Director of the National ­Cancer Institute.

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

MORE IN THIS ISSUE

By Jo Cavallo

O

n the March 1, 2014, issue of The ASCO Post we talked with Francis S. Collins, MD, PhD, Director of the National Institutes of Health (NIH), about the future of biomedical research at the NIH during this time of constrained federal funding. We continue that conversation here with our interview of Douglas R. Lowy, MD, Deputy Director of the National Cancer Institute (NCI).

Earlier this year, the U.S. Congress passed the FY2014 appropriations bill, which increased the NIH budget by $1 billion, including $4.923 billion for the NCI. However, the new budget does not restore NIH funding to

n March 11, ASCO released its first-ever comprehensive assessment of the daunting challenges facing America’s ability to continue to deliver high-quality care to all patients with cancer. ASCO President Clifford A. Hudis, MD, FACP, intro-

duced the assessment at a Congressional news briefing in Washington, DC. He was joined by Rep. Earl B ­ lumenauer [D-OR], Carolyn Hendricks, MD, PA, in private practice in Bethesda, Maryland, and Blase Polite, MD, Chair of the ASCO Health Disparities Advisory Group and Assistant Professor of MediThis [innovation in cancer cine at The University of Chicago Medicine. care delivery] is the innovation The report, The State that brings greatest value to of Cancer Care in America: 2014, cites a triple threat to our practices, our patients, and that objective: the growing their families, and the lifesaving demand for services—by 2025, demand for cancer treatments that everyone wants care is expected to jump to see. by 42% as the popula—Clifford A. Hudis, MD, FACP tion ages—and a looming workforce shortage of

Oncology Meetings Coverage Genitourinary Cancers Symposium ���������������������������������������� 3, 5, 6 Gastrointestinal Cancers Symposium ������ 10 Highlights of ASH in North America ���������������������������������� 11, 16 Issues in Mammography Screening �������������������������������������������� 21–26 Prostatectomy vs Radiotherapy ����� 34–41 Direct From ASCO �������������������������� 66–69 Sagar Lonial, MD, on Future Trends in Managing Myeloma �������������������95 Inside the Black Box: FDA Speaks About the ‘Bad Ad’ ������������� 101

continued on page 72

Send your comments to editor@ASCOPost.com

A Harborside Press® Publication

The ASCO Post | APRIL 15, 2014

PAGE 2

Harborside Press® Publishing Staff

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

Conor Lynch, Executive Editor Conor@harborsidepress.com David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Samuel Silver, MD, PhD University of Michigan Health System

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Bishoy Morris Faltas, MD Weill Cornell Medical College

Associate Editors

John A. Fracchia, MD New York Urological Associates

Manmeet Ahluwalia, MD, FACP Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

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

Alison Freifeld, MD University of Nebraska Medical Center

Jamie H. Von Roenn, MD American Society of Clinical Oncology

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

Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

George D. Demetri, MD Dana-Farber Cancer Institute

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

Paul F. Engstrom, MD Fox Chase Cancer Center

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

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-

hibited. For permission inquiries, contact permissions@ 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;

George W. Sledge, MD Indiana University

Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

International Editors 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 Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com Sarah McGullam, Assistant Editor Sarah@harborsidepress.com 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, Ronald Piana, Matthew Stenger, Marian Wiseman

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

Disclosure information available at ASCOPost.com.

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

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.

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 | APRIL 15, 2014

PAGE 3

Genitourinary Cancers Symposium Genitourinary Oncology

State-of-the-Art Update on Renal Cell Carcinoma

A Conversation With David I. Quinn, MBBS, PhD, FRACP, and With Arie Belldegrun, MD, FACS, and Allan Pantuck MD, MS, FACS

By Richard J. Boxer, MD, FACS

D

uring the course of the 2014 Genitourinary Cancers Symposium, The ASCO Post had the opportunity to speak with several of the world’s leading authorities about the state of the art in screening, diagnosis, and treatment for prostate and kidney cancers. In this second installment of a two-part report on genitourinary malignancies, we talk to David I. Quinn, MBBS, PhD, FRACP, Head of Genitourinary Medical Oncology at the USC Norris Comprehensive Cancer Center, Los Angeles, and Arie Belldefrun, MD, FACS, and Allan Pantuck, MD, MS, FACS, Professors of Urologic Oncology at the David Geffen School of Medicine at UCLA, about the present and future care of the patient with renal cell carcinoma.

A Conversation With DAVID I. QUINN, MBBS, PhD, FRACP

First-Line Therapy Please describe current medical oncology approaches to first-line therapy for metastatic renal cell carcinoma.

The current first-line therapy for most patients with good- to intermediate-risk metastatic renal cell carcinoma is a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. A small

dence has been established for sunitinib (Sutent) in this setting since 2007, but more recently, data from the COMPARZ study1 suggests that pazopanib (Votrient) has similar efficacy to sunitinib with a better side-effect profile in many patients.

Lower levels of evidence support the use of other VEGF receptor tyrosine kinase inhibitors such as sorafenib (Nexavar) and axitinib (Inlyta) as well as the VEGF ligand inhibitor bevacizumab (Avastin), in the first-line setting.

For patients with poor-risk metastatic renal cell carcinoma, there is level 1 evidence to support use of an intravenous mTOR inhibitor over interferon alfa. Lower-level evidence supports the use of VEGF receptor tyrosine kinase inhibitors in the poor-risk setting also.

Second-Line Therapy What about second-line therapy for metastatic or recurrent disease?

Second-line therapy selection depends on the first-line approach that preceded it, and some would argue that the efficacy and tolerability of the first-line agent should also inform second-line selection.

For patients who received first-line highdose IL-2, level 1 evidence supports the use of VEGF receptor tyrosine kinase inhibitors in the second-line setting, with axitinib being the common choice based on data from the AXIS study.2 Patients who received a VEGF receptor tyrosine kinase inhibitor in the first line can be treated with either another

Level 1 evidence has been established for sunitinib in [the firstline] setting since 2007, but more recently, data from the COMPARZ study suggests that pazopanib has similar efficacy to sunitinib with a better sideeffect profile in many patients.

—David I. Quinn, MBBS, PhD, FRACP

group of patients with good performance status should consider high-dose interleukin 2 (IL-2, Proleukin) therapy, but the toxicity and commitment to inpatient administration precludes this approach in many patients.

The selection of the specific VEGF receptor tyrosine kinase inhibitor used for first-line therapy has evolved. Level 1 evi-

VEGF receptor tyrosine kinase inhibitor or an mTOR inhibitor in the second line. Renal cell carcinoma experts are divided over this choice, which represents an area of equipoise and debate.

Data from the RECORD-1 study provides level 1 evidence for the oral mTOR inhibitor everolimus (Afinitor) over best supportive care alone after a VEGF re-

ceptor tyrosine kinase inhibitor. Data from the AXIS study supports the use of axitinib over sorafenib in this setting. Interestingly, the progression-free survival for everolimus and axitinib after sunitinib therapy in these different trials was approximately 4 months. A trial of everolimus vs axitinib after a single VEGF receptor tyrosine kinase inhibitor might be definitive but has not been undertaken.

The INTORSECT trial3 compared the intravenous mTOR inhibitor temsirolimus (Torisel) to the VEGF receptor tyrosine kinase inhibitor sorafenib after sunitinib therapy. There was minimal difference in progression-free survival between the two agents, but patients given sorafenib in this trial had a 4-month better overall survival.

Extrapolating these data to clinical practice has been difficult. Nevertheless, many oncologists have noted a benefit with sorafenib, including improved overall survival in the secondline setting among patients who had received first-line sunitinib for longer than 6 months in the INTORSECT trial. Poor-risk patients given temsirolimus in the first line are routinely given a VEGF receptor tyrosine kinase inhibitor in the second line if their performance status is adequate.

Third Line and Beyond And what options are appropriate for third-line therapy in these patients?

Third-line therapy is dependent on prior therapy. Both mTOR inhibitors and VEGF receptor tyrosine kinase inhibitors have activity. Based on RECORD-1,4 everolimus has activity compared to best supportive care, whereas the recently reported GOLD study5 showed that use of sorafenib resulted in an overall survival of 11 months in patients treated with prior VEGF- and mTOR-directed therapies.

Treatment beyond third-line therapy may be warranted in some patients who have had good disease control duration or responses to prior VEGF- or mTOR-directed agents and good performance status. Many clinicians use sorafenib or bevacizumab in this setting, although there is no evidence base to support this. n Disclosure: Dr. Quinn has received honoraria for scientific advisory board involvement for Pfizer, Bayer, Genentech, and Novartis.

References available online at www. ascopost.com.

A Conversation With ARIE BELLDEGRUN, MD, FACS, and ALLAN PANTUCK, MD, MS, FACS

Cancer Immunotherapy What is the role of immunotherapy in the treatment of metastatic renal cell carcinoma?

The harnessing of the immune system as an effective treatment for cancer was recently selected by the journal Science as the top scientific Breakthrough of the Year for 2013.1 With this declaration, we are entering into a new era of enthusiasm about the use of immunotherapy in the treatment of cancer, and this shift will undoubtedly have a significant impact on the treatment of advanced renal cell carcinoma as much as any other cancer type over the next decade.

Historically, metastatic renal cell carcinoma did not fit the standard oncologic paradigm and proved to be largely resistant to the usual treatment regimens employed in combating other types of cancer. Trials of cytotoxic chemotherapy, radiation therapy, and hormonal therapy all failed to demonstrate any appreciable effects on survival. Instead, in the 1980s and 1990s, renal cell carcinoma, along with melanoma, became the model for the development of immune-based therapies.

The first iteration in the development of cancer immunotherapy treatment regimens—the use of nonspecific cytokine treatments that included IL-2 and interferon—created an important treatment option for patients with metastatic renal cell carcinoma that remained the mainstay of treatment for nearly 15 years. Until the approvals of the first antiangiogenic VEGF tyrosine kinase inhibitors in 2005 and 2006, high-dose, bolus intravenous IL-2 was the only treatment approved by the U.S. Food and Drug Administration (FDA) for patients with metastatic renal cell carcinoma, an approval granted in 1992 for its ability to produce durable complete responses in a small subset of patients.

Data from seven phase II clinical trials of IL-2 involving a total of 255 patients with metastatic renal cell carcinoma demonstrated an overall response continued on page 5

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | APRIL 15, 2014

PAGE 5

Genitourinary Cancers Symposium Renal Cell Carcinoma continued from page 3

rate of 15%, which included complete response in 7% of patients and partial response in 8% of patients.2,3 Subsequent modern trials with high-dose, bolus IL-2 such as the Cytokine Working Group’s Select trial, have demonstrated response rates nearing 30% and of greater quality and durability.4 Taken together, these studies clearly demonstrated the benefit that immunotherapy can provide for a subset of patients with metastatic renal cell carcinoma.

Although immunotherapy was once the standard of care, the advent of oral therapies that target angiogenesis and other signal transduction pathways and that produced significant clinical benefits in larger patient subsets prompted a reassessment of the role of immunotherapy in advanced renal cell carcinoma. Due to their broad activity and relatively tolerable toxicity profiles, the last 10 years saw a shift away from the use of cytokine-based treatment of metastatic renal cell carcinoma to the use of these newer targeted oral therapies.

In contrast to the results achieved with IL-2, the cytostatic molecularly targeted therapies (eg, sorafenib, sunitinib, everolimus) do not produce durable remissions when therapy is discontinued, and treatment resistance inevitably develops. In recent years, however, an improved understanding of immunology and tumor biology has led to the development of novel immunotherapeutic treatment strategies that include vaccines such as sipuleucel-T (Provenge), the first and thus far only therapeutic cancer vaccine to achieve FDA approval (in 2010), as well as immune checkpoint inhibitors (eg, ipilimumab [Yervoy] approved in 2011, nivolumab), and the adoptive transfer of engineered T cells (eg, tumor-infiltrating lymphocytes, or T cells engineered to express a recombinant T-cell receptor [TCR] or chimeric antigen receptor [CAR]).5 It is the latter two strategies in particular that have generated newfound enthusiasm for cancer immunotherapy.

Checkpoint Blockade to Eliminate Immune Suppression Please describe the concept of checkpoint blockade in renal cell carcinoma therapy.

Since the groundbreaking work of James Allison and others in the 1990s unravelling the molecular mechanisms governing the host response to tumors and identifying the signaling pathways

involved in limiting the immune response, a successful therapeutic strategy has emerged based on the development of various agents that enhance the anticancer immune response by “taking the brakes off ” these immunosuppressive, inhibitory (“checkpoint”) pathways.6 To date, the most clinically important checkpoint molecules mediating tumor-induced immune suppression are cytotoxic T-lymphocyte antigen-4 (CTLA-4) as well as the programmed death-1 (PD-1) receptor and its ligands. CTLA-4 acts as a signal dampener acting primarily within the lymph nodes to regulate the early activation of naive and memory T cells. PD-1, by contrast, is induced on T cells after activation in response to inflammatory signals and limits T-cell function in peripheral tissues.7 The anti–CTLA-4 monoclonal antibody ipilimumab improved survival in a phase III trial in patients with metastatic melanoma8 and was subse-

have found reductions in tumor size of more than 80% in the majority of patients in one study,10 and a 4-year survival rate of approximately 20% in another.8

Adoptive Immunotherapy How has adoptive immunotherapy been used in renal cell carcinoma treatment, and where you think the new era of treating metastatic renal cell carcinoma is headed?

Adoptive immunotherapy refers to the passive transfer of immune cells with antitumor activity into a tumorbearing host. Currently, there are three main strategies that have been extensively studied for the adoptive immunotherapy of cancer.

The first use of adoptive immunotherapy of cancer was based on the use of tumor-infiltrating lymphoctyes. The antitumor activity of tumor-infiltrating lymphoctyes is thought to be mediated through interaction between the tumor cell and the T-cell receptor and is major

The next decade will witness a new renaissance in the use of immunotherapy of renal cell carcinoma. This will be based on combinations of nonspecific immunotherapies, targeted immunotherapies utilizing engineered T cells, augmentation of the anticancer immune response, and likely even combinatory approaches simultaneously using standard molecularly targeted approaches.

—Arie Belldegrun, MD, FACS, and Allan Pantuck, MD, MS, FACS

quently approved by the FDA in 2011 for the treatment of patients with that indication. However, the fully human anti–PD-1 monoclonal antibody BMS936558/MDX-1106/ONO -4538 (nivolumab), has already demonstrated impressive antitumor activity in phase I/Ib studies of not only renal cell carcinoma, but also castration-resistant prostate cancer, non–small cell lung cancer, and colorectal cancer.9 What is notable about the clinical results using checkpoint inhibitor therapy is the high level of antitumor activity (eg, the spectrum of tumors that appear to be responsive, and the durability of the responses). In advanced melanoma, for example, investigators

GUEST EDITOR

histocompatibility complex (MHC)restricted.11 Early trials of tumor-infiltrating lymphoctyes in metastatic renal cell carcinoma such as the UCLA experience combining tumor-infiltrating lymphoctyes with low-dose IL-2 plus interferon demonstrated the feasibility of this approach, with an intriguing 35% response rate that includes durable remissions.12 However, a subsequent multicenter phase III trial randomly assigning subjects with metastatic renal cell carcinoma to low-dose IL-2 alone vs low-dose IL-2 plus tumor-infiltrating lymphoctyes was negative.13 After randomization of 160 subjects, intentto-treat analysis revealed response rates

Richard J. Boxer, MD, FACS

Richard J. Boxer, MD, FACS, is Visiting Professor at the David Geffen School of Medicine at UCLA, Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin (Milwaukee), and former Professor of Clinical Urology at the University of Miami. He is also an Associate Editor of The ASCO Post. of 9.9% vs 11.4% (IL-2 vs IL-2/tumorinfiltrating lymphoctyes).

Nevertheless, this negative trial was fraught with difficulty, especially with regard to the successful preparation of tumor-infiltrating lymphoctyes at a centralized facility. Of the subjects randomly assigned to the tumor-infiltrating lymphoctye arm, 41% did not receive these cells because of processing difficulties.

To date, tumor-infiltrating lymphoctye therapy has proven effective only in the treatment of metastatic melanoma. This limitation has arisen primarily because it has not proven to be possible to consistently and successfully isolate, culture, establish, and expand large populations of tumor-reactive T cells with anticancer activity from the tumors of the majority of patients having other tumor types.

The two other strategies of adoptive T-cell immunotherapy have found ways to circumvent this problem.14 T-cell receptor therapy utilizes patients’ easily acquired peripheral T cells, which are then genetically engineered using viral vectors to transduce and express a specific recombinant Tcell receptor capable of recognizing a specified tumor antigen (eg, CAIX, MART-1, NY-ESO). Clinical trials of T-cell receptor therapy have shown unexpected anticancer activity in a number of solid tumor indications including melanoma and other unanticipated diseases such as colorectal cancer and synovial sarcoma.15,16 continued on page 6

The ASCO Post | APRIL 15, 2014

PAGE 6

Genitourinary Cancers Symposium Renal Cell Carcinoma continued from page 5

Although T-cell receptor–transduced T cells are engineered to express a particular T-cell receptor, they still require tumor recognition in the context of MHC restriction, and therefore, they can be used only in a subset of patients. They are vulnerable to the wellknown mechanism of tumor evasion of immune recognition through MHC downregulation.

The third strategy for adoptive Tcell therapy circumvents these issues as well. In this option, peripherally acquired T cells are transduced by a chi-

meric antigen receptor that combines the variable region of an antibody domain with a CD3/T-cell signaling molecule. More recent second- and thirdgeneration chimeric antigen receptor iterations include other costimulatory molecules such as CD28 and 4-IBB.17 The ability of the chimeric antigen receptor to recognize tumor antigens and engage native T-cell receptor– mediated activation is derived from non–MHC-restricted antibody binding, which is capable of antigen recognition and binding with exquisite sensitivity. Moreover, like T-cell receptor trials, clinical trials of modern chi-

meric antigen receptor strategies have demonstrated great potential across a spectrum of tumor types, with the greatest success thus far being seen in a variety of hematologic malignancies expressing the CD19 antigen.18,19 The use of T-cell receptor and chimeric antigen receptor technology has only just begun to be applied to renal cell carcinoma.20 The next decade will witness a new renaissance in the use of immunotherapy of renal cell carcinoma. This will be based on combinations of nonspecific immunotherapies such as IL-2, targeted immunotherapies utilizing engineered T cells, aug-

mentation of the anticancer immune response through the use of immune checkpoint blockade, and likely even combinatory approaches simultaneously using standard molecularly targeted approaches. n Disclosure: Drs. Pantuck and Belldegrun are scientific founders and equity holders of Kite Pharma Inc, a Los Angeles–based biotechnology company dedicated to the development of adoptive T-cell receptor and chimeric antigen receptor engineered T-cell cancer therapies. Dr. Belldegrun is Executive/ Director of Kite Pharma.

References available online at www. ascopost.com.

Bladder Cancer Patient With Rare Genetic Mutations Shows Exceptional Response to Everolimus/Pazopanib Combination

A

patient with advanced bladder cancer experienced a complete response for 14 months to the drug combination everolimus (Afinitor) and pazopanib (Votrient) in a phase I trial, and genomic profiling of his tumor revealed two alterations that may have caused this exceptional response, according to a study published in Cancer Discovery.1 This information can help identify patients with cancer who may respond to everolimus. “Exceptional responders” are those who had a complete or partial response for at least 6 months to treatment in a clinical trial in which less than 10% of patients responded, according to the National Cancer Institute.

“Studying exceptional responses can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents,” said Nikhil Wagle, MD, an Instructor in Medicine at Dana-Farber Cancer Institute, Boston, and an Associate Member at the Broad Institute in Cambridge, Massachusetts. “We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents.

Phase I Trial “We conducted a phase I clinical trial of two anticancer agents—the mTOR inhibitor everolimus, and pazopanib, another drug used to treat kidney cancer—and one of our patients developed

near complete remission of his bladder cancer that lasted for 14 months,” said Dr. Wagle. “We performed wholeexome sequencing of the patient’s tumor, and to our surprise, we identified two mutations in the gene MTOR, which is the target of everolimus.”

In this phase I trial, the investigators recruited nine patients with advanced solid tumors, including five with bladder cancer, whose diseases had progressed despite treatment with standard therapies. Patients received 1 to 13 cycles of everolimus and pazopanib.

One of five patients with bladder

Two Mutations

Study Implications

The two mutations, MTOR E2419K and MTOR E2014K, had never been identified in humans, according to Dr. Wagle, although one of the mutations had previously been well studied by scientists in yeast and in human cell lines.

Dr. Wagle and colleagues conducted further studies in a laboratory setting to understand the nature of the two mutations, and found that they activated the mTOR-mediated cell signaling pathway. These mutations likely rendered the patient’s cancer dependent on the mTOR pathway to survive, which is the likely reason the cancer became exqui-

“Results of our study suggest that we should make a catalog of activating genomic alterations in the genes in the mTOR pathway,” said Dr. Wagle. “Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors,” he added.

“This study is yet another example of how therapies targeted toward the genetic features of a tumor can be highly effective, and our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients,” he continued. “There are many more patients out there with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them.” n

...our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients —Nikhil Wagle, MD

cancer had a complete response, as evaluated by imaging, which lasted for 14 months. To understand why his tumor responded dramatically, the investigators performed complete sequencing of the coding regions of his tumor genome, which included about 25,000 genes, and identified two mutations in MTOR.

sitely sensitive to the mTOR inhibitor everolimus, explained Dr. Wagle.

Three other patients with bladder cancer in this clinical trial had stable disease for less than 6 months, and a patient with cancer in his adrenal gland had prolonged stable disease for 13 months. None of the patients with lung cancer benefited from this trial.

Disclosure: This study was funded by the Next Generation Fund at the Broad Institute of MIT and Harvard, the National Human Genome Research Institute, GlaxoSmithKline, and Novartis. Dr. Wagle is an equity holder and a consultant to Foundation Medicine.

Reference 1. Wagle N, Grabiner BC, Van Allen EM, et al: Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

Cancer Discov. March 13, 2014 (early release online).

Visit The ASCO Post website at ASCOPost.com

Advertisement not displayed in digital edition at advertiser’s request

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | APRIL 15, 2014

PAGE 9

News Interventional Radiology

Georgetown Researchers Study Nonsurgical, Minimally Invasive Approach to Benign Prostatic Hyperplasia

P

hysicians at MedStar Georgetown University Hospital and Georgetown University Medical Center, Washington, DC, are studying the safety and effectiveness of prostate artery embolization in men with enlarged prostate glands and urinary obstruction. According to the National Institutes of Health, benign prostatic hyperplasia occurs in more than half of men in their 60s and 90% of men in their 70s and 80s.

Symptoms of benign prostatic hyperplasia include difficulty urinating, more frequent and urgent urination, especially at night, and a weak urine flow.

“While the condition is not cancer and is not life-threatening, the symptoms can be very severe and substantially affect a man’s quality of life,” said James Spies, MD, principal investigator of the

Advertisement not displayed in digital edition at advertiser’s request

“We go in through the artery at the top of the leg, and the procedure usually takes 2 hours or less,” said Dr. Spies, who is also Professor of Radiology at Georgetown University School of Medicine.

Studies conducted in other countries suggest the procedure is effective in most men and that injuries to other structures are rare.

“This procedure does carry some potential risks,” said Dr. Spies. “This study will focus on the safety of the procedure, particularly to make sure there are no injuries to the bladder or rectum, which are very close to the prostate. The study will also measure the severity of symptoms before and for 5 years after the procedure.”

Since 2001, Dr. Spies has pioneered uterine fibroid embolization in women

We hope [prostate artery embolization] will be a less invasive, less drastic approach that will be safe and effective.

— James Spies, MD

study and Chair of Radiology at MedStar Georgetown. “Because so many men are affected by this condition, the potential impact of an effective minimally invasive treatment could be substantial.”

Alternatives to treating benign prostatic hyperplasia include drug therapy, transurethral resection of the prostate, or removal of the prostate by way of an open abdominal operation, said Dr Spies. “We hope [prostate artery embolization] will be a less invasive, less drastic approach that will be safe and effective.”

About the Procedure Prostate artery embolization is a nonsurgical, minimally invasive procedure that injects small beads into the arteries surrounding the prostate. The beads block the prostate’s blood supply, and the prostate begins to shrivel and shrink. The patient stays in the hospital for one night and can usually return to regular activities within several days.

and is considered an international expert in interventional radiology. In that procedure, the same kinds of tiny beads are used to block the blood supply to the fibroid, which causes it to shrink and die.

Enrollment Criteria This is the first prostate artery embolization study authorized in the United States by the Food and Drug Administration under an Investigational Device Exemption and will allow the research team to study the safety and effectiveness of the treatment.

To participate in the study, patients must be at least 50 years of age but not older than 90, have had symptoms of benign prostatic hyperplasia for at least 6 months, and meet certain criteria for urine flow and size of the prostate gland. They cannot have had prior surgery for benign prostatic hyperplasia or have prostate cancer. Each patient will be screened for prostate cancer as a part of the protocol. n

The ASCO Post | APRIL 15, 2014

PAGE 10

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Cetuximab Fails to Improve Survival in Nonoperable Esophageal Cancer

By Caroline Helwick

M

ore data have emerged that discount the potential for benefit with epidermal growth factor receptor (EGFR) inhibitors in esophageal cancer. The latest comes from the RTOG 0436 randomized phase III trial in patients with nonoperable esophageal cancer, the results of which were presented at the 2014 Gastrointestinal Cancers Symposium.1 “The addition of cetuximab [Erbitux] to weekly cisplatin/paclitaxel and daily radiation therapy did not improve overall survival in patients with esophageal cancer,” said Mohan Suntharalingam, MD, of the University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore.

“These data add to the growing evidence that currently available EGFR inhibitors fail to improve survival of unselected patients treated nonoperatively with concurrent chemoradiation.”

Study Design The study enrolled 344 patients with adenocarcinoma or squamous carcinoma. Approximately 80% of patients had stage T3/T4 disease and 20% had stage T1/T2 disease. Twothirds of patients had nodal involvement. Both arms received weekly paclitaxel at 50 mg/m2 and cisplatin at 25 mg/m2 with daily radiation to 50.4 Gy (1.8 Gy per fraction). In the experimental arm, patients also received

cetuximab at 400 mg/m2 on day 1 followed by 250 mg/m2 of cetuximab weekly. The primary endpoint was an improvement in overall survival with the addition of cetuximab to concurrent chemoradiotherapy.

Study Outcomes At 2 years, the overall survival rate was 44% for the cetuximab/chemoradiotherapy arm and 41.7% for the

“The study did show that achieving a clinical complete response at 6 to 8 weeks improved overall survival,” Dr. Suntharalingam noted. Risk of dying was doubled for patients who did not achieve a clinical complete response.

“By histology, this held up. This provides evidence that endoscopic response rate post-treatment is predictive of overall survival,” he said.

In a multivariate analysis for overall

The addition of cetuximab [Erbitux] to weekly cisplatin/paclitaxel and daily radiation therapy did not improve overall survival in patients with esophageal cancer.

—Mohan Suntharalingam, MD

chemoradiotherapy-alone arm, for a hazard ratio (HR) of 0.92 that was not statistically significant (P = .70), he reported.

By histology, overall survival was also similar. Clinical response rates (assessed at endoscopy 6 to 8 weeks after completion of treatment) also were not improved with the addition of cetuximab, regardless of histology. Complete responses were observed in 56% of all patients with adenocarcinoma who received cetuximab vs 59% of the control arm (P = .72), and in 59% of squamous cell patients who received cetuximab vs 64% of the control arm (P = .78).

Addition of Cetuximab to Chemotherapy Offers No Benefit in Esophageal Cancer ■■ In RTOG 0436, patients with nonoperable esophageal cancer derived no overall survival benefit from the addition of cetuximab to chemoradiotherapy, regardless of histology.

■■ Patients who achieved a clinical complete response to treatment had significantly better overall survival.

survival, poor performance status (HR = 1.56; P = .0015) and larger lesion size (HR = 1.72; P = .0002) were associated with worse survival.

Still Work to Be Done Manish A. Shah, MD, Director of Gastrointestinal Oncology at the Center for Advanced Digestive Care at Weill Cornell Medical College, New York, discussed the results at the meeting and noted that the failure of cetuximab in this setting is “consistent with previous results in metastatic disease.” In the REAL3 study, panitumumab (Vectibix) did not improve survival, and in the EXPAND study, cetuximab failed.

It is unclear why EGFR inhibitors are ineffective in esophageal cancers, he said, noting that while EGFR mutations are actually not among the most common mutations in esophageal cancers, EGFR amplification does occur frequently. This may suggest that other downstream redundant path-

ways may be involved in resistance to this class of targeted therapy. “It’s complicated,” he said.

Ongoing Trials Dr. Shah suggested that the best approach to improving survival in this

Manish A. Shah, MD

disease is to improve response to therapy, optimize targeted therapy, and improve the understanding of tumor biology. These challenges are being tackled in ongoing trials.

Cancer and Leukemia Group B (CALGB) 80803 is evaluating early assessment by positron-emission tomography to assess the efficacy of chemotherapy, with switching of therapy in nonresponders. Targeted therapy with trastuzumab (Herceptin) added to chemoradiotherapy is being evaluated in the Radiation Therapy Oncology Group (RTOG) 1010 study. And RTOG 0436, the study presented at the symposium, has tissue on 85% of patients, which may elucidate those most likely to respond to these drugs, he said. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Suntharalingam M, Winter K, Ilson DH, et al: The initial report of RTOG 0436: A phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. 2014 Gastrointestinal Cancers Symposium. Abstract LBA6.

Presented January 16, 2014.

Delivered to your inbox every weekday evening.

Visit ASCOPost.com to learn more.

ASCOPost.com | APRIL 15, 2014

PAGE 11

ASH Highlights of North America Hematology

Better Options Emerging for Salvage Therapy in Hodgkin Lymphoma

By Caroline Helwick

E

merging effective treatment options for salvage therapy in Hodgkin lymphoma were described by Anas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York, at the 2014 Highlights of ASH in North America meeting in Miami.

“This is an exciting time in Hodgkin lymphoma. New agents appear promis-

transplant, treated with brentuximab vedotin at 1.8 mg/kg every 3 weeks for up to 16 cycles.

In this high-risk population known to have a poor prognosis, the median time to relapse after autologous transplant was 6.7 months. Patients received a median of nine cycles of brentuximab vedotin, which led to an overall response rate of 75%, with complete

This is an exciting time in Hodgkin lymphoma. New agents appear promising, and based on mature results of clinical trials, we may be able to reduce our patients’ exposure to potentially toxic therapy and improve outcomes in challenging patients.

—Anas Younes, MD

ing, and based on mature results of clinical trials, we may be able to reduce our patients’ exposure to potentially toxic therapy and improve outcomes in challenging patients, such as the elderly,” Dr. Younes said.

Brentuximab Vedotin After Autologous Transplant Three-year follow-up data from a recently completed multicenter phase II trial of brentuximab vedotin (Adcetris) in patients with relapsed or refractory Hodgkin lymphoma after autologous transplant were presented at the 2013 American Society of Hematology (ASH) Annual Meeting by Ajay K. Gopal, MD, of University of Washington/Fred Hutchinson Cancer Research Center, Seattle, and colleagues.1 The drug contains a potent antitubulin agent (monomethyl auristatin E), a protease-cleavable linker, and an anti-

remissions achieved in 33% of these patients.

The patients were analyzed approximately 3 years after their first dose of brentuximab vedotin. Of the 102 patients enrolled, 51 (50%) were still alive, yielding a median overall survival of 40.5 months and estimated 3-year survival rate of 54%. Median progression-free survival by central independent review was 9.0 months for patients achieving a complete or partial response and only 2.8 months for those with stable or progressive disease.

“The long-term follow-up of complete and partial responses shows that 25% or so continue to be in remission, and this is remarkable,” Dr. Younas commented.

The most common grade 3/4 adverse events were neuropathy (9%

grade 3) and neutropenia (14% grade 3, 6% grade 4).

“This brings us to the ongoing debate about the optimal treatment for patients failing autotransplant and now achieving a complete response with brentuximab. Should we send them immediately to allogeneic transplant, or wait? It seems that patients can remain in complete remission for several years,” he noted.

“My personal preference for patients achieving a rapid complete response with brentuximab is to wait,” he said.

“Why? The toxicity associated with allogeneic stem cell transplant in this setting remains fairly high, and its efficacy in Hodgkin lymphoma is not as good as it is with other lymphoid malignancies.

Furthermore, the data suggest we can re-treat with brentuximab and achieve a second response, and then do an allogeneic transplant.”

Brentuximab, ICE in Sequence Pretransplant 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET) normalization is the strongest predictor of outcome after autologous transplant for patients with relapsed or refractory disease. Alison J. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, and colleagues used a PET-adapted sequential treatment approach with brentuximab vedotin and augmented ICE (ifosfamide, carboplatin, etoposide) prior to autotransplant as salvage therapy.2 The phase II study included 40 patients with relapsed/refractory disease who experienced treatment failure on one prior regimen. Patients received weekly brentuximab vedotin at 1.2 mg/ kg for 3 weeks on, 1 week off, for two cycles followed by PET. Patients whose

Novel Approaches to Hodgkin Lymphoma ■■ In patients with relapsed or refractory Hodgkin lymphoma following autologous stem cell transplant, treatment with brentuximab vedotin led to a median overall survival of 40.5 months and an estimated 3-year survival rate of 54%, in a phase II study of 102 patients.

Ajay K. Gopal, MD

CD30 monoclonal antibody.

The study involved 102 patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell

■■ As salvage therapy, a PET-adapted sequential treatment approach, brentuximab vedotin followed by augmented ICE in those who failed to achieve a response to brentuximab alone, produced an 80% complete response rate and adequate stem cell collection. ICE was avoided in 30% of patients.

■■ Pancreatitis appears to be a rare but potentially life-threatening adverse effect of brentuximab vedotin.

■■ Panobinostat in combination with ICE produced a complete response rate of 71% in relapsed/refractory patients.

Alison J. Moskowitz, MD

PET normalized proceeded to autologous transplant, while those remaining PET-positive received two cycles of augmented ICE prior to being considered for transplant.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ICE produced an 80% complete response rate and an adequate stem cell collection, and it facilitated the referral to autologous stem cell transplant for virtually all patients, the authors reported.

“With this approach, 30% of patients avoided ICE salvage therapy,” Dr. Younes noted. Of 40 evaluable patients, 36 completed transplant, 3 will undergo transplant shortly, and 1 remains on treatment for persistent disease. The study was amended for an additional 20 patients, who will receive three cycles of brentuximab vedotin prior to the first PET (before ICE).

Pancreatitis as a Side Effect of Brentuximab Pancreatitis was reported to be an adverse event of brentuximab vedotin treatment in a study by Mitul Gandhi, MD, of Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, and colleagues reported at the ASH Annual Meeting.3 “Pancreatitis is a previously unidentified, rare (< 1%) but potentially lifethreatening toxicity of brentuximab,” Dr. Younes said.

The study described one index case and eight additional cases of pancreatitis in patients receiving the drug, two of which were fatal. The index patient was a 65-year-old with no conventional risk factors for pancreatitis. She received two cycles of brentuximab vedotin prior to AVD and developed grade 3 diarrhea and abdominal pain after the first dose. Nine days after the second dose, she was hospitalized with acute, severe pancreatitis. She died 6 days later of sepsis and multisystem organ failure. continued on page 12

The ASCO Post | APRIL 15, 2014

PAGE 12

ASH Highlights of North America Salvage Therapy in Hodgkin Lymphoma continued from page 11

The autopsy specimen demonstrated fat necrosis and coagulation necrosis of the pancreas, with CD30 positivity found in 35% of analyzed cells, “which was surprising,” Dr. Younes noted. An analysis of the eight additional cases indicated the condition develops early, after about two standard doses of the drug.

“Be aware of this. In patients who experience abdominal pain following treatment with brentuximab, especially during the first few cycles, stop the treatment and investigate for pancreatitis. The good news is, it’s very rare,” he said.

“This is only a phase I study, but at face value the results are probably slightly better than what we expect with ICE alone,” Dr. Oki suggested. A randomized phase II study has been initiated. n Disclosure: Dr. Younes reported consultancy, research funding, and/or

honoraria from Novartis, Seattle Genetics, Millennium, and Syndax.

References 1. Gopal AK, Chen R, Smith SE, et al: 2013 ASH Annual Meeting. Abstract 4382. Presented December S:6.75” 9, 2013.

2. Moskowitz A, Schoder H, Gerecitano

JF, et al: 2013 ASH Annual Meeting. Abstract 2099. Presented December 7, 2013.

3. Gandhi M, Evens AM, Fenske TS, et al: 2013 ASH Annual Meeting. Abstract 4380. Presented December 9, 2013.

4. Oki Y, Fanale M, Westin JR, et al: 2013 ASH Annual Meeting. Abstract 252.

Presented December 9, 2013.

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

Panobinostat for Hodgkin Lymphoma The potent oral histone deacetylase inhibitor panobinostat given in combination with standard ICE led to an overall response rate of 86%, with complete responses in 15 of 21 patients (71%) in a phase I study reported by Yasuhiro Oki, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues.4 Panobinostat was given on Monday, Wednesday, and Friday, beginning 1 week before the first ICE treatment and continued during ICE through the second cycle. The third cycle was given without panobinostat, based on con-

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

Yasuhiro Oki, MD

cerns over stem cell collection. The starting dose of panobinostat was 20 mg, with a target dose of 30 mg.

Of the 18 responders, 17 patients had autologous transplant without additional treatment (except for stem cell mobilization). Three patients received one or more additional treatments, then went on to transplant. There were no issues with harvest or engraftment, Dr. Younes reported.

Send Us Your NEWS Write to editor@ASCOPost.com.

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.

All submissions will be considered for publication © 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/13 [03-13-00091-A]

B:1

T:1

Announcements

ASH Awards Bridge Grants to 15 Investigators he American Society of Hematology (ASH) recently announced the names of 15 researchers (see sidebar on page 15) who will receive interim support from the Society for hematology research pro-

posals. These proposals earned high scores but could not be funded by the National Institutes of Health (NIH) amid severe funding reductions, The support will S:6.75” come in the form of 1-year, $100,000 ASH Bridge Grants,

awards intended to help bridge these ASH member investigators to their next NIH research grant by funding efforts to gather additional data to strengthen the resubmission of their applications.

Bridge to NIH Funding The 15 noteworthy ASH Bridge Grant recipients announced recently join 29 hematologists who have been granted funding since ASH commitcontinued on page 14

PROD

T

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

median

median

months

months

11.2

ED AE/AS AD

4.0

CW

COMETRIQ™ (n=219)

CD

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 13

S&H

17.5”

ASCOPost.com | APRIL 15, 2014

Cosmos Commu

The ASCO Post | APRIL 15, 2014

PAGE 14

Announcements ASH Bridge Grants continued from page 13

ted $9 million in Society funds to create the program in July 2012. Among these 29 talented investigators, nearly one-third have already successfully obtained NIH funding.

Following a decade of flat funding for the agency, in 2013 the NIH budget was slashed by more than 5%

as part of sequestration. While Congress restored nearly $1 billion to the NIH budget for fiscal year 2014, funding for U.S. biomedical research remains insufficient to address the need for treatments for blood diseases worldwide. The current federal appropriation to NIH is more than $700 million short of the agency’s pre-sequestration budget,

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

“Despite small signs of improvement, the current NIH funding climate is far from perfect and the impact on biomedical innovation has been devastating,” said ASH President Linda J. Burns, MD, of the University of Minnesota in Minneapolis.

“While our early success rates suggest that the ASH Bridge Grant program is making an impact, it is still a tem-

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

porary fix for a larger problem. Lawmakers must understand the damaging effect that unpredictable funding will have on research and patients and invest in biomedical research.”

The studies supported by ASH’s third round of bridge grants span the breadth of hematology. Funded projects range from exploration of new therapeutic targets for multiple my-

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 | APRIL 15, 2014

PAGE 15

Announcements

Early success rates suggest that the ASH Bridge Grant program is making an impact, [but] it is still a temporary fix for a larger problem.

—Linda J. Burns, MD, ASH President

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

2

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

eloma and osteolytic bone disease, to the causes and cures of anemias and iron overload disorders and the connection between autoimmunity and cancer. Other funded studies include one that evaluates drug regimens for leukemias and lymphomas based on genetic factors and another that aims to refine prognostic tools for chronic lymphocytic leukemia.

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]

To learn more about ASH’s Bridge Grant Program, visit www.hematology .org/bridgegrants. n

ASH Bridge Grant Recipients (Announced March 2014) • Adam N. Goldfarb, MD, University of Virginia, Charlottesville • Alvin H. Schmaier, MD, Case Western Reserve University Medicine, Cleveland • Demin Wang, PhD, BloodCenter of Wisconsin, Milwaukee • Don M. Wojchowski, PhD, Maine Medical Center Research Institute, Portland, and Tufts University School of Medicine, Boston • Elizabeta Nemeth, PhD, University of California, Los Angeles • Jatinder K. Lamba, PhD, University of Minnesota, Minneapolis • John G. Conboy, PhD, Lawrence Berkeley National Laboratory, Washington, DC • Joel S. Bennett, MD, University of Pennsylvania, Philadelphia • Joanne E. Murphy-Ullrich, PhD, University of Alabama at Birmingham, Alabama • John K. Cowell, PhD, Georgia Regents University, Augusta • Jordan Jacobelli, PhD, National Jewish Health, Denver • Keith McCrae, MD, Cleveland Clinic Foundation, Cleveland • Michael B. Jordan, MD, Cincinnati Children’s Hospital, Cincinnati • Trista E. North, PhD, Beth Israel Deaconess Medical Center, Boston • Neil E. Kay, MD, Mayo Clinic, Rochester

The ASCO Post | APRIL 15, 2014

PAGE 16

ASH Highlights of North America Hematology

‘Double-Hit’ Lymphomas a Challenge for the Oncologist

By Caroline Helwick

“D

ouble-hit” lymphomas remain challenging tumors, and the best means of treatment remains somewhat elusive, according to studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans, and experts who commented on these findings.

“We still don’t have a standard of care, much less a home run,” said Myron S. Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, who spoke on the topic at the 2014 Highlights of ASH in North America meeting in Miami.

The ASCO Post also spoke with Daniel J. Landsburg, MD, a fellow in the Division of Hematology/Oncology at the Hospital of the University of Pennsylvania, Philadelphia, who noted, “Double-hit lymphoma is a very interesting disease that is difficult to treat effectively. I think that targeted therapies hold promise, but we are not there yet.”

Double-hit lymphomas are highgrade B-cell lymphomas characterized

an] plus cyclophosphamide, doxorubicin, vincristine, prednisone), as compared to patients with similar histologies lacking the dual genetic anomalies. This often prompts the use of more intensive treatments, Dr. Landsburg added.

Impact of Induction and Consolidation Transplant At the ASH highlights meeting, Dr. Czuczman described a 15-center study

by Mitul Gandhi, MD, of Robert H.

ifosfamide, carboplatin, etoposide).

The 106 patients primarily had rearrangements of MYC and BCL2. The most common histology was diffuse large B-cell lymphoma (53%), followed by B-cell lymphoma–unclassified (42%), and Burkitt-like lymphoma (5%). Fourteen patients (13%) were consolidated with transplant after intensive induction. Three additional patients underwent transplant in partial remission after R-CHOP. “We see that the results without

It’s the worst of both worlds….

You have Bcl2 protein expression, which renders cells antiapoptotic and more difficult to kill, and a MYC rearrangement that makes cells more proliferative. You can kill MYC-positive cells, but if you add resistance to chemotherapy you get the double hit.

—Myron S. Czuczman, MD

Daniel J. Landsburg, MD

by dual chromosomal rearrangements, specifically of MYC and either BCL2 or, less commonly, BCL6. “It’s the worst of both worlds,” Dr. Czuczman said. “You have Bcl2 protein expression, which renders cells antiapoptotic and more difficult to kill, and a MYC rearrangement that makes cells more proliferative. You can kill MYC-positive cells, but if you add resistance to chemotherapy you get the double hit.”

Outcomes are typically poor with standard immunochemotherapy regimens, ie, R-CHOP (rituximab [Ritux-

Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, and colleagues. These investigators retrospectively evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation, in patients with double-hit lymphoma.1 Patients were treated with R-CHOP or one of the following intensified regimens: R-hyperCVAD (rituximab plus cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, methotrexate [cycle A], alternating with methotrexate, leucovorin, cytarabine [cycle B]); R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclohosphamide, doxorubicin); R-CODOX-M/IVAC (rituximab plus cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, cytarabine); or R-ICE (rituximab plus

‘Double-Hit’ Lymphomas ■■ B-cell lymphoma patients with genetic rearrangements in MYC and BCL2 or BCL6 have “double-hit” lymphoma that carries a very poor prognosis.

■■ No baseline characteristic, aside from the genetic profile, can identify these patients.

■■ Type of induction treatment does not impact progression-free or overall survival, but R-EPOCH seems to have the highest response rates.

transplant are pretty dismal,” Dr. Czuczman said. “R-EPOCH is a little better, but there is no significant difference in overall survival.” Median progressionfree survival and overall survival for the entire cohort was 16.2 months and 34.8 months, respectively, at a median follow-up time of 23 months.

While the type of induction chemoimmunotherapy did not improve progression-free or overall survival in double-hit lymphoma patients, the alternative regimens were associated with higher response rates than R-CHOP, especially R-EPOCH where complete responses were almost 80%, compared to approximately 45% with R-CHOP and 60% with the other regimens. With R-EPOCH, as well, only about 10% of patients had progressive disease as their best response.

“The study confirmed that doublehit lymphoma is associated with a poor prognosis, although a subset of patients can achieve a durable complete response. R-EPOCH was associated with improved rates of complete response and decreased rates of primary refractory disease. The study also showed that stem cell transplant does not clearly improve overall survival compared to observation alone, in patients who achieve a complete response,” he said at the

ASH highlights meeting. While transplant can produce better outcomes, he added, early relapse is common.

Can Baseline Characteristics Be Helpful?

At the ASH Annual Meeting, Dr. Landsburg presented an analysis of 53 patients with B-cell lymphoma who underwent diagnostic fluorescence in situ hybridization (FISH).2 The study evaluated whether double-hit status can be predicted by clinicopathologic features, which theoretically could be useful in streamlining expensive tests, and it documented the impact of double-hit status on survival. Double-hit lymphoma was identified in 32% of patients, while a sole MYC gene rearrangement was found in 17%.

“No factor, including age, [lactate dehydrogenase], stage, [International Prognostic Index], or histology, was predictive of double-hit status,” Dr. Landsburg reported.

Patients with double-hit lymphoma were treated with R-hyperCVAD (41%), R-CHOP (41%), and other regimens (18%) at the discretion of the physician. Compared to patients lacking double hits, these patients were significantly less likely to achieve a complete response (41% vs 81%, P = .002) and had a significantly shorter median overall survival (8.2 vs 56.8 months, P < .001).

In the multivariate regression analysis for overall survival, only double-hit– positive status was a significant predictive factor, carrying a hazard ratio (HR) of 7.3 (P = .013). In the univariate analysis, MYC rearrangement was significant (HR = 5.0, P = .004), along with double-hit status (HR = 9.2, P < .001), he reported. A sole MYC rearrangement did not appear to carry a worse prognosis than normal MYC status, as median overall survival was 50.8 months in this group and was not reached in patients lacking a MYC rearrangement (P = .33).

“Double-hit status cannot be inferred by baseline disease- or patient-related characteristics and is most predictive of overall survival in this cohort of B-cell lymphoma patients,” he concluded. “These findings support the practice of routine FISH for gene rearrangements in order to increase the identification of double-hit patients who may benefit from risk-adapted therapy.”

At the University of Pennsylvania, most patients receive R-hyperCVAD.

ASCOPost.com | APRIL 15, 2014

PAGE 17

ASH Highlights of North America “Relapses are very tough to salvage, so if a patient is young and healthy, we give intensive chemotherapy up front and hope to get them into remission,” Dr. Landsburg said. He noted that, unlike R-EPOCH, the “B” cycle of R-hyperCVAD provides penetration into the central nervous system, but R-EPOCH is easier to give. “We feel better about giving hyperCVAD, but it is a difficult regimen for patients to tolerate, and you

need to monitor closely for toxicity,” he added.

The investigators plan to validate their findings in a larger unselected cohort of diffuse large B-cell lymphoma patients, the group most impacted by double hits. Both experts agreed on the urgent need for novel approaches to overcome the unfavorable biology of this malignancy. They felt that the Bcl2 inhibitor ABT-199 is a promising

compound, as it might be able to downregulate Bcl2 and resensitize patients to chemotherapy. n

Disclosure: Drs. Czuczman and Landsburg reported no potential conflicts of interest.

References 1. Gandhi M, Petrich AD, Cassaday RD, et al: Impact of induction regimen and consolidative stem cell transplantation in patients with double hit lym-

phoma: A large multicenter retrospective analysis. 2013 ASH Annual Meeting. Abstract 640. Presented December 9, 2013.

2. Landsburg D, Nasta D, Svoboda J, et al: “Double-hit” cytogenetic status is not predicted by baseline clinicopathologic characteristics and is highly associated with overall survival in B cell lymphoma patients. 2013 ASH Annual Meeting. Abstract 4338. Presented December 9, 2013.

Awards

AACR Awards Webster Cavenee, PhD, Award for Leadership, Achievements

W

ebster K. Cavenee, PhD, was honored with the eighth annual American Association for Cancer Research (AACR) Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research at the AACR Annual Meeting held recently in San Diego. Dr. Cavenee is Director of the Ludwig Institute for Cancer Research, San Diego, and Distinguished

Webster K. Cavenee, PhD

Professor at the University of California, San Diego. He was recognized for his pioneering work in cancer genetics, for his leadership and global efforts against, glioblastoma multiforme; and for his service to the AACR for more than 25 years, including serving as AACR President in 1998-1999.

Groundbreaking Discoveries “Dr. Cavenee is an outstanding basic cancer researcher who made groundbreaking discoveries that fundamentally changed our understanding of tumor initiation and progression,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “His impact on international cancer research extends far beyond his own scientific achievements. He is a key leader in our

global efforts to accelerate the pace of scientific discovery and improve survival for patients with glioblastoma multiforme. In addition, he has volunteered an enormous amount of his professional life to furthering the work of the AACR. Dr. Cavenee is truly deserving of this award, which acknowledges an all-around champion of cancer research.” Dr. Cavenee said he was honored to be chosen to receive the AACR Margaret Foti Award, noting “This is especially gratifying because of the stellar group of previous awardees and the magnificent accomplishments of the namesake of the award.”

The Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research, established in 2007, recognizes an individual whose leadership and extraordinary achievements in cancer research, or in support of cancer research, have made a major impact on the field.

Pioneering Work in Genetics Much of Dr. Cavenee’s career has been spent unraveling the inherited genetic changes that predispose individuals to cancer. His pioneering work in retinoblastoma provided the first indisputable genetic evidence for the existence of tumor suppressor genes in humans and confirmed the “two-hit” hypothesis that had been proposed more than a decade earlier. He went on to identify other recessive genetic lesions that predispose individuals to Wilms tumor, osteosarcoma, and rhabdomyosarcoma, and established the concept of loss of heterozygosity, now

known to contribute to multiple cancers, both spontaneous and hereditary.

Advanced Understanding of Glioblatoma Multiforme Dr. Cavenee has also made key contributions to understanding the biology of glioblastoma multiforme. His research in this area has helped illuminate the molecular mechanisms that drive the growth, migration, and survival of glioblastoma multiforme cells and identified potential new therapeutic approaches.

In addition to his extraordinary research accomplishments, Dr. Cavenee is an active leader in global efforts against glioblastoma multiforme. He is a member of the Strategic Scientific Advisory

as a member of numerous committees.

In addition to his term as AACR President, he was a member of the AACR Board of Directors from 1994 to 1997.

Dr. Cavenee was named to the inaugural class of Fellows of the AACR Academy last year. He has been recognized with numerous other awards throughout his career. Dr. Cavenee is also an elected member of the National Academy of Sciences of the United States of America and the Institute of Medicine of the National Academies.

Dr. Cavenee received his undergraduate degree from Kansas State University in Manhattan, Kansas, and his doctorate from the University of

Dr. Cavenee is truly deserving of this award, which acknowledges an allaround champion of cancer research.

—Margaret Foti, PhD, MD (hc)

Council of the Defeat GBM Research Collaborative, which is a research-based effort launched by the National Brain Tumor Society that aims to double the 5-year survival rate for glioblastoma multiforme patients in 5 years.

Commitment to AACR Dr. Cavenee has served in various leadership positions for the AACR and

Kansas Medical School in Kansas City.

After completing postdoctoral work at the Jackson Laboratory and the University of Utah, Dr. Cavenee held professorships at the University of Cincinnati in Ohio and McGill University in Montreal, Quebec, Canada. He has been Director of the Ludwig Institute for Cancer Research, San Diego, since 1991. n

Visit The ASCO Post website at ASCOPost.com

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Important Safety Information Hypertension including hypertensive crisis has been observed.

Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.

Hemorrhagic events, including fatal events, have been reported.

INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal perforation and fistula, including death, have occurred.

Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

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

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

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

INLYTA was the 1st agent to demonstrate

SUPERIOR EFFICACY to sorafenib

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

6.7

months

vs

4.7

months

median PFS

median PFS

INLYTA

sorafenib

(n=361) (n=362) 95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose.

Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily ) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation.

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

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

INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily.

Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water.

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability.

Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria.

Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily.

Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.

Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side.

5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side.

CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib.

Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy.

Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib.

Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy.

In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension.

Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions].

In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.

Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib.

Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted.

Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.

Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.

Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients

AXU606812

(7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib.

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm.

Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE 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 clinical practice.

The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib.

The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development.

Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.

The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.

The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib.

Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib INLYTA Sorafenib (N=359) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).

The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib.

Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality

N

INLYTA All Grade Gradesa 3/4 % %

N

Sorafenib All Grade Gradesa 3/4 % %

Hematology Hemoglobin decreased 320 35 <1 316 52 4 Lymphocytes (absolute) decreased 317 33 3 309 36 4 Platelets decreased 312 15 <1 310 14 0 White blood cells decreased 320 11 0 315 16 <1 Chemistry Creatinine increased 336 55 0 318 41 <1 Bicarbonate decreased 314 44 <1 291 43 0 Hypocalcemia 336 39 1 319 59 2 ALP increased 336 30 1 319 34 1 Hyperglycemia 336 28 2 319 23 2 Lipase increased 338 27 5 319 46 15 Amylase increased 338 25 2 319 33 2 ALT increased 331 22 <1 313 22 2 AST increased 331 20 <1 311 25 1 Hypernatremia 338 17 1 319 13 1 Hypoalbuminemia 337 15 <1 319 18 1 Hyperkalemia 333 15 3 314 10 3 Hypoglycemia 336 11 <1 319 8 <1 Hyponatremia 338 13 4 319 11 2 Hypophosphatemia 336 13 2 318 49 16 a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

© 2013 Pfizer Inc.

All rights reserved.

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended.

If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration].

CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.

USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions].

There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/ kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis.

Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).

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

Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied.

Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger.

No dosage adjustment is required in elderly patients.

Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B).

No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B).

INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).

Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted.

Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).

OVERDOSAGE There is no specific treatment for INLYTA overdose.

In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).

In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis.

In cases of suspected overdose, INLYTA should be withheld and supportive care instituted.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib.

Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.

INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively).

In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).

PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances).

Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.

Rx only September 2013

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet.

2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

November 2013

ASCOPost.com | APRIL 15, 2014

PAGE 21

Journal Spotlight Breast Cancer

No Mortality Benefit of Mammography Screening in 25-Year Follow-up of Canadian National Breast Screening Study

By Matthew Stenger

A

s reported in BMJ by Anthony B. Miller, MD, Professor Emeritus at the Dalla Lana School of Public Health, University of Toronto, and colleagues, the 25-year follow-up of the Canadian National Breast Screening Study has shown no mortality benefit of annual mammography screening for breast cancer compared with physical examination or usual care. Mammography screening was associated with substantial overdiagnosis.

node-positive (P = .053), and 68.2% vs 100% were palpable. Palpable cancers had larger average size than cancers detected only on mammography (2.1 vs 1.4 cm, P < .001) and were more likely to be node-positive (34.7% vs 16.5%, P < .001).

The investigators noted, “Annual mammography screening detected a significant number of small non-pal-

[O]ur data show that annual mammography does not result in a reduction in breast cancer specific mortality for women aged 40 to 59 beyond that of physical examination alone or usual care in the community.

The data suggest that the value of mammography screening should be reassessed.

Study Details In the study, 89,835 women aged 40 to 59 years from 15 screening centers in six Canadian provinces were randomly assigned to five annual mammography screens (n = 44,925) or no mammography (n = 44,910) during 1980 to 1985.

Women aged 40 to 49 years in the mammography group and women aged 50 to 59 years in both groups received annual physical breast examinations, and women aged 40 to 49 years in the control group received a single breast examination followed by usual care in the community. The main outcome measure was deaths from breast cancer.

Incidence The subjects were followed for incident breast cancer for up to 25 years (mean, 21.9 years). During the 5-year screening period, 666 invasive cancers were diagnosed in the mammography group and 524 were diagnosed in the control group. An additional 2,584 and 2,609 cancers were diagnosed during further follow-up. Of the 666 cancers detected in the mammography group during the screening period, 484 (73%) were screendetected, 176 (27%) were interval cancers (detected within 1 year of last screening), and data were missing for 6.

During the screening period, the mean sizes of the diagnosed cancers were 1.91 cm in the mammography group and 2.10 cm (P = .01) in the control group; 30.6% vs 32.4% were

survival rate for women with cancer diagnosed by mammography only (nonpalpable) was 79.6%. In the mammography group, women with nonpalpable cancer had significanlty longer survival than those with palpable cancer (HR = 0.58, P < 10-4), and those with screen-detected cancer had longer survival vs those with interval cancer (HR = 0.61, P = .001).

—Anthony B. Miller, MD, and colleagues

pable breast cancers, but half of these were examples of over-diagnosis.”

Survival by Characteristics A total of 1,005 women (1.1% of total population) died from breast cancer during the 25-year follow-up, including 351 (29%) of 1,190 who were diagnosed during the screening period. The 25year survival was 70.6% for women with breast cancer detected in the mammography group and 62.8% for those with cancers diagnosed in the control group (hazard ratio [HR] = 0.79, P = .02).

The authors noted, “Although the difference in survival after a diagnosis of breast cancer was significant between those cancers diagnosed by mammography alone and those diagnosed by physical examination screening, this is due to lead time, length time bias, and over-diagnosis.”

Survival rates for women with palpable cancer were similar in the two groups (66.3% vs 62.8%), and the

Mammography Screening Reconsidered ■■ In 25-year follow-up of the Canadian National Breast Screening Study, annual mammography screening was not associated with reduced breast cancer mortality.

■■ Mammography was associated with substantial overdiagnosis of breast cancer.

Breast Cancer and Overall Mortality Of the 666 women (of 44,925) in the mammography group and 524 (of 44,910) in the control group diagnosed with cancer during the 5-year screening period, 180 and 171, respectively, died from breast cancer during the 25-year follow-up.

The overall hazard ratio for death from breast cancer diagnosed during the screening period was 1.05 (95% confidence interval [CI] = 0.85–1.30, P = .63).

The hazard ratio remained similar if the screening period was extended to 6 years (1.06, P = .55) or 7 years (1.07, P = .46).

Findings were similar among women aged 40 to 49 years (HR = 1.09, P = .58) and among women aged 50 to 59 years (HR = 1.02, P = .88).

Over total follow-up, 3,250 women in the mammography arm and 3,133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. There was no significant difference between groups in 25-year cumulative mortality from breast cancer (HR = 0.99, 95% CI = 0.88–1.12, P = .87).

A total of 9,477 women (10.6%) died during the follow-up period.

There was no significant difference between the mammography group

and the control group in 25-year cumulative mortality from all causes (HR = 1.02, 95% CI = 0.98–1.06, P = .28).

Overdiagnosis By the end of the 5-year screening period, there were 142 excess cases of breast cancer in the mammography group (666 vs 524). At 15 years after enrollment, the excess number of cancers in the mammography group became constant at 106 cancers. The excess number represents 22% (106/484) of all screen-detected cancers. Thus, there was one case of overdiagnosis of breast cancer for every 424 women screened by mammography during the trial.

The investigators concluded, “[O]ur data show that annual mammography does not result in a reduction in breast cancer specific mortality for women aged 40 to 59 beyond that of physical examination alone or usual care in the community. The data suggest that the value of mammography screening should be reassessed.”

They further noted, “[I]n technically advanced countries, our results support the views of some commentators that the rationale for screening by mammography should be urgently reassessed by policy makers. Nevertheless, education, early diagnosis, and excellent clinical care should continue to be provided to women to ensure that as many breast tumours as possible are diagnosed at or less than 2 cm.” n Disclosure: The study was supported by the Canadian Breast Cancer Research Alliance, Canadian Breast Cancer Research Initiative, Canadian Cancer Society, Health and Welfare Canada, National Cancer Institute of Canada, Alberta Heritage Fund for Cancer Research, Manitoba Health Services Commission, Medical Research Council of Canada, le Ministère de la Santé et des Services Soçiaux du Québec, Nova Scotia Department of Health, and Ontario Ministry of Health. The study authors reported no potential conflicts of interest.

Reference 1. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomised screening trial. BMJ 348:366, 2014.

See commentaries on this report on pages 22, 23, and 24.

The ASCO Post | APRIL 15, 2014

PAGE 22

Perspective

Flaws in CNBSS Are Vast, Impact on Screening Recommendations Is Nil

By Therese B. Bevers, MD

T

he recent report from the Canadian National Breast Screening Study (CNBSS)—published in BMJ and reviewed in this issue of The ASCO Post—concluded that annual mammography in women aged 40 to 59 does not result in a reduction in mortality from breast cancer beyond that of physical examination alone or usual care in the community. In their conclusion, the study investigators stated, “the rationale for screening by mammography should be urgently reassessed by policy makers.”1 This prompted a flurry of news reports, most notable of which was a New York Times article that described the CNBSS as “one of the largest and most meticulous studies of mammography ever done, involving 90,000 women and lasting a quarter-century.” The article noted that it “has added powerful new doubts about the value of the screening test for women of any age.”2

formed in asymptomatic individuals.

The diagnostic evaluation of women with palpable masses, typically with diagnostic mammography and ultrasound, falls outside the realm of breast cancer screening. However, women with palpable breast masses were allowed in the CNBSS. The fact that women with known palpable breast masses were included in the CNBSS makes the design of this screening trial questionable. This is further compounded by the timing of their allocation to the mammography or control arms of the trial.

The strengths of the CNBSS are contrasted by a vast collection of flaws that render any findings, past or present, meaningless. As a result, the study does not provide any data in regard to the benefits of mammography that would influence breast cancer screening recommendations.

Flawed From the Beginning The findings of the CNBSS are in sharp contrast to those from other mammography trials, as well as the metaanalysis conducted by the U.S. Preventive Services Task Force that reported a significant reduction in breast cancer mortality for women in this age range.3,4 While the study findings are strengthened by 25 years of outcomes in a cohort of nearly 90,000 women, many would argue with the description that the trial was “meticulously” conducted. The CNBSS has been plagued by a number of published criticisms dating back to the early 1990s.5-9 The issues identified, namely concerns regarding randomization and mammographic quality, are considered by most breast cancer experts to have rendered the CNBSS flawed from the beginning, thus eliminating any ability of the trial to accurately discern the benefits and harms of mammographic screening.

Screening is, by definition, perDr. Bevers is Professor in the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center, Houston. She chairs the National Comprehensive Cancer Network’s guideline panels on Breast Cancer Screening and Diagnosis and Breast Cancer Risk Reduction.

The Opinions expressed are her own and are not meant to represent the consensus of the NCCN panel.

mographic screening was 75%. The women in the control arm of the CNBSS had a greater than 90% 5-year survival—even better than modern results with screening and improved therapy.7 Such a skewed allocation is unlikely to have occurred by chance and would minimize or eliminate any impact of mammographic screening on breast cancer mortality.

Although the investigators have attempted to mitigate this bias by eliminating prevalent cancers in their analysis,1 it should be understood that the CNBSS

—Therese B. Bevers, MD

Skewed Allocation In order to avoid bias in the randomization process, those carrying out the allocation of participants to the study arms should not know anything about them other than the variables upon which the randomization is performed. In the CNBSS, instead of randomization being conducted at study entry, it occurred after the performance of a physical examination.1 Knowledge of the clinical breast exam findings prior to allocation to the intervention or control arms of the study creates the potential for it to influence the randomization process.

Disproportionate assignment of women with a poor prognosis (ie, those with palpable masses and lymph nodes) to the intervention arm would result in more advanced breast cancers in the intervention arm.

In fact, in the CNBSS, the number of women 40 to 49 years old in the mammography arm who had breast cancers with four or more lymph node metastases exceeded that of the control group by 19:5 (380%).5 The 5-year survival for women aged 40 to 49 years who underwent mam-

is not, by definition, a trial of screening mammography. Additionally, given that a fundamental rule of randomized controlled trials was violated, all analyses of this trial, including this analysis, are confounded by this limitation.

Imaging Quality and Interpretation In addition to concerns regarding the randomization process in the CNBSS, concerns have been described regarding mammographic quality, acquisition of images, and image interpretation.5-7,9,10 At the start of the trial, image quality was suboptimal. Second-hand mammographic equipment was used. Images were cloudy and cancers were harder to see, as grids that reduce scatter were not utilized.

The technologists were not taught proper positioning. Notably, mediolateral oblique views were not initially obtained, precluding identification of cancers in the axillary tail. The radiologists were not experienced in the interpretation of mammographic images, resulting in cancers being missed on interpretation. The reference phys-

icist for the CNBSS stated that “...quality was far below state-of-the-art, even for that time [early 1980s]”.11 It should be noted that a retrospective review of the CNBSS mammography by three external reviewers confirmed that technical quality improved after 1984. However, this same external review showed that, for the majority of the trial (years 1–4), over half of the mammograms were judged as poor or unacceptable. It was not until the final 2 years that image quality was judged to be satisfactory in over 70% of cases.12 When mammographic technique and interpretation are unsatisfactory, the benefits of mammography cannot be assessed. This prompted one of the external reviewers to comment that “because of poor mammography, the results of this trial will always be suspect”.6 As a result of the imaging limitations, cancers were more difficult to see or were missed, resulting in cancers being diagnosed at a more advanced stage. This minimizes or eliminates the mortality reduction that might have been demonstrated by screening mammography.

Although we rely on evidence from trials of screening mammography dating back to the 1960s, it is important to realize that the technology of today’s mammograms is vastly superior.

It is analogous to comparing a 1960s television to the high-definition viewing that is enjoyed today. We are finding cancers on today’s screening mammograms at a significantly smaller size than seen on early mammograms, certainly much smaller than the average size of 1.9 cm in the mammography arm in the CNBSS.1

Conclusions The strengths of the CNBSS are contrasted by a vast collection of flaws that render any findings, past or present, meaningless. As a result, the study does not provide any data in regard to the benefits of mammography that would influence breast cancer screening recommendations. It is well recognized that, even in the era of adjuvant therapy, women with early-stage breast cancer have a better survival than those who present with late-stage disease. At this time, our greatest tool for the early detection of breast cancer remains screening mammography. n

ASCOPost.com | APRIL 15, 2014

PAGE 23

Perspective

The Canadian National Breast Screening Trial Had So Many Flaws That Its Results Should Not Be Used to Guide Screening Recommendations

By Daniel B. Kopans, MD, FACR

I

f a randomized, controlled trial of therapy for breast cancer was submitted for publication in which 1. The drug being tested was old and ineffective, and 2. prior to randomization, the women underwent a clinical breast examination and the study coordinators knew who had the largest cancers, and 3. allocation was on open lists so that it was possible to place the larger cancers into the treatment arm, and 4. a “statistically significant” excess of women with large cancers was assigned to the treatment arm, and 5. there was no benefit from using the drug, and 6. the study concluded that all chemotherapy was ineffective in reducing breast cancer deaths, the “study” would be rejected without any second thoughts, except that an ethics investigation might be initiated. Why is this obvious for a therapy trial, but such errors and violations are completely ignored by analysts when they actually happen in a major mammography screening trial?

Results Contrary to Other Trials The trial in question is the Canadian National Breast Screening Study (CNBSS) whose recent update— Dr. Kopans is Professor of Radiology, Harvard Medical School, and Senior Radiologist, Breast Imaging Division, Massachusetts General Hospital, Boston.

Therese B. Bevers, MD continued from page 22 Disclosure: Dr. Bevers reported no potential conflicts of interest.

References 1. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: A randomised screening trial.

BMJ 348:g366, 2014.

2. Kolata G: Vast study casts doubts on value of mammograms. New York Times Feb 11, 2014.

reviewed in this issue of The ASCO Post—claims that mammography screening did not reduce deaths for women aged 40 to 59 years.1 These results are contrary to the other randomized, controlled trials of screening that have shown as much as a 31% decline in deaths2 for women offered screening (ie, intent-to-treat population) and an even greater reduction in

of the Canadian trial, so that the scatter could hide small cancers.

Proper positioning is required to image as much breast tissue as possible, yet there was no training for the technologists. The mediolateral oblique position allows the maximum amount of breast tissue to be imaged, but this was not employed in the CNBSS. Large volumes of breast tissue

The CNBSS was a large trial, but larger numbers do not compensate for major trial errors.

—Daniel B. Kopans, MD, FACR

deaths among women who were actually screened. The benefit has been confirmed in numerous observational studies.3-15 The ability of radiologists to find small cancers is directly related to the image quality of the mammograms.

Unfortunately, a trial that should have tested the value of state-of-the-art mammography did just the opposite.

The CNBSS employed old, often outdated, and even second-hand mammography devices.16 Scatter radiation clouds the images, which makes looking at them like looking through a soot-covered window. Grids to clear up scatter were not employed for most

I was invited to review the quality of the mammograms from this study with two other radiologists, and we found that the images were poor to unacceptable for a large part of the investigation.16,17 Their own reference physicist wrote: “[I] identified many concerns regarding the quality of mammography carried out in some of the NBSS

3. Tabar L, Vitak B, Chen TH, et al: Swedish two-county trial: Impact of mammographic screening on breast cancer mortality during 3 decades. Radiology 260:658663, 2011.

4. Nelson HD, Tyne K, Naik A, et al: Screening for breast cancer: An update for the U.S. Preventive Services Task Force. Ann Intern Med 151:727-737, 2009.

5. Warren Burhenne LJ, Burhenne HJ: The Canadian National Breast Screening Study: A Canadian critique. AJR Am J Roentgenol 161:761-763, 1993.

6. Kopans DB: The Canadian Screening Program: A different perspective. AJR Am J

Roentgenol 155:748-749, 1990.

7. Kopans DB, Feig SA: The Canadian National Breast Screening Study: A critical review. AJR Am J Roentgenol 161:755-760, 1993.

8. Kopans DB: Canadian National Breast Screening Study. Lancet 350:810,1997.

9. Tarone RE: The excess of patients with advanced breast cancers in young women screened with mammography in the Canadian National Breast Screening Study. Cancer 75:997-1003, 1995.

10. American College of Radiology and Society of Breast Imaging: BMJ article on breast cancer screening effective-

were not imaged, leading to missed cancers. The technologists and radiologists had no special training in mammography and mammographic interpretation.

Dubious Imaging Quality

screening centers. That quality [in the NBSS] was far below state of the art, even for that time (early 1980’s).”18 Not a single radiologist involved in the CNBSS screening trial has defended its results.

Because of the poor quality of the mammograms, only 32% of the cancers in the mammography arm were not palpable—this should be at least 60%—and there was only a 2-mm difference in the average size of the cancers in both arms. Ineffective chemotherapy disqualifies a treatment trial.

Ineffective mammography should disqualify the CNBSS results.

Fundamentals of Random Allocation As oncologists well know, random allocation is critical in randomized, controlled trials. The CNBSS violated the fundamentals of random allocation. Every woman had a clinical breast examination before allocation.

Women with breast masses and axillary adenopathy were identified to the study coordinators.19 Allocation was on open lists. The coordinator need only skip a line to insure that a woman with a lump was assigned to the screening arm. This would be unacceptable in a treatment trial; why is it acceptable in a screening trial?

The coordinators were never interviewed20 to find out if there was actual subversion, but the excess of women with advanced cancers allocated to the continued on page 24

ness: Incredibly flawed and misleading.

Posted February 11, 2014. Available at www.acr.org/News-Publications/News/ News-Articles/2014/ACR/BMJ-Article-on-Breast-Cancer-Screening-Effectiveness-Incredibly-Flawed-and-Misleading. Accessed February 16, 2014.

11. Yaffe MJ: Correction: Canada Study. Letter to the editor. J Natl Cancer Inst 155:748-749, 1993.

12. Baines CJ, Miller AB, Kopans DB, et al: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 155:743-747, 1990.

The ASCO Post | APRIL 15, 2014

PAGE 24

Perspective

Overdiagnosis of Breast Cancer: New Research Directions

By Sudhir Srivastava, PhD, MPH, and Barnett S. Kramer, MD, MPH

C

urrently, one of the most challenging problems in oncology is to accurately predict whether neoplastic lesions detected by screening tests will progress. The focus on developing evermore sensitive cancer screening tests has produced the clinical dilemma of overdiagnosis. Overdiagnosis occurs when a cancer case identified by a screening test would have gone undiagnosed otherwise and not caused clinical symptoms or death in the person’s lifetime. It triggers overtreatment, which causes not only overutilization of resources, but also substantial physical, emotional, and financial harm to the patient, and sometimes even treatment-related death.

In a recent study, examination of the Surveillance, Epidemiology, and End Results (SEER) data for trends in breast cancer incidence from 1976 through 2008 among women 40 years of age or older showed that overdiagnosis accounted for an estimated 31% of all breast cancers diagnosed in 2008.1 However, population-based ecologic trends can only provide suggestive evidence of Dr. Srivastava is Chief, Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. Dr. Kramer is Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health.

The opinions expressed in this article represent those of the authors, and not official positions of the U.S. Department of Health and Human Services or the National Institutes of Health.

Daniel B. Kopans, MD, FACR continued from page 23

screening arm21 was statistically significant.22 Support for the notion that there was almost certainly compromise of the allocations is seen in the amazing survival of women in the CNBSS control group who only received usual care after an initial clinical breast exam.

The 5-year breast cancer survival rate in Canada at the time was 75%, but women in the control arm had better than 90% 5-year survival. There is no way that this incredible survival could occur with “usual care.” It is clear that

overdiagnosis. Randomized controlled screening trials with long-term followup provide more direct evidence.

Recently, as reviewed in this issue of The ASCO Post, the Canadian National Breast Screening Study, with 25-year follow-up data, reported a lack of mor-

we should not overlook strategies to mitigate harms. Specifically, how can we mitigate the harms of overdiagnosis?

The problem can be addressed at several levels. Two obvious approaches are to (1) improve patient (and physician) understanding of overdiagnosis, and (2)

While debates on the efficacy of mammography screening continue, we should not overlook strategies to mitigate harms. Specifically, how can we mitigate the harms of overdiagnosis?

—Sudhir Srivastava, PhD, MPH, and Barnett S. Kramer, MD, MPH

tality benefit of annual mammography screening for breast cancer compared with physical examination or usual care in women aged 40 to 59 years.2 This was not a new finding from the trial. The new, headline-grabbing results of the trial were that about 1 in 5 of the screendetected invasive cancers was overdiagnosed (and if ductal carcinoma in situ had been included, the proportion would be even higher).

While debates on the efficacy of mammography screening continue,

women with advanced cancers at allocation were moved into the screening arm. Furthermore, if cancers were shifted from the control group to the screened group, this could also explain the supposed “overdiagnosis” in the screening arm.

The CNBSS was a large trial, but larger numbers do not compensate for major trial errors. The U.S. Preventive Services Task Force and the American Cancer Society are reviewing their screening guidelines.

The results of the CNBSS should be dropped from the reviews or viewed,

promote the development of additional complementary tissue- and blood-based biomarkers that can be used to predict behavior of screen-detected lesions.

Understanding and Communication How best to improve understanding and communication between physicians and patients? Recently there has been a call for changing the terminology for early, nonlethal lesions.3,4 A change in terminology to reflect what we do know

at best, with great skepticism. n Disclosure: Dr. Kopans reported no potential conflicts of interest.

References 1. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomised screening trial. BMJ 348:g366, 2014.

2. Tabár L, Vitak B, Chen TH, et al: Swedish two-county trial: Impact of mammographic screening on breast cancer mortality during 3 decades. Radiology 260:658663, 2011.

about the underlying biology of tumors may diminish the angst associated with the word “cancer,” a term that can drive overtreatment. Taking the lead from the field of cervical cancer screening, some have suggested changing the term “ductal carcinoma in situ’” (DCIS) to “ductal intraepithelial neoplasia” (DIN).

Unfortunately, the dilemma of overtreatment would still not be fully resolved for the patient or physician by simply changing terminology, because the ability to predict lesion progression remains limited by our understanding of the underlying molecular drivers. This suggests new avenues for research.

There are already a few molecular indicators. For example, interval breast cancers (those missed in spite of screening) are 1.8- to 2.6-fold more likely to be estrogen receptor (ER)negative compared to screen-detected tumors,5,6 and are also more likely to be diagnosed at a more advanced, clinically aggressive stage.7,8 A more refined molecular characterization of screen-detected lesions could improve therapeutic decisions. However, because of the heterogeneous nature of breast cancer and its interaction with the surrounding tissue microenvironment, it is unlikely that single genes or gene products will suffice.

With the advent of the “omics” revolution, there has been an explosion in our knowledge of the molecular basis for breast cancer and the identification of intrinsic subtypes of breast cancer and correlation of these subtypes with disease prognosis.9-11 However, these studcontinued on page 26

3. Tabar L, Vitak B, Tony HH, et al: Beyond randomized controlled trials: Organized mammographic screening substantially reduces breast carcinoma mortality.

Cancer 91:1724-1731, 2001.

4. Duffy SW, Tabar L, Chen H, et al: The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 95:458469, 2002.

5. Otto SJ , Fracheboud J, Looman CWN, et al: Initiation of population-based mammography screening in Dutch municipalities and effect on breast-cancer mortalcontinued on page 25

ASCOPost.com | APRIL 15, 2014

PAGE 25

Perspective

Daniel B. Kopans, MD, FACR continued from page 24

ity: A systematic review. Lancet 361:411417, 2003.

6. van Schoor G, Moss SM, Otten JD, et al: Increasingly strong reduction in breast cancer mortality due to screening. Br J Cancer 104:910-914, 2011.

7. Otto SJ, Fracheboud J, Verbeek ALM, et al: Mammography screening and risk of breast cancer death: A population-based case-control study. Cancer Epidemiol Biomarkers Prev 21:66-73, 2012.

8. Swedish Organised Service Screening Evaluation Group: Reduction in breast cancer mortality from organized service screening with mammography: 1. Further confirmation with extended data. Cancer Epidemiol Biomarkers Prev 15:45-51, 2006.

9. Hellquist BN, Duffy SW, Abdsaleh S, et al: Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: Evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Cancer 117:714-722, 2011.

10. Coldman A, Phillips N, Warren L, et al: Breast cancer mortality after screening mammography in British Columbia women. Int J Cancer 120:1076-1080, 2007.

11. Kopans DB: Beyond randomized, controlled trials: Organized mammographic screening substantially reduces breast cancer mortality. Cancer 94:580581, 2002.

12. Hofvind S, Ursin G, Tretli S, et al: Breast cancer mortality in participants of the Norwegian Breast Cancer Screening Program. Cancer 119:3106-3112, 2013.

13. Paap E, Holland R, den Heeten GJ, et al: A remarkable reduction of breast cancer deaths in screened versus unscreened women: A case-referent study. Cancer Causes Control 21:15691573, 2010.

14. Mandelblatt JS, Cronin KA, Bailey S, et al: Effects of mammography screening under different screening schedules: Model estimates of potential benefits and harms.

Ann Intern Med 151:738-747, 2009.

15. Broeders M, Moss S, Nyström L, et al: EUROSCREEN Working Group.

The impact of mammographic screening on breast cancer mortality in Europe: A review of observational studies. J Med Screen 19(suppl 1):14-25, 2012.

16. Baines CJ, Miller AB, Kopans DB, et al: Canadian National Breast Screening Study: Assessment of technical quality by external review. AJR Am J Roentgenol 155:743-747, 1990.

17. Kopans DB: The Canadian Screening Program: A different perspective. AJR

Am J Roentgenol 155:748-749, 1990.

18. Yaffe MJ: Correction: Canada Study. Letter to the editor, J National Cancer Inst 85:94, 1993.

19. Bailar JC, MacMahon B: Randomization in the Canadian National Breast Screening Study: A review for evidence

of subversion. Can Med Assoc J 156:193199, 1997.

20. Kopans DB: NBSS: Opportunity to compromise the process. Letter to the editor. Can Med Assoc J 157:247, 1997.

21. Kopans DB, Feig SA: The Canadian National Breast Screening Study:

A critical review. AJR Am J Roentgenol 161:755-760, 1993.

22. Tarone RE: The excess of patients with advanced breast cancers in young women screened with mammography in the Canadian National Breast Screening Study. Cancer 75:997-1003, 1995.

Genentech is investigating the potential of selectively blocking PD-L1. Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

Exploring the PD-L1 network: a new frontier in oncology PD-L1 plays a central role in cancer’s ability to evade the immune system1 Cancer cells use various mechanisms to circumvent the immune system, including certain ligands such as programmed death-ligand 1 (PD-L1) that can deactivate T-cell–mediated cytotoxicity.

This deactivation inhibits the immune system, thereby enabling tumor growth.1

Inhibition of the PD-L1 network requires careful consideration of its components The complex PD-L1 network is comprised of several interactions, including: • PD-1/PD-L1: PD-1, expressed on activated T cells, binds to PD-L1 to inhibit immune activation and reduce T-cell–mediated cytotoxicity2 • PD-1/PD-L2: PD-1 also binds to PD-L2, a ligand expressed on antigenpresenting cells (APCs), which can result in inhibition of some immune responses and play a vital role in maintaining immune homeostasis2-4 • B7.1/PD-L1: B7.1, found on both activated T cells and APCs, binds to PD-L1 and can contribute to suppression of antitumor T-cell responses2 Because of the complexity of the PD-L1 network, blockade strategies must be carefully considered.

Dendritic cell

PD-L1

PD-1

T cell

PD-L2

B7.1 TCR PD-L1

MHC

Tumor cell

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 3. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.

Proc Natl Acad Sci U S A. 2003;100:5336-5341. 4. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002316900 Printed in USA.

The ASCO Post | APRIL 15, 2014

PAGE 26

Perspective

Sudhir Srivastava, PhD, MPH Barnett S. ­Kramer, MD, MPH continued from page 24

ies have not been well linked to the mode of detection. Without better annotation on method of detection, sorting out the spectrum of behavior of screen-detected lesions is extremely difficult.9-11

Pilot Program The National Cancer Institute’s Early Detection Research Network (EDRN) (www.cancer.gov/edrn) investigators have therefore initiated a pilot program to study the biologic behavior of breast cancer that incorporates annotation of method of diagnosis, along with the other well-known risk factors for progression. There is also a separate Funding Opportunity Application (FOA) to study the spectrum of changes associated with tissue microenvironment, genomic and proteomic changes, and

genomic heterogeneity both between and within premalignant lesions combined with imaging to study the biology of early breast cancer lesions.

When possible, tissues from cohorts that prospectively follow patients for progression will be used. We also encourage studies of similarities and differences in molecular characteristics between interval-detected cancers and screen-detected cancers or cancers that recur after initial ­therapy.

These new research directions could help guide clinical decision-making with respect to both extent of treatment and frequency of follow-up for breast cancer survivors. The goal is to develop clinical strategies that may retain any benefits of screening while diminishing the harms inherent in increasingly sensitive screening tests. n

Disclosure: Drs. Srivastava and Kramer reported no potential conflicts of interest.

References 1. Bleyer A, Welch HG: Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 367:1998-2005, 2012.

2. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomized screening trial. BMJ 348:g366, 2014.

3. Esserman LJ, Thompson IM, Reid B: Overdiagnosis and overtreatment in cancer. JAMA 310:797-798, 2013.

4. Dunn BK, Srivastava S, Kramer BS: The word “cancer”: How language can corrupt thought. BMJ 347:f5328, 2013.

5. Nelson HD, Tyne K, Naik A, et.al: Screening for breast cancer: An update for the US Preventive Services Task Force.

Ann Intern Med 151:727-742, 2009.

6. Collett K, Stefansson IM, Eide J, et al: A basal epithelial phenotype is more frequent in interval breast can-

cers compared with screen detected tumors. Cancer Epidemiol Biomarkers Prev 14:1108-1112, 2005.

7. Porter PL, El-Bastawissi AY, Mandelson MT, et al: Breast tumor characteristics as predictors of mammographic detection. J Natl Cancer Inst 91:2020-2028, 1999.

8. Otto SJ, Fracheboud J, Verbeek AL, et al: Mammography screening and risk of breast cancer death. Cancer Epidemiol Biomarkers Prev 21:66-73, 2012.

9. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000.

10. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418-8423, 2003.

11. Curtis C, Shah SP, Chin SF, et al: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346-352, 2012.

Don’t Miss These Important Reports in This Issue of The ASCO Post Myron S. Czuczman, MD, on ‘Double-Hit’ Lymphomas see page 16

State-of-the-Art Update in Renal Cell Carcinoma David I. Quinn, MBBS, PhD, FRACP, Arie Belldegrun, MD, FACS, and Allan Pantuck, MD, MS, FACS see page 3

Cathy Eng, MD, FACP, on Colorectal Cancer Surveillance see page 29

Jennifer S. Temel, MD, on Physican Bias in Recommending Palliative Care see page 48

Max S. Wicha, MD, on Targeting Cancer Stem Cells in Breast Cancer see page 43

Visit The ASCO Post online at ASCOPost.com

Jennifer Sipos, MD, on Thyroid Cancer see page 50

N OW E N RO L L I N G

Pivotal Trial in gpNMBOverexpressing Metastatic Triple-Negative Breast Cancer • METRIC is a pivotal, open-label, prospectively controlled, randomized trial of glembatumumab vedotin in glycoprotein NMB-overexpressing triple-negative breast cancer (TNBC)

• gpNMB is an internalized transmembrane glycoprotein that is frequently overexpressed in TNBC tumors – gpNMB overexpression is associated with reduced recurrence-free survival in TNBC • Glembatumumab vedotin is an investigational antibody-drug conjugate (ADC) that targets tumors

1-4

3

Patients with metastatic TNBC overexpressing gpNMB* N=300

*Stratified

2:1 Randomization

expressing gpNMB4,5

Glembatumumab vedotin 1.88 mg/kg IV Day 1 of 21-day cycles Treat until unacceptable toxicity or disease progression Capecitabine 1250 mg/m2 BID Days 1-14 of 21-day cycles

by prior receipt of 0 or 1 line of therapy for advanced disease and anthracycline response.

Key Trial Endpoints

• Primary: Objective response rate (ORR) and/or progression-free survival (PFS) • Secondary: Duration of response (DOR) and overall survival (OS) Key Inclusion Criteria

• No more than one prior chemotherapy-containing regimen for advanced breast cancer • Prior receipt of anthracycline-containing chemotherapy in any setting, with no further anthracycline therapy indicated

• Taxane resistance after neoadjuvant/adjuvant therapy or in the advanced disease setting

For more information, visit www.metricstudy.com, www.clinicaltrials.gov/show/NCT01997333, or e-mail info@celldex.com.

References: 1. Weterman MAJ, Ajubi N, van Dinter IMR, et al. Int J Cancer. 1995;60:73-81.

2. Singh M, Del Carpio-Cano F, Belcher JY, et al. Crit Rev Eukaryot Gene Expr. 2010;20(4):341-357.

3. Rose AAN, Grosset A-A, Dong Z, et al. Clin Cancer Res. 2010;16(7):2147-2156. 4. Maric G, Rose AAN, Annis MG, Siegel PM. Onco Targets Ther. 2013;6:839-852. 5. Burris HA III. 2013 ASCO Educ Book. 2013:e99-e102. ©2014 Celldex Therapeutics, Inc.

All rights reserved.

MT1

1/14

The ASCO Post | APRIL 15, 2014

PAGE 28

Journal Spotlight Gastrointestinal Oncology

FACS Trial: Intensive Follow-up Increases Surgical Treatment of Recurrence With Curative Intent in Colorectal Cancer

By Matthew Stenger

I

n the FACS trial, reported in JAMA, John N. Primrose, MD, FRCS, of University of Southampton, England, and colleagues compared outcomes with intensive follow-up with carcinoembryonic antigen (CEA) measurement, computed tomography (CT), both, or minimum follow-up after curative surgery for primary colorectal cancer.1 Intensive strategies resulted in a significantly greater proportion of patients undergoing surgical treatment of recurrence with curative intent.

Study Details In the trial, 1,202 patients who had undergone curative surgery for primary colorectal cancer, including adjuvant treatment if indicated, between January 2003 and August 2009 at 39 UK hospitals were randomly assigned to CEA only (n = 300), CT only (n = 299), CEA/CT (n = 302), or minimum follow-up (n = 301) to detect recurrent cancer treatable with curative intent (primary endpoint).

Patients had to have no residual disease, microscopically clear margins, and Dukes stage A to C (TNM stage 1–3) disease; patients were disease-free based on colon imaging with no evidence of metastatic disease, as confirmed by CT or magnetic resonance imaging liver scan and chest CT scan, and had postoperative blood CEA level ≤ 10 μg/L after surgery or adjuvant therapy.

CEA was measured every 3 months for 2 years and then every 6 months for 3 years. CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years and then annually for 3 years. The minimum follow-up group had no scheduled follow-up except a single CT scan of the chest, abdomen, and pelvis at 12 to 18 months if requested at study entry by hospital clinicians; otherwise, patients received

follow-up if symptoms occurred.

Patients had a mean age of 69 years, 61% were male, 29% had significant comorbidity, 41% had received adjuvant chemotherapy and 12% had received preoperative radiotherapy.

Treatment groups were balanced for baseline characteristics. Dukes stage was A in 19% to 24%, B in 45% to 51%, and C in 28% to 31.5%.

Increased Surgical Treatment With Curative Intent After mean follow-up of 4.4 years, cancer recurrence was detected in 16.6% of patents. Overall, 5.9% of patients received surgical treatment with curative intent for recurrence, with there being little difference according to Dukes stag-

Follow-up for Recurrence in Colorectal Cancer ■■ Intensive monitoring was associated with a significantly higher rate of surgical treatment with curative intent for recurrences.

■■ There was no advantage of combining CEA measurement and CT. ■■ Intensive monitoring was not associated with any increase in overall survival.

group, and 4.3% (adjusted OR = 3.10, P = .01) in the CEA/CT group. The odds ratio for the CEA/CT group was similar to that with CT or CEA alone, suggesting that no additive effect is achieved by using both together.

The intensive interventions tended to detect recurrence earlier, although differences in earlier detection were not statistically significant. No patients in the

Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. —John N. Primrose, MD, FRCS, and colleagues

ing—ie, 5.1% of patients with Dukes stage A, 6.1% with stage B, and 6.2% with stage C. Surgical treatment of recurrence with curative intent occurred in 2.3% of patients in the minimum followup group, 6.7% in the CEA group, 8.0% in the CT group, and 6.6% in the CEA/ CT group (P = .02 for trend).

Compared with minimum followup, the absolute difference in percentage treated with curative intent was 4.4% (adjusted odds ratio [OR]= 3.00, P = .02) in the CEA group, 5.7% (adjusted OR = 3.63, P = .004) in the CT

minimum follow-up group had curative resection after 2 years, whereas curative resections were performed in patients in all of the intensive groups beyond 2 years (P = .03).

Survival The trial was not powered to detect difference in survival. There was no significant difference across the four groups with regard to overall mortality (18.7% in CEA group, 20.1% in CT group, 15.9% in CEA/CT group, and 15.9% in minimum follow-up group; P = .45)

or colorectal cancer–specific mortality (10.7%, 11.7%, 8.9%, and 9.3%; P = .66).

The investigators noted, “Although the observed 2% aggregate survival advantage of the minimum follow-up group vs the more intensive followup groups is unlikely to be due to bias (central death registration in the United Kingdom means there was no loss to follow-up), it could be due to chance.

An observed absolute 6% increase in surgery with curative intent predicts a 2% to3% survival advantage with intensive follow-up. The confidence intervals around both the total mortality and colorectal cancer–specific mortality rates indicate that our results are still consistent with this outcome.”

The investigators concluded, “Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small.” n

Disclosure: The study was funded by the UK National Institute for Health Research Health Technology Assessment program. For full disclosures of the study authors, visit jama. jamanetwork.com.

Reference 1. Primrose JN, Perera R, Gray A, et al: Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: The FACS randomized clinical trial. JAMA 311:263-270, 2014.

Follow us on

ASCOPost.com | APRIL 15, 2014

PAGE 29

Perspective

Will Colorectal Cancer Surveillance Change Based on the Results of the FACS Trial?

By Cathy Eng, MD, FACP

C

olorectal cancer is a common malignancy that will impact 1.4 million individuals globally each year.1 Approximately 70% to 75% of patients will present with locally advanced disease.

For patients with stage III colon cancer, adjuvant chemotherapy is commonly offered, whereas chemotherapy for those with stage II disease is of questionable benefit. In any case, following surgical resection, patients are commonly followed on surveillance for up to 5 years before being deemed disease-free.

Common surveillance recommendations for stage II/III patients (eg, ASCO and National Comprehensive Cancer

CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years and then annually for 3 years; the minimum follow-up group received follow-up if symptoms occurred.

The original primary endpoint was overall survival, but due to slow accrual, the trial was amended. The revised primary endpoint was surgical treatment of recurrence with curative intent after a minimum follow-up of 3 years.

It was determined that a sample size of 590 patients was needed per factorial group (CEA vs no CEA, CT vs no CT) for 80% power to detect a minimum 3% absolute effect of intensive monitoring.

The FACS trial has its merits….

However, the study findings and the investigators’ conclusions failed to impact my current approach to surveillance of my patients with locally advanced disease.

—Cathy Eng, MD, FACP

Network guidelines) include quarterly physical exam for years 1 to 3, then biannual exam in years 4 and 5, with a computed tomography (CT) scan of the chest, abdomen, and pelvis annually.

A colonoscopy is typically completed 1 year from the original surgical date and then every 3 years thereafter. It has been reported that 72% to 80% of all recurrences occur within the first 3 years.2

Statistical modeling indicated that a 3% difference in treatment with curative intent translated into overall survival would be the smallest difference indicating cost-effectiveness. For comparison of the minimal intervention group with the CEA, CT, and CEA-plus-CT groups, a sample size of 1,180 would provide 51%, 70%, and 84% power to detect differences of 3%, 4%, and 5%, respectively.

FACS Trial Design

Treatment of Recurrence

As recently reported in JAMA and reviewed in this issue of The ASCO Post, Primrose et al have completed the FACS (Follow-up After Colorectal Surgery) trial.3 Between January 2003 and August 2009, 1,202 patients from 39 UK hospitals were randomly assigned to one of four arms: intensive monitoring with carcinoembryonic antigen (CEA) only, CT only, CEA plus CT, or minimum follow-up. CEA was measured every 3 months for 2 years and then every 6 months for 3 years, and

After a median follow-up of 4.4 years, cancer recurrence was detected in 16.6% of patients, with no statistical difference noted between the investigational arms (P = .08). Overall, 65.3% of all recurrences were detected on scheduled follow-up, with clinical symptoms or incidental findings accounting for detection of recurrence in the remaining patients.

In brief, 5.9% of patients underwent surgical treatment with curative intent for disease recurrence. The absolute difference between surgical intervention and minimal follow-up in each arm ranged from 4.3% to 5.7%. The authors noted there was no significant difference in all four arms for overall mortality (P = .45) or colorectal cancer–specific mortality (P = .85). They concluded that in-

Dr. Eng is Associate Professor, GI Medical Oncology Department, Associate Medical Director, Colorectal Center, The University of Texas MD Anderson Cancer Center, and Co-Chair, SWOG Rectal Subcommittee.

tensive surveillance improved the likelihood of surgical intervention for curative intent, but the combined approach of CEA plus CT is unlikely to demonstrate improved benefit in overall survival.

Given concerns about the rising cost of health care, the FACS trial has its merits. The investigators attempted to determine if one method of surveillance was of greater benefit for detection of cancer recurrence using one of two very accessible modalities—CEA level or CT scan of the chest, abdomen, and pelvis—or the two modalities in combination. However, the study findings and the investigators’ conclusions failed to impact my current approach to surveillance of my patients with locally advanced disease.

Study Shortcomings For patients with surgically resected locally advanced disease, a control arm of minimal follow-up without any scheduled follow-up (excluding a single CT scan of the chest, abdomen, and pelvis at 12–18 months) would be considered ethically, medically, and legally inappropriate. Furthermore, it would be difficult to believe that with a mean participant age of 69 years, these patients who are largely residing in an urban environment were not still under the supervision of at least a primary care physician, given their previous diagnosis of cancer.

None of the arms takes into account the actual physical examination of the patient. As medical students, we were instilled with the knowledge that the majority of your diagnosis is in fact determined by a thorough history and physical. The case report forms provided documented data on treatment recurrence and intent. No mention of the actual examination or the extent of examination was made.

The authors also failed to acknowledge that the baseline CEA level is not elevated in approximately 15% to 30% of colorectal cancer patients. In these instances, a CT scan may be our only option for detection of cancer recurrence. However, these patients were randomized independently, regardless of detection or no detection of an elevated baseline CEA.

Further Considerations Oddly enough, the investigational arm of CT follow-up included performance of a CT scan biannually for

the first 2 years. Why the investigators chose such a close interval of CT monitoring is unclear; this is unlikely to be cost-effective. Current guidelines recommend only an annual CT scan.

It is presumed that central diagnostic imaging review was also not completed, given that there is no mention of that process in the published report. However, if the endpoint is surgical intervention, diagnostic imaging quality and capabilities would be of critical importance. It is also appears that the pathology specimens were also not centrally reviewed for surgical margins, optimal number of lymph nodes dissected, or circumferential radial margin in the rectal carcinoma specimens. Moreover, there was no mention of deferral of adjuvant chemotherapy, type of chemotherapy provided in stage III colon cancers, or role of neoadjuvant chemoradiation therapy in the rectal cancer patients.

The primary endpoint of surgical intervention for recurrence is also not a standard endpoint, but was adopted in acknowledgment of the lack of feasibility in completing the trial. If we are to really make an impact on use of surveillance as a tool in colorectal cancer, colorectal cancer–specific survival would be a more appropriate primary endpoint. Thereby, early detection could not only document the impact of surgical intervention with curative intent but would also address the importance of initiating systemic chemotherapy in patients with recurrent disease that is not deemed to be surgically resectable. n

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

References 1. American Cancer Society: Global Cancer Facts & Figures, 2nd ed. Atlanta, American Cancer Society, 2011.

2. Sargent DJ, Patiyil S, Yothers G, et al: End points for colon cancer adjuvant trials: Observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 25:4569-4574, 2007.

3. Primrose JN, Perera R, Gray A, et al: Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: The FACS randomized clinical trial. JAMA 311:263-270, 2014.

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

3

6

9

12

15

18

21

24

27

30

33

36

39

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

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).

b

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%)

0

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%) 3 (1%)

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

Dysgeusia

68 (16%)

0

33 (8%)

0

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%)

0

30 (7%)

0

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%)

0

Psychiatric disorders

Depression

51 (12%)

1 (<1%)

24 (6%)

0

7

8

a

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

17

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 | APRIL 15, 2014

PAGE 34

Journal Spotlight Genitourinary Oncology

Complications Other Than Incontinence or Erectile Dysfunction After Prostatectomy or Radiotherapy for Prostate Cancer

By Matthew Stenger

S

tudies of complications of surgery or radiotherapy for prostate cancer generally focus on incontinence and erectile dysfunction. In a populationbased cohort study reported in The Lancet Oncology, Robert Nam, MD, MSc, FRCS(C), Professor of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, and colleagues assessed the frequency of other complications related to such treatment and found high rates of hospitalization, urologic procedures, anal/rectal procedures, open surgeries, and, in those receiving

significantly younger (median, 62 vs 70 years, P < .0001; 42% vs 13% < 60, 50% vs 37% 60–70, and 7% vs 49% > 70 years, P < .0001 for trend) and had significantly lower comorbidity scores using Johns Hopkins ACG Case-Mix System sum of aggregated disease groups scoring (P < .0001).

Complication Rates Among all patients, the 5-year cumulative incidence of admission to hospital for a treatment-related complication was 22.2%, with 2.4% of patients having

Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy.

—Robert Nam, MD, MSc, FRCS(C), and colleagues

radiotherapy, secondary malignancies.1 Radiotherapy was associated with higher rates of hospitalization, anal/rectal procedures, open surgical procedures, and secondary malignancy and a lower rate of urologic procedures vs surgery.

Study Details The study included administrative hospital data, physician billing codes, and cancer registry data from 32,465 men who received either radical prostatectomy (n = 15,870), surgery, or radiotherapy alone (n =16,595) for prostate cancer between 2002 and 2009 in Ontario. Five-year rates of treatment-related hospital admissions, urologic procedure, anal/rectal procedures, open surgical procedures, and secondary malignancies were identified. Rates were compared with those in a control group of men without history of prostate cancer drawn from a health insurance database who were matched (1:1) for age and year of treatment/inception.

Patients undergoing surgery were

a stay longer than 1 day. Five-year rates were 32.0% for urologic procedures, 13.7% for anal/rectal procedures, 0.9% for open surgical procedures, and 3.0% for second primary malignancies.

The most common urologic procedure was cystoscopy (62% of proce-

copy (67% of procedures in the radiotherapy group and 82% in the surgery group). The most common open surgical procedures were genitourinary/gastrointestinal fistula repair (36% of procedures) and open bladder neck repair (27%) in the radiotherapy group and cystotomy (76%) in the surgery group.

The most common sites of secondary malignancy were gastrointestinal (27% of all sites) and lung (25%) in the radiotherapy group and gastrointestinal (25%), genitourinary (20%), and hematologic (20%) in the surgery group.

Comparison With General Population After adjustment for age, comorbidity, and year of inception, patients had significantly elevated risk vs the general population for hospital admission (hazard ratio [HR] = 17.9, P < .0001), urologic procedures (HR = 6.8, P < .0001), anal/rectal procedures (HR = 2.2, P < .0001), and open surgical procedures (HR = 6.0, P < .0001).

Among patients receiving radiotherapy, there was a significantly greater rate of second malignancy vs expected cancers in the general population among all patients (standardized incidence ratio [SIR] = 2.0, 95% confidence interval [CI] = 1.7–2.3) and among those aged between 40 and 65 years (SIR = 3.5, 95% CI = 2.3–4.7) and a no significant increase was found among those aged 65 to 90 years (SIR = 0.8, 95% CI = 0.7–1.0).

Complications After Prostate Cancer Treatment ■■ Patients had 5-year rates of 22.0% for hospitalization, 32.0% for urologic procedures, 13.7% for anal/rectal procedures, 0.9% for open surgical procedures, and 3.0% for second primary malignancies.

■■ Radiotherapy vs surgery was associated with increased risk of hospital admission, anal/rectal procedures, open surgical procedures, and secondary malignancy and reduced risk of urologic procedures.

dures in the radiotherapy group and 58% in the surgery group). The most common causes of hospitalization were radiation proctitis in the radiotherapy group (41% of admissions) and urinary obstruction in the surgery group (70%).

The most common anal/rectal procedure was lower gastrointestinal endos-

Among patients undergoing surgery, there was no significant increase among all patients (SIR = 0.8, 95% CI = 0.6– 1.0), a nonsignificant increase among those aged between 40 and 65 years (SIR = 1.3, 95% CI = 0.9–1.8), and a significant reduction among those aged 65 to 90 years (SIR = 0.4, 95% CI = 0.3-0.6).

Factors Associated With Increased Risk On multivariate analysis, older age and higher comorbidity score were associated with increased risk of minimally invasive urologic procedures (HR = 1.01, P < .0001; HR = 1.08, P < .0001), hospital admission (HR = 1.007, P < .0001; HR = 1.08, P < .0001), anal/rectal procedures (HR = 1.02, P = .011; HR = 1.10, P < .0001), and secondary malignancy (HR = 1.04, P < .0001; HR = 1.04, P < .0001).

The single most important predictor for complications was the type of index treatment patients underwent. Patients receiving radiotherapy vs surgery had significantly greater risk for admission to hospital during years 2 to 5 (HRs = 1.62-10.8, P < .0001 for all) with a reduced risk during year 1 (HR = 0.86, P < .0001), significantly increased risk of rectal/anal procedures (HR = 2.72, P < .0001) and secondary malignancy (HR = 2.08, P < .0001), and increased risk of open surgery in years 2 to 5 (HRs = 1.53-3.68, P = .002 for year 2, P < .0001 for years 3–5). Risk of urologic procedures was reduced in patients receiving radiotherapy (HR = 0.66, P < .0001).

The investigators concluded, “Complications after prostate cancer treatment are frequent and dependent on age, comorbidity, and the type of treatment. Patients and physicians should be aware of these risks when choosing treatment for prostate cancer, and should balance them with the clinical effectiveness of each therapy.” n

Disclosure: The study was supported by the Ajmera Family Chair in Urologic Oncology and by the Institute for Clinical Evaluative Sciences, which is funded by the Ontario Ministry of Health and Long-Term Care. The study authors reported no potential conflicts of interest.

Reference 1. Nam RK, Cheung P, Herschorn S, et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: A population-based cohort study. Lancet Oncol 15:223–231, 2014.

See commentaries on this report on pages 35 and 40.

ASCOPost.com | APRIL 15, 2014

PAGE 35

Perspective

Prostatectomy vs Radiotherapy: A Study for Cautious Interpretation

By Ronald C. Chen, MD, MPH, and Anthony L. Zietman, MD

M

en with newly diagnosed localized prostate cancer face a decision between prostatectomy and radiotherapy, treatments deemed similarly effective but with wellestablished trade-offs in terms of treatment-related morbidity. Numerous clinical trials and other prospective studies, from both academic and community settings, have consistently demonstrated that prostatectomy causes more urinary incontinence and erectile dysfunction,1,2 with a 0.5% risk for perioperative mortality;3 whereas radiation causes more urinary irritation and bowel/rectal symptoms,2,4 with a small risk of second malignancy.5 Both treatments carry a risk for cancer recurrence. It is also true that older patients, with more underlying comorbid conditions and with more aggressive cancers, tend to receive radiation therapy, whereas younger, healthier patients with less aggressive cancers tend to receive prostatectomy.6 The study by Nam et al7— reviewed in this issue of The ASCO Post—must be interpreted with caution against the background of this well-established knowledge.

treatment, and the associated effects from these treatments, thus creates an artificial study cohort that does not reflect clinical reality or provide meaningful guidance for treatment decision-making.

In contrast, the study specifically includes postradiotherapy prostate biopsies as “events”; these are actually diagnostic procedures to determine whether a local recurrence has

cians who treat prostate cancer. Not surprisingly, if one counts only admissions that lasted more than 1 day, the number of events dropped almost 10-fold to something more realistic and recognizable.

As each admission must be associated with a “diagnosis,” it would be helpful to know how diagnosis is coded for the large number of 1-day, procedure-only admissions. A valida-

It is not at all clear that the event rates from this study are due to treatment (although an unknown proportion certainly is)…. Patients with localized prostate cancer and their physicians considering modern radical prostatectomy or radiotherapy options must be cautious when reviewing findings of this study.

—Ronald C. Chen, MD, MPH, and Anthony L. Zietman, MD

Key Bias First, the reader should notice that this study selectively excluded the most common consequences of radical prostatectomy—namely, urinary incontinence, erectile dysfunction, and cancer recurrence (by eliminating all patients who received radiotherapy after surgery). The latter is especially important.

When a patient is deciding between prostatectomy and radiotherapy, he and his physician are unable to predict whether postprostatectomy radiotherapy will ultimately be needed. One-third or more of those who undergo a radical prostatectomy will have an indication for adjuvant or salvage radiotherapy.8 Eliminating patients who require postprostatectomy Dr. Chen is Assistant Professor in the Department of Radiation Oncology, University of North Carolina at Chapel Hill. Dr. Zietman is Associate Director of the Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston.

occurred in radiotherapy patients.

When a comparative morbidity study selectively disregards the most common consequences of one treatment option, as has occurred here, the other option will inevitably appear to have higher rates of the measured outcomes.

Canadian Context The outcome of “hospital admissions” in this article needs to be viewed in context of the health-care environment in Ontario. The reader may not be aware, but it is relatively common practice in Ontario to admit patients one night for procedures usually performed on an outpatient basis in the United States. Importantly for this article, this includes routine colonoscopies.

At first glance, the finding that one-third of radiotherapy patients experienced “hospitalization” as a result of treatment-related morbidity (Figure A in the article) contradicts the clinical experience of most clini-

tion study using chart review of a select number of these patients would have provided significant insight to address this fundamental methodologic problem.

Other Confounding Factors Another important methodologic issue that must be addressed in all observational studies, and that is especially pertinent for studies comparing surgery and radiation, is that of patient selection and confounding.

Patients who are young and healthy enough to receive radical prostatectomy can, in fact, have better “outcomes” than the general noncancer population!

As reported by Nam et al,7 the standardized incidence ratio for development of a second malignancy comparing radical prostatectomy patients to noncancer controls was 0.8. On the other hand, the vast majority of second cancers after prostate radiotherapy were in body areas not directly in the treatment field,

including lung, head/neck, central nervous system, and breast. It is difficult to conclude that a radical prostatectomy reduced a patient’s risk for second cancers by 20%, and similarly difficult to believe that prostate radiotherapy caused numerous lung cancers as early as 5 years after treatment. Rather, these results strongly suggest unbalanced patient characteristics not fully accounted for by the analysis of this study.

While sophisticated analytic approaches such as propensity score and instrumental variable methods can be used to minimize bias in observational studies,9 these approaches were not described in the article.

Indeed, this study lacked detailed information on key confounding factors, most notably smoking history (which presumably was higher in radiotherapy patients and directly causes lung, head/neck, and other cancers) and prostate cancer diagnostic information (more aggressive cancers are usually treated by radiotherapy instead of surgery; some metastatic patients were likely included in the analysis due to lack of staging information).

The inability to account for these well-established confounding factors can easily explain the relatively small absolute differences between surgical and radiation patients in open surgeries (0.3% difference), hospital admissions more than 1 day (1.8%), and second cancers. Regarding the outcomes of open surgeries and hospital admissions, the authors again selectively excluded the known outcomes of radical prostatectomy (100% risk of open surgery and hospitalizations more than 1 day, both directly attributable to the treatment), compared to the 1.1% open surgery and 3.3% admission rates of radiotherapy patients, which have an unclear causal link to treatment.

We must add that the patient decision nowadays often revolves around the choice of robotic surgery or intensity-modulated radiation therapy, two new approaches that certainly alter, and arguably improve, outcomes. This study may have lost some contemporary relevance by excluding robotic surgery continued on page 38

Kyprolis速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate.

Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients.

Monitor for cardiac complications and manage promptly.

Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated.

Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.

Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

KYPROLIS is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle.

In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%).

KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2013 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243R1 December 2013

The ASCO Post | APRIL 15, 2014

PAGE 38

Perspective

Ronald C. Chen, MD, MPH Anthony L. Zietman, MD continued from page 35

and by being unable to specifically study intensity-modulated radiation treatment due to lack of necessary data.

Conclusions The authors spoke the truth when they stated that “patients want to know the frequencies and severities of various complications associated with different treatments.” Unfortunately, this study was unable to address this central goal, which

is to inform treatment decision-making.

In light of several important methodologic limitations, the authors reached too far to suggest causality between prostatectomy/radiotherapy and the “treatment-related complications.”

It is not at all clear that the event rates

KYPROLIS™ (carfilzomib) for Injection KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If2 tolerated in Cycle 1, the cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m . If tolerated Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in2 in subsequent 2 dose should be escalated to 27 mg/m beginning in Cycle 2 or and continued at 27 mg/m subsequent cycles.

Treatment may be continued until disease progression until unacceptable toxicity in occurs [see cycles.and Treatment may be continued disease progression until unacceptable Dosage Administration].

The doseuntil is calculated using the or patient’s actual bodytoxicity surfaceoccurs area [see at Dosage and Administration].

The dose is calculated using the patient’s actual body surface areaa at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon 2 baseline.

Patients with a 2body surface area greater than 2.2 m should receive a dose based upon a body surface area of 2.2 m . Dose adjustments do not need to be made for weight changes of less than area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than orbody equalsurface to 20%. or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Cycle 1 Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days Days 8Day 9Day 10–14 Days 15Day 16Day 17–21 Days 22–28 Days 1Day 2Day 3–7 3–7 208 209 10–14 2015 2016 17–21 22–28 KYPROLIS No No No No 201 202 KYPROLIS 2 No 20 20 20 No 20 20 No No 20 (20 mg/m ):2 Dosing Dosing Dosing Dosing (20 mg/m ): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days Day Day Days Day Day Days Day Days Days Day 2 3–7 8 9 10–14 15 16 17–21 22–28 1 3–7 278 279 10–14 2715 2716 17–21 22–28 KYPROLIS No No No No 271 272 KYPROLIS 27 Dosing No 27 27 Dosing No 27 27 Dosing No Dosing No 27 (27 mg/m2): Dosing Dosing Dosing Dosing (27 mg/m2): a Ifaprevious cycle dosage is tolerated.

If previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor Hydration and Fluid Hydrate patients to reduce risk of renal Maintain toxicity and of tumor lysis syndrome (TLS) withMonitoring.

KYPROLIS treatment [see Warnings andthePrecautions]. adequate lysisvolume syndrome with KYPROLIS [seeblood Warnings and Precautions]. adequate fluid status(TLS) throughout treatmenttreatment and monitor chemistries closely. PriorMaintain to each dose in fluid volume status throughout and monitor closely. Prior to each dose in Cycle 1, give 250 mL to 500 mLtreatment of intravenous normal blood saline chemistries or other appropriate intravenous fluid.

Cycle 1, give 250 mL 500 mL of intravenous normal saline other appropriate intravenous fluid.

Give an additional 250 to mL to 500 mL of intravenous fluidsor as needed following KYPROLIS Give an additional 250 intravenous mL to 500 mL of intravenous as needed following administration.

Continue hydration, as needed, fluids in subsequent cycles.

Also KYPROLIS monitor administration.

Continue hydration, needed,and in Precautions]. subsequent cycles.

Also monitor patients during this period intravenous for fluid overload [see as Warnings Dexamethasone patients during this period for fluid overload [see Warnings and Precautions].

Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of Premedication.

Pre‑medicate dexamethasone 4 mg orallythe or first intravenously priorescalation to all doses KYPROLIS during Cycle 1 and priorwith to all KYPROLIS doses during cycle of dose to of during and prior all KYPROLIS doses during the cycle ofand dose escalation to 27KYPROLIS mg/m2 to reduceCycle 1 the incidence andtoseverity of infusion reactions [seefirst Warnings Precautions].

2 27 mg/mdexamethasone to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate premedication (4 mg orally or intravenously) if these symptoms develop or Reinstateduring dexamethasone orally or intravenously) if these symptoms develop or reappear subsequentpremedication cycles. Dose(4 mg Modifications based on Toxicities.

Recommended reappear during subsequent cycles.

Dose Modifications based on Toxicities.

Recommended actions and dose modifications are presented in Table 2. actions Dose and dose modificationsforareToxicity presented in Table 2. a Table 2: Modifications during KYPROLIS Treatment Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity Recommended Action Hematologic Toxicity a • Withhold dose. Recommended Action • Grade 3 or 4 Neutropenia a Withhold dose.

Grade 3 or 4 Neutropenia • • If fully recovered before next scheduled dose, continue • • Grade 4 Thrombocytopenia • at If fully recovered before next scheduled dose, continue • Warnings Grade 4 Thrombocytopenia same dose level. [see and Precautions] at same dose level. [see Warnings and Precautions] • If recovered to Grade 2 neutropenia or Grade 3 • thrombocytopenia, If recovered to Grade 2 neutropenia or Grade 3 reduce dose by one dose level 2 thrombocytopenia, reduce 2dose one20 mg/m dose level (from 27 mg/m2 to2 20 mg/m , OR by from to 2 (from 27 mg/m to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m ).2 15 mg/m ).

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretionAction of the physician.

Non-Hematologic Toxicity Recommended Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline.

Cardiac Toxicity Withhold until resolved or returned to baseline.

Cardiac Toxicity • • After resolution, consider if restarting KYPROLIS at Grade 3 or 4, new onset or worsening of: • a reduced After resolution, consider if restarting KYPROLIS at dose is appropriate (from 27 mg/m2 to • Grade 3 or 4, new onset or worsening of: congestive heart failure; 2 2 2 (from 27 mg/m a reduced dose is 20 mg/m appropriate to , OR from to 15 mg/m2).

20 mg/m congestive heart failure; • • decreased left ventricular 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • function; decreased left ventricular • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. function; • or myocardial ischemia previous dose at the discretion of the physician.

• Warnings or myocardial ischemia [see and Precautions] [see Warnings and Precautions] Pulmonary Hypertension • Withhold until resolved or returned to baseline.

Pulmonary Withhold until resolved or returned to baseline.

• • Restart at the dose used prior to the event or reduced [see Warnings Hypertension and Precautions] • dose Restart at the dose used prior to the event or reduced [see Warnings and Precautions] (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 2 to 20 mg/m OR from 20 mg/m2 (from2),27 mg/m to dose 15 mg/m at the discretion of the2,physician.

2 to 15 mg/m ), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Pulmonary Complications • Withhold until resolved or returned to baseline.

Pulmonary Complications • Consider restarting at the next scheduled treatment • Grade 3 or 4 • with Consider restarting at the next scheduled treatment • Warnings Grade 3 or 4 one dose level reduction (from 27 mg/m2 to [see and Precautions] 2 (from 27 mg/m with one2, dose level20 mg/m reduction OR from to 15 mg/m2). 2 to 20 mg/m [see Warnings and Precautions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Hepatic Toxicity Withhold until resolved or returned to baseline.

Toxicity • • After resolution, consider if restarting KYPROLIS is • Hepatic Grade 3 or 4 elevation of • appropriate; may be reinitiated at a reduced dose (from After resolution, consider if restarting KYPROLIS is • transaminases, Grade 3 or 4 elevation of bilirubin or other 2 appropriate; may be reinitiated at a reduced dose (from 27 mg/m to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) transaminases, liver abnormalitiesbilirubin or other 2 27 mg/m tomonitoring 20 mg/m2,ofORliver from 20 mg/m2 to 15 mg/m2) with frequent function. liver abnormalities [see Warnings and Precautions)] with frequent monitoring of liver function.

• If tolerated, the reduced dose may be escalated to the [see Warnings and Precautions)] • previous If tolerated, the reduced dose may be escalated to the dose at the discretion of the physician. previous dose at the discretion of the physician. (continued) (continued)

from this study are due to treatment (although an unknown proportion certainly is). In light of these considerations, patients with localized prostate cancer and their physicians considering modern radical prostatectomy or radiotherapy options must be cautious when

a Table 2: Dose Modifications forfor Toxicity KYPROLIS Treatment (continued) a Table 2: Dose Modifications Toxicityduring during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• • Serum creatinine equal to or or to baseline and monitor renal function.

Serum creatinine equal to or • • If attributable to KYPROLIS, restart at the next scheduled greater than 2 ×2 baseline If attributable to KYPROLIS, restart at the next scheduled greater than × baseline treatment at a reduced dose (from 27 mg/m2 to2 [see Adverse Reactions] to treatment at a reduced dose2 (from 27 mg/m [see Adverse Reactions] from 20 mg/m to 15 mg/m2).

20 mg/m2, OR 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used • If not attributable to KYPROLIS, restart at the dose used prior to the event. prior to the event.

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 • Restart at the dose used prior to the event or reduced • Grade 3 or 4 2 dose (from 27 mg/m2 to2 20 mg/m2, OR [see Adverse Reactions] 2 from 20 mg/m (from2),27 mg/m to 20 mg/m OR from 20 mg/m2 [see Adverse Reactions] to dose 15 mg/m at the discretion of the ,physician. to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment Consider restarting at the next scheduled treatment • toxicities Grade 3 or 4 non-hematological • with one dose level reduction (from 27 mg/m2 to2 with one 27 mg/m to toxicities 2 dose level reduction 2 , OR from 20 mg/m2 to(from 15 mg/m ).

20 mg/m 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. previous dose at the discretion of the physician. a

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg Administration Precautions.

The quantity of KYPROLIS single‑use (60 mg carfilzomib) may exceed the required dose. Caution shouldcontained be used in in one calculating the vial quantity carfilzomib) may exceed the Do required dose.

Cautionwith should be used as in an calculating the other quantity delivered to prevent overdosing. not mix KYPROLIS or administer infusion with deliveredproducts. to prevent not mix KYPROLIS with or an infusion other medicinal Theoverdosing. intravenousDoadministration line should be administer flushed withasnormal salinewith or 5% medicinal products. intravenous administration line should be flushed with normal should saline or Dextrose Injection, USPThe immediately before and after KYPROLIS administration.

KYPROLIS not5% Dextrose Injection, USP immediately before and after KYPROLIS administration.

KYPROLIS should be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitutionnot be administered KYPROLISAdministration. should be administered overvials 2 to 10 minutes. and Preparation asfora bolus.

Intravenous KYPROLIS contain no Reconstitution antimicrobial and Preparation Intravenous Administration.

KYPROLIS vials contain no antimicrobial preservatives and are for intended only for single use. Unopened vials of KYPROLIS are stable until the preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete reconstituted solutionprior contains carfilzomib Reconstitution/Preparation at a concentration of 2 mg/mL. Read the complete preparation instructions to reconstitution.

Steps: 1. Remove vial preparation instructions to reconstitution.

Steps: 1. Remove from refrigerator just priorprior to use.

2. AsepticallyReconstitution/Preparation reconstitute each vial by slowly injecting 29 mLvial from refrigerator just prior to use.

2.

Aseptically reconstitute each vial by slowly injecting 29 Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow of any tocake DOto NOT SHAKE to avoid foam generation. foaming occurs, allow solution restorinpowder vial foroccurs. about 2 5 minutes, until foaming subsides. 4.If After reconstitution, solution rest inforvialintravenous for about 2 to 5 minutes,The untilreconstituted foaming subsides.

After reconstitution, KYPROLIS to is ready administration. product 4.should be a clear, KYPROLIS is ready for intravenous administration.

The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.and from the dilute intothe50 unused mL 5%portion.

Dextrose USPof intravenous bag.

6. Administration] Immediately discard thevial vialand containing TheInjection, stabilities reconstituted 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Table 3: Stability of Reconstituted KYPROLIS Stabilitya per Container Stabilitya per Container Storage Conditions of Reconstituted Storage Conditions of Reconstituted IV Bag KYPROLIS b IV Bag KYPROLIS Vial Syringe (D5W ) Vial Syringe (D5Wb) Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours a

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP. a Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial WARNINGS Cardiac Arrest, Heart administration.

Failure, Myocardial Ischemia.

DeathAND due PRECAUTIONS: to cardiac arrest has occurred withinCongestive a day of KYPROLIS New Ischemia.

Deathofdue to cardiaccongestive arrest hasheart occurred within day of KYPROLIS administration.

New onset or worsening pre‑existing failure with adecreased left ventricular function or onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk 4 cardiac [see events until recovery and consider whether restart based onClass a benefit/risk assessment Dosage and Administration].

Patients withtoNew YorkKYPROLIS Heart Association III and assessment Dosage and Administration].

Patients with New York Association Class III and IV heart failure,[see myocardial infarction in the preceding 6 months, andHeart conduction abnormalities IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater medications were not eligible for the clinical trials. These patients may be at(PAH) greater riskuncontrolled for cardiacbycomplications.

Pulmonary Hypertension.

Pulmonary arterial hypertension risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for patients. hypertension Evaluate with until cardiac imaging and/or other tests as and indicated. pulmonary resolved or returned to baseline considerWithhold whetherKYPROLIS to restart for pulmonary hypertension until resolved or returned baseline consider whether to restart KYPROLIS based on a benefit/risk assessment [see toDosage andand Administration].

Pulmonary KYPROLIS based on a benefit/risk assessment [see Dosage and Administration].

Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea Complications. occurred in 5%; no Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were Dosage andbyAdministration Adverse Reactions].

Infusion Infusionmyalgia, reactions were characterized a spectrum ofand systemic symptoms including fever,Reactions. chills, arthralgia, facial characterized by a spectrum of systemicshortness symptoms including fever, chills, arthralgia, facial flushing, facial edema, vomiting, weakness, of breath, hypotension, syncope, chestmyalgia, tightness, facial edema, vomiting, weakness, shortness of breath, chest tightness, or flushing, angina. These reactions can occur immediately following or up hypotension, to 24 hours syncope, after administration of or angina.Administer These reactions can occur prior immediately following or up tothe 24 incidence hours afterand administration KYPROLIS. dexamethasone to KYPROLIS to reduce severity of of KYPROLIS. to patients KYPROLIS to reduce incidenceand andto severity reactions [seeAdminister Dosage anddexamethasone Administration].prior Inform of the risk andthesymptoms contact of reactions [see Dosage andinfusion Administration].

Inform the risk and symptomsTumor and toLysis contact physician if symptoms of an reaction occur [seepatients PatientofCounseling Information]. physician if symptoms of an infusion reaction occur [see Patient Counseling Information].

Tumor Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% Lysis of Syndrome.

Tumor syndrome (TLS) following KYPROLIS patients.

Patients withlysis multiple myeloma andoccurred a high tumor burden should administration be consideredinto< be1% at of patients. with to multiple myeloma and ensure a high that tumor burdenareshould be considered to be at greater risk Patients for TLS. Prior receiving KYPROLIS, patients well hydrated [see Dosage risk for TLS.Monitor Prior toforreceiving ensure that patients well hydrated Dosage andgreater Administration]. evidenceKYPROLIS, of TLS during treatment, and are manage promptly.[see Interrupt and Administration]. evidence TLS Administration].Thrombocytopenia. during treatment, and manage promptly.

Interrupt KYPROLIS until TLS is Monitor resolvedfor[see Dosageofand KYPROLIS KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia.

KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following patients administration experienced thrombocytopenia, 4 in Thrombocytopenia following KYPROLIS resulted in a doseincluding reductionGrade in 1% of 10%. patients and discontinuation of KYPROLIS a doseMonitor reduction in 1% of patients andduring discontinuation treatment withadministration KYPROLIS in resulted < 1% of inpatients. platelet counts frequently treatment of treatment withReduce KYPROLIS in < 1%dose of patients.

Monitor platelet[see counts frequently during treatment with KYPROLIS. or interrupt as clinically indicated Dosage and Administration]. with KYPROLIS. Reduce or interrupt as of clinically [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure.dose Cases hepaticindicated failure, including fatal cases, have been Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

ASCOPost.com | APRIL 15, 2014

PAGE 39

Perspective

reviewing findings of this study. n

Disclosure: Drs. Chen and Zietman reported no potential conflicts of interest.

References 1. Alemozaffar M, Regan MM, Cooperberg MR, et al: Prediction of

erectile function following treatment for prostate cancer. JAMA 306:1205-1214, 2011.

2. Resnick MJ, Koyama T, Fan KH, et al: Long-term functional outcomes after treatment for localized prostate cancer.

N Engl J Med 368:436-445, 2013.

3. Alibhai SM, Leach M, Tomlinson G, et al: 30-day mortality and major complications after radical prostatectomy: Influence of age and comorbidity.

J Natl Cancer Inst 97:1525-1532, 2005.

4. Chen RC, Clark JA, Talcott JA: Individualizing quality-of-life outcomes

reported (< (< 1%).

KYPROLIS can can cause elevations of serum transaminases and and bilirubin. Withhold of Selected Adverse Drug Reactions.

Renal Events: The The mostmost common renalrenal reported 1%).

KYPROLIS cause elevations of serum transaminases bilirubin. Withhold Description Description of Selected Adverse Drug Reactions.

Renal Events: common KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other reactions werewere increase in blood creatinine (24%) and and renalrenal failure (9%),(9%), which werewere mostly KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other adverse adverse reactions increase in blood creatinine (24%) failure which mostly liverliver abnormalities until resolved or returned to baseline.

After resolution, consider if restarting Grade 1 or Grade 2 in severity.

Grade 3 renal adverse reactions occurred in 6% of patients and and abnormalities until resolved or returned to baseline. After resolution, consider if restarting Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients KYPROLIS is appropriate.

Monitor liver enzymes frequently [see Dosage and Administration and Grade 4 events occurred in 1%.

Discontinuations due to increased blood creatinine and acute renal KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal pregnant woman based on its mechanism of action and findings in animals. There are no adequate and function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including pregnant woman based on its mechanism of action and findings in animals. There are no adequate and function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. of the labeling: DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase of the labeling: DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by • Pulmonary Hypertension [see Warnings and Precautions] concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected • Pulmonary Hypertension [see Warnings and Precautions] concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected • Pulmonary Complications [see Warnings and Precautions] to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

• Pulmonary Complications [see Warnings and Precautions] to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

• Infusion Reactions [see Warnings and Precautions] USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and • Infusion Reactions [see Warnings and Precautions] USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and • Tumor Lysis Syndrome [see Warnings and Precautions] Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while • Tumor Lysis Syndrome [see Warnings and Precautions] Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while • Thrombocytopenia [see Warnings and Precautions] being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS • Thrombocytopenia [see Warnings and Precautions] with KYPROLIS. Based ontoitsamechanism of actionCarfilzomib and findings in animals, KYPROLIS • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] canbeing causetreated fetal harm when administered pregnant woman. caused embryo‑fetal • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] can fetal rabbits harm when administered a pregnant caused embryo‑fetal The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical toxicity incause pregnant at doses that weretolower than in woman. patients Carfilzomib receiving the recommended The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical toxicity in pregnant rabbits at doses that were lower than becomes in patientspregnant receivingwhile the taking recommended trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, dose.

If KYPROLIS is used during pregnancy, or if the patient this trials ofand patients withClinical multipleTrials myeloma wereExperience. fatigue, anemia, nausea, thrombocytopenia, dyspnea,drug, dose.

If KYPROLIS duringof pregnancy, if the topatient becomes pregnant taking this diarrhea, pyrexia.

Safety Because clinical trials are conducted the patient shouldisbeused apprised the potentialorhazard the fetus.

Carfilzomib was while administered diarrhea, pyrexia.

Clinical Trialsreaction Safetyrates Experience. clinical are conducted drug, the patient should beand apprised the potential hazard to the fetus. Carfilzomib administered under widely and varying conditions, adverse observed inBecause the clinical trialstrials of a drug cannot intravenously to pregnant rats rabbitsofduring the period of organogenesis at doses ofwas 0.5, 1, and varyingwith conditions, reaction observed in and the clinical of a the drugrates cannot 2 mg/kg/day intravenously to pregnant during the in period of organogenesis at doses of 0.5, 1, and be under directlywidely compared rates in adverse the clinical trials rates of another drug, may nottrials reflect in rats and 0.2,rats 0.4,and andrabbits 0.8 mg/kg/day rabbits.

Carfilzomib was not teratogenic be directly compared with Arates anotherand/or drug,refractory and may multiple not reflect the rates at any andan0.8 mg/kg/day in rabbits. Carfilzomib teratogenic 2 mg/kg/day in rats and 0.2, 0.4,was observed in medical practice. total inof the 526clinical patientstrials with ofrelapsed myeloma dose tested.

In rabbits, there increase in pre‑implantation loss at ≥was 0.4 not mg/kg/day observed in medical practice. A total of 526 patients with relapsed and/or refractory myeloma any dose tested. rabbits, there an increase in loss pre‑implantation lossinatfetal ≥ 0.4 mg/kg/day received KYPROLIS as monotherapy or with pre‑dose dexamethasone.

Patients receivedmultiple a median of andatan increase in earlyInresorptions andwas post‑implantation and a decrease weight at received KYPROLIS monotherapy or with pre‑dose dexamethasone.

Patients receiveddue a median an increase early and post‑implantation decrease inin rabbits fetal weight four treatment cycles as with a median cumulative KYPROLIS dose of 993.4 mg. Deaths to all of the and maternally toxic in dose of resorptions 0.8 mg/kg/day.

The doses of 0.4 loss and and 0.8 amg/kg/day are at four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all approximately the maternally dose respectively, of 0.8 mg/kg/day.

The doses of dose 0.4 and 0.8 mg/kg/day in 2rabbits are causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not 20%toxic and 40%, of the recommended in humans of 27 mg/m based 2 causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not approximately 20% Nursing and 40%,Mothers. respectively, theknown recommended dose in humans of 27 in mg/m based attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, on body surface area.

It isofnot whether KYPROLIS is excreted human attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, on body surface area.

Nursing Mothers.

It is not known whether KYPROLIS is excreted in human cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since many drugs are excreted in human milk and because of the potential for serious adverse cardiacindisorder), end‑organ in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since manyinfants drugsfrom are excreted in ahuman milk and because the potential for serious adverse infection 4 patients (sepsis,failure pneumonia, respiratory tract bacterial infection), dyspnea and reactions in nursing KYPROLIS, decision should be made of whether to discontinue nursing infection hemorrhage in 4 patients tract bacterial infection), dyspnea in nursing infants frominto KYPROLIS, decision shouldofbethe made to discontinue nursing intracranial in 1(sepsis, patient pneumonia, each, and 1 respiratory patient found dead of unknown causes.

Seriousand or toreactions discontinue the drug, taking account athe importance drugwhether to the mother.

Pediatric intracranial hemorrhage in 1 inpatient each, andThe1 most patient found dead of adverse unknownreactions causes.were Serious Use.or The to discontinue drug, takingofinto account inthepediatric importance of thehave drugnot to the Pediatric adverse reactions were reported 45% patients. common serious safety andthe effectiveness KYPROLIS patients beenmother. established. adverse reactions were reported in 45% patients. The most common serious adverse reactions were Geriatric Use. The and ofeffectiveness of KYPROLIS in pediatric patients have not been in established. pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse Use.safety In studies KYPROLIS there were no clinically significant differences observed safety pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse Use. In patients studies ofless KYPROLIS there were noand clinically significant in safety reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive andGeriatric efficacy between than 65 years of age patients 65 yearsdifferences of age andobserved older. Renal reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive and efficacy between patients less than 65 years of age and patients 65 years of age and older. heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial Renal in heart failurereactions (2%), cardiac arrest, increased bloodare creatinine, acute4.renal failure (1% patients Impairment.

The renal pharmacokinetics KYPROLIS were in a Phase 2 trial in each).

Adverse occurring at dyspnea, a rate of 10% or greater presentedand in Table with normal function and and thosesafety with of mild, moderate, andevaluated severe renal impairment each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma andofpatients on2 chronic dialysis. average, patients were27treated usingbeyond.

KYPROLIS 2 Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma doses 15 mg/m on2 Cycle 1, 20 On mg/m on Cycle 2, and mg/m2for on 25.5 cycles Cycles 3 and Patients Treated with KYPROLIS of 15 mg/mand on safety Cycle of1, KYPROLIS 20 mg/m2were on Cycle 2, and 27bymg/m on Cycles 3 and renal beyond.

Patients Treated with KYPROLIS Thedoses pharmacokinetics not influenced the degree of baseline Patients (N = 526) The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrationsrenal Patients [n (%)](N = 526) impairment, including the patients on dialysis.

Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical [n (%)] has not been studied, shouldImpairment. be administered after the dialysis [see Clinical Grade 3 Grade 4 All Pharmacology section of fullthePI].drug Hepatic The safety, efficacy andprocedure pharmacokinetics Grade 3 Grade 4 Alla Pharmacology full PI]. Hepatic Impairment. safety, efficacy and pharmacokinetics Events Events Event Grades of KYPROLIS have section not beenofevaluated in patients with baselineThe hepatic impairment.

Patients with the Events Events Event Gradesa of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the Fatigue 292 (55.5) 38 (7.2) 2 (0.4) following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper Fatigue 292 (55.5) 38 (7.2) 2 (0.4) limitfollowing laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Anemia 246 (46.8) 111 (21.1) 7 (1.3) limit of normal (ULN)with andNew bilirubin ≥ 2 ×Association ULN [see Clinical sectionwere of full Cardiac Anemia 246 (46.8) 111 (21.1) 7 (1.3) Impairment.

Patients York Heart Class IIIPharmacology and IV heart failure notPI]. eligible Nausea 236 (44.9) 7 (1.3) 0 Impairment.

Patients New York Heart Association Class III and IV heart failure were not eligible for the clinical trials.

Safetywith in this population has not been evaluated.

Nausea 236 (44.9) 7 (1.3) 0 Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) for the clinicalThere trials.isSafety in thisspecific population has not evaluated.

OVERDOSAGE: no known antidote for been KYPROLIS overdosage. In the event of an Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) OVERDOSAGE: is noand known specific antidotesupportive for KYPROLIS Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b b overdosage, monitor There the patient provide appropriate care.overdosage. In the event of an Dyspnea 182 (34.6) 25 (4.8) 1 (0.2) overdosage, monitor the patient and provide appropriate supportive Diarrhea 172 (32.7) 4 (0.8) 1 (0.2) NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, andcare.

Impairment of Fertility.

Diarrhea 172 (32.7) 4 (0.8) 1 (0.2) NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of inFertility.

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic the Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib wasnot clastogenic in the Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was mutagenic Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 in vitro chromosomal aberration test in peripheral blood lymphocytes.

Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 Headache 145 (27.6) 7 (1.3) 0 in marrow the in vitro bacterial reverse (Ames)with test carfilzomib and was nothave clastogenic in conducted. the in vivo No mouse bone micronucleus assay. mutation Fertility studies not been Headache 145 (27.6) 7 (1.3) bone onmarrow micronucleus Fertility during studies with carfilzomib conducted.

Cough 137 (26.0) 1 (0.2) 0 0 effects reproductive tissues assay. were noted 28‑day repeat‑dosehave rat not and been monkey toxicity No Cough 137 (26.0) 1 (0.2) 0 effects reproductive were noted chronic during toxicity 28‑day studies. repeat‑dose rat Toxicology and monkeyand/ toxicity Blood creatinine increased 127 (24.1) 13 (2.5) 1 (0.2) studies or inon6‑month rat andtissues 9‑month monkey Animal Blood creatinine increased (24.1) 13 (2.5) 1 (0.2) studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg Lymphopenia 126127 (24.0) 84 (16.0) 11 (2.1) 2 or Pharmacology.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg Lymphopenia 126 (24.0) 84 (16.0) 11 (2.1) (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) Edema peripheral 126 (24.0) 3 (0.6) 0 (approximately 1.3 times recommended humans serum of 27 levels mg/m2ofbased on body experienced hypotension, increased heart rate,dose andin increased troponin‑T. The surface repeatedarea) Edema peripheral (24.0) 3 (0.6) Vomiting 117126 (22.2) 5 (1.0) 0 0 experienced hypotension, increased heart rate,atand increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in Vomiting 117 (22.2) 5 (1.0) 0 Constipation 110 (20.9) 1 (0.2) 0 bolus using intravenous of carfilzomib at ≥ 2clinically mg/kg/dose in in ratsmortalities and 2 mg/kg/dose monkeys dosingadministration schedules similar to those used resulted that were in Constipation 110 (20.9) 1 (0.2) 0 monkeys using dosing schedules similar to those used clinically resulted in mortalities that Neutropenia 109 (20.7) 50 (9.5) 4 (0.8) due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluidwere Neutropenia (20.7) due to toxicities occurring in the cardiovascular gastrointestinal (cardiac failure, (necrosis/hemorrhage), cardiac fibrosis, pericardial accumulation, cardiac hemorrhage/degeneration), renalfluid Back pain 106109 (20.2) 15 50 (2.9)(9.5) 04 (0.8) accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Back pain (20.2) 15 (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) Insomnia 94106 (17.9) 0 (2.9) 0 0 (glomerulonephropathy, tubular innecrosis, dysfunction), half andthe pulmonary (hemorrhage/inflammation) systems.

The dose of 2 mg/kg/dose rats is approximately recommended dose in humans Insomnia (17.9) Chills 84 94 (16.0) 1 (0.2)0 0 0 systems. doseonofbody 2 mg/kg/dose in rats approximately half theinrecommended dose in humans of 27 mg/m2The based surface area.

Theisdose of 2 mg/kg/dose monkeys is approximately Chills 84 (16.0) 1 (0.2) 2 Arthralgia 83 (15.8) 7 (1.3) 0 0 of 27 mg/m based on bodydose surface area. The doseonofbody 2 mg/kg/dose in monkeys is approximately equivalent to the recommended in humans based surface area.

Arthralgia 83 (15.8) 7 (1.3) 0 equivalent to the recommended dose in humans based on body surface area.

Muscle spasms 76 (14.4) 2 (0.4) 0 PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with Muscle spasms 76 (14.4) 2 (0.4) PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms:

Hypertension 75 (14.3) 15 (2.9) 2 (0.4)0 KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: Hypertension 75 (14.3) 15 (2.9) 2 (0.4) fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS Asthenia 73 (13.9) 12 (2.3) 1 (0.2) rigors, chest pain, cough, or swelling of the pressure. feet or legs.

Advise patients KYPROLIS mayfever, causechills, fatigue, dizziness, fainting, and/or drop in blood Advise patients not that to drive or Asthenia 73 (13.9) 12 (2.3) 1 (0.2) Hypokalemia 72 (13.7) 14 (2.7) 3 (0.6) may machinery cause fatigue, fainting, drop in blood pressure. patients not to drive or operate if theydizziness, experience any ofand/or these symptoms.

Advise patientsAdvise that they may experience Hypokalemia 72 (13.7) Hypomagnesemia 71 (13.5) 2 14 (0.4)(2.7) 03 (0.6) operateofmachinery if they experience any of these patients that theyoccurs may experience shortness breath (dyspnea) during treatment withsymptoms.

KYPROLIS.Advise This most commonly within Hypomagnesemia 71 (13.5) 2 (0.4) shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within Leukopenia 71 (13.5) 27 (5.1) 1 (0.2)0 a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.

Leukopenia 71 (13.5) 27 (5.1) 1 (0.2) a day of dosing.

Advise patients to contact their physicians if they experience shortness of breath.

Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience Pain in extremity 70 (13.3) 7 (1.3) 0 Counsel patients to avoid dehydration, patients receiving therapy may experience vomiting and/or diarrhea.

Instruct patientssince to seek medical adviceKYPROLIS if they experience symptoms Pain in extremity 7 (1.3) Pneumonia 67 70 (13.3) (12.7) 52 (9.9) 3 (0.6)0b vomiting and/or diarrhea. Instruct patients seek medical if they experience symptoms of dizziness, lightheadedness, or fainting spells.toCounsel femalesadvice of reproductive potential to use Pneumonia (12.7) 3 (0.6)b Aspartate aminotransferase increased 66 67 (12.5) 15 52 (2.9)(9.9) 1 (0.2) of dizziness, lightheadedness, faintingpregnancy spells. Counsel reproductive to use effective contraceptive measures toorprevent during females treatmentofwith KYPROLIS.potential Advise the Aspartate aminotransferase increased 66 66 (12.5) 1 (0.2) Dizziness (12.5) 5 15 (1.0)(2.9) 1 (0.2) effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately.

Dizziness (12.5) 5 (1.0) patient if she becomestreatment pregnantwhile during treatment, to contact herIf physician immediately.

Advise Hypoesthesia 64 66 (12.2) 3 (0.6) 01 (0.2) patients notthat to take KYPROLIS pregnant or breastfeeding. a patient wishes to restart Hypoesthesia 64 (12.2) 3 (0.6) patients notafter to take KYPROLIS treatment while pregnant or breastfeeding.

If aher patient wishesAdvise to restart breastfeeding treatment, advise her to discuss the appropriate timing with physician.

Anorexia 63 (12.0) 1 (0.2) 0 0 breastfeeding after advise her discuss thethey appropriate timingtaking with her physician.

Advise patients to discuss withtreatment, their physician any tomedication are currently prior to starting 63 (12.0) 1 (0.2) PainAnorexia 63 (12.0) 12 (2.3) 0 0 patientswith to KYPROLIS, discuss with their tophysician any new medication they are currently taking to starting treatment or prior starting any medication(s) during treatment withprior KYPROLIS. Pain 12 (2.3) Hyperglycemia 62 63 (12.0) (11.8) 16 (3.0) 3 (0.6)0 treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS. Hyperglycemia (11.8) 16 (3.0) Chest wall pain 60 62 (11.4) 3 (0.6) 03 (0.6) Chest wall pain (11.4) 3 (0.6) Hypercalcemia 58 60 (11.0) 13 (2.5) 8 (1.5)0 Hypercalcemia (11.0) 8 (1.5) Hypophosphatemia 55 58 (10.5) 24 13 (2.5) (4.6) 3 (0.6) Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 a b National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

One event was Grade 5 severity.

U.S.South San Francisco, CA 94080 Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 b One event was Grade 5 severity.

U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

reporting: How localized prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual function. J Clin Oncol 27:39163922, 2009.

5. Murray L, Henry A, Hoskin P, et al: Second primary cancers after radiation for prostate cancer: A systematic review of the clinical data and impact of treatment technique. Radiother Oncol. January 30, 2014 (early release online).

6. Chen RC, Carpenter WR, Hendrix LH, et al: Receipt of guideline-concordant treatment in elderly prostate cancer patients. Int J Radiat Oncol Biol Phys 88:332338, 2014.

7. Nam RK, Cheung P, Herschorn S, et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: A population-based cohort study. Lancet Oncol 15:223-231, 2014.

8. Thompson IM, Valicenti RK, Albertsen P, et al: Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol 190:441-449, 2013.

9. Concato J: Is it time for medicine-based evidence? JAMA 307:1641-1643, 2012.

More on This Topic See page 40.

The ASCO Post

Like us on

Facebook facebook.com/TheASCOPost

The ASCO Post | APRIL 15, 2014

PAGE 40

Perspective

Long-Term Complications of Prostate Cancer Treatment May Have Been Underappreciated

By Kyle O. Rove, MD, Ty T. Higuchi, MD, PhD, and E. David Crawford, MD

T

he recent study by Nam et al in The Lancet Oncology—reviewed in this issue of The ASCO Post—provides a fresh perspective on complications other than incontinence or erectile dysfunction that commonly arise after primary treatment of localized prostate cancer.1 The authors conducted a population-based retrospective cohort study using administrative databases to compare 5-year cumulative incidences of hospital admissions, minimally invasive urologic procedures, rectal or anal procedures, open surgical procedures, and secondary neoplasms. Strikingly, the authors uncovered the fact that the rates of these complications may be far higher than previously thought.

The authors are to be commended for looking beyond the two most common adverse events after primary therapy to other complications that are perhaps less appreciated by clinicians and patients alike but that can have serious, detrimental effects on future quality of life.2 The study provides sound, detailed methodologic approaches to allow others to validate these results in additional populations.

wonder whether these numbers would hold true. With these data at hand, the principle of primum non nocere should weigh even more heavily on those who administer prostate cancer treatment.

Divergence of Experience If a patient does choose to undergo treatment, these data demonstrate a divergence of experience between radiation and surgery. Patients who received both surgery and radiation were excluded. Those choosing forms of radiotherapy experienced higher 5-year incidences of hospital admissions (≥ 1 day), rectal or anal procedures, open surgical procedures, and secondary malignancies than those who chose radical prostatec-

stay were more common in the radiotherapy group, this is not entirely unexpected given the older age and increased comorbidity in these patients.

Contentiously, the authors did opt to count post-radiation prostate biopsy as a complication (accounting for 6% of all complication events in that group). The authors note that biopsy after radiation is not “expected or routine.” One could argue against inclusion of these events on the basis that they represent patients with biochemical failure, which is a feature of any prostate cancer treatment.

Still, omission would detract from the totality of post-treatment procedures.

Conversely, one could argue that the authors should have considered adjuvant

Notable Implications The population-based nature of the data with age-matched controls provides a clear picture of what a patient can expect in the 5 years following treatment for prostate cancer. Specifically, patients undergoing treatment were 17.9 times more likely to be admitted to the hospital, 6.8 times more likely to undergo a urologic procedure, twice as likely to have a rectal or anal procedure, and 6.0 times as likely to have an open surgical procedure as compared to the general population.

While these data do not elucidate any information on stage or grade of prostate cancer, the implications from the standpoint of any overdiagnosis and subsequent overtreatment of prostate cancer are astounding, primary treatment modality aside.3 While capturing similar data for patients who choose active surveillance might be impossible with an administrative dataset (there are no such procedural billing codes, to these authors’ knowledge, that would capture patients on active surveillance), one must Dr. Rove is a resident in general urology; Dr. Higuchi is Assistant Professor, Surgery/Urology; and Dr. Crawford is Professor of Radiation Oncology, Division of Urology, University of Colorado, Anschutz Medical Campus, Aurora.

Given the complexity of discussing treatments, a multidisciplinary approach … is paramount to providing the patient with an unbiased, accurate picture of treatment and expectations that allows careful consideration of the risks and benefits of each treatment approach.

—Kyle O. Rove, MD, Ty T. Higuchi, MD, PhD, and E. David Crawford, MD

tomy, implying increased rates of urethral and ureteral stricture, proctitis and rectal problems, and refractory cystitis.

The study is limited by an inability to specify what form of radiotherapy was delivered (external-beam conformal radiation, intensity-modulated radiation therapy, image-guided radiation therapy, brachytherapy, or stereotactic radiation).

Some forms of radiotherapy likely provide differing rates of toxicity, but this study does not elucidate such differences.

Those opting for radiation were, however, less likely to undergo subsequent urologic procedures (cystoscopy, catheterization, urethral dilation or incision, or calculi or clot removal) than the surgical group (hazard ratio = 0.66, 95% confidence interval [CI] = 0.63–0.69).

Furthermore, while longer lengths of

or salvage radiation after prostatectomy as a complication, but they state quite correctly they wanted to avoid contamination of the two groups.

One curiosity in this large, population-based study is how 35 patients underwent open bladder neck repair after radiotherapy, whereas no prostatectomy patients suffered a similar fate, despite a larger incidence of catheterization and urethral dilation/incision in the surgical cohort—proving that bladder neck contracture occurs commonly with both treatments. This speaks highly to the biases of treatment sought and received when patients are under the care of a urologist as opposed to a radiation oncologist.

This same argument applies to the control group population: Patients who did not receive regular care by a urolo-

gist might have avoided some procedures that would have otherwise been delivered or indicated. Prostate cancer patients are often highly motivated to seek attention and treatment, more so than the general population. This form of spectrum bias may speak to the higher-than-expected incidence of complications reported in this study.4

Elephant in the Room Addressing the elephant in the room, the authors studied the rate of secondary malignancy after radiation treatment, comparing the incidence from years 5 through 9 (accounting for lag time after delivery of radiation) in both the control population and surgically treated patients. Risk of secondary cancer was 309 per 100,000 person-years in the radiotherapy group and 113 per 100,000 person-years in the surgery group, with a standardized incidence ratio (comparing incidence in each group to expected rates of cancer in an age-adjusted general population) of 2.0 (95% CI = 1.7–2.3) for radiotherapy and 0.8 (95% CI = 0.6–1.0) for surgery.

The authors determined there was no improvement in rate of secondary malignancy when the analysis was restricted to patients who received contemporary radiation treatment with three-dimensional treatment planning. The literature cites rates ranging from 1.9% to 9% after radiotherapy for prostate cancer.5-8 Despite the large range within the literature, given the lag time, one can assume older patients with shorter life expectancies to suffer lower rates of secondary neoplasm than younger, healthier patients, confirming previous data.8 These data, however small, show that the risk of secondary cancer attributable to radiation is not zero, and this will likely generate much discussion within the radiation oncology community.

This study is limited in the degree of certainty in tying secondary events to treatment for prostate cancer, as the use of administrative databases may overestimate the risk of these events.9,10 Unfortunately, androgen-deprivation therapy could not be accounted for due to a lack of data on all patients. Robotic-assisted laparoscopic prostatectomy was also excluded given lack of broad adoption during the study period. Including these patients for subanalysis might further influence the results and provide insight into the modern delivery of prostate cancer treatment.

ASCOPost.com | APRIL 15, 2014

PAGE 41

Perspective

Still, this study provides a unique global view of activities following treatment of prostate cancer on a population scale.

Informed Decision-Making In an era of patient-centered medicine, informed decision-making is key.

This study demonstrates that there are vastly different types and rates of complications between primary treatment modalities across a modern population of prostate cancer patients.

To address these differences, clinicians must have an open conversation with patients that details possible adverse effects of treatment, including urinary incontinence and erectile dysfunction.

Furthermore, we know that patient retention of information after any single clinic visit can be dismally low, owing to a number of factors including socioeconomic status, patient anxiety, and foreignness of information to be digested. Given the complexity of discussing treatments, a multidisciplinary approach (some combination of urologist, radiation oncologist, medical oncologist, pathologist, radiologist, and patient advocate) is paramount to providing the patient with an unbiased, accurate picture of treatment and expectations that allows careful consideration of the risks and benefits of each treatment approach.11-13

therapy for prostate cancer—a SEER analysis of brachytherapy versus external beam radiotherapy. Int J Radiat Oncol Biol Phys 72:58-68, 2008.

8. de Gonzalez AB, Curtis RE, Kry SF, et al: Proportion of second cancers attributable to radiotherapy treatment in adults. Lancet Oncol 12:353-360, 2011.

9. Resnick MJ, Koyama T, Fan K-H, et al:

Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 368:436-445, 2013.

10. Sewell JM, Rao A, Elliott SP: Validating a claims-based method for assessing severe rectal and urinary adverse effects of radiotherapy.

Urology 82:335-340, 2013.

11. Gomella LG: Prostate cancer. Nat Rev

Urol 9:360-362, 2012.

12. Magnani T, Valdagni R, Salvioni R, et al: The 6-year attendance of a multidisciplinary prostate cancer clinic in Italy. BJU Int 110:9981003, 2012.

13. Stewart SB, Bañez LL, Robertson CN, et al: Utilization trends at a multidisciplinary prostate cancer clinic. J Urol 187:103-108, 2012.

Now Enrolling

BIRCH

A Study of MPDL3280A (an engineered anti-PDL1 antibody) in Patients With PD-L1–positive Locally Advanced or Metastatic Non-small Cell Lung Cancer (NCT02031458, Study ID GO28754)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

Locally advanced or metastatic NSCLC PD-L1–positive patients

N=300

MPDL3280A1 (an engineered anti-PDL1 antibody)

Central testing for PD-L1 IHC status

Disclosure: Drs. Higuchi and Crawford reported no potential conflicts of interest. Dr. Rove receives honoraria from UBM Medica.

References 1. Nam RK, Cheung P, Herschorn S, et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer. Lancet Oncol 15: 223-231, 2014.

2. Elliott SP, McAninch JW, Chi T, et al: Management of severe urethral complications of prostate cancer therapy. J Urol 176:2508-2513, 2006.

3. Bangma CH, Roemeling S, Schröder FH: Overdiagnosis and overtreatment of early detected prostate cancer. World J Urol 25:3-9, 2007.

4. Potosky AL, Davis WW, Hoffman RM, et al: Five-year outcomes after prostatectomy or radiotherapy for prostate cancer.

J Natl Cancer Inst 96:1358-1367, 2004.

5. Baxter NN, Tepper JE, Durham SB, et al: Increased risk of rectal cancer after prostate radiation. Gastroenterology 128:819824, 2005.

6. Liauw SL, Sylvester JE, Morris CG, et al: Second malignancies after prostate brachytherapy. Int J Radiat Oncol Biol Phys 66:669-673, 2006.

7. Abdel-Wahab M, Reis IM, Hamilton K: Second primary cancer after radio-

Primary Endpoints:

Secondary Endpoints:

• Objective response rate (ORR), IRF-assessed,

• Duration of response

according to RECIST v1.1

• Progression-free survival

• ORR, investigator-assessed, according to

• Overall survival

modified RECIST

• Safety: incidence of AEs • Pharmacokinetics: maximum serum concentration • Pharmacokinetics: minimum serum concentration

under steady-state conditions within a dosing interval

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Locally advanced or metastatic NSCLC (stage IIIB,

stage IV, or recurrent)

• History of autoimmune disease • Active hepatitis B or hepatitis C

• Representative FFPE tumor specimens

• HIV-positive

• PD-L1–positive status by IHC tested at a

• Prior treatment with CD137 agonists, anti-CTLA4,

central laboratory • Measurable disease, defined by RECIST v1

anti-PD1, or anti-PDL1 antibodies or pathwaytargeting agents

• ECOG performance status of 0 or 1 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

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

© 2014 Genentech USA, Inc. All rights reserved. BIO0002315202 Printed in USA.

The ASCO Post | APRIL 15, 2014

PAGE 42

Expert’s Corner Survivorship

Detecting Accelerated Aging in Adult Survivors of Childhood Cancer A Conversation With Kirsten K. Ness, PhD

By Jo Cavallo

L

ast fall, Kirsten K. Ness, PhD, published her study1 on the prevalence of frailty as a sign of accelerated aging in adult survivors of childhood cancer, and the results are startling.

Among the 1,922 participants in the study, the prevalence of prefrailty was 31.5% among women and 12.9% among men; the prevalence of frailty was 13.1% among women and 2.7% among men. And prevalence increased with age.

Prefrailty and frailty were defined as experiencing two and three of the following: low muscle mass, self-reported exhaustion, low energy expenditure,

of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital, Memphis, about the results of the study, the causes of accelerated aging in young adult survivors, and what oncologists can do to spot and stop the process of accelerated aging in their patients.

Role of Gender In the study, female survivors were more susceptible to frailty than their male counterparts. Do you know why?

As a general rule, female childhood cancer survivors have worse outcomes than males. We don’t know why. Women have low levels of testosterone, and

Evaluating the causes of this phenomenon is important because frailty predicts onset of chronic conditions and mortality. If we can figure out what causes the phenotype, we may be able to find an effective intervention and either prevent it or stop the process from progressing.

—Kirsten K. Ness, PhD

slow walking speed, and weakness— problems often found among adults who are 65 years and older. (Nationally, an estimated 9.6% of women and 5.2% of men aged 65 and older are frail.)

Participants in the study were members of the St. Jude Lifetime cohort, an institutional review board–approved clinical study designed to evaluate health among survivors of childhood cancers as they age. All the survivors were treated at St. Jude Children’s Research Hospital between 1962 and 2003, are at least 18 years old, and are at least 10 years from their original cancer diagnosis. Most survivors in this study were younger than age 40. In a comparison group of 341 adults with no history of childhood cancer, none qualified as frail.

The ASCO Post talked with Dr. Ness, Associate Member of the Department

one of the side effects of insufficient testosterone among men is low-muscle mass, so the reason could be hormonal.

But we don’t really know the exact reason because hormonal factors weren’t part of our analysis.

Pathobiology In your study, the prevalence of frailty among young adult childhood cancer survivors was similar to that among adults aged 65 and older. What causes the accelerated aging in these survivors?

We do not know the pathobiology of that finding yet. We are going to be studying what I consider an aging phenotype in these survivors next. We have to look at what is causing accelerated aging, and whether it is related to damage to the survivors’ organs or organ function caused by chemotherapy, ra-

diation, or surgery, or the cancer itself.

Evaluating the causes of this phenomenon is important because frailty predicts onset of chronic conditions and mortality. If we can figure out what causes the phenotype, we may be able to find an effective intervention and either prevent it or stop the process from progressing.

Cancer Type Were there certain cancers that put these childhood cancer survivors at greater risk for frailty?

Survivors of brain tumors and softtissue sarcomas were at the highest risk for frailty. Most survivors of brain tumors had brain surgery, and many also were treated with cranial irradiation, the most common treatment factor associated with the frailty outcome.

Children who receive radiation to the hypothalamic-pituitary axis can have growth hormone deficiency. Even if the deficiency is subtle, growth hormone is necessary for the formation of organs, especially muscle, which may explain low muscle mass and weakness.

Effects of Cancer vs Aging Did the conditions of frailty manifest differently in cancer survivors than in older adults?

In older adults, we usually see an onset of muscle weakness before we see a loss of muscle mass, and in this cohort that wasn’t the case. In older adults, the initial problem with function is likely a result of age-related changes in neurologic function, rather than muscle wasting. In this younger group of cancer survivors we speculate that low-lean mass may be related to suboptimal muscle development related to cancer or its treatment.

Prevention Measures How can prefrailty and frailty be prevented or slowed in adult survivors of childhood cancers?

Clinical screening for frailty should include evaluation of unexplained weight loss, handgrip strength, an

Download The ASCO Post iPad App Free From iTunes Today!

assessment of walking speed, and questions about fatigue and weekly physical activity levels. Health-care providers who identify patients at risk for becoming frail or who are already frail, should refer them for a proper rehabilitation intervention that includes resistance training and nutritional counseling.

Although there are ongoing phase I and phase II clinical trials investigating hormone mimetics in cancer patients with muscle wasting, potential application in a childhood cancer survivor population has not been evaluated. The best way to prevent frailty in young cancer survivors and ensure that they have optimal muscle function is to provide appropriate rehabilitation and nutrition as soon as they finish their cancer therapy. Lifestyle counseling is also important. Smoking should be discouraged, and physical activity encouraged.

How much exercise should young cancer survivors engage in to minimize the threat of accelerated aging or prevent it from happening altogether?

Cancer survivors who were exposed to certain chemotherapeutic agents, such as anthracyclines, need to be evaluated by their oncologist and/or cardiologist before starting an exercise program. This doesn’t mean they can’t exercise, but that their exercise may need to be modified or supervised.

In general, children and adolescents should participate in at least 60 minutes of exercise every day. Young adult survivors should have at least 30 minutes of exercise five times a week and resistance training 2 days a week. n

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

Reference 1. Ness KK, Krull KR, Jones KE, et al: Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: A report from the St Jude lifetime cohort study. J Clin Oncol 31:4496-4503, 2013.

ASCOPost.com | APRIL 15, 2014

PAGE 43

Future of Oncology Breast Cancer

Targeting Cancer Stem Cells in Breast Cancer: A Potential Clinical Strategy

By Caroline Helwick

P

reclinical models have suggested that cancer stem cells play a role in tumor recurrence and metastasis following adjuvant therapy, and Max S. Wicha, MD, and his research team are deciphering the mechanisms by which this might happen. A true understanding of cancer stem cells will have important therapeutic implications, according to Dr. Wicha, who is Director of the University of Michigan Comprehensive Cancer Center, Ann Arbor, and Distinguished Professor of Oncology.

In brief, the research to date on cancer stem cells has led to four pivotal findings poised to impact cancer care: (1) tumor regression is an inadequate endpoint for treatment response, (2) cancer stem cells may be resistant to therapy, (3) effective therapies should target cancer stem cells while sparing normal stem cells, and (4) genes in the cancer stem cell self-renewal pathway may provide new therapeutic targets.

MicroRNAs and Stem Cells MicroRNAs play important roles in normal cellular differentiation and oncogenesis, and work from Dr. Wicha’s lab has demonstrated they can regulate the transition among cancer stem cell states.

His team defined a set of microRNAs that are over- or underexpressed in stem cells, one of which they considered particularly interesting: microRNA-93 (mir-93), which is located in the MCM7 gene and is believed to function as a tumor suppressor. They found that low mir-93 expression is associated with tumor-initiating capacity, while its overexpression diminishes the presence of cancer stem cells.

Using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, they demonstrated that mir93 modulates the fate of breast cancer stem cells by regulating their proliferation and differentiation states. Enforced expression of mir-93 completely blocks tumor development and metastases by reducing breast cancer stem cells.

Targeting Stem Cells in the Adjuvant Setting Additional experiments showed that the overexpression of mir-93 inhibits the growth of established tumor xenografts, a finding that is clinically applicable as it suggests the effects of targeting stem cells can be “more dramatic” in the adjuvant as compared to advanced disease setting, he said.

To simulate the adjuvant setting, Dr. Wicha and colleagues induced mir-93 and/or administered docetaxel immediately after tumor cell implantation. Although tumors grew after 4 to

a modest effect in reducing the growth of established tumors. Resistance to cytotoxic chemotherapy—in this experiment, docetaxel—was also abrogated in the presence of mir-93.

“If you just give chemotherapy, you suppress the growth of a tumor, but when you stop treatment—as we do in the clinic—the tumor returns. If you knock out stem cells, even transiently, and then stop treatment, the animals are cured,” Dr. Wicha said. “Together these studies suggest that mir-93 regulates the cancer stem cell population and that this population mediates tumor growth

If you just give chemotherapy, you suppress the growth of a tumor, but when you stop treatment—as we do in the clinic—the tumor returns. If you knock out stem cells, even transiently, and then stop treatment, the animals are cured.

—Max S. Wicha, MD

5 weeks in control animals, no tumor growth was observed following mir-93 induction and/or 8 weeks of docetaxel treatments in the experimental groups.

After 10 additional weeks of follow-up, tumors developed in all mice who received docetaxel alone but in none who received mir-93 induction, whether or not they received docetaxel.

They extended these observations to primary breast tumors by examining the effect of mir-93 induction on three primary breast xenografts directly established from patients’ tumors. Again, induction of mir-93 upon cell implantation completely prevented tumor growth, this time in a human model.

Taking the experiment a step further, they established that mir-93 overexpression inhibited cell invasion and metastasis when occurring in the adjuvant setting, but in advanced disease the scenario was different: mir-93 had only

following adjuvant therapy.”

The models predict that the efficacy of stem cell–targeting agents should be most pronounced in the adjuvant setting, where tumor growth from micrometastasis is dependent on stem cell self-renewal, Dr. Wicha said.

Why Cytotoxic Chemotherapy Fails In their experiments with docetaxel, Dr. Wicha and colleagues found that while the taxane killed cancer cells, the dying cells actually stimulated the production of cancer stem cells through the release of interleukins (ILs).

“We found that a potent regulator of stem cells is a series of cytokines, in particular, IL-6 and IL-8,” he said. IL-8 binds to the cytokine receptor CXCR1, and this stimulates self-renewal of stem cells through the Wnt pathway. “That’s why we get an increase in cancer stem

cells with cytotoxic chemotherapy,” he explained.

Repertaxin is an inhibitor of CXCR1 that potently blocks the chemotherapyinduced increase in cancer stem cells.

A phase I clinical trial is evaluating the strategy of adding repertaxin to paclitaxel, and early results suggest relative lack of toxicity.

The IL-6 inhibitor tocilizumab (Actemra) also appears promising as a means of reversing resistance to trastuzumab (Herceptin) in the HER2overexpressing population. HER2 is believed to be an important driver of breast cancer stem cells, he pointed out.

Drawing upon the fact that deletion of PTEN, a tumor-suppressor gene, is a common genetic mutation in breast cancer, the researchers modeled PTEN deletion in HER2-overexpressing cells and found that cells became resistant to trastuzumab by activating an inflammatory loop that involves IL-6. Blockade of the IL-6 pathway with drugs such as tocilizumab can completely reverse this resistance, he said.

“With trastuzumab, you actually stimulate the growth of HER2-positive PTEN-deleted tumors, but you can completely reverse this if you combine trastuzumab and tocilizumab,” he said.

“Tocilizumab overcomes de novo and acquired trastuzumab resistance.”

These two inhibitors are just the beginning of new therapeutics aiming to put the cap on stem cells by targeting probably half a dozen pathways that are stem cell regulators, he predicted.

“At our cancer center in Michigan, we now have nine clinical trials underway with inhibitors of notch, hedgehog, Wnt, HER2/AKT, and the cytokines CXCR1 and IL-6 receptors,” he said.

“Over the next few years, we will see many more trials targeting stem cells.” n Disclosure: Dr. Wicha has financial holdings with is a scientific advisor for OncoMed Pharmaceuticals, is a scientific advisor for Verastem, Paganini, and MedImmune, and receives research support from Dompe Pharmaceuticals and MedImmune.

Visit The ASCO Post website at ASCOPost.com

XOFIGO® IS INDICATED

for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Not an actual patient. Models used for illustrative purposes only.

Important Safety Information1 for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and • Contraindications: Xofigo is contraindicated in women who are or leukopenia—has been reported in patients treated with Xofigo. may become pregnant. Xofigo can cause fetal harm when administered Monitor patients with evidence of compromised bone marrow reserve to a pregnant woman closely and provide supportive care measures when clinically indicated.

• Bone Marrow Suppression: In the randomized trial, 2% of patients Discontinue Xofigo in patients who experience life-threatening in the Xofigo arm experienced bone marrow failure or ongoing complications despite supportive care for bone marrow failure pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with • Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo bone marrow failure was ongoing at the time of death. Among Xofigo, the absolute neutrophil count (ANC) should be the 13 patients who experienced bone marrow failure, 54% required ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin blood transfusions. Four percent (4%) of patients in the Xofigo arm ≥10 g/dL. Prior to subsequent administrations, the ANC should and 2% in the placebo arm permanently discontinued therapy due to be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue bone marrow suppression. In the randomized trial, deaths related Xofigo if hematologic values do not recover within 6 to 8 weeks to vascular hemorrhage in association with myelosuppression were after the last administration despite receiving supportive care observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy of serious infections (10%), and febrile neutropenia (<1%) was similar concomitant chemotherapy with Xofigo have not been established.

© 2013 Bayer HealthCare Pharmaceuticals and Algeta ASA. All rights reserved.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer AG. ALGETA is a trademark of Algeta ASA.

600-10-0009-13b

11/13

Printed in USA

Prolong life.

Treat bone metastases.

30%

reduction in the risk of death vs placebo (hazard ratio [HR]=0.695)1

The first agent to extend overall survival by exerting an antitumor effect on bone metastases in CRPC1,2 • Exploratory updated analysisa: 3.6-month increase in median overall survival vs placebo (HR=0.695; 95% confidence interval [CI]: 0.581-0.832)1 —14.9 months for Xofigo (95% CI: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8)1

• Prespecified interim analysis: 2.8-month increase in median overall survival vs placebo, P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)1 —14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

• Overall survival benefit supported by delay in time to first symptomatic skeletal event (SSE), favoring Xofigo.b The majority of events consisted of external beam radiation therapy to bone metastases1 • 1-minute intravenous injection every 4 weeks for 6 injections1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b SSEs defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention.

a

To learn more, visit www.xofigo-us.com

Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients.

The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations.

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination.

Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing.

19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the Renal and urinary disorders As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized.

In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go.

8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go.

Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation

by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies.

There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers.

Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination.

When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. Š 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: 05/2013 "3

The ASCO Post | APRIL 15, 2014

PAGE 48

Palliative Care in Oncology Overcoming Physician Bias in Recommending Palliative Care A Conversation With Jennifer S. Temel, MD

By Jo Cavallo

I

n 2010, Jennifer S. Temel, MD, published her landmark study in The New England Journal of Medicine showing that the introduction of palliative care early after a diagnosis of metastatic non–small cell lung cancer, along with cancer therapy, not only provided patients with a better quality of life but also appeared to prolong their survival.1 Dr. Temel’s study is largely credited with raising interest in integrating palliative care into standard oncology care to improve patients’ symptoms from their cancer and its treatment and helping to separate the association of palliative care with end-of-life hospice care.

Despite improvements in the perception of palliative care as a support to active treatment to relieve physical and emotional symptoms and improve quality of life rather than as a last resort if the cancer is no longer controllable, a recent study looking at oncologist barriers to palliative care referrals found that obstacles remain to fully integrating such programs into mainstream cancer care, including “persistent conceptions of palliative care as an alternative philosophy of care incompatible with cancer therapy.”2 And another recent article by Dr. Temel and her colleagues in The New England Journal of Medicine found that “most health care professionals believe [palliative care] is synonymous with end-of-life care.”3 “My perception of why oncologists can be reluctant to refer patients to palliative care is that they do not have a clear understanding of how palliative care can be helpful to their patients,” said Dr. Temel, who is Clinical Director of Thoracic Oncology at Massachusetts General Hospital, Associate Director of the Dana-Farber/Partners Cancer Care Hematology/Oncology Fellowship, and Associate Professor at Harvard Medical School, Boston.

The ASCO Post talked with Dr. Temel about physician bias in referring patients to palliative care, misperceptions about such care, and its role in active treatment.

A Complex Area Please talk about the bias oncologists may have against introducing palliative care as part of standard oncology care at the time of diagnosis or during active treatment.

I think there are still a lot of misperceptions on the part of clinicians—physicians and nurses—that palliative care and hospice care are synonymous, so many of them still believe that if you are administering cancer-directed therapy, you can’t offer palliative care at the same time.

These misperceptions persist because the fields of hospice care and palliative care did grow up together, and many palliative care organizations are also hospice organizations, so it is a confusing area. It is especially complex because the rules concerning hospice care are unclear, and some

attendant physical and psychological symptoms that can interfere with their enjoyment and quality of life.

I think cancer care is in a transition right now because, in the past, patients with metastatic disease like lung cancer lived only a short time. Now we have patients living for years with their metastatic disease—with brain or bone metastases or the sequelae of their cancer treatment—so it is getting more important to define the role of palliative care in conjunction with active treatment.

For some diseases like lung cancer, we didn’t have any experience in

We now have clear data from a number of randomized studies that receiving palliative care simultaneously with cancer care improves symptoms and quality of life.

There are even some data from our group and others that it might also impact survival.

—Jennifer S. Temel, MD

hospice organizations do have the ability to provide cancer treatment along with end-of-life care. So it can be very confusing for clinicians to understand the distinctions.

I think another reason there is confusion is that most clinicians are really only exposed to palliative care in the hospital setting where it does predominantly entail end-of-life care.

So even what they are seeing clinically is tying palliative care with end-of-life care, and they can’t really envision how they can be doing palliative care for outpatients and for patients who are doing well.

Grey Zone of Survivorship As patients live longer with their cancer and its treatment side effects, isn’t it imperative to treat all symptoms, including pain, fatigue, and psychosocial issues?

Yes. I’m a thoracic oncologist, and there have been so many amazing recent discoveries in lung cancer treatment; patients are absolutely living longer, and that is wonderful. However, they are often living longer with many

taking care of long-term survivors, but now our clinics are filled with them—which is great. Still, I don’t think we know how best to manage the treatment toxicities seen in these longer-term survivors with metastatic disease. Additionally, I think the psychological coping for patients who are given a life-threatening diagnosis like lung cancer or pancreatic cancer, and who then end up becoming long-term survivors is challenging for them and can present a burden that we have not even begun to understand.

So I think there is a new challenge to think about here: how to bring palliative care to people who are in this grey zone of being survivors with their metastatic cancer.

The Oncologist’s Responsibilities In addition to the confusion over the definition of palliative care, are there other issues preventing oncologists from considering palliative care for their patients?

When I started this work a decade ago, many oncologists had the sense

GUEST EDITOR

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is Senior Director of ASCO’s Education, Science and Professional Development Department. that it is their job to provide the psychological support to help patients cope with their cancer and to manage their symptoms, and to refer them to palliative care would be shirking their responsibilities as a good doctor. That attitude is in contrast to the data clearly showing that oncologists are just not able to do all of these tasks—and not because their intentions are poor.

It is really hard, within the confines of a 15- or 20-minute office visit, to focus on all of the issues a patient is facing, including all of the cancer treatment toxicities, and then make sure that you still have the time, resources, and clinic space to focus on these other essential aspects of cancer care.

When to Refer How do you assess a patient for palliative care and make the judgment that your patient needs palliative care?

There is currently not a standard trigger for when people need palliative care, although many researchers are studying this issue in patients with serious illnesses. We are conducting a large follow-up trial to our previous study,1 in which we randomly assigned patients with advanced non–small cell lung cancer to early or standard palliative care. We plan to analyze the data from this trial to determine who benefits most from palliative care, but we do not have that data yet.

I think the number-one criterion for referring a patient to palliative

ASCOPost.com | APRIL 15, 2014

PAGE 49

Palliative Care in Oncology care is that the patient, family, or clinicians feel that the patient has issues or symptoms that aren’t being adequately managed by the oncology team.

Explaining Palliative Care How can oncologists approach the subject of palliative care with patients so there can be a thoughtful process of shared decision-making?

When clinicians explain the purpose of palliative care to patients, clarify that it isn’t reserved just for those at the end of life, and talk about some of the benefits of palliative care regarding symptom management and improved mood, most patients are excited to meet with a palliative care specialist.

Just explaining to patients and their families what palliative care is and being sure that you make the distinction that it is not synonymous with hospice care really helps alleviate fear.

the importance of patients receiving palliative care while on active treatment?

We now have clear data from a number of randomized studies that receiving palliative care simultaneously with cancer care improves symptoms and quality of life. There are even some data from our group and others that it might also impact survival. n

Disclosure: Dr. Temel potential conflicts of interest.

reported

no

References 1. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010.

2. Schenker Y, Crowley-Matoka

M, Dohan D, et al: Oncologist factors that influence referrals to subspecialty palliative care clinics. J Oncol Pract.

December 3, 2013 (early release online).

3. Parikh RB, Kirch RA, Smith TJ, et al: Early specialty palliative care— translating data in oncology into practice. N Engl J Med 369:2347-2351, 2013.

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

Closing Thoughts Do you have any final thoughts about

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Advertising

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

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.

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 | APRIL 15, 2014

PAGE 50

Issues in Oncology Head and Neck Cancer

Thyroid Cancer On the Rise: Is It Clinically Meaningful?

By Caroline Helwick

A

ccording to data from the Surveillance, Epidemiology, and End Results (SEER) program, rates for new cases of thyroid cancer in the United States have been rising on average 6.4% each year over the past 10 years, and death rates have been rising on average 0.9% each year over the same period.

The ASCO Post asked thyroid cancer expert Jennifer Sipos, MD, Associate Professor of Medicine at The Ohio State University (OSU), Columbus, to help us explore the rise in thyroid cancer diagnoses, and to describe where her research team’s efforts are taking the field.

Trends in Incidence and Research Funding Mounting evidence suggests that thyroid cancer is on the rise. Is this why more money is being directed toward thyroid cancer research?

Since around 1975, the incidence of thyroid cancer has nearly tripled, from about 5 cases per 100,000 persons to more than 14, virtually all due to increases in papillary thyroid cancer.1 For the follicular, medullary, and anaplastic forms, the incidence has remained stable.

It’s shocking that if we project the current trend through 2019, the inci-

dence will double and thyroid cancer will become the third most common cancer in women of all ages, according to a recent study.2 Managing these patients from diagnosis through treatment, and the lifetime of follow-up that is required, will cost the United States $18 billion to $21 billion, the research showed.

In spite of its growing frequency, however, thyroid cancer remains significantly underfunded. In 2009, the National Cancer Institute allotted only $14.7 million to thyroid cancer research, which makes it 30th among all cancers in NCI funding.2 Recently, OSU obtained an $11 mil-

will allow us to study several important areas, including the development of better biomarkers and treatment options for patients with progressive metastatic medullary thyroid cancer and the identification of persons most at risk for toxicity from radioactive iodine.

‘Epidemic of Diagnosis’?

A recent study by Davies and Welch suggested that the increased incidence of thyroid cancer appears to be an “epidemic of diagnosis” rather than disease, mostly due to the detection of small papillary cancers (see sidebar).1 Can you comment on this?

When you look carefully at the data, as several research teams have done, you see an increase in [thyroid] cancers of all sizes, not just the small tumors, as you would expect with overdiagnosis.

—Jennifer Sipos, MD

lion Thyroid Cancer SPORE (Specialized Program of Research Excellence) grant, through the leadership of Matthew Ringel, MD, who is Professor of Medicine and Director of Endocrinology, Diabetes and Metabolism. This

Recent Study Finds Tripling in Thyroid Cancer

A

ccording to a recent report by Davies and Welch,1 the incidence of thyroid cancer in the United States has nearly tripled since 1975, from 4.9 to 14.3 per 100,000 persons, with most of the increase due to papillary thyroid cancer, which has increased from 3.4 to 12.5 per 100,000 persons. The researchers had previously reported a doubling in thyroid cancer incidence, largely due to the detection of small papillary cancers, and they conducted the current study to determine whether the incidence had stabilized.

They used data from the Surveillance, Epidemiology, and End Results (SEER) program and the National Vital Statistics System to analyze trends from 1975 to 2009, finding a relative rate of 2.9 for the general incidence and 3.7 for papillary thyroid cancers. The absolute increase in women, from 6.5 to 21.4 per 100,000 women, was almost four times greater than that of men (from 3.1 to 6.9 per 100,000 men). They found the mortality rate, however, to be stable at approximately 0.5 deaths per 100,000.

Davies and Welch concluded, “this is not an epidemic of disease but rather an epidemic of diagnosis. The problem is particularly acute for women, who have lower autopsy prevalence of thyroid cancer than men but higher cancer detection rates by a 3:1 ratio.” n Reference 1. Davies L, Welch HG: Current thyroid cancer trends in the United States.

JAMA Otolaryngol Head Neck Surg. February 20, 2014 (early release online).

Their belief is that these small cancers are a casualty of overdiagnosis and are not clinically meaningful, and I agree to a certain extent. We are getting computed tomography (CT) scans for so many minor indications that we are finding disease that would otherwise go undetected. In autopsy series, we find that 10% to 15% of individuals have occult thyroid cancer, and surgical series as well suggest that up to 10% of persons undergoing surgery for reasons other than cancer end up with a diagnosis of thyroid cancer. Most are tiny tumors < 2 cm. Davies and Welch are deriving data from such registries.

But when you look carefully at the data, as several research teams have done, you see an increase in cancers of all sizes, not just the small tumors, as you would expect with overdiagnosis.

Cramer at al examined the SEER cancer data registry between 1983 and 2006 and found an increase of 19.2% per year in papillary tumors < 1.0 cm, a 12.3% per year increase in tumors measuring 1.1 to 2.0 cm, a 10.3% per year increase in tumors of 2.1 to 5.0 cm, and a 12.0% per year increase in tumors > 5 cm, all statistically significant (P < .0001).3 Most new diagnoses are for cancers < 2 cm in people under the age of 45 who got CT scans for other reasons.

About 40% of thyroid nodules are iden-

tified by imaging modalities that were not ordered for the thyroid. But there may be other disease-related factors besides increased diagnosis.

Other Risk Factors What might these other risk factors be?

The primary risk factor for thyroid cancer is radiation exposure, particularly at a young age. This is primarily in the form of external-beam irradiation in the head and neck area, and especially before age 15. We believe that such radiation at this age increases the risk of nodules and probably cancer, but it is harder to quantify.

Of course, we are also all exposed to radiation through diagnostic imaging, air travel, perhaps dental x-rays, and so forth. But there are not many studies of risk from this level of exposure.

The other theory pertains to exposure to environmental compounds that have an extremely long biologic half-life—hundreds of years. Polybrominated diphenyl ethers (PBDEs) are compounds used as flame retardants, building materials, electronics, plastics, and other products. They are ubiquitous in the environment and have attracted attention as health hazards. Some research suggests PBDEs are endocrine disrupters and could be implicated in the development of nodules and neoplasms.

Another theory pertains to insulin resistance, since persons with higher insulin levels are more likely to have nodules and a higher thyroid volume. Insulin is a growth factor and has some interaction with the thyroid-stimulating hormone receptor. This has led to the theory that persons with insulin resistance are at increased risk for thyroid cancer.

To some degree, there is a genetic link as well. Ohio State University has a large repository of data, which we have been mining for years, and we have documented that about 5% of persons with papillary thyroid cancer and 25% with medullary thyroid cancer have a familial history.

Nodule Assessment and Management When there is an incidental finding of a thyroid nodule, what is your next step?

Once you know there is a nodule, you have to investigate further. You assess the risk of malignancy in that nodule based on ultrasound features and other associated findings. Further management depends on patient-related factors—for continued on page 52

Amgen is exploring the expanded potential of biomarker analysis in metastatic colorectal cancer (mCRC)

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

The ASCO Post | APRIL 15, 2014

PAGE 52

Issues in Oncology Thyroid Cancer

Genetic Profiling

continued from page 50

Genetic profiling is becoming critical in all malignancies. How are you applying this in thyroid cancer?

We believe some individual mutations may be important in thyroid cancer, though BRAF and to some extent RAS are the only ones being used clinically now. We are starting to apply these in advanced disease, and we have drugs targeting BRAF. There is also evidence to suggest that RAS-positive tumors respond better than RAS-negative tumors to the MEK inhibitor selumetinib.

Larger studies are trying to ferret out these differences. We have implemented them in advanced disease, and we are researching how to use genetics to project which cancers will be more aggressive.

example, age and comorbidities. An 87-year-old with an incidental nodule is less concerning than a 28-year-old with the same finding, and the older patient probably has comorbidities that would prohibit surgery. The clinical context is important.

There is definite evidence that small cancers that are left alone often are not clinically meaningful. If they are never diagnosed, the person dies with them, not from them. But we can’t just disregard all small cancers. An aggressive cancer that metastasizes to a 4cm lesion in the lung began as a localized tumor less than 1 mm and grew. We have to stratify patients.

Hopefully, molecular testing will help us do this proactively in the future, to be able to determine the need for surgery and the need for radioactive iodine, which we normally wouldn’t give for a small cancer. We need to learn which cancers need close monitoring.

Research at OSU How is Ohio State University moving the field of thyroid research forward?

OSU has a long history of important discoveries that have changed our understanding of the pathogenesis of thyroid

cancer and how we treat it. One particular researcher, Sissy M. Jhiang, PhD, was integral in outlining the role of RET/ PTC translocations in the pathogenesis of thyroid cancer and in identifying the sodium-iodide symporter in salivary and breast tissues. The latter discovery led to Dr. Jhiang’s interest in the pathogenesis of salivary damage from radioactive iodine therapy. While some may view this as merely an inconvenience in the entire scheme of treating a malignancy, salivary damage—with its resultant dry mouth and occasionally, pain—can significantly impact quality of life.

Currently, we cannot predict who will develop this complication, which is generally, but not always, dose-dependent. We are studying patient factors such as age, gender, family history of autoimmune disease, and preexisting salivary conditions, and we are looking for predictive biomarkers in saliva, to determine if we can predict individual risk. The goal is to apply these data clinically in counseling pa-

tients, in modifying treatment, and in the research setting, to develop future treatments that avoid salivary injury in all patients. This is an exciting opportunity to impact patient care and a great example of the bench-to-bedside research projects that are ongoing at Ohio State. n

Disclosure: Drs. Sipos and Jhiang reported no potential conflicts of interest.

References 1. Davies L, Welch HG: Current thyroid cancer trends in the United States.

JAMA Otolaryngol Head Neck Surg. February 20, 2014 (early release online).

2. Aschebrook-Kilfoy B, Schechter RB, Shih Y-CT, et al: The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev 22:1252-1259, 2013.

3. Cramer JD, Fu PF, Harth KC, et al: Analysis of the rising incidence of thyroid cancer using the Surveillance, Epidemiology and End Results national cancer data registry. Surgery 148:1147-1153, 2010.

News Smoking

Electronic Cigarette Use and Smoking Among Adolescents

“U

se of e-cigarettes does not discourage, and may encourage, conventional cigarette use among U.S. adolescents.” This was the conclusion of a cross-sectional analysis of survey data from a representative sample of middle and high school students who completed the National Youth Tobacco Survey (NYTS) in 2011 (n = 17,353) and 2012 (n = 22,529). The results were reported in JAMA Pediatrics by Lauren M. Dutra, ScD, and Stanton A. Glantz, PhD, of the Center for Tobacco Research and Education at the University of California, San Francisco.1

Survey Details The National Youth Tobacco Survey is an anonymous, self-administered questionnaire “developed to inform national and state tobacco prevention and control programs,” the study authors explained.

“Conventional cigarette experimenters were defined as adolescents who responded yes to the question ‘Have you ever tried cigarette smoking, even 1 or 2 puffs?’ Ever smokers of conventional cigarettes were defined as those who replied ‘100 or more cigarettes (five or more packs)’ to the question ‘About how many cigarettes have you smoked in your entire life?’ Current smokers of conventional cigarettes

were those who had smoked at least 100 cigarettes and smoked in the past 30 days.”

Among cigarette experimenters, ever using an e-cigarette was associated with higher odds of ever smoking cigarettes (odds ratio [OR] = 6.31; 95% confidence interval [CI] = 5.39–7.39) and current cigarette smoking (OR = 5.96; 95% CI = 5.67–6.27). Current use of ecigarettes was positively associated with ever smoking cigarettes (OR = 7.42; 95% CI = 5.63–9.79) and current cigarette smoking (OR = 7.88; 95% CI = 6.01–10.32). Use of e-cigarettes also was associated with lower 30-day, 6-month, and 1-year abstinence from cigarettes.

“This is a cross-sectional study, which only allows us to identify associations, not causal relationships. Our results are also limited by the lack of information about motivation for using ecigarettes,” the authors acknowledged.

“As with adults, dual use of e-cigarettes and conventional cigarettes is high among adolescents and increasing rapidly,” the investigators stated. “Adolescents who had ever experimented with cigarettes (smoked at least a puff) and used e-cigarettes were more likely to report having smoked at least 100 cigarettes and to be current smokers than adolescents who never used e-cigarettes.

Thus, in combination with the observations that e-cigarette users are heavier smokers and less likely to have stopped smoking cigarettes, these results suggest that e-cigarette use is aggravating rather than ameliorating the tobacco epidemic among youths. These results call into question claims that e-cigarettes are effective as smoking cessation aids.”

Vigorous Debate An accompanying editorial by Frank J. Chaloupka, PhD, of the Institute for Health Research at the University of Illinois at Chicago, points out that the rapid rise in the use of e-cigarettes has “stimulated a vigorous debate in the tobacco control community over the potential public health impact” and how e-cigarettes, also known as electronic nicotine delivery systems should be regulated.2 Currently, they are largely unregulated and aggressively marketed, although the U.S. Food and Drug Administration “is soon expected to release a proposed deeming rule that would encompass the variety of other tobacco products currently not subject to FDA regulation, including [electronic nicotine delivery systems],” Dr. Chaloupka reported.

The struggle to develop appropriate policies for e-cigarettes, in part “reflects the desire to maximize the use of

[these devices] as a smoking cessation tool, while at the same time preventing youths from starting with [e-cigarettes] and moving on to conventional cigarettes,” Dr. Chaloupka wrote, adding: While not harmless, moving current smokers from cigarettes to [e-cigarettes] would almost certainly lead to significant reductions in the health and economic consequences of smoking. However, the high rates of use of both [e-cigarettes] and conventional cigarettes among current [e-cigarette] users suggest that many are using them as a way to satisfy their nicotine addiction in venues where smoking is not allowed rather than as a means to quit smoking entirely, raising concerns that the public health impact of [ecigarettes] could be minimal.

“Adopting the right mix of policies will be critical to minimizing potential risks to public health while maximizing the potential benefits,” he concluded. n References

1. Dutra LM, Glantz SA: Electronic cigarettes and conventional cigarette use among US adolescents. JAMA Pediatr.

March 6, 2014 (early release online).

2. Chaloupka FJ: Tobacco control policy and electronic cigarettes. JAMA Pediatr. March 6, 2014 (early release online).

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

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

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

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

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

The ASCO Post | APRIL 15, 2014

PAGE 58

Journal Spotlight Breast Cancer

SSO-ASTRO Consensus Guideline continued from page 1

ative cancer types. The panel hopes that the recommendations will spare many patients unnecessary surgery and encourage patients to select lumpectomy rather than mastectomy when medically appropriate.

Monica Morrow, MD, of Memorial Sloan Kettering Cancer Center and SSO, and Meena S. Moran, MD, of Yale University and ASTRO, were panel Co-Chairs. Nehmat Houssami, MD, PhD, of University of Sydney School of Public Health, performed the systematic review. The guideline was produced with a grant from Susan G. Komen and is endorsed by ASCO and the American Society of Breast Surgeons.

The clinical questions addressed by the panel and the resulting recommen-

ated with at least a twofold increase in ipsilateral breast tumor recurrence. This increased risk in ipsilateral recurrence is not removed by delivery of a radiation boost, systemic therapy (endocrine therapy, chemotherapy, biologic therapy), or favorable biology. (Level of evidence: meta-analysis and secondary data from prospective trials and retrospective studies.)

Do margin widths wider than “no ink on tumor cells” reduce the risk of ipsilateral breast tumor recurrence?

Recommendation: Negative margins (no ink on tumor) optimize ipsilateral breast tumor recurrence. Wider margin widths do not significantly lower this risk. The routine practice of obtaining wider negative margin widths is not indicated. (Level of evidence: metaanalysis and retrospective studies.)

What are the effects of endocrine or biologically targeted therapy or systemic chemotherapy on ipsilateral breast tumor recurrence? Should a patient who is not receiving any systemic treatment have wider margin widths?

Recommendation: Rates Monica Morrow, MD Meena S. Moran, MD of ipsilateral breast tumor recurrence are reduced with the dations, along with level of evidence for use of systemic therapy. In the rare cireach recommendation, are provided cumstance of a patient not receiving below. adjuvant systemic therapy, there is no evidence suggesting that margins wider Guidelines Summary than no ink on tumor are needed. (LevWhat is the absolute increase in risk of el of evidence: multiple randomized triipsilateral breast tumor recurrence with als and meta-analysis.) a positive margin? Can the use of radiation boost, systemic therapy, or favorable Should unfavorable biologic subtypes tumor biology mitigate this increased risk? (such as triple-negative breast cancers) reRecommendation: Positive mar- quire wider margins (than no ink on tumor)? gins, defined as ink on invasive cancer Recommendation: Margins wider or ductal carcinoma in situ, are associ- than no ink on tumor are not indicated

New Guidelines on Breast Tumor Surgical Margins ■■ There is no evidence that surgical margins wider than “no ink on tumor” provide additional reduction in risk for ipsilateral breast tumor recurrence.

■■ The recommendations can spare many patients unnecessary surgery and encourage patients to select lumpectomy rather than mastectomy.

based on biologic subtype. (Level of evidence: multiple retrospective studies.)

Should margin width be taken into consideration when determining wholebreast radiation delivery techniques?

Recommendation: The choice of whole-breast radiation delivery technique, fractionation, and boost dose should not be dependent on margin width. (Level of evidence: retrospective studies.)

Is the presence of lobular carcinoma in situ at the margin an indication for reexcision? Do invasive lobular carcinomas require a wider margin (than no ink on tumor)? What is the significance of pleomorphic lobular carcinoma in situ at the margin?

Recommendation: Wider negative margins than no ink on tumor are not indicated for invasive lobular cancer.

Classic lobular carcinoma in situ at the margin is not an indication for reexcision. The significance of pleomorphic lobular carcinoma in situ at the margin is uncertain. (Level of evidence: retrospective studies.)

Should increased margin widths be considered for patients of young age (≤ 40 years)?

Recommendation: Young age (≤ 40 years) is associated with both increased ipsilateral breast tumor recurrence after breast-conserving therapy and increased local relapse on the chest

wall after mastectomy and is also more frequently associated with adverse biologic and pathologic features. There is no evidence that increased margin width nullifies the increased risk of ipsilateral breast tumor recurrence in young patients. (Level of evidence: secondary data from prospective randomized trials and retrospective studies.)

What is the significance of an extensive intraductal component in the tumor specimen, and how does this affect margin width?

Recommendation: An extensive intraductal component identifies patients who may have a large residual ductal carcinoma in situ burden after lumpectomy. There is no evidence of an association between increased risk of ipsilateral breast tumor recurrence when margins are negative. (Level of evidence: retrospective studies.) n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology– American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With WholeBreast Irradiation in Stages I and II Invasive Breast Cancer. Ann Surg Oncol. February 10, 2014 (early release online); Int J Radiat Oncol Biol Phys 88:553-564, 2014; J Clin Oncol. February 10, 2014 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post Anthony B. Miller, MD, on the Canadian National Breast Screening Study see page 21

Theresa Keegan, PhD, MS, on Survival in Younger Women With Breast Cancer see page 82

Comments on the Canadian National Breast Screening Study Therese B. Bevers, MD see page 22 Daniel B. Kopans, MD, FACR see page 23 Sudhir Srivastava, PhD, MPH, and Barnett S. Kramer, MD, MPH see page 24

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | APRIL 15, 2014

PAGE 59

Perspective

SSO-ASTRO Margin Guideline: Why Now and What Does It Mean?

By Monica Morrow, MD

A

lthough breast-conserving therapy has been a standard practice for more than 20 years, controversy still exists over what constitutes the appropriate margin of normal breast tissue around a tumor that minimizes local recurrence while maintaining a good cosmetic outcome. Surveys of surgeons1 and radiation oncologists2 failed to identify a margin width that more than 50% of respondents endorsed as adequate. As a consequence, reexcision to obtain more widely clear margins is a frequent procedure, performed in 19% of stage I and stage II breast cancer patients in a population-based sample reported by Morrow et al3 and 23% of a large convenience sample reported

by McCahill et al.4 In the study by McCahill et al, 48% of the reexcisions were performed for margins that were negative, defined as “no ink on tumor cells” (ie, no cancerous cells touching the edge of the lumpectomy specimen).

Lack of Data The margin question has never been directly addressed in a prospective randomized trial. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial used a margin definition of no ink on tumor cells5 and found no statistically significant differences in survival or local recurrence between patients treated with breastconserving therapy and those treated with mastectomy. The NSABP B-06 trial was the only one of the randomized trials comparing breast-conserving therapy and mastectomy to employ a microscopic margin definition; in spite of this, over time, bigger margins came to be perceived as better margins, leading to the current state of confusion.

Breast cancer care has changed dramatically in the 30 years since the initial trials of breast-conserving therapy.

Mammography is greatly improved, pathologic examination of lumpectomy specimens is more detailed, and the majority of patients with invasive breast cancer receive systemic therapy. These Dr. Morrow is Chief of the Breast Service and Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center, and Professor of Surgery at Weill Cornell Medical College, New York. She is also Co-Chair of the SSO-ASTRO Margin Panel.

factors, coupled with the frequent use of reexcision, led the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) to convene a consensus panel to address the question of the optimal margin width in breast-conserving therapy.

The resultant guideline was published in Annals of Surgical Oncology, International Journal of Radiation Oncology Biology Physics, and Journal of Clinical Oncology6 and is summarized in this issue of The ASCO Post.

A systematic review and meta-analysis of the literature7 was the primary evidence base for the consensus. In evaluating the results of the meta-analysis, the consensus group gave strong weight to three factors: (1) a negative

methodology used. However, the panel felt that the large experience of the NSABP using the margin definition of no ink on tumor with low rates of local recurrence,11 coupled with the lack of standardization of margin assessment, indicated that margins of ink not touching tumor and 1 mm were unlikely to be meaningfully different.

Practical Implications The practical implications of the consensus statement are substantial.

Rules that many practices and tumor boards have put into place stating that all margins must be 1 mm, 5 mm, 1 cm, or some other arbitrary width are not supported by the evidence and should be abandoned.

The practical implications of the consensus statement are substantial. Rules that many practices and tumor boards have put into place stating that all margins must be 1 mm, 5 mm, 1 cm, or some other arbitrary width are not supported by the evidence and should be abandoned.

—Monica Morrow, MD

margin does not indicate the absence of residual tumor in the breast8; (2) measurement of margin width is an inexact science9; and (3) rates of local recurrence vary with tumor biology and are decreased with systemic therapy.10

Study Specifics The margins meta-analysis included 26,162 patients in 33 studies published between 1965 and 2013.7 In spite of the fact that only 40% of included patients received any systemic therapy, the median crude rate of local recurrence was only 5.3% (95% confidence interval = 2.3%–7.6%). No statistically significant differences in local recurrence were seen when margins of 1 mm, 2 mm, and 5 mm were compared using statistical tests for association and trend. Adjustment of the model for covariates of patient age, median year of study recruitment, estrogen receptor status, use of endocrine therapy, and reexcision did not change these results.

The meta-analysis was unable to directly compare margins of no ink on tumor to 1-mm margins due to both the small number of studies employing this margin definition and the statistical

The consensus guideline does not imply that there are no indications for margins more widely clear than no ink on tumor. Patients at risk for a high residual disease burden, who can be recognized by large amounts of tumor in proximity to the margin, particularly when coupled with the discontinuous growth pattern seen with infiltrating lobular carcinoma or an extensive intraductal component in association with invasive cancer, should continue to undergo reexcision. However, the need for reexcision should be determined on a case-by-case basis.

This margin guideline acknowledges the reality of breast cancer treatment in the current era and uses these advances to decrease the burden of treatment for patients. This approach will also decrease health-care costs. The consensus panel members hope it will be widely adopted by the breast cancer community. n Disclosure: Dr. Morrow is Co-Chair of the SSO-ASTRO Margin Panel.

References 1. Azu M, Abrahamse P, Katz SJ, et al: What is an adequate margin for breast-con-

serving surgery? Surgeon attitudes and correlates. Ann Surg Oncol 17:558-563, 2010.

2. Taghian A, Mohiuddin M, Jagsi R, et al: Current perceptions regarding surgical margin status after breast-conserving therapy: Results of a survey. Ann Surg 241:629-639, 2005.

3. Morrow M, Jagsi R, Alderman AK, et al: Surgeon recommendations and receipt of mastectomy for treatment of breast cancer.

JAMA 302:1551-1556, 2009.

4. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467475, 2012.

5. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989.

6. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer. Ann Surg Oncol. February 10, 2014 (early release online); Int J Radiat Oncol Biol Phys 88:553564, 2014; J Clin Oncol. February 10, 2014 (early release online).

7. Houssami N, Macaskill P, Marinovich L, et al: The association of surgical margins and local recurrence in women with earlystage invasive breast cancer treated with breast-conserving therapy: A meta-analysis.

Ann Surg Oncol. January 29, 2014 (early release online).

8. Holland R, Veling SH, Mravunac M, et al: Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 56:979990, 1985.

9. Houssami N, Morrow M: Margins in breast conservation: A clinician’s perspective AND what the literature tells us. J Surg Oncol 2014 (in press).

10. Bouganim N, Tsvetkova E, Clemons M, et al: Evolution of sites of recurrence after early breast cancer over the last 20 years: Implications for patient care and future research.

Breast Cancer Res Treat 139:603-606, 2013.

11. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27:2466-2473, 2009.

The ASCO Post | APRIL 15, 2014

PAGE 60

News Health-Care Policy

American College of Radiology Issues Statement on Budgetary Efforts to Curtail Imaging and Radiation Oncology Self-Referral

T

he American College of Radiology (ACR) recently issued a statement applauding steps to reign in medical imaging and radiation oncology self-referral included in the President’s fiscal year 2015 budget. However, prior authorization for imaging services, also included in the FY2015 budget, is unnecessary and will ultimately raise costs, interfere in the doctor-patient relationship and restrict ready access to imaging care, maintained the ACR.

medical imaging studies for Medicare patients. This is a far more effective and efficient policy than blanket prior authorization,” said Dr. Ellenbogen.

He continued, “Electronic order-

ing systems, based on these criteria, are compatible with hospital electronic health records systems and are shown to reduce duplicate and unnecessary scanning and associated costs with-

out taking decisions out of doctors’ hands or affecting access to care. This approach enjoys bicameral, bipartisan support. We will continue to work with Congress to advance this policy.” n

Activated T Cell Inactivated T Cell

Paul H. Ellenbogen, MD, FACR

Government Accountability Office (GAO) reports have examined self-referral of medical imaging and radiation oncology services and found significant and inappropriate increases in referrals when physicians are allowed to self-refer. This drains Medicare of hundreds of millions of dollars each year, according to the ACR. “Imaging use and associated costs are down significantly since 2006. Only self-referred imaging grew significantly since the middle of last decade. It is past time for government to address self-referral,” said Paul H. Ellenbogen, MD, FACR, Chair of the ACR Board of Chancellors.

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

Downside of Prior Authorization Radiology benefits managers and prior authorization programs take medical decisions out of doctors’ hands, may delay or deny lifesaving imaging, and often result in longer waiting times for patients to receive care. A 2011 Moran Company report found that prior imaging authorization would produce no meaningful cost savings, could cost insurers and the government more than it saves, and impose tremendous administrative burdens on already strapped physician practices, commented the ACR. “The Sustainable Growth Rate Repeal and Medicare Provider Payment Modernization Act of 2014 would require ordering providers to consult physician-developed appropriateness criteria when prescribing advanced

Artist’s interpretation based on scanning electron microscopy.

ASCOPost.com | APRIL 15, 2014

PAGE 61

Palliative Care

Individualized Care Key to Cancer Pain Management at Sidney Kimmel Comprehensive Cancer Center

By Margot J. Fromer

L

earning about the particulars of each cancer patient’s pain and treating each case uniquely is the key

to keeping pain manageable. That is the goal of the Duffey Pain and Palliative Care Program at The Sidney Kim-

mel Comprehensive Cancer Center in Baltimore. The team consists of physicians, nurse practitioners, pharmacists,

social workers, and clergy, and was established in 2009.

Numerous multidisciplinary teams at medical institutions across the country work in a variety of styles with greater or lesser success. This one is highly effective and committed.

Pain Education

Discover PD-1: An immune checkpoint pathway1

Pain is pain, and aside from differences in quality and intensity, there it is, plain and simple, begging for relief. Right?

No, said Thomas J. Smith, MD, FACP, FASCO, Harry J. Duffey Family Professor of Palliative Care and Director of Palliative Medicine, Johns Hopkins Medical Institutions. “Pain is not simple at all. It is always defined by the patient, but it’s up to us to determine

Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

Pain is not simple at all.

It is always defined by the patient, but it’s up to us to determine not only where and how it hurts, but under what circumstances it worsens, and perhaps most important, how the patient reacts to it.

—Thomas J. Smith, MD, FACP, FASCO

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2.

References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.

2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565.

5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477.

6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1105870-0000 02/14 merck.com

not only where and how it hurts, but under what circumstances it worsens, and perhaps most important, how the patient reacts to it. How is it affecting his or her life?”

All this takes a good deal of time to sort out—time that most oncologists with a full caseload do not have.

People experience pain entirely alone. We can see some of its effects, but we cannot feel it, and the patient sitting continued on page 62

The ASCO Post | APRIL 15, 2014

PAGE 62

Palliative Care Cancer Pain Management

ing, constipation and fatigue, existential suffering, worry about family, and anything else that preys on the mind and body. “We know that pain itself is an aggregate of many factors, and when we take the time to talk about it, we usually can determine the problems and find ways to alleviate them.”

continued from page 61

in front of a physician is entirely different from everyone else. Nevertheless, patients can talk about their pain, and the pain clinic professionals may be the only ones who really listen. This is almost always the first step toward relief.

Pain education revolves around patients, of course, teaching them the sources of cancer pain and the best ways to control it. “But the team teaches one another,” said Dr. Smith.

This is especially true every Thursday at noon, when about 25 people in the Palliative Care Program gather to discuss patients who are newly diagnosed, or who present challenges for pain control, or about whom one of the team members has questions. The ASCO Post was recently invited to attend one of these informal meetings at Sidney Kimmel.

Time Is the Critical Factor Oncology has gotten busier, and effective pain control takes longer than most oncologists have. “By the time you evaluate the progress of the disease and

Stuart A. Grossman, MD

figure out a new or continuing treatment plan and decide what tests are needed, the office visit is over, and you haven’t even begun to address the patient’s pain,” said Stuart A. Grossman, MD, Professor of Oncology, Medicine, and Neurosurgery. Real conversations about pain tend to be long, and Medicare and other insurers don’t reimburse for the time.

What about the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requirement that pain be assessed in all patients, which is commonly done using a 0–10 numeric pain rating scale? Doesn’t that establish what a patient is feeling, and isn’t it sufficient?

Suzanne A. Nesbit, PharmD, CPE

No, said Suzanne A. Nesbit, PharmD, CPE, Clinical Pharmacy Specialist in Pain Management and Research Associate, Department of Oncology. “Pain is more than a number on a scale, although that is a starting point. The challenge is to find out what else is going on that has an effect on the pain. That’s one of the things we can do that most oncologists can’t. We have the luxury of time, and pain control is our only function.”

Barriers to Pain Relief As Michael J. Fisch, MD, MPH, noted in the March 1 issue of The ASCO Post (“Cancer Pain: The Humbling Reality”), about two-thirds of cancer patients have pain, and 42% of those patients do not receive adequate analgesia or have their pain addressed at all. Even after an initial pain assessment, the majority do not improve. There are many reasons for this, some obvious and some not.

Dr. Smith said that many patients hide their pain because they use it as a barometer of cancer progression—the worse the pain, the worse the disease.

“But if we know or suspect this, we can educate them about why cancer hurts,

Michael J. Fisch, MD, MPH

what it means, and how it may or may not be related to disease progression.”

“Everyone processes pain differently,” said Catherine B. Saiki, CRNP, a nurse practitioner. Often it’s not only physical sensations; it’s general suffer-

“zonked” by drugs, the vulnerability of having opioids in the house.

The reasons for poor pain control are myriad. Some are perfectly rational and some are more fanciful. But with time to sit and listen, the experience to ask the right questions, and the empathy to accept the answers, the pain team responds to each patient’s needs.

How the Team Works

Catherine B. Saiki, CRNP

Members of the team ask patients what their understanding is about the disease and the pain it causes—and they listen to the responses. They ask what bothers them most, what they believe about the future, and what they might like that future to be.

Ms. Saiki described cases of patients who are in obvious pain but insist they don’t need opiates. “They refuse to acknowledge how bad their pain is until I ask ‘if this was happening to your own child, wouldn’t you want him/her to feel better?’” “Oh, yes,” they reply.

“That’s all it takes,” Ms. Saiki said.

Money is another barrier. “Not all patients have good prescription drug coverage, and many of the newest and most effective drugs are surprisingly expensive,” said Dr. Grossman. “Yes, there are many generic ones that are relatively cheap, but you can guess which ones the drug companies are flogging.”

Then there are religious issues. Some patients believe that their disease is part of God’s plan, that they were predestined to suffer, or that God wants them to suffer. (“Then why did God make poppies?” quipped a team member.)

“Spiritual pain can compound physical pain, and I have seen a half-hour visit with a clergy person make all the difference in a patient’s willingness to allow us to help,” said Dr. Smith.

Patients try to hide their pain for other reasons as well: not wanting to be a bother or to seem cowardly, fear of addiction to opioids, unwillingness to be

The palliative care program has six inpatient beds, said Ms. Saiki. “These are for the sickest patients, who stay until their symptoms have stabilized so they can go home or to a hospice.”

“We see about five patients per clinic, three times a week,” said Dr. Nesbit.

“Over the first 2 years (2009–2011), we had approximately 900 clinic visits.” Most patients are seen two or three times, usually a week apart, to get them started on effective pain control, and then on an as-needed basis.

Julie Waldfogel, PharmD, CPE, another pharmacist on the team, said that the oncologists and other clinicians at Sidney Kimmel are generally supportive of the pain program. “Referrals come primarily from medical and radiation oncologists, as well

Julie Waldfogel, PharmD, CPE

as nurses in the infusion center,” she said. There are some self-referrals, but they are rare, and the team requires that they be followed by a Hopkins oncologist.

“We’ve heard often from oncologists that in their appointments with patients, they don’t have the time to get to symptom management and appreciate that we’re available to help. I think that the continued referrals we receive are proof of that,” she added. n Disclosure: Drs. Smith, Grossman, Nesbit, and Waldfogel, and Ms. Saiki reported no potential conflicts of interest.

NOW ENROLLING A Phase 3 Trial for Newly Diagnosed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients are found to express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ACT IV is an international, randomized, double-blind, controlled, phase 3 study of rindopepimut added to standard of care temozolomide in patients with newly diagnosed EGFRvIII-positive glioblastoma Rindopepimut Every 2 weeks x 2, then monthly

+

1:1 Randomization

Diagnosis/Resection Chemoradiation EGFRvIII-positive glioblastoma

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles

Treat until tumor progression, intolerance, or withdrawal of consent

Blinded KLH Control Every 2 weeks x 2, then monthly

+

N=~440

Temozolomide Days 1-5 in 28 day cycle 6-12 cycles KLH=keyhole limpet hemocyanin.

Key Inclusion Criteria

Key Exclusion Criteria

• Newly diagnosed glioblastoma

• Evidence of metastatic disease, diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• Attempted resection followed by chemoradiation with temozolomide • Provide a tumor specimen which tests positive for EGFRvIII at the protocol specified central laboratory • ECOG PS ≤ 2, and dexamethasone ≤ 2 mg/day (or equivalent) for ≥ 3 days prior to randomization

• Other treatments for glioblastoma • Unequivocal progression during chemoradiation therapy Key Trial Endpoints: • Primary: Overall Survival (OS) • Secondary: Progression-free Survival (PFS)

ECOG PS=Eastern Cooperative Oncology Group Performance Status.

For more information visit glioblastomastudy.com and http://www.clinicaltrials.gov/show/NCT01480479 or e-mail info@celldextherapeutics.com.

1. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722-4729. 3. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

All rights reserved.

6/13

JA

The ASCO Post | APRIL 15, 2014

PAGE 64

Health-Care Policy AACR Congressional Briefing

Cancer Research Funding Still Tight—and Getting Tighter

By Margot J. Fromer

M

argaret Foti, PhD, MD (hc), CEO of the American Association for Cancer Research (AACR), welcomed about 150 congressional staffers to a March briefing in Washington, DC, with a plea for increased federal funding.

“Extraordinary progress is being made in cancer research today, as evidenced by the more than 14 million

to me after a year of treatment and 2 years so far of tamoxifen was learning about the research that showed a clear benefit of an extra 5 years of tamoxifen.

This takes a lot of the scariness out of being a survivor.”

Rep. Wasserman Schultz, along with Sen. Amy Klobuchar (D-MN) sponsored S. 994, the Breast Cancer Educa-

Our work is far from finished, and we need to ensure that NIH and NCI are funded at levels that will ensure their ability to make more lifesaving progress.

—Margaret Foti, PhD, MD (hc)

survivors in the United States, but despite remarkable advances, cancer remains a significant problem,” she noted.

“This year alone, more than 1.6 million Americans will receive a cancer diagnosis, and more than 580,000 will die of the disease. Our work is far from finished, and we need to ensure that NIH [National Institutes of Health] and NCI [National Cancer Institute] are funded at levels that will ensure their ability to make more lifesaving progress. Cancer patients are in desperate need of this commitment.”

She added that many of AACR’s 34,000 members, which include scientists, clinicians, other health professionals, and advocates, depend to a greater or lesser extent on federal funding, which has decreased by 20% overall during the past decade. Moreover, although the cancer death rate has decreased by 1% each year over the same period, it runs up $216 billion annually in direct and indirect costs.

Two Congressional Cancer Survivors Rep. Mike Fitzpatrick (R-PA), a colon cancer survivor, thanked AACR for its research efforts, as well as its pledge to increase federal funding. He said that having had cancer has changed his perspective of what is important and has made him a more compassionate legislator.

Rep. Debbie Wasserman Schultz (D-FL) is a breast cancer survivor and also expressed gratitude toward AACR. “One of the good things that happened

tion and Awareness Requires Learning Young (EARLY) Act of 2009. “Given that nearly 200,000 women under the age of 40 get breast cancer, we wanted

Rep. Debbie Wasserman Schultz

to ensure that they learn the facts about it, know how their bodies function, and advocate for their own health.”

Clinical/Translational Research Expert Supports Funding Charles L. Sawyers, MD, AACR President and Chairman of the Human Oncology, Pathogenesis Program, Memorial Sloan Kettering Cancer Center, and Investigator at the Howard Hughes Medical Institute, New York, who concentrates on signaling pathways, said that this is a pivotal moment in cancer research and the wrong time to “de-escalate efforts.”

He noted that in the past 18 months, the U.S. Food and Drug Administration has approved 13 new drugs and six new uses for agents previously approved.

Moreover, there are now 41 targeted therapy drugs, among them imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), and ponatinib (Iclusig).

Charles L. Sawyers, MD

“We are making enormous progress in genomics,” said Dr. Sawyers. “It is now possible to efficiently and economically read every base of the DNA from any patient’s cancer and to compare it to the sequence of their normal cells. Because of this technology, we know that we can eventually perform large-scale genomic analyses that will be essential catalysts for further progress. We cannot slow down now.”

In addition, coordinated efforts will soon exploit whole-genome sequencing to identify genetic mutations in a variety of cancer types and subtypes.

They are the Cancer Genome Atlas, the International Cancer Genome Consortium, and the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project.

Dr. Sawyers said that federal funds continue to be necessary not only for biomedical research, but for expansion of electronic health records, a highly skilled and diverse workforce, increased patient participation in clinical trials, and improved quality and consistency of biospecimen resources.

Two Clinician-Scientists Stephen Schuster, MD, Director of the Lymphoma Program at Abramson

Stephen Schuster, MD

Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, whose major interest is B-cell leukemia and lymphoma, agreed that progress has been remarkable to date, but that “bad stuff will start to happen in 5 years if we don’t keep making the quantum

leaps that have been the hallmark of the past 2 decades.”

He noted that all the speakers had different perspectives on cancer, but all had come to the same conclusion: Without continued funding, progress will slow dangerously.

Crystal Mackall, MD, Chief of the NCI Pediatric Oncology Branch and Immunology Section Head, described her work in immunotherapy. She told a moving story of a little boy with B-cell leukemia whose older brother died of a different form of the disease. His parents were, of course, doubly devastated when he was diagnosed—even more so when he ran out of treatment options.

But he enrolled in an NCI cell therapy clinical trial—and after only one treatment, achieved lasting remission. Said Dr. Mackall, if it had not been for the institute’s ability to discover the therapy and run the trials, this child, too, would have died.

A CML Patient Hans Loland is now in remission from chronic myelogenous leukemia (CML). Like the little boy with leukemia described by Dr. Mackall, he too was preceded in death by someone close: his best friend, who also had CML. After being diagnosed with an unusual mutation and unresponsive to both imatinib and dasatinib, his physician said they were out of things to try.

But Mr. Loland heard about a phase I trial of ponatinib at the Oregon Health & Science University, Portland. It was thought to block the protein that causes most cases of CML. He drove there from his home in Seattle to meet with the principal investigator and came away from the meeting encouraged. He decided to give himself 3 months on the trial, even though the routine care would not be covered by insurance. He also decided to pay $30,000 to $40,000 out of pocket—until his employee selfinsurance came to his financial rescue and picked up the tab.

Two years ago, he and his wife felt secure enough to add another son to their family. n Disclosure: Dr. Foti reported no potential conflicts of interest. Dr. Sawyers is on the board of directors of Novartis and on the scientific advisory boards of Agios, Beigene, Blueprint, Nextech, Seragon, and Tracon.

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

The ASCO Post | APRIL 15, 2014

PAGE 66

Direct From ASCO

Philanthropy Spotlight

Raj Mantena, RPh, Makes $1 Million Donation to Conquer Cancer Foundation to Help Build the Future of Cancer Care

I

t is a challenge faced time and time again by oncologists: how to achieve the best possible outcomes for patients while simultaneously controlling costs, providing care that is both high quality and high value. Raj Mantena, RPh, the first individual to donate $1 million dollars to the Conquer Cancer Foundation, has spent his career wrestling with that challenge.

Mr. Mantena’s educational background in clinical pharmacy provided a foundation for an extraordinary entrepreneurial career in health care.

Over the past 20 years, he has founded or cofounded a number of groundbreaking companies in the oncology arena that all focused on improving cancer care. At the forefront of each of his ventures has been a genuine concern for increasing the quality of care received by patients while simultaneously improving the efficiency of the delivery of cancer treatment.

Throughout Mr. Mantena’s career this question of how to improve patient outcomes and the overall efficiency of cancer care has never been far from his mind, and it was Mr. Mantena’s continued drive to find answers and create solutions that eventually lead him to the Conquer Cancer Foundation and ASCO.

thenticity and the credibility” to tackle cancer care’s biggest challenges, he said.

He learned more about the Foundation’s work firsthand when Dr. Marsland invited him to the 2011 ASCO Annual Meeting in Chicago. Throughout the meeting, Mr. Mantena was introduced to the Foundation’s prestigious Grants & Awards Program; its support of superlative educational opportunities for physicians and patient information resources, including ASCO’s patient information website Cancer.Net; and finally, a fledgling project that was little known at that time but had enormous promise: a rapid-learning system called CancerLinQ™.

Unquestionably, Raj Mantena’s experience as an entrepreneur in the field of oncology—experience engaging the right people and the right resources to create something new that benefits both patients and health-care providers—is a key aspect of his philanthrop-

Raj Mantena, RPh (right), accepts thanks from then-Conquer Cancer Foundation Chair Martin J. Murphy, DMedSc, PhD, FASCO, at the 2012 ASCO Annual Meeting.

CancerLinQ represents an important breakthrough,” said Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer Foundation. “His gift

I am interested in CancerLinQ and chose to support this initiative because it is going to provide researchers and clinicians with critical, comprehensive information about the treatment of cancer patients and will result in more amazing health outcomes in the future.

—Raj Mantena, RPh

A History of Innovation Mr. Mantena was introduced to the Conquer Cancer Foundation through his colleague and friend Thomas Marsland, MD, who is a member of the Conquer Cancer Foundation Board of Directors.

Mr. Mantena was interested in the Conquer Cancer Foundation not only

ic support of the Conquer Cancer Foundation and ASCO. Mr. Mantena was happy to provide support for Cancer.Net—calling it “an amazing ­ site for cancer patients and their caregivers”—but it was clear from the start that his passion was in the new and lifesaving promise of CancerLinQ.

is a catalyst for the Conquer Cancer Foundation and the total CancerLinQ project, and he is a truly transforma-

CancerLinQ: A New Universe in Cancer Care

Thomas Marsland, MD

because of its mission, but for how the expertise and front-line experience of ASCO’s membership drive that mission to achieve tangible results for patients and cancer care providers. This expertise provides the Foundation with “the au-

CancerLinQ is a cutting-edge health information technology platform that will harness “big data” to revolutionize how we care for people with cancer. The result will be higher quality, higher value care with better outcomes for patients, powered by vast quantities of information that are now lost to file cabinets and unconnected servers. It represents the next major step in ASCO and the Conquer Cancer Foundation’s efforts to improve the quality of cancer care.

“Mr. Mantena’s support of

Nancy R. Daly, MS, MPH

tive ally for us in our mission to build a world free from the fear of cancer.”

Mr. Mantena puts it somewhat more simply: “I am interested in CancerLinQ and chose to support this initiative because it is going to provide researchers and clinicians with critical, comprehensive information about the treatment of cancer patients and will result in more amazing health outcomes in the future.”

Encouraging Others Mr. Mantena’s support is not limited to his personal philanthropy; he is eager to introduce others to the Conquer Cancer Foundation and encourage them to join him in supporting the vision of a world free from the fear of cancer. In 2013, Mr. Mantena offered matching gift challenges to individual donors at the ASCO Annual Meeting, during a challenge month in September, and at the close of the year, each time providing a dollar-fordollar match to double the impact of individual gifts—in total, more than $800,000.

Mr. Mantena’s generosity to the Conquer Cancer Foundation has produced significant benefits in the ongoing fight against cancer, from fueling the oncologist-approved patient information on Cancer.Net, to tapping the power of clinical information through CancerLinQ, to supporting the full gamut of the Foundation’s programs via his matching gift challenges. But utimately his gifts, alongside the gifts of every other individual who supports the Foundation, are in pursuit of a singular goal: better patient outcomes. We are extremely grateful for Mr. Mantena’s support because whether through research, education, or quality care innovation, improving outcomes for patients worldwide is at the heart of what it means to truly Conquer Cancer. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | APRIL 15, 2014

PAGE 67

Direct From ASCO

Amended 2013 Conflicts of Interest Policy Expands Requirements for Financial Disclosures

T

he Society’s 2013 Policy for Relationships with Companies is scheduled to go into effect on April 22, with one large change to its original requirements. The policy will still require the full disclosure of all financial relationships by all authors; however, since announcing the new policy in April 2013, the ASCO Board of Directors made the decision to delay the enforcement of Section V of its policy.

Section V restricted the submission of original research to an ASCO educational program, scientific program, or ASCO journal if a first, last, or corresponding author had participated in the speakers’ bureau, was employed by, or held a significant ownership interest in a company sponsor of that research.

Instead, when the new policy goes into effect, ASCO will require the disclosure of these financial relationships, but will not restrict submission based on the responses. During the next 3 years, ASCO will gather information to learn more about these relationships such as how frequently they occur and whether they occur more frequently in certain research settings.

“Essentially, we are going to move forward with what we were planning to do if the policy had been implemented,” said

Richard L. Schilsky, MD, Chief Medical Officer at ASCO. “The information gathered over the next couple of years will be brought to the ASCO Board, and a decision will be reached to go ahead with

innovative scientists working as employees of the pharmaceutical industry from submitting their work to ASCO meetings and publications. Additionally, there is an increasing amount of re-

We feel this will add a greater level of transparency and will eliminate arbitrary or potentially biased decisions about what is relevant and what is not. Instead, the reader can decide if those relationships are important.

—Richard L. Schilsky, MD

the full implementation or to modify it in some way based upon what we learn.”

Concerns Raised After the announcement of the revised 2013 policy, several concerns were raised from medical leaders and scientists working within the pharmaceutical and biotech industry—many of whom were ASCO members—and respected national leaders from public agencies, Dr. Schilsky said.

Among the concerns were that the 2013 policy would restrict credible and

search of great interest to ASCO members that can only be carried out using proprietary databases and technology that these companies own.

“There were concerns that by limiting the roles of those authors, we would effectively limit the dissemination of their research to our members,” Dr. Schilsky said.

Changing Health-Care Landscape When reconsidering the policy, the

ASCO Board also took into consideration some elements of the changing health-care landscape in the United States. In recent years, there has been a steady decrease in funding from the National Institutes of Health that is changing the structure and support of scientific research.

With fewer funds available, more research is occurring inside pharmaceutical companies or is being conducted through collaborations between the research community and pharmaceutical and biotechnical companies, increasing the likelihood that there may be a relationship between a lead author and a corporate entity.

In addition, since the 2013 Policy was written, the Sunshine Act has been implemented requiring that commercial firms publicly report any payments or transfers of value to physicians.

“All of these things have made the landscape more complex than it has been in the past,” Dr. Schilsky said.

“Given the landscape and the points raised about the author restriction policy, the ASCO Board ultimately decided that ASCO should take a step back and collect data before implementing the restrictions.” continued on page 69

Become a Cornerstone of the Conquer Cancer Foundation

H

ave you given any thought to the legacy you would like to leave? For many of you, your professional legacy will include the patients you have cared for, the research you have conducted, the students you have mentored, and the lives you have touched in the world of cancer care. You also have your per-

sonal legacy: your family, your friends, and your community. Through thoughtful estate planning, all of these entities can benefit from your life-long work.

There are many ways individuals can use their estate to fulfil personal and philanthropic goals, and the Conquer Cancer Foundation’s planned giving website (www.conqercancerfoundation .org/plannedgiving) has extensive tools to help, whether you’re just beginning to think about estate planning, or look-

ing into more sophisticated options like charitable lead or remainder trusts.

Cornerstone Membership Perhaps you’ve already included the Conquer Cancer Foundation in your estate plan or you’re considering doing so. If so, we hope you will consider becoming a member of Cornerstone. The Foundation established Cornerstone in 2013 in recognition of those individuals who have notified the Foundation of their intention to make a gift through their estate.

Members of Cornerstone have the pleasure of knowing that they will be leaving a strong foundation of support for cancer researchers and practitioners as well as for patients and their families.

Members of Cornerstone are also recognized for their commitment to the future of cancer care through donor listings, special event invitations, and other opportunities.

Cancer will touch the life of nearly every person on the planet. Our goal

April is the Conquer Cancer Foundation’s Make-a-Will Month

B

y simply designating Conquer Cancer Foundation as a beneficiary of your estate, you will be leaving a legacy that builds the future of cancer research and cancer care. Typical bequest language is: “I give [the sum of $__] OR [__% of my estate] OR [all or __% of the rest, residue, and remainder of my estate] to the Conquer Cancer Foundation of the American Society of Clinical Oncology, a Virginia nonstock corporation located at 2318 Mill Road, Suite 800, Alexandria, Virginia, 22314 (Federal Tax ID: 31-1667995), to be used for its general purposes.” n at the Conquer Cancer Foundation is to build a world free from the fear of cancer, so that the moment of a cancer diagnosis is not a life-threatening crisis, but just one in a string of the many moments that make up our lives. We need your help to guarantee that the necessary resources will be available to help conquer cancer well into the future. Your commitment to honor the Conquer Cancer Foundation as a ben-

eficiary in your estate planning helps to build a strong future for our field and our patients.

To learn more about your estate planning options, visit www .co n q u erc an cer f o u n d at i o n .o rg / plannedgiving or contact our Planned Giving office at (571) 483-1700. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | APRIL 15, 2014

PAGE 68

Direct From ASCO

Science and Society: Register to Attend the 2014 ASCO Annual Meeting

J

oin oncology professionals from around the world for the 2014 ASCO Annual Meeting, which will be held May 30 through June 3 in Chicago. This year’s meeting will offer opportunities to learn about, debate, and discuss practicechanging advances in the field, and also

highlight promising clinical and scientific results that will broaden and accelerate global progress against cancer.

Register to attend and reserve your hotel room by Wednesday, April 23, for the best rates. Visit am.asco.org and select “Registration and Hotel Information” on the left

navigation bar to complete your registration and make your hotel reservation.

Pre–Annual Meeting Seminars Enhance your Annual Meeting experience and explore additional oncologyrelated topics of interest during ASCO’s

You wouldn’t accept ambiguity here.

Why would you in a breast cancer recurrence test?

Intermediate…now what? The answer is MammaPrint®, the only breast cancer recurrence assay backed by peer-reviewed, prospectve outcome data showing 97% accuracy in identfying low risk patents1. So when it says low risk, you can believe it. And, with the ability to uncover more clinically actonable biology, no wonder MammaPrint is the fastest growing breast cancer recurrence assay2.

Convenient online ordering available at www.agendia.com Agendia, Inc. 22 Morgan, Irvine, CA 92618 (888) 321-2732 www.agendia.com © 2014 1 Drukker CA, et al. Int J Cancer. 2013 Aug 15;133(4):929-36.

2 Documents available in the public domain.

five Pre–Annual Meeting Seminars. Each seminar will be held onsite at McCormick Place from 12:30 PM on May 29 (lunch included) until 11:00 AM on May 30 (breakfast included). Visit am.asco.org and select “Pre–Annual Meeting Seminars” on the left navigation bar for more information and to register for the following: • Hematology for the Oncologist (new in 2014): Cosponsored with the American Society of Hematology, this seminar will focus on hematologic issues that medical oncologists commonly encounter in a consultative practice. Experts in the field will discuss clinical aspects of bleeding and clotting disorders, new oral anticoagulants, iron therapy, and other topics in benign hematology.

• Improving Quality of Cancer Care and Patient Safety for High-Value Oncology Practice (new in 2014): This limited-attendance seminar will offer interactive sessions centered on value, safety, quality measurement, and quality improvement for oncology practices. Take home feasible strategies to evaluate your practice’s policies, engage staff in identifying and addressing problems, and promote quality improvement for high-value cancer care.

• Clinical Care in Oncology for the Advanced Practice Provider: Designed specifically for advanced practice providers such as physician assistants and nurses, this seminar’s topics will include effective team-based care, improving productivity and value, and survivorship care. This seminar will also provide continuing nursing education (CNE) credits is cosponsored by the Association of Physician Assistants in Oncology and the Oncology Nursing Society.

• New Drugs in Oncology: Theoretical and practical aspects of recently approved drugs and emerging therapies on their way to approval will be discussed, offering attendees a unique opportunity to hear unbiased academic, regulatory, clinical, and industry perspectives.

• Genetics and Genomics for the Practicing Clinician: Featuring a variety of engaging sessions, including a multidisciplinary tumor board and case-based discussions, this session will cover tumor and germ line topics, new technologies, and the tests and tools available to oncologists.

These live activities have been approved for AMA PRA Category 1 Credit™. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | APRIL 15, 2014

PAGE 69

Direct From ASCO

ASCO Calls for Clear Guidance on Tobacco Cessation Benefits in the Affordable Care Act

A

SCO has signed a joint letter to U.S. Department of Health and Human Services Secretary Kathleen Sebelius asking for clear and comprehensive guidance on the tobacco cessation benefit in the Affordable Care Act regulations.

In the letter, the organizations applaud the Department of Health and Human Services for its recent release of the 50th anniversary Surgeon General’s report, The Health Consequences of Smoking—50 Years of Progress, which called for more rapid progress against tobacco use. Under current Affordable Care Act regulations, insurance companies must provide coverage for tobacco cessation services; however, ASCO and the other organizations remain concerned about tobacco users’ limited access to the free services provided under the legislation.

The letter cites a 2012 study by

Georgetown University’s Health Policy Institute that found that many health insurance plans do not provide the full range of coverage mandated by the Affordable Care Act. Due to unclear contract language found in many plans as well as the narrow interpretation of the law held by many insurance companies, the signing organizations recommend that the Department of Health and Human Services, the U.S. Department of Labor, and the U.S. Department of the Treasury issue guidance to the health insurance industry clarifying that “tobacco cessation interventions” include coverage of both counseling sessions and Food and Drug Administrationapproved medications. n

ASCO Signs Joint Open Letter to End Tobacco Sales

A

SCO has joined 26 of the nation’s leading public health and medical organizations in signing a joint letter calling on drug stores and other retailers to end the sale of cigarettes and other tobacco products.

The open letter came just weeks after CVS Caremark announced it would stop selling tobacco products in all of its pharmacy stores in the United States. In the letter, the organizations urge drug stores and other retailers to follow CVS Caremark’s example and end tobacco sales, citing tobacco prod-

Volume 7, Issue 3

May 2011

Journal of oncology Practice Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al

Help Your Patients Learn About Their Cancer Care Team

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

O

n the Cancer.Net Blog, your patients can read about the various health professionals involved in their diagnosis, treatment, and survivorship and listen to podcasts with these professionals discussing their roles in caring for people with cancer. This month, the Cancer.Net Blog highlighted physician assistants. Direct your patients to www.cancer.net/blog

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

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

The Authoritative Resource for Oncology Practices

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

ucts as the number one cause of preventable disease and death.

The letter emphasizes that retailers dedicated to improving health and saving lives must not continue to profit from the tobacco products that severely harm the people who use them. The organizations signing the letter believe that reducing the availability of such products will ultimately help end the tobacco epidemic. n

What’s Hot in

JOP

JOP.ascopubs.org to learn more and subscribe to the blog so they don’t miss next month’s topic in this series. n © 2014. American Society of Clinical Oncology. All rights reserved.

Rural Oncology: Overcoming the Tyranny of Distance for Improved Cancer Care

by Mathew George, et al

Physician Perspective on Incorporation of Oncology Patient Quality-of-Life, Fatigue, and Pain Assessment Into Clinical Practice

Conflicts of Interest continued from page 67

Additional 2013 Changes Authors should also be aware that the 2013 policy has broadened the requirements for financial disclosures for all research authors. The 2005 policy required the disclosure of financial relationships that the authors felt were specifically relevant to the submitted original research.

The updated policy requires a general financial disclosure by all authors of any compensation received for employment, leadership positions, consulting activities, speaking engagements, and expert testimony, as well as ownership interests, research funding, licensing

fees, and royalties associated with intellectual property interests.

“We feel this will add a greater level of transparency and will eliminate arbitrary or potentially biased decisions about what is relevant and what is not,” Dr. Schilsky said. “Instead, the reader can decide if those relationships are important.”

Abstract submissions and author presentations for the 2014 ASCO Annual Meeting will still fall under the 2005 policy. The 2014 Breast Cancer Symposium will be the first ASCO meeting under the 2013 Conflicts of Interest Policy. n

by Joleen M. Hubbard, et al

Can Patient Comorbidities Be Included in Clinical Performance Measures for Radiation Oncology?

by Jean B. Owen, et al

Cost-Effectiveness Analysis Comparing Conventional Versus Stereotactic Body Radiotherapy for Surgically Ineligible Stage I Non–Small-Cell Lung Cancer

by Gunita Mitera, et al

Oncology Pharmacists in Health Care Delivery: Vital Members of the Cancer Care Team

by Lisa Marie Holle, et al

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

Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther.

2011;19:1008-1016. Š2013 Amgen Inc. All rights reserved. 11/13 74385-R2-V7

Fight it ONCOLYTIC IMMUNOTHERAPY

Cancer cell

is an innovative area of research that uses a modified virus designed to help T cells find and fight cancer cells as part of a hypothesized systemic, tumor-specific immune response.1

Learn more at: www.oncolyticimmunotherapy.com

Amgen. Leading the way in the study of Oncolytic Immunotherapy.

The ASCO Post | APRIL 15, 2014

PAGE 72

Issues in Oncology Cancer Care in America continued from page 1

oncologists; changes in health-care delivery systems; and the economic pressures of maintaining small community oncology practices.

Booming Incidence According to the report, by 2030, the number of new cancer cases in the United States will increase by 45%,

ter, and Professor of Medicine at Weill Cornell Medical College.

According to an ASCO analysis of the U.S. oncology workforce, oncologists are already in short supply in many rural areas. ASCO’s findings show that only 3% of oncologists practice in rural communities, where nearly one in five Americans lives. In addition, more than 70% of U.S. counties have no medical oncologist at all.

Over the past several years, the cost of chemotherapy drugs has risen and the reimbursement of chemotherapy drugs has fallen, and it’s taken my practice to the breaking point.

—Carolyn B. Hendricks, MD, PA

from 1.6 million to 2.3 million per year—largely the result of an aging population—and cancer will overtake heart disease as the leading cause of death. Along with the additional increases in cancer incidence, there will also be a rapidly growing population of cancer survivors, from 13.7 million today to nearly 18 million by 2022, most of whom will need ongoing care to monitor for disease recurrence and the long-term effects of their initial treatment.

Fewer Oncologists While the demand for cancer care will be on the rise over the coming decade, the supply of oncologists is projected to grow by only 28%, leaving a shortage of almost 1,500 oncologists, further straining the oncology health-care system. The anticipated retirement of many oncologists—currently, nearly one of every five cancer specialists is over the age of 64—as well as high levels of burnout, potentially leading to reduced clinical load or early retirement, are two factors contributing to the projected workforce shortage.

“On average, an oncologist sees about 300 new patients in a year, and if we increase the demand, the math suggests that almost half-a-million people will be facing some kind of challenge in accessing care,” Dr. Hudis said. Dr. Hudis is Chief of the Breast Cancer Medicine Service and Attending Physician at Memorial Sloan Kettering Cancer Cen-

Demise of Community Practices Further jeopardizing access to high-quality oncology care in rural regions and across America as well, is the reduction in the number of small and midsize community practices that find it necessary to shutter their doors, merge with larger practices or hospitals, or sell their businesses altogether because of loss of revenue from cutbacks in Medicare payments and other factors, such as the high cost of chemotherapy drugs.

Carolyn B. Hendricks, MD, PA, a medical oncologist specializing in breast cancer,, spoke at the ASCO press briefing about the difficulty she is having keeping her private practice open.

“Right now, I’m considering closing my practice. Over the past several years, the cost of chemotherapy drugs has risen and the reimbursement of chemotherapy drugs has fallen, and it’s taken my practice to the breaking point,” said Dr. Hendricks. “Chemotherapy drug pricing is tied directly to how much chemotherapy is purchased, so in a really small practice like mine, or in any small practice … we pay more for the same chemotherapy drugs than larger practices, but we have the same safety and staffing requirements, and want to deliver the same level of high-quality care.”

ity and delivery of cancer care and reduce the impact of the projected oncology workforce shortages, ASCO is calling on federal policymakers and other stakeholders in the oncology community to help create an environment where quality patient care can thrive. ASCO’s recommendations include: The development and testing of new health-care delivery and payment models that preserve the viability of small community practices while encouraging high-quality care.

Ending persistent financial threats to community practices caused by sequester-related cuts to Medicare physician payments, and by the sustainable growth rate (SGR) formula, Medicare’s current reimbursement system that has become a source of tremendous instability within health care and a perennial threat to care for millions of seniors.

The embracement and support of physician-led quality initiatives, such as ASCO’s established Quality Oncology Practice Initiative (QOPI®) and the CancerLinQ™ rapid learning system currently under development.

ASCO is also recommending support of the SGR Repeal and Medicare Provider Payment Modernization Act of 2014 (S. 2000/H.R. 4015), which would eliminate the flawed SGR system, provide special support for practices in underserved areas, and support an array of innovative healthcare payment, delivery, and quality initiatives, such as the ones included in The State of Cancer Care in America report.

“Congress right now has an unprecedented opportunity to address

this challenge. The SGR Repeal and Medicare Provider Payment Modernization Act of 2014 is the vehicle to do this,” said Dr. Hudis. “We are specifically asking—urging—lawmakers to pass this legislation so that the cancer community can move beyond this repeated crisis mode that we’ve been in over and over again and instead focus on the pursuit of cancer care delivery innovation and scientific advance. This is the innovation that brings greatest value to our practices, our patients and their families, and the lifesaving treatments that everybody wants to see.”

According to Dr. Hudis, ASCO will release periodic reports on the progress being made in these areas.

[Editor’s note: As we went to press, Congress passed legislation to provide a 12-month patch to the flawed SGR formula. The final bill replaces the 24% cut in payment (that would otherwise have been triggered) with a 0.5% provider payment update through the end of the year and no update from January 1 through April 1, 2015. See page 138 for a statement by Dr. Hudis about the new patch. And for the latest SGR-­ related news, readers can visit ASCO’s SGR landing page at http://www.asco .org/advocacy/repeal-sgr-formula-now.]

A copy of The State of Cancer Care in America: 2014 is available at http:// www.asco.org/practice-research/­cancercare-america. To watch a webcast of the briefing presented on Capitol Hill in Washington, DC, visit http://www.asco .org/practice-research/state-cancer-careamerica-2014-hill-briefing-webcast. n Disclosure: Drs. Hudis, Hendricks, and Polite, and Rep. Blumenauer reported no potential conflicts of interest.

Finding Solutions According to the report, to address the challenges facing the qual-

ASCO President Clifford Hudis, MD, FACP, of Memorial Sloan Kettering Cancer Center; Rep. Earl B ­ lumenauer [D-OR]; Carolyn Hendricks, MD, PA; and Blase Polite, MD, of University of Chicago. Photo courtesy of ASCO.

ASCOPost.com | APRIL 15, 2014

PAGE 73

Announcements

NIH Opens Its Doors to Research for Extramural/Intramural Collaboration

T

en projects that will enable nongovernment researchers to conduct clinical research at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, were announced recently.

Through these 3-year, renewable awards of up to $500,000 per year, scientists from institutions across the United States will collaborate with government scientists at the NIH Clinical Center.

“This initiative will provide top scientists outside NIH the opportunity to utilize the sizable resources of our clinical center,” said NIH Director Francis S. Collins, MD, PhD. “The collaborative process they undertake with researchers

Endeavor to Stimulate Collaboration The awards will support projects on a variety of diseases and health conditions, including three specific to cancer research (see page 77), namely, clinical trials of a new drug treatment to prevent relapse in

childhood acute myelogenous leukemia, genetic makeup of certain types of prostate cancer, and stem cell gene therapy following R-EPOCH for non-Hodgkin lymphoma in AIDS patients, to gain insights that could yield new information for prevention and treatment efforts.

“These are the first awards in this unique program,” said Sally Rockey, PhD, NIH Deputy Director for Extramural Research. “We need to do all we can to stimulate collaborations among the country’s best scientific minds in and outside the NIH campus,” Dr. Rockey said. n

Francis S. Collins, MD, PhD

here on campus will set a framework for important biomedical discoveries and needed treatments,” Dr. Collins said.

The new grants will provide extramural researchers from academia and industry with direct access to the broad resources of the NIH Clinical Center.

Outside scientists will be able to test promising laboratory discoveries using emerging technologies and tools and collaborate on clinical protocols in partnership with NIH investigators.

John I. Gallin, MD

“We are very excited about opening the doors of the Clinical Center to our extramural colleagues who will bring additional cutting-edge research projects and new partnerships that will enrich ongoing efforts translating scientific discovery into tomorrow’s cures at the Clinical Center and in partnering institutions around the country,” said John I. Gallin, MD, Director of the NIH Clinical Center.

Advertisement not displayed in digital edition at advertiser’s request

The ASCO Post | APRIL 15, 2014

PAGE 74

Health-Care Policy

Informed Consent: Not Just About Blood Tests and Procedures Anymore HIPAA and genomics complicate matters.

By Margot J. Fromer

O

n February 24, the Institute of Medicine National Cancer Policy Forum convened a workshop, “Contemporary Issues in Human Subjects Protection in Cancer Research,” in Washington, DC.

Steven Piantadosi, MD, PhD

In his introduction to the workshop, Steven Piantadosi, MD, PhD, Director, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, said, “In the years since implementation of federal regulations governing clinical research, the number of clinical studies has grown substantially, trials have become more complex, and multicenter trials are common. In addition, the increase in biobanking and genomic analysis has changed the landscape of clinical research, which raises important questions for institutions that conduct research and the patients who participate in it.

“The clinical trials endeavor is in an unquiet state,” he commented.

Advanced Notice of Proposed Rulemaking Holly Taylor, PhD, Associate Professor of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, and Core Fac-

Holly Taylor, PhD

ulty Johns Hopkins Berman Institute of Bioethics, Baltimore, reviewed a number of current issues related to the ethical conduct of human subject research.

These included the status of the Advanced Notice of Proposed Rulemaking (ANPRM) issued by the Department of Health and Human Services and Of-

fice of Science and Technology Policy recommending changes to the Federal Regulations that guide the ethical conduct of human subject research (45 CFR 46). The notice was posted in July 2011, with the following key topics: • Protecting research subjects from privacy breaches by adopting Health Insurance Portability and Accountability Act (HIPAA) provisions as a universal standard. Specifically, de-identified data collected for non-research purposes does not require consent other than that obtained before data collection. However, data collected for research, with or without identifiers, requires consent.

• Calibrating institutional review board assessment according to level of risk. Expedited review was to be revised and simplified including the elimination a requirement for continuing review.

• Using a single institutional review board for all sites of domestic multisite studies, with an aim to address the inefficiency of multiple reviews of the same protocol by many local institutional review boards.

• Creating a more systematic approach for collection and analysis of data about unanticipated problems and adverse events.

• Extending federal protection to all research, regardless of funding source, and harmonizing agency regulations and guidance documents.

The American Association for Cancer Research, Association of American Cancer Institutes, and ASCO responded to these proposed policies.

They supported ANPRM in general but were concerned about the need to delineate responsibilities between an external institutional review board and requirements for the local institution to oversee researchers, adoption of ­HIPAA as the universal rule for privacy protection, and consent requirements in regard to de-identified data.

Their recommendations included: redefine what is and is not “human subjects research,” adopt a new category of “excused” research and institute procedures for implementing it, and forgo consent for use of de-identified data.

The White House’s Office of Management and Budget was expected to issue a revised ANPRM by October 2013 for review by 17 federal agencies.

But that hasn’t happened yet and may be stalled for the foreseeable future.

HIPAA Is Everywhere HIPAA is ubiquitous, and its presence in medical research is no exception. According to Melissa Bianchi, JD, Partner at Hogan Lovells, HIPAA allows protected health information to be used for research with subject consent. A few important notes: 1. Under the new changes to the HIPAA rule, consents no longer need to be specific to the research study. Instead, a HIPAA consent now may permit future research as long as the future research is adequately described such that the research subject would reasonably expect that his or her PHI could be used or disclosed for that purpose.

2. It does not confer compound authorizations (corollary activities such as biospecimen banking) unless the consent clearly distinguishes among various research components, provides opportunity to opt out, and does not involve psychotherapy notes.

Melissa Bianchi, JD

Cancer researchers and sponsors, said Ms. Bianchi, now have considerably more flexibility to use protected health information. Nevertheless, HIPAA still takes identification of data seriously, and there are only two ways to de-identify them (ie, to render data anonymous). First, a statistician must determine that the risk of identifying an individual is very small. Second, 18 specific identifiers must be removed, known as the “safe harbor” method.

Once protected health information is de-identified, it is no longer protected health information. It is not subject to HIPAA, and it may be used for any legal purpose.

Limitations of De-identification According to Bradley Malin, PhD, Associate Professor of Biomedical Informatics, Vanderbilt University, Nashville, however, de-identification is not a panacea. There is always a risk of re-identifying people, and any system can be broken into. The challenge, therefore, is

to determine an appropriate level of risk and to ensure accountability for the data.

“We must be reasonable and practi-

Bradley Malin, PhD

cal,” he said. “We need to ask how people can be identified, and if they are, what harm can come of it.”

Alice Leiter, JD, Policy Counsel, Health Privacy Project, Center for Democracy and Technology, Washington, DC, distinguished between research and operations. The latter, she said, includes quality assessment and improvement, outcomes evaluation, and population-based studies to improve health, reduce costs, and develop protocols, provided that “obtaining generalizable knowledge is not the primary purpose.”

She added that the Center for Democracy and Technology believes that HITECH focuses disproportionately on the identifiability of data and whether consent is required. “De-identification is an important protection tool, but it is not infallible. Also, consent, though important, tends to be weak in practice.”

Other ways to protect privacy, she suggested, include a more risk-based framework in which publication of study results is not treated as inherently risky, less reliance on consent and more on other models of patient engagement (such as input into the research and sharing results with them), new mechanisms of accountability and oversight, and creation and maintenance of public trust in research.

Informed Consent Problems Informed consent is a mess and often doesn’t do the job it’s intended for.

Institutional review boards require too much unnecessary information, investigators use too much medical jargon, cooperative groups have made consent forms too long and complicated, and industry adds meaningless legalese.

Terrance Albrecht, PhD, Associate Center Director, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, noted that

ASCOPost.com | APRIL 15, 2014

PAGE 75

Health-Care Policy

the process of obtaining consent for a trial should take the time necessary to be patient-centered and to have a meaningful, helpful dialogue with the patient and the patient’s family members or companions.

She said that their research has shown that the consent process falls far short of the ideal. For instance, participants often didn’t know that they were consenting to research, not treatment; confidentiality was not explained; nor

tional review boards. Investigators have the same goals, and it is easier and less time-consuming to write long, complex documents than short, simpler ones.”

Institutional review boards are not subject to regulatory requirements about consent forms, so they too may take the easy way out and overload the forms with institutional boilerplate in legalese.

“Potential research participants are culpable as well,” said Dr. Botkin.

“They trust clinicians and investigators to make decisions for them; they’re often embarrassed to admit they don’t understand. They may be afraid of angering or disappointing their doctors—so they say nothing. Moreover, Jeffrey Botkin, MD

continued on page 76

Terrance Albrecht, PhD

was the need for a signature. Patients may not have been told that participation was voluntary and that they could withdraw at any time. They may not have understood randomization or what publication means, or even the purpose of the study.

Laura Cleveland, Patient Advocate, Cancer and Leukemia Group B Alliance, agreed that consent forms are too long and overwhelming, form readability levels vary greatly but are generally too high, and there is often no one with the patient while he or she reads the document.

‘Consent Is a Process’ Michael Paasche-Orlow, MD, Associate Professor of Medicine, Boston University, echoed Ms. Cleveland’s remarks and deepened the general criticism. “Literacy levels in this country are usually far below what is demanded of potential research subjects. What’s more, consent is a process, not merely a form presented to potential subjects.

Because subjects comprehend far less than is desirable, we ought to shorten and simplify the forms. Even then, readability is only part of the problem; the vocabulary is confusing, if not downright incomprehensible.”

Jeffrey Botkin, MD, Associate Vice President for Research Integrity, University of Utah, Salt Lake City, discussed why some of the problems exist and persist. “Sponsors want to make information about risks and benefits as comprehensive and accurate as possible. They also want to reduce legal liability and develop consent forms they think will be acceptable to institu-

Advertisement not displayed in digital edition at advertiser’s request

The ASCO Post | APRIL 15, 2014

PAGE 76

Health-Care Policy Informed Consent continued from page 75

the public is poorly educated about medical research, and patients tend to be passive and dependent, fearful and anxious.”

Improving Consent Dr. Paasche-Orlow suggested a technique called teach-back. In this way, investigators ensure that potential subjects understand not only the pa-

“It is the investigator’s responsibility to confirm that potential subjects substantively understand what they are being asked to undertake,” Dr. Paasche-Orlow told The ASCO Post.

“If comprehension cannot be confirmed, the person should not be enrolled.”

He added, “When it comes to the consent process, we need to help our research assistants shift from a model of persuasion to a model of pedagogy.”

It is the investigator’s responsibility to confirm that potential subjects substantively understand what they are being asked to undertake. If comprehension cannot be confirmed, the person should not be enrolled.

—Michael Paasche-Orlow, MD

rameters of the research itself but also what their participation means. Saying things like, “I want to make sure we have the same understanding about this research,” or “I would like to hear your understanding of the research project,” can provide an idea of what’s going on in the subject’s mind.

In addition, Dr. Paasche-Orlow recommends asking the subject questions about what has been explained, and letting him or her look at the form. “It’s about comprehension, not memory,” he noted.

“Listen for parroting and technical terminology, and if it’s there, explain further,” he continued. “Ask open-ended questions such as ‘Tell me in your own words what this research is about, and what it means to participate,’” he said.

The investigator should correct misinformation until he or she is certain the subject understands. Moreover, the investigator should take responsibility for the information imparted (“I haven’t explained things clearly”) and should never blame the subject for lack of understanding.

Ethics and Genome-Based Research “The cost of sequencing a single genome has dropped from $10 million to under $10,000, so genomic research such as multiplex panels for cancer susceptibility and genomic tumor profiling has been accelerating,” said Angela Bradbury, MD, Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

This creates new problems, just one of which is what to do with individual research results. “As large prospective cohort studies with banked DNA have become more common, there has been increasing debate over the obligations, if any, to share [individual research results] with research participants,” said Dr. Bradbury.

There are reasons for and against, she continued. Among the latter are the danger of blurring the distinction between research and clinical care, potential for misunderstanding or overinterpretation of clinical significance, compromising privacy, and cost.

Among the former are benefiting subjects and respect for their autonomy, as well as acknowledging the increasing interdependence of research and clinical care.

Dr. Bradbury said that more thought needs to be given to determining when and if researchers are obliged to return individual research results, how much, if any, depends on context, or if it is permissible at all. Then, which results should be returned, who covers the cost, and is lab confirmation necessary?

Principles and Recommendations

Angela Bradbury, MD

And sometimes it’s not clear. Some results have been confirmed and are clearly actionable; that is, a clinical intervention is possible. However, deciding what is and is not actionable and has clinical or other utility is not so clear-cut.

Gail Jarvik, MD, PhD, Head and Professor, Division of Medical Genetics, University of Washington School of Medicine, said that an actionable gene is a clearly deleterious mutation for which specific evidence-based interventions can improve health. However, regardless of the results that turn up in the course of research, informed consent should address what is to become of the results, and participants should know that.

Gail Jarvik, MD, PhD

In fact, one study revealed that 90% of research participants want individual research results even if no action can be taken. Moreover, 50% to 70% of people who spoke with a genetic counselor wanted to receive individual research results.

Dr. Jarvik and her team have devised a number of principles and recommendations about return of results to research subjects. These include: • Research differs from clinical care in terms of goals as well as procedures.

As a result, the information returned may differ, but clinically valid actionable information resulting from research should be offered to subjects.

• Participants have the right to refuse the results—those related to the study and incidental ones—unless the study requires return of results.

This should be understood and agreed to at the start.

• Resources for research should be directed primarily at scientific discovery. Therefore, there is no duty to look for actionable genomic findings beyond those discovered naturally in the course of an investigation.

Researchers should offer genomic results that are valid, medically important, and actionable.

• Researchers may be ethically and scientifically justified in returning all genomic information, but care should be taken when benefits and harms are uncertain. There is as yet no best way is to return results, but research ought to attempt to discover the benefits and harms to subjects as a result of receiving genomic information. n Disclosure: Drs. Piantadosi, Taylor, Albrecht, Paasche-Orlow, Botkin, Jarvik, and Bradbury and Ms. Bianchi reported no conflicts of interest. Dr. Malin is a paid consultant for Sanofi and Celgene.

For More on Health-Care Policy and Other Issues in Oncology Decision Time for Lung Cancer Screening in High-Risk Populations see page 89 The FDA’s Bad Ad Program see page 101 Statement by ASCO President on Congressional Failure to Act on Sustainable Growth Rate see page 138

ASCOPost.com | APRIL 15, 2014

PAGE 77

Awards

NCI Awards for Extramural/Intramural Research

T

hree of the 10 projects recently awarded grants by the National Institutes of Health (see page 73) focused on cancer research. These include the following:

Grant No. 1 U01 CA18303001 Title: Therapeutic Elimination of Stem Cells for Relapsed Pediatric AML Extramural Investigators: Drs. Yang Liu, Reuven Schore, Joseph Devaney, Pamela Hinds, and Jichuan Wang, Children’s Research Institute at Children’s National Medical Center, Washington, DC Intramural Investigators: Brigitte Widemann, Terry Fry, and Katherine Warren, NCI

Intramural Investigators: Drs. W. Marston Linehan, Murali Cherukuri, Peter Choyke, Deborah Citrin, James Mitchell, Peter Pinto, and Ramaprasad Srinivasan, NCI, and Dr. Bradford Wood, National Institutes of Health Clinical Center

Grant No. 1 U01 CA18301201 Title: Stem Cell Gene Therapy Following R-EPOCH for Non-Hodgkin Lymphoma in AIDS Patients Extramural Investigators: Drs. John Zaia, Joseph Alvarnas, David Di-

Giusto, and Amrita Krishnan, Beckman Research Institute of City of Hope, Los Angeles Intramural Investigators: Drs. Kieron Dunleavy, Richard Little, Frank Maldarelli, and Wyndham Wilson, NCI n

Grant No. 1 U01 CA18302701 Title: Integrative Molecular Imaging and Sequencing of Prostate ­Cancer Extramural Investigators: Drs. Arul Chinnaiyan, Rohit Mehra, Nallasivam Palanisamy, Dan Robinson, Yi-Mi Wu, University of Michigan Medical School, Ann Arbor

The ASCO Post Advertisement not displayed in digital edition at advertiser’s request Follow us on

@ASCOPost

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

The ASCO Post | APRIL 15, 2014

PAGE 78

Dermatologic Events in Oncology Accidental Extravasation of Chemotherapy

By Seppo W. Langer, MD PhD

A

ccidental extravasation of chemotherapy is a rare but feared complication of cancer treatment. Risk factors for extravasation include medication-related factors (such as the vesicant properties

cording to vesicant potential, ranging from the high-risk vesicant drugs (eg, anthracyclines and vinca alkaloids) to irritants (eg, platinum compounds, topoisomerase I inhibitors, and taxanes) and the neutral drugs.

GUEST EDITOR

Clinical Manifestation

Seppo W. Langer, MD PhD

of the compound, or the volume, concentration, and duration of the infusion), patient-related factors (such as fragile veins, obesity, impaired consciousness, and lymphedema, and iatrogenic factors (including insufficient training, poor infusion technique, and use of improper cannulas).

Cancer chemotherapy is generally divided into three main classes acDr. Langer is Chief Physician and Head, Department of Thoracic and Neuroendocrine Oncology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark.

The clinical hallmarks of vesicant extravasations are acute pain, swelling, erythema, and a burning or tingling sensation. If left untreated, blistering may develop immediately or within days after the extravasation and may be followed by induration, discoloration, and, in severe cases, signs of tissue destruction (Fig. 1). After weeks to months, the slowly growing ulceration may invade and destroy deeper structures such as tendons and joints.

The healing process is severely protracted, and a vesicant extravasation in an immunocompromised cancer patient is a major risk factor for bacterial colonization.

The resulting formation of scar tissue can contribute to long-term cosmetic and functional deficits.

Treatment delay, termination of further planned chemotherapy, and even death from wound complications may be the ultimate outcome.

Fig. 1: Skin changes 2 days after accidental extravasation of doxorubicin in the left cubital fossa of a patient with advanced breast cancer. The extravasation was left untreated initially.

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.

Treatment and Prevention In the event of suspicion of an extravasation, the infusion should be promptly stopped, and attempts should be made to aspirate through the cannula. Areas of redness or edema should be marked and photographed for documentation.

The effects of anthracycline extravasations can be counteracted by prompt initiation of intravenous infusion of the systemic antidote, dexrazoxane. Depending on the type of the extravasated compound, the volume, and the area of extravasation, treatment options include cooling (or heating in cases involving vinca alkaloids), topical dimethyl sulfoxide, and subcutaneous hyaluronidase.

In selected cases, surgical tissue flushing with saline is used. In the event of necrotizing extravasation, surgical excision with wide margins and perhaps also skin grafting may be necessary (Fig. 2). Long-term follow-up includes treatment of cosmetic changes and the effects of nerve and muscle damage.

Extravasation is largely preventable by ensuring adequate education of the treating staff, information for patients, and use of proper injection techniques and remedies. International extravasation guidelines are now available and should also be available at an institutional level. n Disclosure: Dr. Langer reported no potential conflicts of interest.

Fig. 2: Same patient 6 weeks after surgical treatment.

For More on Dermatologic Care for Patients With Cancer, visit ASCOPost.com ■■ Acneiform Rash Caused by EGFR Inhibitors ■■ Ipilimumab-Induced Dermatologic Adverse Events ■■ Hand-Foot Syndrome Due to Capecitabine or Doxorubicin

When mCRC tumors

after progression on an oxaliplatin-containing regimen, should you consider an alternative approach?

ZALTRAP® (ziv-aflibercept), in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

ZALTRAP inhibits angiogenesis by trapping VEGF-A, VEGF-B, and PLGF as shown in pre-clinical studies1-3,* * The clinical significance is unknown.

Important Safety Information for ZALTRAP® (ziv-aflibercept) WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage.

GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation.

Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed.

WARNINGS AND PRECAUTIONS Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

— Bleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP/ FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade 3-4 hemorrhagic events, including GI hemorrhage, hematuria, and post-procedural hemorrhage, occurred in 3% of ZALTRAP/ FOLFIRI patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial hemorrhage and pulmonary hemorrhage/ hemoptysis including fatal events have occurred in patients receiving ZALTRAP. — Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage.

GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. — Across three clinical trials (colorectal, pancreatic, and lung cancer), GI perforation (all grades/Grade 3-4) occurred in 0.8%/0.8% of ZALTRAP patients and 0.3%/0.2% for placebo patients.

— Monitor patients for signs and symptoms of GI perforation.

Discontinue ZALTRAP in patients who experience GI perforation.

ZALTRAP impairs wound healing in animal models. Grade 3 compromised wound healing occurred in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI and none of the patients treated with placebo/FOLFIRI. — Discontinue ZALTRAP in patients with compromised wound healing.

— Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed.

— For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed.

Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.

ZALTRAP.com/HCP

An

increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP. — There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who developed Grade 3-4 hypertension, 54% had onset during the first two cycles of treatment.

— Monitor blood pressure at least every two weeks, treat with appropriate anti-hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment.

Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles.

Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy.

Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3-4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE.

Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. — Proteinuria was reported in 62% of ZALTRAP/FOLFIRI patients compared to 41% of placebo/FOLFIRI patients. Grade 3-4 proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/ FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.

— Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24-hour urine collection in patients with a dipstick of ≥2+ for protein or UPCR >1.

— Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours.

— If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg.

— Discontinue ZALTRAP if nephrotic syndrome or TMA develops.

A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. — Grade 3-4 neutropenia occurred in 37% of ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI patients.

Grade 3-4 febrile neutropenia occurred in 4% of ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI patients. Grade 3-4 neutropenic infection/sepsis occurred in 1.5% of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI patients.

— Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.

Incidence

of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI. — Grade 3-4 diarrhea was reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of placebo/FOLFIRI patients.

Grade 3-4 dehydration was reported in 4% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients.

— The incidence of diarrhea is increased in patients ≥65 years of age compared to patients <65 years of age. Monitor closely.

RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy.

Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.

ADVERSE REACTIONS

The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

The most common Grade 3-4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.

Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/ FOLFIRI and 7% of patients treated with placebo/FOLFIRI. PREGNANCY AND NURSING MOTHERS

ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.

It

is not known whether ZALTRAP is excreted in human milk.

Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

References: 1. ZALTRAP Prescribing Information. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; October 2013. 2. Tew WP, Gordon M, Murren J, et al. Clin Cancer Res. 2010;16:358-366.

3. Riely GJ, Miller VA. Clin Cancer Res. 2007;13(15 suppl):4623s-4627s.

In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. US.AFL.14.02.002 2/14 Printed in the U.S.A. © 2014 sanofi-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

Rx Only

Brief Summary of Prescribing Information WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

1

INDICATIONS AND USAGE

ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information].

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks.

Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity.

2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)].

• For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)].

For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information.

2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles.

Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial.

Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags.

Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag.

2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.

Do not administer as an intravenous (IV) push or bolus.

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line.

Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and postprocedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)].

5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)].

5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information].

Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/ FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen.

Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)].

5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%).

Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)].

5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/ FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment.

Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)].

5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)].

5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC, proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/ FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.

Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection.

Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg.

Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)].

5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/ FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/ FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea.

5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy.

Confirm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)]

6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1).

The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modification in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/ FOLFIRI compared to placebo/FOLFIRI are shown in Table 1.

Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI (N=605) Primary System Organ Class Preferred Term (%)

ZALTRAP/FOLFIRI (N=611)

All grades

Grades 3–4

All grades

Grades 3–4

6%

0.8%

9%

0.8%

Infections and infestations Urinary Tract Infection Blood and lymphatic system disorders Leukopenia

72%

12%

78%

16%

Neutropenia

57%

30%

67%

37%

Thrombocytopenia

35%

2%

48%

3%

Decreased Appetite

24%

2%

32%

3%

Dehydration

3%

1%

9%

4%

9%

0.3%

22%

2%

11%

1.5%

41%

19%

0

28%

0.2%

Metabolism and nutrition disorders

Nervous system disorders Headache Vascular disorders Hypertension

Respiratory, thoracic and mediastinal disorders Epistaxis

7%

Dysphonia

3%

0

25%

0.5%

Dyspnea

9%

0.8%

12%

0.8%

Oropharyngeal Pain

3%

0

8%

0.2%

Rhinorrhea

2%

0

6%

0

Diarrhea

57%

8%

69%

19%

Stomatitis

33%

5%

50%

13%

Abdominal Pain

24%

2%

27%

4% 1%

Gastrointestinal disorders

Abdominal Pain Upper

8%

1%

11%

Hemorrhoids

2%

0

6%

0

Rectal Hemorrhage

2%

0.5%

5%

0.7%

Proctalgia

2%

0.3%

5%

0.3%

4%

0.5%

11%

3%

3%

0

8%

0

Proteinuria*

41%

1%

62%

8%

Serum creatinine increased

19%

0.5%

23%

0

Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysesthesia Syndrome Skin Hyperpigmentation Renal and urinary disorders

General disorders and administration site conditions Fatigue

39%

8%

48%

13%

Asthenia

13%

3%

18%

5%

AST increased

54%

2%

62%

3%

ALT increased

39%

2%

50%

3%

Weight decreased

14%

0.8%

32%

3%

Investigations

Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4),

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion

including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/ FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.

The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

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

7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose.

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

8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)].

The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age.

8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information].

There are no data available for patients with severe hepatic impairment.

8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept.

Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.

10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks.

Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2013 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-OCT13

Revised: October 2013

The ASCO Post | APRIL 15, 2014

PAGE 82

Expert’s Corner Breast Cancer

Determining Why Younger Women With Breast Cancer Are Less Likely to Survive Than Their Older Counterparts A Conversation With Theresa Keegan, PhD, MS

By Jo Cavallo

Theresa Keegan, PhD, MS

A

lthough cancer survival rates among pediatric and older adult patients continue to rise, survival rates for adolescents and young adults (AYAs), defined by the National Cancer Institute as those between the ages of 15 and 39, have remained stagnant for decades. In breast cancer especially, AYAs face a worse prognosis than older women and their 5-year survival rates are lower.

While the incidence of triple-negative tumors is known to be more common among younger women and African American women, this alone does not account for the survival disparities seen in comparison with older women.

A recent study by Theresa Keegan, PhD, MS, Research Scientist at Cancer Prevention Institute of California, Fremont, has found additional biologic subtypes of breast cancer in AYAs that are directly linked to their risk of dying from the disease.1 Dr. Keegan and her colleagues analyzed data from the California Cancer Registry of over 5,300 AYAs diagnosed with breast cancer between 2005 and 2009 and studied 3-year survival rates by biologic subtype: triple-negative; hormone receptor (HR)-positive and HER2-negative; HR-positive and HER2-positive; and HR-negative and HER2-positive. The researchers also evaluated data from 53,860 women between the ages of 40 and 64 diagnosed with breast cancer.

They found that adolescents and young adults diagnosed with the tri-

ple-negative subtype (found in 19% of participants) were 2.7 times more likely to die from their disease, and those diagnosed with the HR-negative/HER2-positive subtype had a 1.6 times greater risk of dying from the disease than women with the HR-positive/HER2-negative subtype (found in 41% of participants). These subtypes also occurred in higher proportions in young adult women than in older women. In addition, AYAs were more likely to be diagnosed with stage III and IV disease and high-grade tumors than were older women.

The ASCO Post talked with Dr. ­Keegan about her study results and the role of socioeconomic status in breast cancer survival.

Mortality Risk Factors What factors are involved in poorer survival rates of adolescents and young adults compared to older women with breast cancer?

A number of factors contribute to the increased risk of death in AYAs. For example, there is no routine screening for breast cancer in this age group and,

did a study in 2012 using a very similar data set to our current study.2 We looked at the incidence of breast cancer in younger women and how it differs in younger and older women, and we found that there were certain subtypes of breast cancer, such as triple-negative, that were more common in young women and have a poorer prognosis. We also found that young women were more likely to have later stage of disease at diagnosis and highgrade disease.

When you put all these factors together, we hypothesized that AYAs would have poorer survival, as prior studies have found.

African American Women Please talk about some of the factors that impact poorer outcomes in young adult African American women with breast cancer.

It is well established that African American women across all ages have poorer outcomes following a breast cancer diagnosis than white women.

We also found that this was the case in our study. African American women

A number of factors contribute to the increased risk of death in [adolescents and young adults]. For example, there is no routine screening for breast cancer in this age group and, as a result, young women tend to get diagnosed with a later stage of disease.

—Theresa Keegan, PhD, MS

as a result, young women tend to get diagnosed with a later stage of disease.

In our study, it really was a diagnosis of later-stage disease that explained the short-term survival differences. So our main prevention message is that if a young adult has any concerns about breast abnormalities, she should see her doctor immediately.

Another factor that impacts survival is that the distribution of breast cancer subtypes are different in younger women than in older women. We

tend to be diagnosed more often with triple-negative breast cancer, which has a poorer prognosis.

However, in our study, even after factoring in the higher rates of triple-negative breast cancer, African American women still had poorer overall survival. There are a lot of theories as to why African American women may do worse, including getting diagnosed at a later stage of disease, which we also considered. What we could not look at and what could still be influ-

encing their prognosis is what happens after their diagnosis. Are these patients adhering to treatment and getting the follow-up care they need? We haven’t been able to consider how these factors contribute to worse survival.

We also found that the patient’s socioeconomic status and type of health insurance influences outcome. Fortunately, most women, regardless of their insurance status, will get initial treatment for their cancer. But it is what happens after their first course of treatment and during surveillance that can make the difference.

For example, is their insurance covering most of the medical expenses or are there high copays for treatment?

Other costs associated with follow-up care that impact women with a lower socioeconomic status include the expenses incurred traveling to the doctor’s office or medical center or for childcare.

Our study and others suggest that we need a better understanding of the factors that are contributing to a worse cancer outcome in African American women. What we know is that African American women are diagnosed with breast cancer at a much lower rate than non-Hispanic white women, but their outcomes are much worse. It’s very important to focus on why.

We also need additional research to more fully understand how the distribution of breast cancer subtypes and other factors influence long-term survival in younger women compared to older women. n

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

References 1. Keegan TH, Press DJ, Tao L, et al: Impact of breast cancer subtypes on 3-year survival among adolescent and young adult women. Breast Cancer Res 15:R95, 2013.

2. Keegan TH, DeRouen MC, Press DJ, et al: Occurrence of breast cancer subtypes in adolescent and young adult women. Breast Cancer Res 14:R55, 2012.

ASCOPost.com | APRIL 15, 2014

PAGE 83

News Technology

Utah Center for Genetic Discovery to Integrate Genome Data Into Patient Care

T

he USTAR Center for Genetic Discovery is partnering with California-based Omicia, Inc, to make analyzing a patient’s genome as routine as performing a blood test. The center, codirected by Mark Yandell, PhD, and Gabor Marth, DSc, was launched this month with $6 million from the University of Utah and the state-funded Utah Science Technology and Research (USTAR) initiative.

Compared to 10 years ago, sequencing the human genome has plummeted in cost by 1 million-fold and can be completed in a fraction of the time. Yet there are still barriers preventing DNA sequence information from routinely being incorporated into patient care.

nome data to clinically relevant findings. Opal is powered by VAAST, a proven disease gene finder algorithm invented by Yandell. Launched less than 2 years ago, VAAST has success-

fully identified causes of inherited diseases, including hard-to-diagnose rare diseases, and is used at 251 institutions worldwide.

The USTAR Center for Genetic

Discovery eventually anticipates commercializing its full suite of software tools, and becoming a top genomic health data service provider for medical centers nationwide. n

Taming Big Data “Current systems are not prepared for the increasing amounts of data we will be seeing within the next few years,” said Dr. Marth, a computer scientist who was instrumental in the success of high-profile projects such as the Human Genome Project, HapMap Project, and 1,000 Genomes Project.

He relocated to the University of Utah from Boston College to apply his skills in a medical setting.

“At some point, all of humanity will be sequenced, and potentially more than one genome per individual,” he continued. Drs. Marth and Yandell will lead efforts to tame the big data to come not only from personal genomes, but also tumor genomes and “metagenomes” from infectious disease agents such as viruses and bacteria.

Knowing the DNA sequence of a cancer patient’s tumor, for example, may reveal a personalized treatment plan for combating the disease. Pinpointing tiny sequence variations in personal genomes will expose inherited diseases that, in some cases, may be life-threatening.

“What we want to be able to do is help the kid who is born with a hard-to-diagnose genetic disorder,” said Yandell. “Our genome interpretation tools will be able to identify that disorder and guide treatment.”

Informatics Platform Together with Omicia, Inc, the USTAR Center for Genetic Discovery is building a Web-accessible informatics platform, called Opal, to distill ge-

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.

© 2014 Amgen Inc. All rights reserved. 77144-R1-V2

The ASCO Post | APRIL 15, 2014

PAGE 84

Awards

ASBMT Honors Mary Horowitz, MD, MS, With Lifetime Achievement Award for Blood and Marrow Transplant Research

M

ary Horowitz, MD, MS, the Robert A. Uihlein, Jr. Chair in Hematologic Research, Professor of Medicine and Chief of Hematology and Oncology at the Medical College of Wisconsin (MCW), was presented with the 2014 Lifetime Achievement Award by the American Society for Blood and Marrow Transplantation (ASBMT) at the organization’s annual meeting. The award recognizes her involvement and support of the blood and marrow transplant community, and her past, present and current stewardship of both the Center for International Blood and Marrow Transplant Research (CIBMTR) and the Clinical Trials ­ Network. She was also commended for her commitment to mentoring the next generation of clinical scientists.

Dr. Horowitz, who is the Chief Scientific Director of CIBMTR, studies the effectiveness of transplantation as a treatment for life-threatening diseases such as leukemia, non-Hodgkin’s lymphoma and other cancers. The Medical

College of Wisconsin collaborates with the National Marrow Donor Program/ Be The Match on blood and marrow transplant research through CIBMTR. Through the leadership of Dr. Horowitz, CIBMTR’s outcomes-oriented and translational research programs have

been continuously funded by the National Institutes of Health for more than 20 years and have been driving forces in the field.

In addition to leadership positions at MCW, Dr. Horowitz serves as Research Director for the Stem Cell Therapeutic

Dr. C. Fred LeMaistre, Immediate-Past President of ASBMT, presented Dr. Horowitz with the ASBMT 2014 Lifetime Achievement Award at the Society’s annual meeting. Dr. LeMaistre is Physician-in-Chief, Hematology and Hematopoietic Cell Transplant, Sarah Cannon.

Outcomes Database of the C.W. Bill Young Cell Transplantation Program and Principal Investigator of the Data and Coordinating Center of the national Blood and Marrow Transplant Clinical Trials Network. Dr. Horowitz and colleagues received a $45 million grant from the National Heart, Lung and Blood Institute of the National Institutes of Health and the National Cancer Institute to fund the Clinical Trials Network, the largest federal grant ever awarded to MCW. She also serves as a member of numerous editorial boards and grant review panels.

A 1980 MCW alumna, Dr. Horowitz completed a fellowship in hematology/oncology and a residency in internal medicine, including a year as chief resident, in the Medical College of Wisconsin Affiliated Hospitals Program. She also completed a Master of Science degree in biostatistics and clinical epidemiology at MCW’s Graduate School of Biomedical Sciences. n

Awards Presented at Annual Meeting of Society of Interventional Radiology

T

he Journal of Vascular and Interventional Radiology, the Society of Interventional Radiology’s (SIR) peer-reviewed scientific journal, together with SIR Foundation, recently presented a number of awards at SIR’s 39th Annual Scientific Meeting in San Diego.

Clinical Research Eliseo Vano, PhD, an adviser to the Spanish Ministry of Health for Radiation Protection in Medical Exposures, received the journal’s Editor’s Award for Outstanding Clinical Research Paper for “Radiation-associated Lens Opacities in Catheterization Personnel: Results of a Survey and Direct Assessments.” Dr. Vano, who has for the last 20 years led a research team funded by Spanish organizations and the European Commission focused on radiation protection in medical imaging and interventional radiology, is Pro-

fessor of Medical Physics on the Faculty of Medicine of the Complutense University of Madrid and Head of the Medical Physics Service at Madrid’s San Carlos University Hospital. He is also a consultant to the International Atomic Energy Agency for topics concerning radiation safety in diagnostic and interventional radiology.

Eliseo Vano, PhD

Marwan Moussa, MD

Ziv J. Haskal, MD, FSIR

Laboratory Investigation Marwan Moussa, MD, of the University of Arkansas Medical School’s (UAMS) Department of Radiology, received the journal’s Editor’s Award for Outstanding Laboratory Investigation for “Adjuvant Liposomal Doxorubicin Markedly Affects Radiofrequency Ablation-induced Effects on Periablational Microvasculature.” Before joining UAMS, Dr. Moussa spent 3 years working at the minimally invasive tumor therapy laboratory at Harvard’s Beth Israel Hospital in Boston,

where he authored and coauthored several original articles and eight abstracts in the areas of combination radiofrequency ablation therapies and irreversible electroporation.

“The Journal of Vascular and Interventional Radiology prides itself on bringing high-level, evidence-based research to the fore,” said Ziv J. ­Haskal, MD, FSIR, Editor-in-Chief.

“Dr. Vano’s article is an important one for radiology professionals; it is an in-depth demonstration of radia-

tion eye injury risks to interventional personnel at occupational levels.

Dr. Moussa’s paper examines chemotherapy delivery and its effects on surrounding tissue during radiofrequency ablation. Enhancing the effect of both of these potent image-guided therapies may allow us to more completely treat liver tumors,” said Dr. Haskal, a Professor with the Department of Radiology and Medical Imaging at the University of Virginia Health System in Charlottesville. n

ASCOPost.com | APRIL 15, 2014

PAGE 85

Awards

Association of Community Cancer Centers Honors Researcher and Community Oncologist With National Award

I

n recognition of his dedication to cancer research and education, and for promoting the goals of cancer prevention, early detection, and quality cancer treatment, John Powderly II, MD, Certified Physician Investigator, President and Founder of Carolina BioOncology Institute, Huntersville,

North Carolina, was recently honored with the Association of Community Cancer Centers (ACCC’s) 2014 David King Community Clinical Scientist Award.

Dr. Powderly is an Adjunct Clinical Assistant Professor of Medicine at Duke University and the University of North Carolina, Chapel Hill.

Champion of Community Oncology “As a research clinician, Dr. Powderly exemplifies the spirit of Dr. King for whom this national award was named,” said ACCC President ­Virginia T. Vaitones, MSW, OSW-C. “Like Dr. King, Dr. Powderly has spent

John Powderly II, MD

his career championing the value of the community clinical oncology program and raising awareness of the role of clinical research in the community cancer setting.”

ACCC’s prestigious award is named after David K. King, MD, FACP, who died after a brief battle with cancer. Dr. King had a long history with ACCC, serving in many capacities, including President of the Association. Dr. King dedicated his professional career to caring for individuals with cancer and advocating for access to quality care, the Community Clinical Oncology Program, and the value of clinical research in the community environment. “I am honored to have received

this award,” said Dr. Powderly. “To be recognized for our hard work in fighting cancer and providing access to immunotherapy trials to patients in the Charlotte area is a wonderful validation of the clinic’s mission.”

David King Community Clinical Scientist Award winners become lifetime members of the ACCC National Academy of Community Oncology Scientists, which serves as a valuable resource to ACCC, the National Cancer Institute (NCI), pharmaceutical companies, and other organizations involved in community cancer research.

The award was presented during the ACCC 40th Annual National Meeting, held recently in Arlington, Virginia. n

Hagop Kantarjian, MD, and Victor Fazio, MD, Named Recipients of 2014 Lifetime Achievement Awards Presented by Castle Connolly Medical Ltd

H

agop Kantarjian, MD, Professor and Chair of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, and Victor Fazio, MD, Chairman Emeritus, Digestive Disease Institute; Department of Colorectal Surgery, Cleveland Clinic, Rochester, were honored recently with the “Lifetime Achievement Award” for their dedication to research and clinical practice. The honors were presented at the Ninth Annual

Hagop Kantarjian, MD

Castle Connolly Medical Ltd National Physician of the Year Awards in New York. The Awards program recognizes and honors exemplary physicians each year who are nationally recognized leaders and contributors in their specialties.

Awards for Clinical Excellence, Leadership

Also honored at the event were three recipients of the “Clinical Excellence Award,” which recognizes physicians who exemplify excellence in clinical medical practice. Recipients included Susan B. Bressman, MD, Alan and Joan Mirken Chair, Departments of Neurology, Mount Sinai Beth Israel, Mount Sinai St. Luke’s and Mount Sinai Roosevelt; ProVictor Fazio, MD

fessor of Neurology, Icahn School of Medicine at Mount Sinai, in New York; Catherine R. deVries, MD, MS, Professor of Surgery, University of Utah, Director of the University of Utah Center for Global Surgery, University of Utah Health Care and Primary Children’s Hospital in Salt Lake City; and Michael Saag, MD, Professor of Medicine and Director of the University of Alabama Center for AIDS Research (CFAR), University of Alabama at ­Birmingham.

For outstanding dedication and work with an organization that has served to heighten the awareness for the need for support and research on that specific cause. Dr. Mehmet Oz, Host of The Dr. Oz Show, author and cofounder of HealthCorps, and Lisa Oz, Host of The Lisa Oz Show, au-

thor and cofounder of HealthCorps, received the “2014 National Health Leadership Award.”

Clinical Excellence in American Medicine The National Physician of the Year Awards program was created by Castle Connolly to acknowledge clinical excellence in American medicine. Nominations are solicited from thousands of physicians across the country and the leadership of more than 1,000 hospitals to identify extraordinary physicians who have made significant and cutting-edge contributions to their areas of medicine.

Castle Connolly Medical Ltd produces America’s Top Doctors, a guide to help consumers in finding quality health care. n

Download

The ASCO Post iPad App FREE from iTunes today!

What if you could use the body’s own T cells to combat Lung Cancer?

With Immuno-Oncology it may be possible.

Current approaches to lung cancer treatment include radiation, surgery and chemotherapy/targeted therapy, all of which are intended to target the tumor. Through our ongoing clinical program, BMS is investigating an entirely new way to treat lung cancer by targeting the immune system. Our research is focused on transforming the way tumor cells and the immune system communicate, including checkpoint pathways; we hope to find new ways to stop lung cancer from evading the immune system, thereby restoring the body’s natural ability to fight it.

If you’re interested in learning more about BMS investigational studies in lung cancer, including a list of study sites, please visit BMS Study Connect to search for lung cancer studies near you. http://www.bms.com/studyconnect/Pages/Home.aspx

©2013 Bristol-Myers Squibb Company.

ONCUS13UB00863-02-01

06/13

Visit us at BMSimmunooncology.com

Leading the way

ASCOPost.com | APRIL 15, 2014

PAGE 87

Journal Spotlight Breast Cancer

Study Shows Pathologic Complete Response to Neoadjuvant Therapy for Breast Cancer of Prognostic Value but Not for Use as Surrogate for Survival

By Matthew Stenger

P

athologic complete response to neoadjuvant therapy has been proposed as a surrogate endpoint for long-term clinical benefit in breast cancer. The U.S. Food and Drug Administration (FDA) established the international Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) working group to perform a pooled analysis of neoadjuvant trials in breast cancer to assess correlation of different definitions of pathologic complete response with event-free survival and overall survival and to assess whether pathologic complete response could be used as a surrogate endpoint for these

trials that met eligibility criteria of having ≥ 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery, having available data for pathologic complete response, eventfree survival, and overall survival, and having median follow-up ≥ 3 years.

A trial-level analysis was performed to evaluate the potential for using pathologic complete response as a surrogate endpoint for event-free survival or overall survival. The associations between treatment effects on pathologic complete response and event-free survival and overall survival were quantified using a weighted linear

Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumor subtypes.

—Patricia Cortazar, MD, and colleagues

outcomes.

Patricia Cortazar, MD, Medical Team Leader and Scientific Liaison, Breast Oncology Group, in the Division of Oncology Products 1, Office of Hematology and Oncology Products, FDA, Silver Spring, Maryland, and colleagues reported on pathologic complete response and long-term clinical benefit in The Lancet.1 The three most commonly used definitions of pathologic complete response—ypT0 ypN0 (absence of invasive cancer and in-situ cancer in the breast and axillary nodes), ypT0/is ypN0 (absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ), and ypT0/is (absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement)—were assessed for association with event-free and overall survival. Response defined as ypT0 ypN0 or ypT0/is ypN0 was associated with improved longterm outcome, with prognostic value being greatest in aggressive tumor subtypes.

However, a trial-level analysis did not support use of pathologic complete response as a surrogate endpoint for improved event-free survival and overall survival.

Study Details The pooled analysis included 11,955 patients from 12 international neoadjuvant

regression model on a logarithmic scale.

Treatment effects on event-free and overall survival were represented as hazard ratios (HRs, calculated with Cox proportional hazards models) and on pathologic complete response as odds ratios (calculated with logistic regression models) within each randomized comparison from among the eligible trials. A two-stage model (adjusting for the estimation error of treatment effect size estimates) was used to calculate the coefficient of determination (R²) to measure the correlation between pathologic complete response and eventfree and overall survival by treatment effect.

Definitions and Survival The frequency of pathologic complete response was 22% for ypT0/is, 18% for ypT0/is ypN0, and 13% for ypT0 ypN0.

Overall, patients who achieved a pathologic complete response on any definition had longer event-free survival and overall survival than did those with residual invasive cancer.

Hazard ratios for event-free survival for ypT0 ypN0 (0.44, 95% confidence interval [CI] = 0.39–0.51) and for ypT0/ is ypN0 (0.48, 95% CI 0.43–0.54) were better than that for ypT0/is (HR = 0.60, 95% CI = 0.55–0.66). Similarly, ypT0 ypN0 (HR = 0.36, 95% CI = 0.30–0.44) and ypT0/is ypN0 (HR = 0.36, 95% CI

= 0.31–0.42) were more closely associated with overall survival than was ypT0/ is (HR = 0.51, 95% CI = 0.45–0.58). The ypT0/is ypN0 definition was thus used in all other analyses.

Response and Outcome The rate of pathologic complete response using this definition was low in patients with low-grade hormone receptor–positive tumors and more than doubled for high-grade hormone receptor–positive tumors. Rates of response were increased in HER2-positive and triple-negative tumors, and highest in patients with hormone receptor–negative tumors and those treated with trastuzu­ mab (Herceptin) among the HER2-positive subgroup.

The hazard ratios for pathologic complete response were 0.49 (95% CI = 0.33– 0.71) for event-free survival and 0.43 (95% CI = 0.23–0.71) for overall survival in the overall hormone receptor–positive, HER2-negative subgroup. The association between response and long-term outcome was stronger in patients with hormone receptor–positive, HER2-negative highgrade (HR = 0.27, 95% CI = 0.14–0.50, for event-free survival; HR = 0.29, 95% CI = 0.13–0.65, for overall survival) vs lowgrade tumors (HR = 0.63, 95% CI = 0.38– 1.04, for event-free survival; HR = 0.47, 95% CI = 0.21–1.07, for overall survival).

Among patients with HER2-positive tumors, pathologic complete response was associated with event-free survival (HR = 0.39, 95% CI = 0.31–0.50) and overall survival (HR = 0.34, 95% CI =

trastuzumab for overall survival).

The association between pathologic complete response and long-term outcomes was strongest in patients with triple-negative breast cancer and patients with HER2-positive, hormone receptor– negative tumors.

Surrogate for Survival?

The trial-level analysis performed to assess whether pathologic complete response could be used as a surrogate endpoint for event-free survival or overall survival included 10 randomized comparisons from among the 12 trials in the pooled analysis and excluded nonrandomized neoadjuvant groups and patients who received additional adjuvant taxane therapy.

At the trial level, there was little association between increases in frequency of pathologic complete response and the effect of treatment on event-free or overall survival.

The coefficient of determination (R²) between improvement in pathologic complete response and event-free survival was 0.03 (95% CI = 0.00–0.25) and that between pathologic complete response and overall survival was 0.24 (95% CI = 0.00– 0.70). Analyses of trial-level association between response and outcome by tumor subtype also showed no correlation between increased frequency of pathologic complete response and treatment effect on event-free or overall survival.

The investigators concluded, “Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumor

Pathologic Complete Response in Breast Cancer Trials ■■ Pathologic complete response definitions representing eradication of tumor from both breast and lymph nodes (ypT0 ypN0 and ypT0/is ypN0) were more strongly associated with event-free and overall survival, with the prognostic value being greatest in aggressive tumor subtypes.

0.24–0.47) regardless of hormone receptor status, with the association having greater strength in the HER2-positive, hormone receptor–negative subgroup (HR = 0.25, 95% CI = 0.18–0.34, for event-free survival; HR = 0.19, 95% CI = 0.12–0.31, for overall survival) and being weaker in the hormone receptor–positive subgroup (HR = 0.58, 95% CI = 0.42– 0.82, for event-free survival; HR = 0.56, 95% CI = 0.23–1.37, with trastuzumab, and 0.57, 95% CI = 0.31–1.04, without

subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved [event-free and overall survival].” n

Disclosure: The study was funded by the FDA. For full disclosures of the study authors, visit www. thelancet.com.

Reference 1. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and longterm clinical benefit in breast cancer. Lancet.

February 14, 2014 (early release online).

The ASCO Post | APRIL 15, 2014

PAGE 88

Perspective

‘How Am I Doing, Doc?’

By Victor G. Vogel, MD, MHS

T

he goal of effective adjuvant therapy is to increase overall survival. It has been suggested cynically that all we need to accomplish, actually, is to delay recurrence until after the time the patients die from another cause. However, patients want to hear from us that “it’s never coming back,” and that is what we treating oncologists hope for, as well.

There are currently no validated measures of the effectiveness of chemotherapy other than to wait for clinical evidence of recurrence. Recurrence in a visceral site almost always means that the disease cannot be cured.

Response to Neoadjuvant Therapy Neoadjuvant therapy has a number of clinical advantages and utilities.

Chemotherapy before surgery permits the initiation of systemic therapy earlier in the disease, although there is no certain evidence that earlier therapy is more effective than traditional adjuvant therapy.

For some patients, it appears that a pathologic complete response portends a longer disease-free survival compared with patients who have residual disease. Early treatment often results in a reduction in the extent of surgery required for primary therapy, although this appears not to predict overall survival accurately.

Finally, neoadjuvant chemotherapy functions as a chemosensitivity assay demonstrating local effectiveness of chemotherapy on the primary tumor. Response, however, appears not to relate directly to the duration of survival or to a reduction in the chance of recurrence.

Limitations of Pathologic Response In a clinical trials setting, the question we wish to answer is one of competitive efficiency and effectiveness: Is treatment A more effective than treatment B? Adjuvant trials unfortunately take a long time to complete, and they are very expensive. In addition, validation of a biomarker is a Dr. Vogel is Director, Breast Medical Oncology/Research, Geisinger Health System, Danville, Pennsylavnia.

circular process in which we first need to observe that a putative marker declines with effective therapy and is associated subsequently with increased survival as the ultimate endpoint.

Disappointingly—as reported by Cortazar and colleagues in The Lancet and reviewed in this issue of The ASCO Post—pathologic complete response in the pooled Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) analysis at the level of clinical trials showed little associa-

Other Potential Biomarkers The ideal biomarker of treatment responsiveness would show that all micrometastases have either disappeared or are quiescent and will not recur. Assessing the response of dormant micrometastases is our great and most pressing clinical trials need, but we don’t yet know how to do that. A marker with such utility remains to be identified.

Several other markers have been proposed as potential surrogates for

The reality is that we can no longer afford the luxury of using either pathologic response or overall survival as the outcome standard for our clinical trials. We need to decrease the cost of conducting adjuvant treatment trials for patients with malignancy, and we need to reduce the time required to identify new and effective agents.

—Victor G. Vogel, MD, MHS

tion with effective treatment in either event-free or overall survival.1 Pathologic complete response is thus a proximate marker of tumor response, but it appears to be neither the most informative nor a valid marker of overall survival.

Pathologic complete response tells us only that the tumor in the organ of origin or in regional lymph nodes has responded to treatment. It does not tell us about the status of micrometastases or their response to therapy.

We want to conclude that if there is a pathologic complete response, there must be an overall complete response and an accompanying increase in overall survival, but this may not be so. Assessing pathologic response at the organ level appears to be too crude to indicate survival duration reliably.

Thus, pathologic complete response is a 19th and 20th century concept. We need a 21st century concept of response accompanied by an insightful genomic or biological marker.

response duration. Circulating tumor cells do not appear to accomplish the task, however, and validation studies have failed to prove their ultimate clinical utility in the adjuvant setting.2,3 Circulating tumor DNA holds promise as a predictor of event-free or overall survival, but no validation studies have been conducted.4 Circulating tumor DNA is detectable in more than 75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers.

In patients with localized tumors, circulating tumor DNA can be detected in up to 70% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma.5 Because circulating tumor DNA is often present in patients without detectable circulating tumor cells, these two biomarkers appear to be distinct entities. How validation studies of these promis-

ing markers should be designed and conducted remains an elusive clinical challenge.

Ultimate Challenge Our challenge is not simply in using a surrogate marker of response. The reality is that we can no longer afford the luxury of using either pathologic response or overall survival as the outcome standard for our clinical trials.

We need to decrease the cost of conducting adjuvant treatment trials for patients with malignancy, and we need to reduce the time required to identify new and effective agents. We also need to exercise great caution to avoid the type II error in rejecting new and effective therapies. Designing such trials will require both ingenuity and creativity.

With our increasing knowledge of the human genome and continuing identification of mutational markers associated with treatment response, we can begin to identify improved intermediate indicators that will make biomarker response a realistic standard in the near future. We will need to incorporate that knowledge into innovative and creative designs of new clinical trials that evaluate our cancer therapies to achieve these laudable and necessary goals. n

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

References 1. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and longterm clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. February 13, 2014 (early release online).

2. Cristofanilli M, Budd T, Ellis, MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

3. Bidard F-C, Peeters DJ, Fehm T, et al: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol. March 11, 2014 (early release online).

4. Krebs MG, Metcalf RL, Carter L, et al: Molecular analysis of circulating tumour cells—biology and biomarkers. Nat Rev Clin Oncol 11:129-144, 2014.

5. Bettegowda C, Sausen M, Leary RJ, et al: Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. February 19, 2014 (early release online).

ASCOPost.com | APRIL 15, 2014

PAGE 89

Issues in Oncology

Decision Time for Lung Cancer Screening in High-Risk Populations

By Ronald Piana

F

or decades, dedicated members of the oncology community have fought to increase the nation’s focus on lung cancer prevention and treatment. Although smoking cessation initiatives have reduced cigarette consumption, lung cancer 5-year survival has remained stagnant at 15%, lagging far below most cancers. A group of experts has long argued that lung cancer screening would markedly increase survival, while others counter that screening is too costly and ineffective.

Speaking with The ASCO Post, Laurie Fenton Ambrose, President and CEO of the Lung Cancer Alliance (LCA), said, “We have conclusive evidence from one of the largest, most expensive randomized controlled trials carried out by the National Cancer Institute (NCI) proving that CT screening can significantly reduce

the benefits of screening outweighed the risks until 2010, when the results of the National Lung Screening Trial (NLST) were made public. The NLST randomly

Peter Bach, MD

assigned more than 53,000 current and former heavy smokers aged 55 to 74 to low-dose helical CT or standard x-ray.

When the trial reached its endpoint of a 20% mortality benefit in the low-dose CT

praised the USPSTF’s B recommendation.

“Screening people at high-risk for lung cancer is a public health imperative. And access—not barriers—to this type of lifesaving preventive service is what Medicare is all about,” stressed Ms. Fenton Ambrose.

However, a small group of doubters of low-dose CT screening still question its cost-effectiveness and clinical benefits.

Earlier this year, the American Academy of Family Physicians (AAFP) released an “I” statement (see below), concluding that the evidence is insufficient to recommend for or against low-dose CT lung cancer screening.3 Doug Campos-Outcalt, MD, the AAFP liaison to the USPSTF, told The ASCO Post, “The AAFP concerns include basing such a significant recommendation on only one study; extending the recommendations beyond the study’s age range (80 instead of 75 years old) and number

The bottom line is that wellconstructed lung cancer screening is as cost-effective as screening for colon, breast, and cervical cancers.

—Laurie Fenton Ambrose

Doug Campos-Outcalt, MD

lung cancer’s mortality. We have recent cost-benefit analyses looking at various populations from the commercial payer side to Medicare concluding that screening those at high risk for lung cancer is as cost-effective as screening for colon, breast, and cervical cancers. And we have responsible screening now being implemented in hospital centers all across the country. Simply put, screening is happening in the real world, by real people, for real people at risk.”

Securing Medicare coverage is essential to initiating lung cancer screening programs. On April 30, 2014, the Centers for Medicare & Medicaid Services (CMS) will be convening a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting to review all the available data, prior to making its final coverage decision. Lung cancer advocates argue that a favorable CMS decision would initiate a paradigm change in the treatment of our nation’s deadliest cancer.

Public Health Imperative The road to this pivotal CMS decision has been long and, at times, frustrating for lung cancer specialists and advocates. For one thing, no convincing data showed

arm, this effectively changed the dialogue in the screening debate.1 In light of the NLST and an updated draft recommendation from the U.S. Preventive Services Task Force (­USPSTF), in September 2013, health policy expert Peter Bach, MD, wrote a formal requestor letter to CMS, stating, in part: In line with the findings and recommendations of the medical literature related to this screening test I am requesting that CMS determine that screening for lung cancer with [low-dose CT], when conducted in centers with appropriate expertise and staffing, is reasonable and necessary for those beneficiaries who are between 55 and 74 years of age, are current smokers (or have quit smoking within the last 15 years), and have a smoking history of at least 30 pack years.2

In December 2013, the USPSTF formally issued a B recommendation on lung cancer screening.3 CMS can consider coverage of screening services if the USPSTF gives the service an A (recommends with high certainty of substantial benefit) or B (recommends with high certainty of moderate benefit, or moderate certainty of moderate to substantial benefit) recommendation. The advocacy community

of screens (3 in the study; potentially up to 25 with the task force recommendations); and the likelihood that benefits will be fewer and harms greater when screening is implemented universally.”

During an interview, Benjamin Levy, MD, Director of Thoracic Medical Oncology at Beth Israel Hospital in New York, said, “Naturally, we need to be cognizant of the pitfalls of screening and be aware of some of the shortcomings including the high false-positivity rate that was seen in the NLST. But we have to put this study in the context of the staggering statistics— up to 65% of lung cancer patients present with advanced-stage disease where the goal of treatment is only palliative and extension of life with treatment is months, not years. Thus, any effort or modality that

What Does An I Statement Mean?

I Statement: Current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

is proven to identify earlier-stage disease, where curative-intent therapy can be offered, is a game changer in my mind.”

In March 2014, a multisociety, multidisciplinary stakeholders group sent a joint consensus document to CMS, urging the agency to act on the USPSTF Decem-

Benjamin Levy, MD

ber recommendation.4 The signatories included the LCA, American College of Radiology, Society of Thoracic Surgeons, and 38 other professional groups. The 28page letter noted: Screening for current and former smokers with [low-dose CT] is the only method ever proven to reduce lung cancer mortality in this high risk population and it has also been shown to be cost effective. The Joint Societies ask that [CMS] move expeditiously in implementing broad national coverage so that individuals at high risk across the country can have access to this lifesaving benefit.

Preparing for MEDCAC Ms. Fenton Ambrose said she was cautiously optimistic about the process ahead. “Typically, once the USPSTF gives an A or B recommendation, the process flows from that point. However, CMS conducts an independent review to analyze the USPSTF recommendation as it applies to their stakeholders. That’s why we’ve been working so hard preparing for our meeting with MEDCAC on April 30.

We are anxious to show how multidisciplinary teams have been hard at work translating scientific validation into public health benefit safely, responsibly, equitably, and cost-effectively.”

Working with numerous stakeholders, the LCA developed a National Framework of Excellence for Lung Cancer Screening and Continuum of Care, best practice guidance for consumers and medical professionals interested in the screening process.

Over 170 hospitals and treatment centers have adopted the National Framework, and almost 100 more are in the pipeline.

Asked about these complex logistics of implementing widespread screening, Ms. Fenton Ambrose also added, “It’s being continued on page 90

The ASCO Post | APRIL 15, 2014

PAGE 90

Issues in Oncology Lung Cancer Screening continued from page 89

done thoughtfully and carefully. And in addition to highlighting what constitutes best-practice care, we will be demonstrating to CMS that the lung cancer screening process is generalizable across a variety of care settings including rural, urban, academic, and community-based practices.

Equally important will be conveying how smoking cessation has been embedded within screening centers of excellence and their strong interest in the collection of data to drive a quality improvement process.”

Ms. Fenton Ambrose stressed that LCA works very closely with the National Comprehensive Cancer Network (NCCN), which was the first professional society to recommend low-dose CT screening for high-risk individuals and to develop comprehensive clinical practice guidelines on lung cancer screening.

“The NCCN clinical guidelines are the gold standard in oncology, and because of NCCN’s agile working structure, they are able to move swiftly to incorporate new research breakthroughs into their working guidelines,” she said.

Patient outreach is another important piece of the screening process. “We need to fully educate the public about who is a candidate for lung cancer screening and let them know that well-organized CT screening has been shown to significantly reduce the possibility of dying of lung cancer,” said Ms. Fenton Ambrose.

Dr. Levy, who was part of a team of lung cancer specialists who collaborated with ASCO on e-learning courses for the oncology community, commented about the need to educate physicians as well.

“Given the increasing role that [lowdose CT] will play for our patients, it is paramount to have Web-based educational programs to address this subject,” he said. The goal, I hope, will be to deliver a balanced discussion that includes both the benefits and risks with screening. These programs will need to reach not only oncologists but also target other disciplines, including pulmonologists and primary care physicians, as they are more likely to evaluate high-risk patients. In addition to addressing the role of CT screening, these e-learning courses will need to highlight the management and treatment decision for early-stage lung cancer. This will give viewers the idea that the algorithm doesn’t just stop once the diagnosis of lung cancer is made.”

Screening Saves Lives Ms. Fenton Ambrose said she was buoyed by the results of a new study showing that the incidence of colon cancer, declining since the mid-1980s, plunged a further 30% last decade

among Americans 50 and older as more people had colonoscopies.5 “We’re confident that lung cancer screening will produce the same reduction in incidence that colonoscopy has produced in colon cancer. Early detection works,” said Ms. Fenton Ambrose.

Dr. Levy echoed Ms. Fenton Ambrose’s

optimism about screening’s effect on lung cancer incidence and survival. “I think we have to keep in mind that the NLST was the first study ever to show a significant reduction in lung cancer mortality with the use of low-dose CT for high-risk patients including those aged S:6.875” 55 to 80 with at least a 30 pack-year history of smoking. In ad-

dition, given that the study was stopped after only three annual CT scans, there are some who would argue that the 20% reduction in mortality might be an underestimate of the true benefit of this modality,” said Dr. Levy.

Ms. Fenton Ambrose noted an important downstream benefit of lung can-

KADCYLA®: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

KADCYLA contains the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker

Indication

Additional Important Safety Information

KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated Left Ventricular Dysfunction (LVD) for the treatment of patients with HER2-positive (HER2+), metastatic • Patients treated with KADCYLA are at increased risk of developing breast cancer (MBC) who previously received trastuzumab and a taxane, LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLAseparately or in combination. Patients should have either: received prior treated group and in 3.3% in the comparator group. Permanently therapy for metastatic disease, or developed disease recurrence during discontinue KADCYLA if LVEF has not improved or has declined further or within six months of completing adjuvant therapy.

Pregnancy Registry • Advise patients to contact their healthcare provider immediately if Important Safety Information they suspect they may be pregnant. Encourage women who may Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, be exposed to KADCYLA during pregnancy to enroll in the MotHER EMBRYO-FETAL TOXICITY Pregnancy Registry by contacting 1-800-690-6720 • Do Not Substitute KADCYLA for or with Trastuzumab Pulmonary Toxicity • Hepatotoxicity: Serious hepatotoxicity has been reported, • Cases of interstitial lung disease (ILD), including pneumonitis, some including liver failure and death in patients treated with leading to acute respiratory distress syndrome or fatal outcome have KADCYLA. Monitor serum transaminases and bilirubin prior to been reported in clinical trials with KADCYLA. In EMILIA, the overall initiation of KADCYLA treatment and prior to each KADCYLA frequency of pneumonitis was 1.2% dose. Reduce dose or discontinue KADCYLA as appropriate in • Treatment with KADCYLA should be permanently discontinued in cases of increased serum transaminases or total bilirubin patients diagnosed with ILD or pneumonitis • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate Infusion-Related Reactions, Hypersensitivity Reactions left ventricular function in all patients prior to and during • Treatment with KADCYLA has not been studied in patients who treatment with KADCYLA. Withhold treatment for clinically had trastuzumab permanently discontinued due to infusion-related significant decrease in left ventricular function reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in overall frequency of IRRs in patients treated with KADCYLA was 1.4% embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception • KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRR reactions, especially during the first infusion © 2013 Genentech USA, Inc. All rights reserved. TDM0001672501 Printed in USA. (07/13)

B:17

T:15

PAGE 91

Issues in Oncology

cer screening: “On the other side of the continuum, lung cancer screening will give us access to biomedical samples that we’ve needed for so long. We may even be poised to see this accelerate research, giving us a better understanding of the disease at an earlier stage. This is a huge moment, certainly for the lung cancer community and for the larger cancer com-

munity. There is no downside to properly conducted lung cancer screening.” n

Disclosure: Ms. Fenton Ambrose and Drs. Levy, Bach, and Campos-Outcalt reported no potential conflicts of interest.

References 1. The National S:6.875” Lung Screening Trial Research Team: Reduced lung-cancer mortality with low-dose ccomputed tomo-

Superior efficacy with a single agent

graphic screening. N Engl J Med 365:395409, 2011.

2. Bach PB: Formal request for a national coverage determination on lung cancer screening with low dose computed tomography. September 9, 2013 [letter]. Available at www.cms.gov.

3. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommenda-

100

30.9 months

90 80

tion Statement. Ann Intern Med. December 31, 2013 (early release online).

4. National coverage analysis for lung cancer screening with low dose computed tomography (CAG-00439N). March 12, 2014 [letter]. Available at www.acr.org.

5. Siegel R, DeSantis C, Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin 64:104-117, 2014.

1

NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS)

Proportion surviving (%)

7.5”

5.5”

ASCOPost.com | APRIL 15, 2014

1

HR=0.682 95% CI: 0.548, 0.849 P=0.0006

70 60 50

KADCYLA (n=495) No. of events: 149

25.1 months

40 30 20

lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months 485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,2

Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS. For more information on KADCYLA, visit KADCYLA.com.

References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791.

B:11.5”

Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively) • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2 HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

T:10.5”

• The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

S:9.875”

• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1

The ASCO Post | APRIL 15, 2014

PAGE 92

Announcements

William Pao, MD, PhD, Joins Roche to Lead Oncology Research

R

oche recently announced that William Pao, MD, PhD, Professor of Medicine and Head of the Hematology-Oncology Division at Vanderbilt University Medical Center, Nashville, will join Roche Pharma Research and Early Development (pRED) as Global Head of

the Oncology Disease and Translational Area (DTA), effective May 1, 2014. He will be responsible for leading Roche’s discovery, translational medicine, and early development of innovative oncology medicines. He will be based in Basel, Switzerland and report to John Reed,

MD, PhD, Global Head of Roche pRED. “William is recognized as one of the world’s leading moS:6.875” lecular oncologists, with world class expertise in targeted cancer therapeutics, translational med-

KADCYLA® (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information.

Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

William Pao, MD, PhD

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action.

If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of KADCYLA. 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 KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, 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 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects.

Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA®, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)].

• Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.

Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment.

In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued.

5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)].

Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

icine, molecular diagnostics, and personalized healthcare strategies using cancer genomics,” said Dr. Reed. “His broad expertise provides Roche with a leader who will ensure our growth and who will position

and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group.

KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)].

5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)].

In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit.

Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity.

• Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients.

Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use.

(Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group.

Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

B:17

T:15

7.5”

5.5”

ASCOPost.com | APRIL 15, 2014

PAGE 93

Announcements

us for continued success as we strive to transform science into medicine.”

In addition to his professorial duties at Vanderbilt, Dr. Pao directed the Division of Hematology and Oncology as well as the Personalized Cancer Medicine unit.

He also played leadership roles across a number of other departments, including Cancer Biology and Pathology/Microbi-

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

2.0

9.0

4.3

Blood and Lymphatic System Disorders

ology/Immunology. Dr. Pao and his research team have contributed to over 160 publications about cancer biology, cancer genomics, and cancer treatment.

Career Highlights S:6.875”

Dr. Pao obtained his undergraduate degree from Harvard and his MD and PhD in biology degrees from Yale. He did his

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

All Grade %

Grade 3 %

Increased bilirubin

17

<1

0

57

2

0

Increased AST

98

7

<1

65

3

0

Grade 4 %

Grade 3 %

Grade 4 %

Neutropenia

6.7

Anemia

14.3

4.1

10.5

2.5

Increased ALT

82

5

<1

54

3

0

Thrombocytopenia

31.2

14.5

3.3

0.4

Decreased platelet count

83

14

3

21

<1

<1

Decreased hemoglobin

60

4

1

64

3

<1

Decreased neutrophils

39

3

<1

38

6

2

Decreased potassium

33

3

0

31

6

<1

Cardiac Disorders Left ventricular dysfunction

1.8

0.2

3.3

0.4

3.3

0

2.5

0

Eye Disorders Lacrimation increased Dry eye

3.9

0

3.1

0

Vision blurred

4.5

0

0.8

0

Conjunctivitis

3.9

0

2.3

0 0.4

Gastrointestinal Disorders Dyspepsia

9.2

0

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

0

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5 20.7

Diarrhea

24.1

1.6

79.7

Constipation

26.5

0.4

11.1

0

Nausea

39.8

0.8

45.1

2.5

General Disorders and Administration 8.2

0.2

0

3.1

0

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

ND

0

0

Portal hypertension*

0.4

0.2

0

0

0

0.8

0

0

0.2

0

9.4

0.6

3.9

0

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

0

Arthralgia

19.2

0.6

8.4

0

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

0

0

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

0

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

0

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

0

Rash

11.6

0

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient.

ND = Not determined

8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.

8.5 Geriatric Use Of 495 patients who were randomized to KADCYLA in the randomized 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients response to KADCYLA. ≥ 65 years old (n=138 across both treatment arms) the hazard ratios A total of 836 patients from six clinical studies were tested at for progression-free survival (PFS) and Overall Survival (OS) were multiple time points for anti-therapeutic antibody (ATA) responses 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post- Population pharmacokinetic analysis indicates that age does not dose time points. The presence of KADCYLA in patient serum at have a clinically meaningful effect on the pharmacokinetics of the time of ATA sampling may interfere with the ability of this assay ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)].

8.6 Females of Reproductive Potential KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective Immunogenicity data are highly dependent on the sensitivity and contraception while receiving KADCYLA and for 6 months following specificity of the test methods used. Additionally, the observed the last dose of KADCYLA. incidence of a positive result in a test method may be influenced If KADCYLA is administered during pregnancy or if the patient by several factors, including sample handling, timing of sample becomes pregnant while receiving KADCYLA, immediately report collection, drug interference, concomitant medication and the exposure to the Genentech Adverse Event Line at 1-888-835-2555. underlying disease. Therefore, comparison of the incidence of Encourage women who may be exposed during pregnancy to enroll antibodies to KADCYLA with the incidence of antibodies to other in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see products may be misleading. Clinical significance of anti-KADCYLA Patient Counseling Information (17)]. antibodies is not yet known.

8.7 Renal Impairment No dedicated renal impairment trial for KADCYLA has been 7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have conducted. Based on the population pharmacokinetics, as well been conducted. In vitro studies indicate that DM1, the cytotoxic as analysis of Grade 3 or greater adverse drug reactions and dose component of KADCYLA, is metabolized mainly by CYP3A4 and modifications, dose adjustments of KADCYLA are not needed in to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, adjustment can be recommended for patients with severe renal telithromycin, and voriconazole) with KADCYLA should be avoided impairment (CLcr less than 30 mL/min) because of the limited data due to the potential for an increase in DM1 exposure and toxicity. available [see Clinical Pharmacology (12.3)].

Consider an alternate medication with no or minimal potential to 8.8 Hepatic Impairment inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is In vitro studies in human liver microsomes indicates that DM1 is unavoidable, consider delaying KADCYLA treatment until the strong metabolized by CYP3A4/5. The influence of hepatic impairment on CYP3A4 inhibitors have cleared from the circulation (approximately the pharmacokinetics of ado-trastuzumab emtansine conjugate has 3 elimination half-lives of the inhibitors) when possible. If a strong not been determined.

CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical reactions. trials, overdose of KADCYLA has been reported at approximately 8 USE IN SPECIFIC POPULATIONS two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal 8.1 Pregnancy case, the patient incorrectly received KADCYLA at 6 mg/kg and died Pregnancy Category D [see Warnings and Precautions (5.3)] approximately 3 weeks following the overdose; a cause of death and Risk Summary a causal relationship to KADCYLA were not established.

KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of 17 PATIENT COUNSELING INFORMATION KADCYLA in pregnant women. No reproductive and developmental • Inform patients of the possibility of severe liver injury and advise toxicology studies have been conducted with ado-trastuzumab patients to immediately seek medical attention if they experience emtansine. Nevertheless, two components of KADCYLA symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (trastuzumab and DM1) are known or suspected to cause fetal harm (especially RUQ abdominal pain), jaundice, dark urine, generalized or death when administered to a pregnant woman. If KADCYLA is pruritus, anorexia, etc. [see Warnings and Precautions (5.1)].

S

haw T. Chen, MD, PhD, has been appointed Executive Vice-President of Regulatory Affairs at Polaris Pharmaceuticals, a subsidiary of Polaris Group.

to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

administered during pregnancy, or if a patient becomes pregnant • Advise patients to contact a health care professional immediately while receiving KADCYLA, apprise the patient of the potential for any of the following: new onset or worsening shortness of breath, hazard to the fetus. Patients should be advised to use effective cough, swelling of the ankles/legs, palpitations, weight gain of contraception during treatment with KADCYLA and for 6 months more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)]. following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient • Advise pregnant women and females of reproductive potential that becomes pregnant while receiving KADCYLA, immediately report KADCYLA exposure can result in fetal harm, including embryo-fetal exposure to the Genentech Adverse Event Line at 1-888-835-2555. death or birth defects [see Warnings and Precautions (5.3), Use in Encourage women who may be exposed during pregnancy to enroll Specific Populations (8.1, 8.6)]. in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see • Advise females of reproductive potential to use effective Patient Counseling Information (17)]. contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA [See Warnings and Precautions (5.3) and Human Data Use in Specific Populations (8.1, 8.6)].

In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some • Advise nursing mothers treated with KADCYLA to discontinue associated with fatal pulmonary hypoplasia, skeletal abnormalities nursing or discontinue KADCYLA, taking into account the importance and neonatal death. These case reports described oligohydramnios of the drug to the mother [see Use in Specific Populations (8.3)]. in pregnant women who received trastuzumab either alone or in • Encourage women who are exposed to KADCYLA during pregnancy combination with chemotherapy. In some case reports, amniotic to enroll in the MotHER Pregnancy Registry by contacting fluid index increased after trastuzumab was stopped. In one 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in case, trastuzumab therapy resumed after the amniotic fluid index Specific Populations (8.1, 8.6)]. improved, and oligohydramnios recurred.

KADCYLA® (ado-trastuzumab emtansine) Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed

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

4862200 Initial U.S. Approval: 02/13 KADCYLA is a trademark of Genentech, Inc. 07/13 TDM0001661001 © 2013 Genentech, Inc.

Shaw T. Chen, MD, PhD

Dr. Chen had previously been with the U.S. Food & Drug Administration (FDA) for over 26 years in new drug development. Most recently he served as FDA’s Deputy Director in the Office of Drug Evaluation at the Center for Drug Evaluation and Research.

B:11.5”

0

7.6

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA).

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)].

Shaw T. Chen, MD, PhD, Joins Polaris Pharmaceuticals

T:10.5”

7.1

Chills

the placental barrier during the early and late phases of gestation.

The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

ors, Dr. Pao is well-respected in the international cancer community, serving as an advisor to the NCI, ASCO, American Association for Cancer Research, and other professional societies, while also serving on the editorial boards of medical research journals including Cancer Research, Clinical Cancer Research, and Journal of Clinical Oncology. n

S:9.875”

Peripheral edema

residency training in Internal Medicine at New York-Presbyterian Hospital/Weill Cornell Medical School, Oncology Fellowship at Memorial Sloan Kettering Cancer Center (MSKCC), and postdoctoral fellowship under Nobel Laureate Harold E. Varmus, MD, currently Director of the National Cancer Institute.

Recipient of many awards and hon-

Unique Skill Set “We are pleased to have Dr. Chen join us,” said Bor-Wen Wu, PhD, MBA, Chief Executive Officer of Polaris Pharmaceuticals, Inc. “His strong regulatory background coupled with his clinical and basic science expertise provide a unique skill set.”

Dr. Chen’s work at the FDA included management of new drug review divisions, drafting and implementing FDA guidance for new class drug products, and establishing modern drug review agency, as well as educating and training regulatory scientists in the Asian Pacific region.

Dr. Chen received his MD degree from the University of Miami, and his PhD from Johns Hopkins University.

He undertook postgraduate training at Johns Hopkins, Yale University, the University of Minnesota, and the U.S. National Institutes of Health, where he was a medical staff fellow in clinical genetics in the Human Genetics Branch. n

The ASCO Post | APRIL 15, 2014

PAGE 94

JOP Spotlight Genitourinary Oncology

Does ‘Specialist Bias’ Contribute to Overtreatment of Prostate Cancer?

By Charlotte Bath

“S

pecialist bias, in which specialists recommend the therapy that they are capable of delivering, is thought to influence the treatment of patients with localized prostate cancer and to contribute to overtreatment of men with limited life expectancy,” Ayal A. Aizer, MD, MPH, and colleagues, from the Harvard Radiation Oncology Program, Massachusetts General Hos-

tients who consulted with a medical oncologist and the 107 who did not.

All patients had histories taken and underwent physical examinations, as well as prostate-specific antigen (PSA) measurements and a transrectal, ultrasound-guided prostate biopsy.

Most of the patients in both groups chose to have a prostatectomy—37 patients (46%) in the group that con-

Our results suggest that medical oncologists might be able to estimate the impact of definitive therapy in patients with limited life expectancy better than other physicians, allowing for minimization of overtreatment of patients with limited life expectancy.

demonstrating that both urologists and radiation oncologists overwhelmingly recommend the therapy that they are capable of delivering.”2 They added, “Our results suggest that medical oncologists might be able to estimate the impact of definitive therapy in patients with limited life expectancy better than other physicians, allowing for minimization of overtreatment of patients with limited life expectancy.”

Hypothesis Not Proven Although the hypothesis of the study—that medical oncologists might not be biased toward a partic-

—Ayal A. Aizer, MD, MPH

pital, Brigham and Women’s Hospital–Dana-Farber Cancer Institute, and Beth Israel Deaconess Medical Center, Boston, stated in explaining the purpose of a study reported online by the Journal of Oncology Practice.1 The purpose of the study, the authors wrote, was “to determine if consultation with a medical oncologist is associated with increased rates of active surveillance in men with low-risk prostate cancer.”

Significant Findings After reviewing data for 188 men with low-risk prostate cancer who were patients at one of three referral centers affiliated with Harvard Medical School, the researchers concluded that consultation with a medical oncologist was associated with increased rates of active surveillance, as well as adherence to National Comprehensive Cancer Network (NCCN) guidelines, and “minimization of overtreatment in men with early prostate cancer and limited life expectancy.”

Demographic and clinical characteristics were similar for the 81 pa-

sulted with a medical oncologist and 46 patients (43%) in the group that did not. External-beam radiation therapy was selected by 12 patients (15%) in the consultation group vs 28 patients (26%) in the nonconsultation group, and brachytherapy was selected by 2 patients (2%) in the consultation group vs 11 patients (10%) in the other group. Active surveillance was selected by 30 patients who consulted with a medical oncologist and 22 patients who did not.

“Consultation with a medical oncologist was associated with increased rates of active surveillance (37% vs 21%, P = .01), an association that remained significant on multivariable logistic regression” (odds ratio [OR] = 2.70, 95% confidence interval [CI] = 1.27–5.75, P = .01), the researchers reported. “When applied to patients with limited life expectancy, this finding remained significant” (OR = 4.74, 95% CI = 1.17–19.25, P = .03), they added.

The authors noted that previous studies have demonstrated physician bias, including “a survey-based study

Alicia K. Morgans, MD

tients at multidisciplinary clinics.

More importantly, “it is impossible to determine causation in the setting of a cross-sectional study,” Dr. Morgans and Dr. Penson asserted. “In other words, it may be that men who were already strongly considering or had decided on active surveillance sought out consultation with a medical oncologist, as opposed to the consultation with the medical oncologist causing them to select active surveillance. Only a prospective study, and preferably a randomized clinical trial, could conclusively show whether consultation with a medical oncologist results in increased use of active surveillance.”

Consultation with a medical oncologist “likely has value to patients and should be encouraged,” the editorialists continued. “Although medical oncologists can provide a unique perspective that urologists and radiation oncologists cannot, it is important to note these other specialists also bring something to the table that should not be ignored. This observation supports the role of multidisciplinary clinics in aiding patients newly diagnosed with prostate cancer to make the most informed decisions possible regarding treatment.”n Disclosure: For full disclosures of the study and commentary authors, visit jop.ascopubs. org.

David F. Penson, MD, MPH

ular treatment modality and more inclined to recommend active surveillance—“certainly has face validity, the results of this study do not prove this,” according to an accompanying editorial by Alicia K. Morgans, MD, and David F. Penson, MD, MPH, of Vanderbilt University Medical Center in Nashville.3 These authors noted that “the study’s restrictive inclusion criteria limit the generalizability of the findings to the larger prostate cancer community.” The criteria excluded men who saw just one prostate cancer specialist, unmarried men, and pa-

References 1. Aizer AA, Paly JJ, Michaelson MD, et al: Medical oncology consultation and minimization of overtreatment in men with low-risk prostate cancer. J Oncol Pract. January 7, 2014 (early release online) 2. Fowler FJ Jr, McNaughton Collins M, Albertsen PC, et al: Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA 283:32173222, 2000.

3. Morgans AK, Penson DF: The more, the merrier: Including a medical oncologist in treatment planning for localized prostate cancer. J Oncol Pract. January 7, 2014 (early release online).

For More on Prostate Cancer Treatment, see pages 34–41.

ASCOPost.com | APRIL 15, 2014

PAGE 95

Future of Oncology Multiple Myeloma

Unraveling the Molecular Complexity of Multiple Myeloma A Conversation With Sagar Lonial, MD

By Jo Cavallo

Sagar Lonial, MD

I

n 2011, the Multiple Myeloma Research Foundation (MMRF) announced the launch of CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), a clinical study at the heart of its Personalized Medicine Initiative. CoMMpass will follow 1,000 newly diagnosed patients with multiple myeloma over the course of 8 years to better understand the molecular and genetic components of the cancer and how they contribute to disease progression and to an individual patient’s response to therapy. The study also aims to generate new leads for targeted drug development.

So far, nearly 500 patients have been accrued into the study, which has a 3-year enrollment time frame and 5-year follow-up. Full accrual is expected by the end of the year.

The design of CoMMpass includes the serial collection of paired bone marrow aspirate and peripheral blood throughout the study to catalogue genomic changes in a patient’s disease from onset to remission and relapse.

The biospecimens will then undergo whole-genome, whole-exome, and RNA sequencing; immunophenotyp-

T

he CoMMpass study is currently enrolling newly diagnosed multiple myeloma patients at clinical centers throughout the United States. For additional information on the study and location of the clinical sites, ­visit www.themmrf.org/research-­ programs/commpass-study.

To access the CoMMpass Researcher Gateway, a public clinical and molecular database, go to research.themmrf.org. n

ing; and BRAF sequencing. (An interim analysis of tumor specimens of 178 patients has identified BRAF V600E mutations at a rate of 5.7%.1) Genomic analysis on all patient samples will be performed at the Translational Genomics Research Institute (TGen) in Phoenix.

The ASCO Post talked with Sagar Lonial, MD, Principal Investigator of the CoMMpass study and Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, about the goals of CoMMpass and how its findings could influence personalized care for patients with myeloma, provide new drug targets, and determine the classification of multiple myeloma subtypes.

Treatment Challenges

CoMMpass Components

Does the molecular diversity of multiple myeloma make it distinct from other blood cancers and more difficult to successfully treat?

As we learn more about cancer and its various types, we lump those types together less and split them into more individual diseases. Many years ago, lymphomas were characterized as six or seven different types; now we know

As part of the CoMMpass trial, patient tumor samples are being collected and analyzed at the time of diagnosis, at clinical remission, and at disease progression. What will the molecular and genomic analysis at these different points tell you about an individual patient’s disease?

There are really two big components to CoMMpass. The first is the

Will determining the molecular changes myeloma undergoes during first-line treatment enable oncologists to more effectively treat a patient’s subsequent cancer recurrences?

Yes, that’s correct. The front-line treatments permitted in CoMMpass include standard-of-care therapies containing a proteasome inhibitor, an immunomodulatory drug, or both. We are trying to understand whether the efficacy of the initial induction therapy is influenced by the molecular characteristics of the tumor at diagnosis. We want to learn why some patients do exceedingly well on a specific type of drug, while other patients do not do as well and may need multiple drugs to keep their myeloma from advancing.

Although we have made many great inroads in [multiple myeloma] and have lots of new drugs, the real questions for the next decade are, how do we put these drugs together for the best outcome, and does a patient’s molecular subtype matter in terms of the drugs he gets?

—Sagar Lonial, MD

molecular characterization of a patient’s tumor using sequencing at the time of initial presentation and then trying to longitudinally follow what happens to that patient after treatment. We want to know how good the patient’s response is over time and how the sequencing mutation discovered at initial diagnosis impacts those clinical characteristics, including response and duration of response.

Then, if and when the disease comes back, we want to know whether there were changes in the mutations or if new mutations developed that were influenced by the therapy or by the original presentations of the mutations themselves. That is really the big-picture question.

that there are at least 50 different types.

So the molecular characterization of lymphoma has been an important way to give lymphoma subtypes different names and potentially treat them in different ways. We may need to do that in myeloma.

In describing and treating myeloma, we’ve been limited by what a pathologist can see under a microscope. We now know that there is much more to the cancer than can be seen microscopically.

Getting to its molecular characterization will help us to differentiate the subtypes of myeloma and potentially outline different treatment algorithms for them.

Through gene-expression profiling, we have been able to discern seven subtypes of myeloma. But in the ­CoMMpass

study, we will be able to have individual tumor specimens molecularly sequenced, which has never been done before, and we will learn much more about the cancer and its subtypes. Gene-expression profiling is certainly useful, but it doesn’t give you all the information you need to treat myeloma. Molecular sequencing may help us identify not just the expression of genes involved in myeloma, but also potential mutations that could be targeted.

Bone Marrow Transplant Now that there are so many effective targeted therapies that offer durable remissions, what is the role of bone marrow transplantation in the front-line treatment of myeloma?

We include transplantation as part of the treatment in the CoMMpass study.

A number of the patients we have enrolled are getting a three-drug induction regimen; they have their stem cells collected and then move on to a transplant.

And every time they have a bone marrow biopsy, a tissue sample is analyzed to look for evidence of minimal residual disease, which is an evolving area in the treatment of myeloma right now.

Minimal residual disease has played an important role in the progression of chronic myeloid leukemia, chronic lymphocytic leukemia, and other similar diseases. We have not really had therapies that are effective enough to evaluate minimal residual disease in myeloma patients until the past 5 years, so this is a question we are starting to address in the CoMMpass study.

Now that we have more effective therapies, the role of bone marrow transplant in myeloma treatment is a question that is being tested in prospective randomized clinical trials. I think we’ll understand soon whether a transplant offers superior benefit in the context of all these great new therapies.

My sense is that with the data we have seen so far, if the goal is to eradicate all evidence of disease and consistently get patients to a [minimal residual disease]– negative state, bone marrow transplants continue to offer that ability. But there may be subsets of myeloma patients who don’t benefit from a transplant. There may be subsets of patients who are incredibly sensitive to the effects of highdose melphalan (Alkeran) used in bone marrow transplantation induction theracontinued on page 96

The ASCO Post | APRIL 15, 2014

PAGE 96

Future of Oncology Sagar Lonial, MD continued from page 95

py, and teasing that out based on molecular subtypes is part of what’s being done in clinical trials. Until we have that data, it is going to be hard to say, yes, everybody should keep getting transplants, or no, they should stop getting them.

The CoMMpass study is an incredibly important study, and I encourage every oncologist who takes care of patients with multiple myeloma to get them into this study, even if it means the patient has to travel to one of the clinical trial sites for a bone marrow biopsy (see the story below for a patient’s perspective on the CoMMpass study).

Although we have made many great inroads in this disease and have lots of new drugs, the real questions for the next decade are, how do we put these

drugs together for the best outcome, and does a patient’s molecular subtype matter in terms of the drugs he gets?

These are going to be the challenges over the next few years.

Impact on Quality of Life The clinical endpoints and outcomes in the CoMMpass study include quality-of-life measures and health-care utilization. Why did you include these parameters in the study design?

We wanted to understand their impact on the patient. For example, we can say that patients should get a three-drug combination therapy as part of their initial treatment, but if the outcomes are similar to those of two-drug combinations and the side effects are less appreciable, we do a disservice to patients when we give them the three-drug combination.

We also want to know if there are

molecular characteristics of a patient’s tumor that will tell us whether that patient will have side effects from a specific treatment. We will not be able to pin that down as well as you can in large randomized trials, but I think that we may get some clues about the impact of treatment on patients’ lives by tracking their side effects and quality-of-life incidents.

Looking Ahead Based on what you are learning so far in CoMMpass and other clinical studies, do you think it will be possible to cure multiple myeloma or provide patients with very long durable remissions?

I think there are probably some patients we are curing now. It’s probably a relatively low percentage—between 5% and 10%—but I believe that ­CoMMpass will help us identify the best drug and the best targets to in-

crease the cure rate in this disease.

The question of cure vs chronic disease is an important question to ask, and the answer may vary based on the type of molecular subtype a patient has. We now know that we can get myeloma patients to [minimal residual disease]–negative disease. The question is, is that low enough? If not, we need to push the barrier further, but do it in a way that does not compromise a patient’s quality of life. n

Disclosure: Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Sanofi.

Reference 1. Keats J, Craig D, Liang W, et al: Interim analysis of the MMRF CoMMpass trial, a longitudinal study in multiple myeloma relating clinical outcomes to genomic and immunophenotypic profiles. 2013 ASH Annual Meeting. Abstract 532. Presented December 9, 2013.

The CoMMpass Trial in Multiple Myeloma One Patient’s Perspective

By Traver Hutchins, as told to Jo Cavallo

W

hen I was diagnosed with multiple myeloma in 2008, at just 47, I was lucky. I was asymptomatic, my cancer was detected through a routine blood test, and I had the smoldering type, so I didn’t need immediate treatment. Plus, I knew that recent advances in more effective therapies were making it possible to halt disease progression should my cancer start to accelerate, and there was the promise of more drugs to come.

Still, getting a diagnosis of an incurable cancer scared me enough to give up running a successful company to spend more time with my family and move to a smaller house to reduce expenses. In retrospect, taking those steps was a mistake and an overreaction to my diagnosis.

When my cancer did start to progress in 2012, I was better prepared. By then I had gotten involved with the Multiple Myeloma Research Foundation (MMRF) [http://www.themmrf .org] and learned about a study it had launched called CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile). The purpose of the study is to collect bone marrow tissue before treatment begins and then at remission and relapse and sequence the biospecimens for genomic analysis. I immediately enrolled in the

study because I want to help advance a better understanding of this cancer and the development of more effective drugs—if not to actually cure myeloma, to at least turn it into a chronic disease that I and other patients can live with for a long, long time.

Crusading for CoMMpass Once my bone marrow tissue was collected, I was prescribed a cocktail

worked for me, I know that many myeloma patients aren’t so fortunate.

I’ve watched a number of friends with myeloma die from their disease, and I know that my situation could change at any time. That is why I am on a crusade to get out the message of the importance of informing newly diagnosed myeloma patients about ­CoMMpass and giving them a chance to get enrolled before they start therapy.

Being part of CoMMpass makes me feel that I’m making a tangible contribution to these scientists’ efforts.

—Traver Hutchins

of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone.

I have the IgG type of myeloma, and that treatment put me in remission.

To help me stay there, I’m on maintenance therapy with low-dose (10-mg) lenalidomide. Although I have some common side effects, including fatigue and numbness in my feet and hands, I’m grateful such a drug exists.

While this regimen of drugs has

Because I believe this study will make such a difference in changing the dynamic of myeloma and its effect on people’s lives, I’m advocating that information about CoMMpass—and any relevant clinical trials for patients with cancer—become part of a checklist of information that is embedded in electronic health records. It would be a good step in helping remind physicians to talk to their myeloma patients

about enrolling in CoMMpass prior to treatment.

Starting Over The clinical prognosis today for many newly diagnosed patients with myeloma is vastly improved from that of my diagnosis 6 years ago. New drug discoveries and the understanding that myeloma isn’t one disease but several are making it possible to turn this incurable cancer into one that I and other patients can live with for many, many years. Curing myeloma would be great, but I’ll gladly take a conversion of this often-deadly disease into a treatable, chronic one.

Because of my involvement with MMRF I know how hard scientists are working to make that goal a reality, and I’m grateful for their dedication. Their work and the progress being made in myeloma have given me the confidence to start a new company, because I now believe I have time ahead of me.

Being part of CoMMpass makes me feel that I’m making a tangible contribution to these scientists’ efforts. I can feel the momentum building, and I’m glad I’m still here to benefit from and celebrate their success. n Traver Hutchins is the CEO of a health services company and lives in Greenwich, Connecticut.

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.

Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints.

Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL

WITH ZELBORAF

Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

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

Percentage surviving

80 60 Not reached

7.9

40 20 0

0

2

4

ZELBORAF (n=337)

6 8 OS (months)

10

12

14

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.

Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms.

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

Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

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

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension.

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

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

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

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

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

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

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

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

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

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

Photosensitivity Mild to severe photosensitivity can occur.

Advise patients to avoid sun exposure and use adequate sun protection.

Institute dose modifications for intolerable grade 2 or greater photosensitivity.

Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

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

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

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

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011.

Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | APRIL 15, 2014

PAGE 100

Announcements

American Association for Cancer Research Elects José Baselga, MD, PhD, as President-Elect 2014–2015

T

he members of the American Association for Cancer Research (AACR) have elected José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center in New York, as

their President-Elect for 2014–2015. Dr. Baselga is an internationally recognized physician-scientist whose research focuses on the clinical development of novel moSafety:7" lecularly targeted agents for the treatment

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily.

Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure.

ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine.

Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)].

ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade Grade All Grade All All a Other Malignancies Grades 3a Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies.

Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

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

5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

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

Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation.

Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)].

5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)].

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)].

In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].

5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.

Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)].

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

5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

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

Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0

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

7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

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

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

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

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

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

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

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

5

3

1

0

15

6

18

0

8

<1

21

0

8

0

7

0

12

0

10

0

0

0

14

0

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

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

10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

cancer through research, education, communication, and collaboration.

“I am deeply honored to serve as President-Elect of the AACR. These are both exciting and challenging times in the fight against cancer. Advances in our knowledge of cancer are resulting in the fulfillment of the promise of precision cancer medicine.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422003 Initial U.S. Approval: August 2011 © 2013 Genentech, Inc

José Baselga, MD, PhD

Unprecedented breakthroughs are occurring in genomics, targeted therapeutics, and immunology, just to name a few,” Dr. Baselga said. “Together with the whole AACR community, I will push forward on multiple fronts including regulatory science and policy, integration of basic and clinical research, and access of clinical trials to our patient population with the clear mission of advancing progress in the prevention and treatment of cancer.”

Dr. Baselga officially became President-Elect at the AACR Annual Meeting 2014, and he will assume the presidency in April 2015.

Safety:10"

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

Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

of cancer, particularly breast cancer.

Dr. Baselga will work collaboratively with the AACR Board of Directors and the AACR membership to further the association’s mission to prevent and cure

Pioneer in Breast Cancer Dr. Baselga is a pioneer in the development of treatments for women with HER2-positive breast cancer. He conducted the initial clinical trial demonstrating that patients with advanced HER2-positive breast cancer benefited from treatment with the anti-HER2 monoclonal antibody trastuzumab (Herceptin). In addition, Dr. Baselga led the clinical development of the second anti-HER2 monoclonal antibody to receive U.S. Food and Drug Administration approval, pertuzumab (Perjeta). His most recent focus in the laboratory and clinic is the identification of mechanisms of resistance to anti-HER2 agents and the clinical development of novel agents—including PI3 kinase inhibitors—that might be able to target these resistance mechanisms.

Prior to joining Memorial Sloan Kettering Cancer Center, Dr. Baselga was the Chief of the Division of Hematology/ Oncology and Associate Director of the Massachusetts General Hospital Cancer Center, and Professor of Medicine at Harvard Medical School in Boston. n

ASCOPost.com | APRIL 15, 2014

PAGE 101

Inside the Black Box The FDA’s Bad Ad Program

A Conversation With FDA’s Office of Prescription Drug Promotion INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures.

In this installment, Robert Dean, MBA, Director, and Michael Sauers, Deputy Director, of Division II in the FDA’s Office of Prescription Drug Promotion discuss the FDA’s Bad Ad program.

T

he Office of Prescription Drug Promotion (OPDP) is located in the FDA’s Center for Drug Evaluation and Research. OPDP’s mission is to protect the public health by ensuring prescription drug information is truthful, balanced, and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement, and education program, and by

course. Can you tell us more about it?

Mr. Sauers: In October 2013, the Bad Ad program launched an e-learning course in partnership with Medscape.

It’s a free, hour-long course that offers CME credit for physicians and Continuing Education (CE) credit for other health-care professionals like nurses, nurse practitioners, pharmacists, and physician assistants.

The takeaway for physicians and other health-care professionals is that while promotion can serve as a valuable means of education, it can also potentially be misleading. And as a concerned health-care professional, there is an avenue for you to help improve the quality of prescription drug information available to you, your colleagues, and your patients.

—Robert Dean, MBA

fostering better communication of labeling and promotional information to both health-care professionals and consumers.

Origins of the Bad Ad Program What is the FDA’s Bad Ad program, and when was it launched?

Mr. Dean: In May 2010, the FDA launched the Bad Ad program. This educational program was designed to raise awareness among physicians and other health-care professionals about untruthful or misleading prescription drug promotion. The program has since had a significant impact on protecting the public health and has been expanded recently to offer new ways to increase awareness of untruthful or misleading prescription drug promotion.

Affiliated CME The Bad Ad program recently launched a Continuing Medical Education (CME)

We encourage all health-care professionals to take this course. It’s easy to use and consists of seven modules. For example, one module goes into the psychology of promotion and talks about the sales techniques that many pharmaceutical representatives use. There’s also a brief test at the end of the course where you watch video snippets and try to spot misleading promotion.

The course is available at www.fda. gov/BadAd. Again, it’s free and only about an hour long. We really want to make it easy for health-care professionals to learn about untruthful and misleading drug promotion.

Program Goals and Impact Why did the FDA create the Bad Ad program? And how does the CME course relate to that?

Mr. Dean: The first goal of the program is to raise awareness among physicians and other health-care profes-

sionals of misleading promotion. The second goal is to streamline the process for those health-care professionals who choose to engage with us to help stop misleading promotion.

Through various activities such as conference exhibits, grand rounds presentations and educational outreach, we believe we are slowly but surely raising awareness, not only from a regulatory perspective of what is false or misleading, but also of what health-care professionals can do to help stop misleading messages from reaching their colleagues and patients. By offering a direct line of communication between health-care professionals and FDA regulatory reviewers (badad@fda.gov), they can be sure that their concerns will be addressed by the appropriate FDA staff.

What has been the impact of the Bad Ad program?

Mr. Sauers: It’s had a significant impact. In the year after the program launched, the FDA received more than triple the number of complaints over the past annual average, with most complaints coming from health-care professionals. For example, we received 37 complaints regarding a misleading TV advertisement for a product called EpiPen. Three days after the first complaints arrived in the FDA’s Bad Ad e-mail inbox, the manufacturer voluntarily withdrew the ad at the FDA’s request and soon issued a correction.

Obviously, the more health-care professionals who know about the Bad Ad program, the more impact the program can potentially have. We’re trying to raise professional awareness of the program; that’s one of the reasons for offering the CME course online and free of charge.

What do you want health-care professionals to take away from the Bad Ad program and CME course?

Mr. Dean: The takeaway for physicians and other health-care professionals is that while promotion can serve as a valuable means of education, it can also potentially be misleading. And as a concerned health-care professional, there is an avenue for you to help improve the quality of prescription drug information available to you, your colleagues, and your patients.

FDA Clinical Reviewers

Robert Dean, MBA

Michael Sauers

Role of Students What about all of the future healthcare professionals who are still in school?

Mr. Sauers: Students hoping to become health-care professionals are actively engaged in forming clinical practice habits that may last throughout their careers, so reaching them now could have a strong impact on how they view prescription drug promotion. Because students will soon be providing care to patients and prescribing the innovative medicines marketed by the pharmaceutical industry, increasing their awareness about misleading drug advertising and promotion will have a lasting public health impact.

To help them become more discerning about promotional information, we’ve developed several case studies based on FDA Warning Letters and Untitled Letters issued to drug companies.

The case studies, which represent common problems with promotion, can be downloaded from the Bad Ad website at www.fda.gov/badad.

We’re also encouraging medical, pharmacy, physician assistant, nursing, and other health-care professional schools to incorporate these cases into their coursework. The cases expose stucontinued on page 103

Tell Your Patients About the New Cancer.Net Blog (and encourage them to subscribe to receive the latest updates)

An interactive resource that explores the cancer topics people are talking about With guest posts by ASCO experts, stories from patients and patient advocates, podcasts, interviews, and much more

www.cancer.net/blog

ASCOPost.com | APRIL 15, 2014

PAGE 103

Inside the Black Box Bad Ad Program continued from page 101

dents to a range of promotional materials including a website, a journal ad, and a television ad, and touch upon numerous promotional practices that don’t comply with FDA regulations.

Through the case studies, students will have an opportunity to evaluate and discuss these real-life examples of misleading drug promotion. The case studies are designed to be used in tandem with the CME/CE course; however, in lieu of continuing education credit, students will receive a certificate of completion for viewing the course.

Common Issues What would you say are the most common types of issues that the FDA encounters with prescription drug promotion?

Mr. Dean: We encounter a wide range of issues while reviewing prescription drug promotion. However, the most common issues that we typically identify include: Overstating the efficacy of a drug.

One example would be if a sales representative says, “Drug X delivers results in as little as 3 days,” and you learn later that clinical trials showed results in 12 weeks.

Omitting or minimizing the risks of the product. A presentation about a prescription drug that describes a drug’s benefits but not its risks is a common example of this violation.

Making comparisons between drugs when there has been no adequate and well-controlled head-to-head study demonstrating a difference.

Office of Prescription Drug Promotion You have told us about the Bad Ad program, but can you tell us about your office?

Mr. Dean: Here at the FDA, OPDP is charged with protecting the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated. OPDP resides within the Center for Drug Evaluation and Research (CDER), which reviews and approves new prescription drugs. Because we are housed in CDER, we are responsible for prescription drug promotion only, while other FDA Centers handle things like dietary supplements, devices, and biologics.

OPDP’s traditional regulatory activities for monitoring prescription drug promotion rely primarily on review of industry promotional pieces

submitted to the FDA, complaints filed by the pharmaceutical industry, and field surveillance at large medical conventions. While these efforts are effective, we realized that in order to increase effectiveness, we needed a way to raise awareness among healthcare professionals about misleading promotion.

As a former pharmaceutical sales representative, I was well aware of prescription drug marketing practices and wanted to develop a program that partnered with health-care professionals to ensure that prescription drug promotion is truthful, accurate, and balanced.

As a result, I created the Bad Ad program with Mike Sauers who is also a former sales representative.

Additional information about OPDP and prescription drug advertising and promotion can be found at www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/drugmarketingadvertisingandcommunications/default.htm.

Are health-care professionals able to communicate with your office if they have questions or if they identify misleading promotion?

Guest Editor

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.

Mr. Sauers: We’ve created a dedicated toll-free number and e-mail address to allow health-care professionals to communicate their concerns to us, or to report potentially misleading prescription drug promotion that either they or their patients have encountered. Call us toll free at 855-RX-BADAD or e-mail BadAd@ fda.gov. n Disclosure: Mr. Dean and Mr. Sauers reported no potential conflicts of interest.

Appointments

Yvonne T. Maddox, PhD, Appointed Acting Director of National Institute on Minority Health and Health Disparities

F

rancis S. Collins, MD, PhD, Director of the National Institutes of Health recently announced the appointment of Yvonne T. Maddox, PhD, as Acting Director of the Na-

Ruffin, NIMHD’s previous Director.

Dr. Maddox assumed her new role on April 1, having previously served as Deputy Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Responsibilities and Activities Across NIH

Yvonne T. Maddox, PhD

tional Institute on Minority Health and Health Disparities (NIMHHD).

This follows the retirement Dr. John

AT NICHD, in addition to advising on budget matters and institute programs, Dr. Maddox led several committees to advance medical research for affected communities to improve their health. Among her many activities across NIH and the Department of Health and Human Services (DHHS), Dr. Maddox chairs

the Federal SIDS/Sudden Unexpected Infant Death Working Group, the NIH Down Syndrome Consortium (an international public-private partnership), has served as Executive Director of the DHHS Cancer Health Disparities Progress Review Group, and has cochaired the DHHS Initiative to Reduce Infant Mortality in Minority Communities.

Dr. Maddox served as the Acting Deputy Director of the NIH from January 2000–June 2002, and she cochaired the first NIH Strategic Plan to “Reduce and Ultimately Eliminate Health Disparities.”

Scientific Roles, Honors As a cardiovascular physiologist,

Dr. Maddox also has served in several scientific roles at the NIH and has authored numerous scientific papers and review articles. She has received many honors and awards, including the Presidential Distinguished Executive Rank Award, Presidential Meritorious Executive Rank Award, DHHS Career Achievement Award, Public Health Service Special Recognition Award, DHHS Secretary’s Award, NIH Director’s Award, National Down Syndrome Society Champion of Change Award, and Research Down Syndrome Foundation Light the Way Award. Her scientific work has been recognized by Morehouse School of Medicine with a HeLa Leadership Award for Excellence in Reproductive Medicine. n

The ASCO Post | APRIL 15, 2014

PAGE 104

2014-2015 Oncology Meetings April 15th Annual Meeting of the American Society of Breast Surgeons April 30-May 4 • Las Vegas, Nevada For more information: www.breastsurgeons.org/index.php

2014 State of the Art Radiation Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org 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 Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/ 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: www.mdanderson.org/conferences

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: http://www. hematology.org/Meetings/

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/

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

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

June 2nd Annual Prostate Symposium: Challenges and Solutions June 6-7 • Winston-Salem, North Carolina For more information: http:// northwestahec.wfubmc.edu 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

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

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

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

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 112

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

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

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

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

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

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

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

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

The ASCO Post | APRIL 15, 2014

PAGE 112

2014-2015 Oncology Meetings continued from page 104

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 | APRIL 15, 2014

PAGE 113

JCO Spotlight Supportive Care

Two Behavioral Interventions Help Cancer Patients Struggling With Sleep Issues, Penn Medicine Study Finds

P

atients with cancer who are struggling with sleep troubles, due in part to pain or side effects of treatment, can count on two behavioral interventions for relief—cognitive behavioral therapy for insomnia and mindfulnessbased stress reduction—Penn Medicine researchers reported in a recent study published online in the Journal of Clinical Oncology.1 While cognitive behavioral therapy for insomnia is the gold standard of care, mindfulness-based stress reduction is an additional treatment approach that can also help improve sleep for cancer patients, the study found.

completion of cancer treatment, with up to 28% meeting a formal diagnosis of insomnia. While there are effective drugs that can help treat insomnia, Dr. Garland says that many cancer patients express a desire not to take additional medications

This study suggests that we should not apply a ‘one-size-fits-all’ model to the treatment of insomnia and emphasizes the need to individualize treatment based on patient characteristics and preferences.

Critical Intervention “Insomnia and disturbed sleep are significant problems that can affect approximately half of all cancer patients,” said lead study author Sheila N. Garland, PhD, a Clinical Psychology Post-Doctoral Fellow at Penn’s Abramson Cancer Center in Integrative Oncology and Behavioral Sleep Medicine. “If not properly addressed, sleep disturbances can negatively influence therapeutic and supportive care measures for these patients, so it’s critical that clinicians can offer patients reliable, effective, and tailored interventions.”

Estimates suggest that anywhere between 36% and 59% of patients with cancer experience disturbed sleep and insomnia symptoms during and after the

tients with cancer. This is the first study to directly compare mindfulness-based stress reduction to cognitive behavioral therapy for insomnia in cancer patients.

When assessed 3 months after completing an 8-week treatment protocol,

—Sheila N. Garland, MD

due to concerns about side effects and the possibility of developing a dependence on the medication.

Study Details The new study involved 111 patients with cancer recruited from a cancer center in Calgary, Alberta, Canada, to one of two randomly assigned interventions for their insomnia, either cognitive behavioral therapy for insomnia (n = 47) or mindfulness-based stress reduction (n = 64). In previous research, mindfulness-based stress reduction has been shown to reduce distress and improve psychological well-being in pa-

the researchers found that both cognitive behavioral therapy for insomnia and mindfulness-based stress reduction reduced insomnia severity across each group. However, the effects in the cognitive behavioral therapy group occurred more rapidly whereas the mindfulnessbased stress reduction group tended to show more gradual improvement over time. Both groups significantly increased their total sleep time and reduced the amount of time it took them to fall asleep or return to sleep during the night. Both groups also experienced improvements in mood and stress-related symptoms following the interventions.

Expanding Treatment Options “That [mindfulness-based stress reduction] can produce similar improvements to [cognitive behavioral therapy for insomnia] and that both groups can effectively reduce stress and mood disturbance expands the available treatment options for insomnia in cancer patients,” said Dr. Garland. “This study suggests that we should not apply a ‘one-size-fits-all’ model to the treatment of insomnia and emphasizes the need to individualize treatment based on patient characteristics and preferences.”

In addition to Dr. Garland, other Penn authors included Alisa J. Stephens, PhD, from the Perelman School of Medicine’s Center for Clinical Epidemiology and Biostatistics. Penn authors collaborated with researchers at the University of Calgary, and the study was supported by the Canadian Cancer Society Research Institute and the Alberta Cancer Board. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Garland SN, Carlson LE, Stephens AJ, et al: Mindfulness-based stress reduction compared with cognitive behavioral therapy for the treatment of insomnia comorbid with cancer: A randomized, partially blinded, noninferiority trial. J Clin Oncol. January 6, 2014 (early release online).

Join the 21st Annual Cancer Survivors’ Celebration Walk & 5K

N

early 4,000 attendees, including more than 700 cancer survivors along with friends and family members, will gather in Chicago’s Grant Park for the Robert H. Lurie Comprehensive Cancer Center of Northwestern University’s Annual Cancer Survivors’ Celebration Walk & 5K Run. This year’s event will be held Sunday, June 1. The ASCO Annual Meeting will be taking place nearby during this time (May 30– June 2) in Chicago’s McCormick Place.

A Celebration of Survivorship This Chicago area community event honors cancer survivors and recognizes health-care professionals who have dedicated their careers to providing patient care and pursuing research.

The Lurie Cancer Center’s Survivors’ Celebration Walk & 5K provides survivors, caregivers, family members, and all whose lives have been touched by cancer a special day to celebrate the amazing strides made in cancer research and patient care. It also recognizes the improvements in quality of life for those living with cancer.

The Survivors’ Celebration Walk & 5K features a leisurely, noncompetitive walk (approximately 3 miles in length) along Chicago’s lakefront. For the second year, participants will also be given the opportunity to participate in a chiptimed, 5K race the morning of the walk.

For more information or to register, visit cancer.northwestern.edu/ walk/index.cfm n

Held on National Cancer Survivors Day, the Lurie Cancer Center’s Cancer Survivors’ Celebration Walk & 5K brings cancer survivors, families, and friends together with the physicians, scientists, and health professionals who support them for a meaningful, memorable morning filled with family-friendly activities.

The ASCO Post | APRIL 15, 2014

PAGE 114

Lab Notes

Ongoing Molecular Research in the Science of Oncology COMBINATION THERAPY Synergy of IAP Antagonist and Demethylating Agents Against AML Stem/Progenitor Cells In a study reported in the Journal of the National Cancer Institute, Carter and colleagues identified deregulated apoptotic components in acute myeloid leukemia (AML) stem/progenitor cells and investigated the effects of the novel inhibitor of apoptosis (IAP) protein antagonist and SMAC mimetic birinapant and demethylating agents in AML. Measurement of protein expression in AML patient and normal samples showed that CD34-positive/CD38negative AML stem/progenitors expressed significantly higher cIAP1 and caspase-8 levels and decreased SMAC levels compared with bulk AML cells.

Birinapant caused death receptor/caspase-8–mediated apoptosis in AML cells, including AML stem/progenitor cells, but not in normal CD34-positive cells.

Demethylating agents modulated extrinsic apoptosis pathway components, and the combination of demethylating agents and birinapant was highly synergistic against AML cells in vitro (combination index < 1) and resulted in prolonged median survival in AML mouse xenograft models (P < .001 for birinapant plus azacitadine vs birinapant alone or vs controls).

The investigators concluded, “cIAP1, SMAC, and caspase-8 appear to play a role in AML stem cell survival, and synergistic targeting of these cells with birinapant and demethylating agents shows potential utility in leukemia therapy.”

Carter BZ, et al: J Natl Cancer Inst 106(2):djt440, 2014.

CANCER PROMOTERS Antioxidants Accelerate Lung Cancer Progression and Reduce Survival in Mice Clinical trials of antioxidants in cancer have yielded inconsistent results. In a study reported in Science Translational Medicine, Sayin and colleagues evaluated the effects of the antioxidants Nacetylcysteine and vitamin E in mouse models of BRAF- and KRAS-induced lung cancer. N-acetylcysteine and vitamin E dietary supplementation markedly increased tumor progression and reduced survival in the mouse models.

RNA sequencing showed that the

structurally unrelated compounds resulted in highly coordinated changes in tumor transcriptome profiles, predominantly featuring reduced expression of endogenous antioxidant genes. Both Nacetylcysteine and vitamin E increased

tumor cell proliferation by reducing reactive oxygen species (ROS), DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 resulted in tumor growth similar to that observed with antioxi-

dant supplementation while eliminating the antioxidant effect, indicating that antioxidants accelerate tumor growth by disrupting the ROS-p53 axis.

The investigators noted, “Because somatic mutations in p53 occur late in

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | APRIL 15, 2014

PAGE 115

Lab Notes

tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive [N-acetylcysteine] to relieve mucus production.”

Sayin VI, et al: Sci Transl Med 6:221ra15, 2014.

BIOMARKERS IDH Mutation Predicts Benefit from Alkylating Chemotherapy in Oligodendroglial Tumors Patients in the Radiation Therapy Oncology Group (RTOG) 9402 study

with 1p/19q codeleted anaplastic oligodendroglial tumors had markedly prolonged overall survival after chemoradiotherapy (with procarbazine, lomustine, and vincristine) compared with radiation therapy alone. Some patients with noncodeleted tumors also benefited from chemoradiotherapy. In a study reported in the Journal

of Clinical Oncology, Cairncross and colleagues examined whether IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas (rs55705857) identified the patients in RTOG 9402 who benefited from chemoradiotherapy.

IDH status could be ascertained in

Advertisement not displayed in digital edition at advertiser’s request

continued on page 116

The ASCO Post | APRIL 15, 2014

PAGE 116

Lab Notes Ongoing Molecular Research continued from page 115

210 of 291 patients, with 156 (74%) having mutations; rs55705857 was evaluable in 245 patients, with 76 (31%) carrying the G risk allele. Both alterations were associated with prolonged progression-free survival after chemoradiotherapy, and mutant

IDH was associated with significantly prolonged overall survival (9.4 vs 5.7 years, hazard ratio [HR] = 0.59, P = .006).

Chemoradiotherapy vs radiotherapy did not prolong median overall survival (1.3 vs 1.8 years, HR = 1.14, P = .67) or 10-year overall survival (6% vs 4%) in patients with wild-type tumors. Me-

dian overall survival was significantly prolonged for chemoradiotherapy vs radiotherapy in patients with codeleted IDH-mutated tumors (14.7 vs 6.8 years, HR = 0.49, P = .01) and those with noncodeleted IDH-mutated tumors (5.5 vs 3.3 years, HR = 0.56, P < .05).

The investigators concluded, “IDH mutational status identified patients

with oligodendroglial tumors who did (and did not) benefit from alkylatingagent chemotherapy with [radiotherapy]. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after [chemoradiotherapy].”

Cairncross JG, et al: J Clin Oncol. February 10, 2014 (early release online).

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | APRIL 15, 2014

PAGE 117

Lab Notes

BIOMARKERS shRNAs Can Identify T-Cell Inhibitory Mechanisms in Tumor Microenvironment Although recent findings indicate that targeting of inhibitory receptors on T cells can produce durable

responses in some cancer patients despite the presence of advanced disease, the mechanisms controlling Tcell function in immunosuppressive tumors have not been well characterized. In a study reported in Nature, Zhou and colleagues showed that it is possible to systemically identify these inhibitory mechanisms in the

tumor microenvironment.

The investigators constructed a pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators become highly enriched in murine tumors after releasing a block on T-cell proliferation in response to tumor antigen recognition in vitro. The shRNAs were iden-

tified by deep sequencing of the shRNA cassette from T cells infiltrating tumor or control tissues. One of the target genes identified was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. Ppp2r2d knockdown in tumors reduced T-cell apoptosis and increased both T-cell prolif-

Advertisement not displayed in digital edition at advertiser’s request

continued on page 118

The ASCO Post | APRIL 15, 2014

PAGE 118

Lab Notes Ongoing Molecular Research continued from page 117

eration and cytokine production.

The investigators concluded, “Key regulators of immune function can … be discovered in relevant tissue microenvironments.”

Zhou P, et al: Nature 506:52-57, 2014.

MECHANISMS OF ACTION Lenalidomide Acts in Myeloma

by Degrading Lymphoid Transcription Factors IKZF1 and IKZF3 The mechanism of action of lenalidomide (Revlimid) in multiple

myeloma and other B-cell neoplasms remains largely uncharacterized. In a study reported in Science, Krönke and colleagues identified one of the effects of lenalidomide in this setting.

Use of quantitative proteomics showed that lenalidomide caused selective ubiquitination and degradation of the lymphoid transcription factors

IKZF1 and IKZF3—critical transcription factors in multiple myeloma—via the CRBN-CRL4 ubiquitin ligase.

A single amino acid substitution in IKZF3 was shown to result in resistance to lenalidomide-induced degradation and to prevent lenalidomide-induced inhibition of cell growth. Further, it was shown that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3.

The investigators concluded, “These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.” n Krönke J, et al: Science 343:301-305, 2014.

Contact

The ASCO Post

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

Advertisement not displayed in digital edition at advertiser’s request

Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

Advertising

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

ASCOPost.com | APRIL 15, 2014

PAGE 119

Clinical Trials Resource Guide

Ongoing Clinical Trials Actively Recruiting Adolescent and Young Adult Survivors of Childhood Cancer Compiled by Jo Cavallo The information in this Clinical ­Trials Resource Guide includes details of actively recruiting clinical studies of adolescent and young adult survivors of childhood cancers, with ages ranging from 11 to 49. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov. The studies are nonrandomized, randomized, or observational and include phase II and phase III clinical trials.

ADOLESCENT AND YOUNG ADULT CHILDHOOD CANCER SURVIVORS Study Type: Randomized/interventional Study Title: A Randomized WebBased Physical Activity Intervention in Adolescent Survivors of Childhood Cancer Study Sponsor and Collaborators: St. Jude Children’s Research Hospital Purpose: Five-year survival following a diagnosis of childhood cancer has reached 83%, making long-term health outcomes among survivors an important concern. The researchers at St. Jude Children’s Research Hospital want to determine if a rewards-based physical activity intervention delivered via an interactive website among young adolescent childhood cancer survivors, ages 11–14, will increase physical activity levels and improve cardiovascular and musculoskeletal health.

Ages Eligible for Study: 11 to 14 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Change in daily average of moderate and vigorous physical activity levels between groups (time frame: baseline, week 12, and week 24) Principal Investigator: Kirsten K. Ness, PT, PhD, St. Jude Children’s Research Hospital; 866-278-5833, info@ stjude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01778127

Study Type: Randomized phase II/ interventional Study Title: Pharmacologic Reversal of Ventricular Remodeling in Childhood Cancer Survivors at Risk for Congestive Heart Failure (PREVENTCHF): A Phase IIB Randomized Placebo-Controlled Trial Study Sponsor and Collaborators: City of Hope Medical Center, National Cancer Institute Purpose: To study the side effects and how well low-dose carvedilol works in preventing congestive heart failure in younger cancer survivors exposed to high-dose anthracyclines for management of childhood cancer Ages Eligible for Study: 16 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Leftventricular (LV) thickness-dimension ratio, reported in terms of LV posterior wall dimension in systole and LV dimension based on the internal diameter in diastole (time frame: up to 24 months) Principal Investigator: Saro H. Armenian, DO, MPH, City of Hope Medical Center; 626-471-7320, sarmenian@coh.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01347970 Study Type: Randomized phase II/ interventional Study Title: Pilot Study of Statin Therapy in Young Adult Survivors of Childhood Cancer Study Sponsor and Collaborators: Clinical and Translational Science Institute of the University of Minnesota Purpose: Adult survivors of childhood cancer are at high risk of developing cardiovascular disease. The primary objective of this study is to evaluate the effects of 6 months of statin therapy on conduit artery endothelial function in young adult survivors of childhood cancer. The investigators hypothesize that, compared to placebo, atorvastatin will significantly increase brachial artery flow-mediated dilation in survivors of childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Ages Eligible for Study: 18 to 39 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Change from baseline in brachial artery flow-mediated dilation at 6 months (time frame: baseline and 6 months) Principal Investigator: Aaron S. Kelly, PhD, Clinical and Translational Science Institute of the University of Minnesota. Contact: Cameron E. Naughton, MPA; 612-625-3623, naugh0009@umn.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01733953 Study Type: Nonrandomized phase II/interventional Study Title: A Phase II Open Label Pilot Study of the Angiotensin-Converting Enzyme Inhibitor, Perindopril, in Pediatric Cancer Survivors With Evidence of Early Cardiac Remodeling or Dysfunction Study Sponsor and Collaborators: The Hospital for Sick Children Purpose: To evaluate the feasibility of conducting a medical intervention trial in childhood cancer survivors with early echocardiographic evidence of cardiac remodeling Ages Eligible for Study: Up to 20 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Proportion of patients consenting to the study (time frame: 18 months) Principal Investigator: Paul Nathan, MD, Director, AfterCare Program; Staff Oncologist, The Hospital for Sick Children. Contact: Kristen George, NP, 416-813-7654, Kristen. george@sickkids.ca For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01948232 Study Type: Randomized phase III/interventional Study Title: EMPOWER Study: Promoting Breast Cancer Screening in Women Who Survived Childhood Cancer Study Sponsor and Collaborators:

Memorial Sloan Kettering Cancer Center; St. Jude Children’s Research Hospital; University of Colorado, Denver; Dana-Farber Cancer Institute; University of Chicago Purpose: To empower women to improve their health in two very important areas: breast and heart health.

This 12-month study will compare two methods of informing participants about potential health risks and ways to stay healthy.

Ages Eligible for Study: 25 to 49 years Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Efficacy (time frame: 12 months) Principal Investigator: Kevin C. Oeffinger, MD, Memorial Sloan Kettering Cancer Center; 646-888-4730 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01579552 Study Type: Observational Study Title: Protocol for the Enrollment on the Official COG Registry, The Childhood Cancer Research Network (CCRN) Children’s Oncology Group Study Sponsor and Collaborators: National Cancer Institute Purpose: To obtain informed consent from parents (and the child, when appropriate) of infants, children, adolescents, and young adults newly diagnosed with cancer to enter their names and certain information concerning their child into the Childhood Cancer research Network Ages Eligible for Study: Up to 18 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Not available Principal Investigator: Crystal L. Mackall, MD, National Cancer Institute; 301-402-5940, mackallc@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01117168 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00082745 n

The ASCO Post | APRIL 15, 2014

PAGE 120

Announcements

MD Anderson Honors Two Champions for Women in Medicine and Research

T

wo champions of gender equality in medicine and research were recently honored by The University of Texas MD Anderson Cancer Center.

Laurie Glimcher, MD, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and Provost for Medical Affairs of Cornell University since 2012, received the 2014 Margaret L. Kripke Legend Award. She spoke about endoplasmic reticulum stressors in disease.

Thomas Burke, MD, Executive Vice President of MD Anderson Cancer Network, was honored with the President’s Leadership Award for Advancing Women Faculty. His remarks addressed gender inclusiveness.

Noted Immunologist, Advocate Dr. Glimcher joined Weill Cornell from Harvard, where she was one of the first women professors awarded tenure.

She is a renowned immunologist. Her

Laurie Glimcher, MD

leadership, Weill Cornell opened an onsite child care center last year.

“I am thrilled and deeply humbled to be the 2014 recipient of the Margaret L. Kripke Legend Award,” Dr. Glimcher said.

CODE: PFZ-14-1

“I’ve dedicated my career to supporting made in nurturing women leaders in the Delivery Support: 212.237.7000 FILE: 01A-006293-02C-752483-Island.indd and recognizing women physicians and biomedical sciences and excited for what scientists so they can not only succeed, we can accomplish in the future.” but go farther than they ever thought they The Kripke Award recognizes a percould. I’m proud of the progress we’ve son who has made significant contribu-

In ER+ breast cancer,

Targeting only the estrogen receptor may miss a root cause of proliferation

Thomas Burke, MD

primary research interests are molecular pathways that regulate CD4 T helper cell development and activation, work that has led to important advancements in understanding immune function.

As President of the American Association of Immunologists, she founded the Primary Caregivers Technical Assistance Programs, known as the Glimcher Initiative, at the National Institutes of Health (NIH). The program, which she also helped establish at Harvard, supports postdoctoral women scientists with child care responsibilities by providing additional funds for laboratory assistance. Under Dr. Glimcher’s

PUB/POST: Island Sp

DESCRIPTION: Palbo MKT Dul Unbranded Spread Ad (2 S

References: 1. Weinberg RA. The Biology of Cancer. New York, NY: Garland Science; 2013. 2. Sotillo E, Grana X. In: Enders GH, ed. Cell Cycle Deregulation in Cancer. New York, NY: Humana Press; 2010:3-22. 3. Finn RS, Dering J, Conklin D, et al. Breast Cancer Res. 2009;11(5):R77. doi:10.1186/bcr2419. 4. Fry DW, Harvey PJ, Keller PR, et al. Mol Cancer Ther. 2004;3(11):1427-1438.

CDK642416 March 2014 © 2014 Pfizer Inc. All rights reserved.

pread

Sizes)

ASCOPost.com | APRIL 15, 2014

PAGE 121

Announcements

tions to the advancement and promo- Kripke Legend Award is being made to tion of women in cancer medicine and a woman who is dean of a major U.S. cancer science. It was established in medical school,” said Elizabeth TraRoseann Panariello LIVE: 14.5” x 10” 2008 PRODUCTION:

by Women Faculty Programs to vis, PhD, MD Anderson associate vice WORKORDER #: 006305 TRIM: 15” x 10.5” honor Professor Emerita Margaret L. president of Women Faculty Programs.

SAP #: S.TEMP.02254 BLEED: 15.5” x 10.75” Kripke, PhD, for her unwavering advo- “Laurie Glimcher is one of the 23 womcacy for and promotion of women in en who have reached the highest level academic medicine and science. of leadership in academic medicine.

“This is the second year in a row the She is an outstanding cancer medicine

researcher and teacher, as well as a longstanding advocate of women, and we are thrilled to have her as the awardee.”

Ensuring Equal Opportunities Dr. Burke joined the faculty of MD Anderson in 1988 and was appointed Professor in 1998. In 2007, he was named Executive Vice President and

Laurie Glimcher, MD

Elizabeth Travis, PhD

Physician-in-Chief, an appointment he held through 2013 when he was named Executive Vice President, MD Anderson Cancer Network.

As the physician in charge of clinical operations, Dr. Burke used his position to identify and promote women faculty to medical director positions. He has mentored many woman faculty, created opportunities, and helped prepare women for leadership positions through special assignments. Dr. Burke is a practicing gynecologic oncology surgeon whose clinical and research work focuses on vulvar and endometrial cancers.

“I have benefited from the wisdom and guidance of many wonderful mentors throughout my education and career,” Burke said. “Several of them were talented women. I am thrilled to be recognized for fostering the professional development of friends and colleagues over the past 25 years at MD Anderson.”

The President’s Leadership Award for

Ronald DePinho, MD

Within the nucleus, cyclin-dependent kinases 4 and 6 (CDK4/6) often continue to drive cell proliferation1-3 • CDK4/6 activation triggers a sequence of events that can lead to a loss of proliferative control2-4 • Research is focusing on the dual inhibition of ER and CDK4/6 in breast cancer3 Visit TargetCDK.com to learn more about the role of CDK4/6 in ER+ breast cancer.

Advancing Women Faculty was initiated last year to recognize the contributions of an MD Anderson faculty member who has had a significant impact on the career advancement of women faculty.

Recipients provide vision and leadership to address practices that inadvertently disadvantage women faculty and serve as change agents by creating an environment where women can flourish and advance to leadership positions.

“I am delighted to honor and recognize two individuals who advocate above and beyond the expected for the career advancement of women faculty,” said Ronald DePinho, MD, President of MD Anderson. “Recipients of both awards are chosen based on demonstrating, through their words and actions, a deep personal and professional commitment to this value.” n

The ASCO Post | APRIL 15, 2014

PAGE 122

Integrative Oncology

By Jyothirmai Gubili, MS, Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center

Reishi Mushroom Scientific name: Ganoderma lucidum Common names: Ling zhi, lin zi, mushroom of immortality

T

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness.

Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. We chose reishi mushroom for this issue because of its popularity among cancer patients.

Compiled by Barrie R. Cassileth, MS, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, Lac, ­Memorial Sloan Kettering Cancer Center.

Overview

A fungus, reishi mushroom is an important component of the traditional medical systems of China, Japan, Korea, and other Asian countries. It is used to increase energy, stimulate the immune system, and promote health.

The medicinal effects of reishi were first documented in the Shen Nong Materia Medica, written in China 2,000 years ago. Reishi has gained popularity around the world over the past few decades and is currently used to promote health and to treat coronary heart disease, arthritis, hepatitis, hypertension, AIDS, and cancer. It is also widely recommended by herbalists as an immune enhancer.

Current evidence of reishi’s anticancer potential is limited to small studies that indicate its ability to enhance immune response in patients with advanced cancer. There are no data to support the idea that reishi can prolong survival.

Because it is difficult to find in the wild, reishi is cultivated on solid substrates, stationary liquid medium, or by submerged cultivation to meet the growing demand. It is marketed in the form of powders, capsules, tinctures, and teas, all of which are produced from the mycelia, spores, or fruiting bodies.

ity,7 alleviates chemotherapy-induced nausea,8 and increases the efficacy of radiotherapy9 and the sensitivity of ovarian cancer cells to cisplatin.10 It may also be useful in preventing cisplatininduced nephrotoxicity.11 In small clinical studies, reishi improved plasma antioxidant capacity12,13 and enhanced immune responses in advanced-stage cancer patients.14 Remission of hepatocellular carcinoma was reported in a few cases in a single study.15 However, a reishi mushroom extract demonstrated toxic effects in leukocytes in vitro.16 More research is needed to determine its safety as an adjunctive cancer treatment.

The Science

Two cases of hepatoxicity, leading to death in one, were reported following use of powdered reishi mushroom.17,18 Chronic diarrhea was reported in a 49-year-old man with non-Hodgkin lymphoma after prolonged consumption of a powdered extract of reishi mushroom.19

The active constituents of reishi mushroom include beta-glucan polysaccharides and triterpenes. In vitro and in vivo studies indicate that reishi extracts have immunomodulatory,1 anti-inflammatory,3 renoprotective,2 and hepatoprotective4 properties. Clinical findings suggest its benefits in improving lower urinary tract symptoms in men,5 exerting mild antidiabetic effects, and improving dyslipidemia.6 Reishi has also been investigated for its anticancer potential. Preclinical data show that it has chemopreventive abil-

OF NOTE Reishi is a popular medicinal mushroom. Physicians should be aware of its interactions with certain prescription drugs, including anticoagulants and immunosuppressants.

Adverse Effects

Herb-Drug Interactions

Anticoagulants/antiplatelets: Reishi may increase the risk of bleeding.20 Immunosuppressants: Reishi can enhance immune response.14 Chemotherapeutic agents: Reishi

can increase plasma antioxidant capacity and may interact with chemotherapeutic agents that rely on free radicals.12 Cytochrome P450 substrates: Reishi polysaccharides inhibit CYP2E1, CYP1A2, and CYP3A, and may cause accumulation of drugs metabolized by these enzymes, thereby increasing the risk of their side effects.21 Disclosure: Ms. Gubili reported no potential conflicts of interest.

References 1. Chen HS, Tsai YF, Lin S, et al: Studies on the immuno-modulating and anti-tumor activities of Ganoderma lucidum (Reishi) polysaccharides. Bioorg Med Chem 12:5595-5601, 2004.

2. Shieh YH, Liu CF, Huang YK, et al: Evaluation of the hepatic and renal-protective effects of Ganoderma lucidum in mice.

Am J Chin Med 29:501-507, 2001.

3. Joseph S, Sabulal B, George V, et al: Antitumor and anti-inflammatory activities of polysaccharides isolated from Ganoderma lucidum. Acta Pharm 61:335-342, 2011.

4. Jin H, Jin F, Jin JX, et al: Protective effects of Ganoderma lucidum spore on cadmium hepatotoxicity in mice. Food Chem Toxicol 52:171-175, 2013.

Learn More About

Herbs, Botanicals, & Other Products Visit the free About Herbs website at

www.mskcc.org/aboutherbs

ASCOPost.com | APRIL 15, 2014

PAGE 123

Integrative Oncology 5. Noguchi M, Kakuma T, Tomiyasu K, et al: Effect of an extract of Ganoderma lucidum in men with lower urinary tract symptoms: A double-blind, placebo-controlled randomized and dose-ranging study.

Asian J Androl 10:651-658, 2008.

6. Chu TT, Benzie IF, Lam CW, et al: Study of potential cardioprotective effects of Ganoderma lucidum (Lingzhi): Results of a controlled human intervention trial. Br J Nutr 107:1017-1027, 2012.

7. Weng CJ, Yen GC: The in vitro and in vivo experimental evidences disclose the chemopreventive effects of Ganoderma lucidum on cancer invasion and metastasis.

Clin Exp Metastasis 27:361-369, 2010.

8. Wang CZ, Basila D, Aung HH, et al: Effects of ganoderma lucidum extract on chemotherapy-induced nausea and vomiting in a rat model. Am J Chin Med 33:807815, 2005.

9. Kim KC, Jun HJ, Kim JS, et al: Enhancement of radiation response with combined Ganoderma lucidum and Duchesnea chrysantha extracts in human leukemia HL60 cells. Int J Mol Med 21:489-498, 2008.

10. Zhao S, Ye G, Fu G, et al: Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol 38:13191327, 2011.

11. Pillai TG, John M, Sara Thomas G: Prevention of cisplatin induced nephrotoxicity by terpenes isolated from Ganoderma lucidum occurring in Southern Parts of India. Exp Toxicol Pathol 63:157160, 2011.

12. Wachtel-Galor S, Szeto YT, Tomlinson B, et al: Ganoderma lucidum (‘Lingzhi’); acute and short-term biomarker response to supplementation. Int J Food Sci Nutr 55:75-83, 2004.

13. Wachtel-Galor S, Tomlinson B, Benzie IF: Ganoderma lucidum (“Lingzhi”), a Chinese medicinal mushroom: Biomarker responses in a controlled human supplementation study. Br J Nutr 91:263-269, 2004.

14. Gao Y, Zhou S, Jiang W, et al: Effects of ganopoly (a Ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients. Immunol Invest 32:201-215, 2003.

15. Gordan JD, Chay WY, Kelley RK, et al: “And what other medications are you taking?” J Clin Oncol 29:e288-e291, 2011.

16. Gill SK, Rieder MJ: Toxicity of a traditional Chinese medicine, Ganoderma lucidum, in children with cancer. Can J Clin Pharmacol 15:e275-e285, 2008.

17. Yuen MF, Ip P, Ng WK, et al: Hepa-

Survivorship: Living Well During and After Cancer A New Book From Barrie Cassileth, PhD

B

arrie Cassileth, PhD, Laurance S. Rockefeller Chair in Integrative Medicine and Chief, Integrative Medicine Service, at Memorial Sloan Kettering Cancer Center (MSKCC) in New York has published a new book called Survivorship: Living Well During and After Cancer. Dr. Cassileth provides readers with up-to-date, evidence-based guidance about integrative medicine along with important information for cancer patients and their families. She explains how

acupuncture, massage therapy, yoga, nutritional counseling, and other integrative approaches may be helpful in alleviating both short- and longterm side effects of cancer and its treatments.

Importantly, Dr. Cassileth also helps to separate the facts from the hype in integrative medicine and to guide readers through cancer treatment and beyond.

For more information about Survivorship: Living Well During and After Cancer, visit http://bit.ly/1dvIoq3 n

Author: Barrie Cassileth, PhD Format: Paperback ISBN: 978-1-938170-35-5 Pages: 216 Publication Date: April 1, 2014 Dimensions: 5.5 × 8.5 Also Available: eBook

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www .mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 268 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. totoxicity due to a formulation of Ganoderma lucidum (lingzhi). J Hepatol 41:686687, 2004.

18. Wanmuang H, Leopairut J, Kositchaiwat C, et al: Fatal fulminant hepatitis associated with Ganoderma lucidum (Lingzhi) mushroom powder. J Med Assoc Thai 90:179-181, 2007.

19. Wanachiwanawin D, Piankijagum A, Chaiprasert A, et al: Ganoderma lucidum: A cause of pseudoparasitosis. Southeast

Asian J Trop Med Public Health 37:10991102, 2006.

20. Tao J, Feng KY: Experimental and clinical studies on inhibitory effect of ganoderma lucidum on platelet aggregation. J Tongji Med Univ 10:240-243, 1990.

21. Wang X, Zhao X, Li D, et al: Effects of Ganoderma lucidum polysaccharide on CYP2E1, CYP1A2 and CYP3A activities in BCG-immune hepatic injury in rats. Biol Pharm Bull 30:1702-1706, 2007.

Save the Date 11th International Conference of the Society for Integrative Oncology October 26–October 28, 2014, Houston The 11th International Conference of the Society for Integrative Oncology will be held in Houston, Texas at the Omni Houston Galleria Hotel October 26-28, 2014.

The conference theme is “Personalized Integrative Oncology: Targeted Approaches for Optimal Outcomes.”

2014 Conference Co-Chairs Richard Lee, MD Peiying Yang, MS, PhD The University of Texas MD Anderson Cancer Center.

For more information, visit integrativeonc.org

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40138 January 2014.

The ASCO Post | APRIL 15, 2014

PAGE 126

Notable

Have You Heard?

A Compilation of Quotes From Oncology-Related News

“I

t’s not a matter of if a child will be seriously poisoned or killed. It’s a matter of when.”

Lee Cantrell, PharmD, Director of the San Diego Division of the California Poison Control System and Professor of Clinical Pharmacy at the University of California, San Francisco, commenting on the potential dangers of “e-liquids,” electronic cigarette refills containing liquid

nicotine along with flavorings and other chemicals. (Richtel M: Selling a poison by the barrel: Liquid nicotine for e-cigarettes.

The New York Times, March 20, 2014) “There is a contradiction in having these dangerous and devastating tobacco products on the shelves of a retail chain that services health care needs.”

Excerpted from a letter written by a

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials 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 clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

group of state attorney generals to retailers with pharmacies in their stores, urging them to stop selling tobacco products. (Chris Isadore @CNNMoney, March 17, 2014) “We are going to have to be more thoughtful about the patients included and the types of trials. We want to run trials that have an impact instead of conducting

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

large trials that cost millions of dollars and find an improvement in progression-free survival of 5 weeks, for example.”

Robert Dreicer, MD, Chair of the Department of Solid Tumor Oncology, Cleveland Clinic, remarking on ASCO’s call to employ clinical trial designs that aim to significantly extend the lives of people with cancer. (Nelson R: Time for ‘smaller and smarter’ clinical trials, says ASCO. Medscape Medical News, March 18, 2014) “There is a marked deterioration of access to the premier cancer centers for people who are signing up for these plans.”

Dan Mendelson, CEO of Avalere Health, a market research firm in, Washington, DC, noting that some of the leading cancer centers are often not included in insurance plans offered under the Affordable Care Act. (Alonso-Zaldivar R: Health law concerns for cancer patients.

Associated Press, March 19, 2014) “One can happen. Two all of a sudden raises eyebrows.”

Noah Kauff, MD, Director of the Ovarian Cancer Screening and Prevention Service and attending physician on the Clinical Genetics Service, at Memorial Sloan Kettering Cancer Center in New York, discussing a study, presented at the Society of Gynecologic Oncology Annual Meeting, that found four cases of aggressive uterine cancer years in women with BRCA 1 mutations years after the women had surgery to remove their ovaries. (Marchione M: Study ties breast gene to high-risk uterine cancer. Associated Press, March 24, 2014) “It is possible that ceritinib may become another standard therapy for patients with ALK-positive lung cancer.”

Alice Shaw, MD, PhD, thoracic oncologist at Massachusetts General Hospital Cancer Center, Boston, and lead author of an article in The New England Journal of Medicine reporting that ceritinib was highly active in patients with advanced, ALKrearranged non–small cell lung cancer, including patients with disease progression during treatment with crizotinib (Xalkori).

(Reinberg S: Experimental drug shows promise for drug-resistant lung cancer.

HealthDay, March 26, 2014). n Have You Heard? is compiled by ­Charlotte Bath.

Send Us Your NEWS Write to editor@ASCOPost.com.

ASCOPost.com | APRIL 15, 2014

PAGE 127

In the News Genitourinary Oncology

Prostate Cancer Study Showing Increased Survival for Younger Men Undergoing Prostatectomy Not Expected to Increase Surgeries

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

E

xtended follow-up in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG4), reported recently in The New England Journal of Medicine,1 found that men with earlystage prostate cancer, particularly those under 65 years old, who were treated with radical prostatectomy had increased survival compared to those assigned to watchful waiting. But differences in how prostate cancer is detected and treated now, compared to the years 1989 through 1999, when these men were randomized to surgery or watchful waiting, may limit the study’s impact to informing discussion

of the issue, stimulated by widespread coverage by major media, including The Wall Street Journal, the Los Angeles Times, The Boston Globe, and CNN. Men who were younger than 65 years and had radical prostatectomy had a significant absolute reduction of 25.5 percentage points in overall mortality and 15.8 percentage points in death from prostate cancer, according to the study. There was no significant reduction in mortality among men aged 65 years or older at time of diagnosis.

“I don’t see these data having a major change in the uptake of surveillance or radical prostatectomy. I think they confirm what we already knew—older men are less likely to benefit from aggressive treatment,” H. Ballentine Carter, MD, said in an interview with The ASCO Post. Dr. Carter is Professor of Urology, Oncology, and Director, Division of Adult Urology, Brady Urological Institute, at Johns Hopkins Medicine in Baltimore. “In my opin-

Expect Questions From Patients

R

esults from the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), showing that men with early-stage prostate cancer, particularly men under 65 years old, treated with radical prostatectomy had increased survival compared to those assigned to watchful waiting, has raised concerns among physicians and their patients. H. Ballentine Carter, MD, Professor of Urology, Oncology, and Director, Division of Adult Urology, Brady Urological Institute, at Johns Hopkins Medicine in Baltimore, told The ASCO Post that he had has many discussions about the study with colleagues, “but also patients, who will bring in the article and say. ‘How should I interpret this?’” Patients who have been diagnosed with early-stage prostate cancer want to know if the study means they should have immediate surgery rather than continue on active surveillance.

Take-Home Message Dr. Carter said that the guidance he offers physicians who are asked about the study by patients is basically what he has said for a long time: “For any man over age 65 who gets diagnosed with low-risk disease, he should not be asking, ‘What treatment should I have?’ He should be asking, ‘Do I need to be treated at all?’ That, to me, is the take-home message.”

For men under age 65 who have very low– to low-risk disease, the decision may be more difficult, taking into account potential benefits and longer life expectancy. As with all patients, that decision “has to be based on personal preferences,” he stressed.

For men with intermediate-risk disease and less than a 10-year life expectancy, “surveillance could be an option for those people, maybe even preferred,” Dr. Carter added. “But for all other people who have more than a 10-year life expectancy with intermediate- and certainly high-risk disease, they should be treated aggressively, because we know that treatment will prolong life.” n

I don’t see these data having a major change in the uptake of surveillance or radical prostatectomy. I think they confirm what we already knew—older men are less likely to benefit from aggressive treatment.

—H. Ballentine Carter, MD

ion, it is just more evidence that active surveillance is a very reasonable option, especially for men over age 65 who have low-risk disease.”

Most Had Palpable Tumors Of the 625 men in SPCG-4, 347 were randomly assigned to radical prostatectomy and 348 to watchful waiting. The mean age of men in both groups was 65, and the mean prostatespecific antigen (PSA) level was approximately 13 ng/mL. Most had T2 tumors. “Only 12% of the patients had nonpalpable T1c tumors at the time of enrollment in the study,” the investigators pointed out.

At 18 years, the cumulative incidence of death was 56.1% in the radical prostatectomy group and 68.9% in the watchful waiting group (a 12.7 percentage point difference, 95% confidence interval [CI] = 5.1–20.3). This corresponded to a 0.71 relative risk of death in the radical prostatectomy group (95% CI = 0.59–0.86, P < .001).

The cumulative incidence of death from prostate cancer at 18 years was 17.7% in the radical prostatectomy group and 28.7% in the watchful waiting group (an 11.0 percentage point difference, 95% CI = 4.5–17.5), which corresponded to a 0.56 relative risk of death in the radical prostatectomy group (95% CI = 0.41–0.77, P = .001).

Pre-PSA Era The SPCG-4 trial was initiated before the era of PSA screening. “By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT),2 initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years,” the SPCG-4 authors noted.

“PSA screening profoundly changes the clinical domain of study,” they con-

tinued. “Among other considerations, the substantial additional lead time necessitates very long follow-up periods in the PIVOT trial to determine the effect of surgery as compared with observation. In the meantime, the SPCG4 offers insight regarding the effectiveness of radical prostatectomy and the natural history of prostate cancer.”

In the SPCG-4 study, “only 5% of prostate cancers were detected with screening; three out of four had palpable disease; almost 50% had PSAs over 10 ng/mL; and one in three had a Gleason score above 6. So this is not a screen-detected group of people,” Dr. Carter noted.

‘Stratification Is Suspect’ “To assess the possible modification of the treatment effect, analyses were stratified according to the patient’s age at diagnosis (< 65 years vs ≥ 65 years) and tumor risk,” the study authors reported. Men with PSA levels < 10 ng/ mL and a Gleason score < 7 or World Health Organization (WHO) grade 1 disease were considered low risk.

Those with PSA levels ≥ 20 ng/mL or higher and Gleason scores > 7 were considered high risk. Men who did not meet criteria for either low or high risk were considered intermediate risk.

“The stratification is suspect because three out of four patients had palpable disease, and that is not what we are dealing with today. These are people who had disease more advanced than what we are detecting today. It doesn’t mean that it is not an informative trial. It is just not generalizable. If anything, it suggests that the results are the worst case scenario, for the control group anyway,” Dr. Carter said.

“If you look at the cumulative rates of death in men with low-, intermediate-, and high-risk disease in the control continued on page 128

The ASCO Post | APRIL 15, 2014

PAGE 128

In the News H. Ballentine Carter, MD continued from page 127

group that didn’t get treated, and then you look at the control group of the PIVOT trial, which is a PSA era trial, you will see that the low-risk cancers of yesterday are the intermediate-risk cancers of today. That is an important caveat, the point being that you can’t take the information from the low-risk cancers in the Scandinavian Prostate Cancer Group study and generalize that to the low-risk cancers of today, because with PSA screening, there is a lead time on average of a decade,” he continued.

“So I think what the Scandinavian Prostate Cancer Group study shows for men under age 65 is that those who are going to benefit the most are those with intermediate- or high-risk disease. I am not suggesting that men under age 65 with low-risk disease should never be treated. I am only suggesting that those with intermediate- or high-risk disease are the people who are more likely to benefit,” Dr. Carter explained.

The authors do note in their conclusion that their analyses according to tumor risk are “merely hypothesisgenerating.”

Dr. Carter commented, “That’s exactly right, because it is not generalizable to today.”

Role of USPSTF Recommendation In 2012, the U.S. Preventive Services Task Force (USPSTF) updated its pros-

tate cancer screening recommendation against PSA-based screening and now “recommends against PSA-based screening for prostate cancer.”3 This is a grade D recommendation, meaning that there “is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”

Asked if this could alter the PSA testing scenario once again, Dr. Carter replied, “No, I don’t think that is true. The only data we really have on changing behavior is from the 2008 USPSTF Grade D recommendation for men over age 75, and that didn’t change behavior at all—not one bit. So I don’t think that men are less likely to get PSA screened. We don’t have that information for after the 2012 USPSTF recommendation yet. But if the past is any indication of the future, that task force recommendation is not going to have any impact unless it impacts payment.”

erectile dysfunction was about the same for men in the SPCG-4 assigned to surgery (84%) or watchful waiting (80%), but urinary leakage was much higher in the surgery group—41% vs 11% in the watchful waiting group—as was distress from these symptoms. More modern surgical techniques and nerve-sparing procedures can mitigate effects of prostatectomy on erectile dysfunction and urinary incontinence, Dr. Carter noted, citing a study by Sanda et al.4 J. Leonard Lichtenfeld, MD, Deputy Chief Medical Officer of the American Cancer Society, commenting in Dr. Len’s Cancer Blog,5 noted that men in

Different Approaches Differences in how prostate cancer is managed now, as compared with the time of the SPCG-4 trial, also involve surgical procedures and follow-up monitoring and treatment.

“The surgical approach then was very different from the surgical approach today,” Dr. Carter noted. According to the study design, “radical excision of the tumor was given priority over nervesparing surgery.”

In a quality-of-life assessment at a mean of 12.4 years, the SPCG-4 researchers found that the prevalence of

J. Leonard Lichtenfeld, MD

the watchful waiting cohort in SPCG-4 never received any curative treatment.

“That is a much different approach to watchful waiting than we currently recommend in the United States, where watchful waiting after a diagnosis of prostate cancer usually means offering curative treatment when the prostate cancer changes its behavior,” Dr. ­Lichtenfeld wrote.

“I think that is a very valid criticism,”

Dr. Carter stated. “We are very carefully monitoring people who get periodic biopsies, periodic PSAs, digital exams, and now [magnetic resonance imaging].”

“About the best thing we can say about this study is it is applicable to men treated the way we used to treat prostate cancer,” Dr. Lichtenfeld’s blog concluded. “But considering how much better we understand and implement watchful waiting, this study should not be used to encourage surgery for every man diagnosed with prostate cancer.” n

Disclosure: Drs. Carter and Lichtenfeld reported no potential conflicts of interest.

References 1. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

2. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012.

3. Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 157:120-134, 2012.

4. Sanda MG, Dunn RL, Michalski J, et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250-1261, 2008.

5. Lichtenfeld JL: It helps to know what watchful waiting really means in prostate cancer treatment. Dr. Len’s Cancer Blog, March 6, 2014. Available at www.cancer. org/aboutus/drlensblog.

American Association for Cancer Research Welcomes New Board of Directors, Nominating Committee Members

T

he members of the American Association for Cancer Research (AACR) have elected five members to serve on the AACR Board of Directors for the 2014–2017 term and four members to serve on the Nominating Committee for the 2014–2016 term. They assumed their roles at the AACR Annual Meeting 2014, held in San Diego, April 5–9.

Board of Directors The following five scientists were elected to the AACR Board of Directors: James P. Allison, PhD, is Chair of the Department of Immunology, Executive Director of the Immunology Platform, Associate Director of the Center for Cancer Immunology Research, Deputy Director of the David H. Koch Center for Applied Research in Genitourinary Cancer, and the Lilian H. Smith Distinguished Chair of

James P. Allison, PhD

Ronald M. Evans, PhD

Immunology at The University of Texas MD Anderson Cancer Center in Houston. He is a leader of the Stand Up To Cancer (SU2C)-Cancer Research Institute Dream Team: Immunologic Checkpoint Blockade and Adoptive Cell Transfer in Cancer Therapy.

Ronald M. Evans, PhD, is Professor at the Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute for Biological Studies in

Scott M. Lippman, MD

La Jolla, California; Investigator with the Howard Hughes Medical Institute; and Adjunct Professor of Biology and Pharmacology at the University of California, San Diego (UCSD).

Scott M. Lippman, MD, is Director of the UCSD Moores Cancer Center; Senior Associate Dean and Associate Vice Chancellor for Cancer Research and Care at UCSD Health Sciences; Professor of Medicine and Chugai Pharmaceutical Chair in Cancer Re-

search at UCSD; Adjunct Professor at the Salk Institute and the Sanford-Burnham Medical Institute in La Jolla; and Adjunct Professor at The University of Texas MD Anderson Cancer Center.

Guillermina Lozano, PhD, is Professor and Chair of the Department of Genetics, Co-Director of the Genetically Engineered Mouse Facility, CoDirector of the Center for Genetics and Genomics, Co-Director of the Sequencing and Microarray Facility, and Co-Director of the Cancer Genetics and Epigenetics Program at The University of Texas MD Anderson Cancer Center; and a member of The University of Texas Graduate School of Biomedical Sciences in Houston.

M. Celeste Simon, PhD, is Professor in the Department of Cell and Development Biology and Scientific Director and Investigator at the Abramson

ASCOPost.com | APRIL 15, 2014

PAGE 129

Announcements

M. Celeste Simon, PhD

An Integrated Approach to Targeting Breast Cancer Molecular Subtypes and Their “Resistance” Phenotypes.

Lillian L. Siu, MD, is a Professor in the faculty of medicine at the University of Toronto in Toronto, Ontario; Director of the Drug Development Fellowship Program, Director of the Phase I Program, Co-Director of the Robert and Maggie Bras and

Margaret R. Spitz, MD, MPH

Family Drug Development Program, and Staff Medical Oncologist at Princess Margaret Hospital in Toronto; and tier I Research Chair in Experimental Therapeutics at Cancer Care Ontario in Toronto.

Margaret R. Spitz, MD, MPH, is Professor at the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. n

Family Cancer Research Institute, University of Pennsylvania in Philadelphia; and an investigator with the Howard Hughes Medical Institute.

Nominating Committee The following four scientists were elected to the AACR Nominating Committee: René Bernards, PhD, is Head of the Division of Molecular Carcinogenesis at the Netherlands Cancer Institute in Amsterdam; Professor of Molecular Carcinogenesis at Utrecht University in Utrecht, Netherlands; and founder and Chief Scientific Officer of Agendia BV in Amsterdam. He is a leader of the SU2C-Dutch Cancer Society (KWF Kankerbestrijding) Sta Op Tegen Kanker Translational Cancer Research Grant: Prospective Use of DNA-guided Personalized Cancer Treatment.

Joe W. Gray, PhD, is Gordon Moore Endowed Chair in the Department of Biomedical Engineering, Director of the Center for Spatial Systems Biomedicine, and Associate Director for Trans-

Advertisement not displayed in digital edition at advertiser’s request

Joe W. Gray, PhD

Lillian L. Siu, MD

lational Research at the Knight Cancer Institute at Oregon Health & Science University in Portland; and a member of the graduate faculty and Professor in the Department of Radiation Medicine in the School of Medicine at Oregon Health and Science University. He is a leader of the SU2C Dream Team:

The ASCO Post | APRIL 15, 2014

PAGE 130

Announcements

USPSTF Appoints New Chair and Co-Vice Chair

T

he U.S. Preventive Services Task Force recently announced the appointments of Michael L. LeFevre, MD, MSPH, as Chair of the Task Force and Kirsten Bibbins-Domingo, PhD, MD, as Co-Vice Chair. Albert L. Siu, MD, MSPH, current Co-Vice Chair, will re-

main in his position. Dr. LeFevre and Dr. Bibbins-Domingo were appointed to their positions by the Director of the Agency for Healthcare Research and Quality.

New Chair Dr. LeFevre has been a member of the

Task Force since January 2005 and was previously appointed Co-Vice Chair in March 2011. He is Vice Chair and Director of Clinical Activities for the Department of Family and Community Medicine at the University of Missouri School of Medicine.

Dr. LeFevre is a practicing family physician, researcher, and widely published author. He has been invited to present to audiences across the country as an expert in the field. Dr. LeFevre’s research and clinical interests include family medicine, evidence-based medicine, information

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | APRIL 15, 2014

PAGE 131

Announcements

technology in clinical care, clinical practice guidelines, and preventive services.

New Co-Vice Chair Dr. Bibbins-Domingo has been a member of the Task Force since July 2010. She is the Lee Goldman, MD endowed Chair in Medicine and Professor of Medicine and of Epidemiology and Biostatistics at

the University of California, San Francisco (UCSF). She is a general internist and attending physician at San Francisco General Hospital and is the Director of the UCSF Center for Vulnerable Populations.

Dr. Bibbins-Domingo’s research is focused on the epidemiology of cardiovascular diseases; race, ethnic, and income disparities in health; and clinical and pub-

Michael L. LeFevre, MD, MSPH

Kirsten Bibbins-Domingo, PhD, MD

lic health interventions aimed at chronic disease prevention.

Dr. LeFevre replaces Virginia A. Moyer, MD, MPH, as Chair of the Task Force and will serve a 1-year term. Dr. Moyer served on the Task Force as a member from January 2003 to December 2008 and as Chair from March 2011 to March 2014. n

Advertisement not displayed in digital edition at advertiser’s request

The ASCO Post | APRIL 15, 2014

PAGE 132

Appointments

City of Hope Names Yuman Fong, MD, Chair, Department of Surgery

C

ity of Hope recently announced the appointment of two new chairs in the Department of Surgery and for the Board of Directors.

Yuman Fong, MD, has been named Chair of the Department of Surgery at City of Hope. Dr. Fong comes to City of

Hope from Memorial Sloan Kettering Cancer Center in New York, where for the last 14 years he held the Murray F. Brennan Chair in Surgery and Professorship in Surgery at Cornell Medical College.

Dr. Fong is a specialist in cancers of the liver, bile duct, gallbladder and pancreas,

Yuman Fong, MD

and he has pioneered many surgical, laparoscopic, robotic and ablative therapies for these cancers. He has been involved in studies aimed at understanding, treating, and preventing these cancers, and in developing widely applicable and minimally invasive technologies for their treatment.

“We are extremely pleased to welcome a surgeon and scientist of Dr. Fong’s caliber to City of Hope,” said Alexandra Levine, MD, MACP, Chief Medical Officer and the Dr. Norman & Melinda Payson Professor in Medicine at City of Hope. “He has been a pioneer both in the operating room and in the laboratory, crafting new surgical techniques and instruments and creating entirely new modalities of therapy.”

Dr. Fong assumed his new position at City of Hope on April 1.

Norman C. Payson, MD, Named Chair, Board of Directors In an earlier announcement, City of Hope announced that Norman C. Payson, MD, was selected as the new Chair of the City of Hope Board of Directors for a 3-year term, which started January 1, 2014. In this capacity, Dr. Payson will take helm of the Institution’s

Advertisement not displayed in digital edition at advertiser’s request

Norman C. Payson, MD

Board of Directors as the research and treatment center launches a new era of growth and scientific investment.

A senior advisor at Apria Healthcare Group since November 2012, Dr. Payson is a former Chief Executive Officer of Oxford Health Plans Inc. and Healthsource Inc. He has more than 30 years of experience building and directing health-care companies during times of growth and change.

Dr. Payson joined the board in 2004 and has served as Chair of its Finance Committee and Strategic Planning Ad Hoc Committee. He is also the Chair of the City of Hope Medical Foundation Board of Directors and, together with his wife, Melinda Payson, helped establish City of Hope’s Graduate Studies Center as well as a graduate fellowship at the school. He succeeds outgoing Chair Sheri Biller. n

ASCOPost.com | APRIL 15, 2014

PAGE 133

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Breast Reconstruction Has Increased Over Time but Varies Widely by Region Analysis of data from 20,560 women undergoing mastectomy for breast cancer found that breast reconstruction use “increased from 46% in 1998 to 63% in 2007 (P< .001), with increased use of implants and decreased use of autologous techniques over time (P < .001),” according to a report published in the Journal of Clinical Oncology. The authors are affiliated with the University of Michigan in Ann Arbor, The University of Texas MD Anderson Cancer Center in Houston, and the Swan Center for Plastic Surgery in Alpharetta, Georgia.

The percentage of women choosing bilateral mastectomy also increased, from 3% in 1998 to 18% in 2007 (P < .001). “Patients receiving bilateral mastectomy were more likely to receive reconstruction [odds ratio [OR] = 2.3, P < .001], and patients receiving radiation were less likely to receive reconstruction [OR = 0.44, P < .001],” the investigators noted. Autologous techniques were more often used in patients who received both reconstruction and radiation (OR = 1.8, P < .001) and less often in patients undergoing bilateral mastectomy (OR = 0.5, P < .001). Delayed reconstruction was performed in 21% of patients.

The study participants were identified through the MarketScan database, a claims-based data set of U.S. patients with employment-based insurance.

The median age was 51 years. The women represented regions across the country, with 49% from the south.

Rates of reconstruction varied dramatically by geographic region, from a low of 18% in North Dakota to a high of 80% in Washington, DC. Current findings suggest that geographic disparities found in previous studies are continuing and “are associated with workforce distribution of plastic surgeons. The finding that breast reconstruction rates are associated with access to plastic surgeons is particularly concerning in light of a recent survey that revealed many plastic surgeons to be decreasing their volume of breast reconstruction surgeries owing to decreasing levels of reimbursement,” the researchers wrote.

“Breast reconstruction has been shown to yield important psychosocial

and quality of life benefits for patients with breast cancer who have undergone mastectomy,” the authors noted.

“Further research and interventions are needed to ensure equitable access to this important component of multidisciplinary treatment of breast cancer.”

Access to Reconstruction An accompanying editorial pointed out that “over the past 10 years, the proportion of women treated with mastectomy may be increasing despite no scientific data demonstrating its superiority over [breast-conserving surgery]. One factor making mastectomy a more palatable option to women and a possible additional driver of increased rates of mastectomy is access to breast reconstruction at the time of or subsequent to mastectomy,” wrote Lindi H. VanderWalde, MD, and Stephen B. Edge, MD, of Baptist Cancer Center in Memphis.

Acknowledging that “disparities in health care still exist with low rates of reconstructions based on regional or institutional difference, and based on sociodemographic factors of the patient,” Dr. VanderWalde and Dr. Edge concluded: In contrast, there is a subset of women with early-stage breast cancer amenable to breast conservation that are pursing bilateral mastectomies with reconstruction. Solutions to improving access to breast reconstruction must be found, while at the same time assuring that we fully communicate the realities of the value of surgical choices, minimize what may otherwise be considered overtreatment, and listen to our patients’ preferences.

domized phase III study. The CA180034 study also found that early molecular and cytogenetic responses (at 3 and 6 months) were associated with improved progression-free and overall survival. The lead author of the study, published in Blood, was Neil P. Shah, MD, PhD, of the University of California, San Francisco, School of Medicine.

Dasatinib is an oral inhibitor of the tyrosine kinase BCR-ABL, which, the investigators explained, “drives the malignant phenotype of leukemic stem cells.” In this dose-optimization study, 670 patients with imatinib-resistant or -intolerant CML in chronic phase were randomly assigned to dasatinib at 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.

Dose Adjustment “To manage inadequate response or adverse events, the protocol allowed dose escalation (up to a total daily dose of 180 mg) or dose interruption or reduction (down to a total daily dose of 20 mg),” the investigators stated. The protocol also permitted switching from a twice-daily to once-daily regimen with the same total daily dose after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention.

Most patients (74%) were imatinibresistant, with the remainder being imatinib-intolerant, and most (77%) received once-daily dosing. At 6 years, 188 patients (28%) remained on study

treatment. In the intent-to-treat population, the groups receiving 100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily, respectively, had estimated 6-year protocol-defined progression-free survival rates of 49%, 51%, 40%, and 47%, and estimated 6-year overall survival rates of 71%, 74%, 77%, 70%, the researchers reported.

A major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of progression-free and overall survival. “Notably, estimated 6-year [progression-free survival] rates based on ≤ 1%, > 1%–10%, and > 10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively.”

Adverse Events Dasatinib was generally well-tolerated. The most common nonhematologic adverse events were musculoskeletal pain, headache, infection, and diarrhea. These generally occurred within 2 years of treatment and were generally mild or moderate (grade 1 or 2). The most common grade 3/4 adverse events were infection, occurring in 6% of patients, and pleural effusion, occurring in 5%. At 6 years, 9% of patients had discontinued treatment because of pleural effusion and ≤ 2.9% discontinued because of any other individual adverse event. The lowest discontinuation rate due to drug toxicity

Jagsi R, et al: J Clin Oncol 32:873875, 2014.

VanderWalde LH, Edge SB. J Clin Oncol 32:919-926, 2014,

LEUKEMIA Long-Term Benefit With Dasatinib After Imatinib Failure in Chronic-Phase Chronic Myeloid Leukemia Patients with chronic myeloid leukemia (CML) in the chronic phase who are resistant or intolerant to imatinib (Gleevec) can experience longterm benefit with dasatinib (Sprycel), according to long-term results of a ran-

©Frank Cotham/The New Yorker Collection/www.cartoonbank.com

continued on page 135

Coming Soon!

A Collaborative Practice Approach to Managing Chemotherapy-Induced Toxicities: Keeping Patients on Their Therapy Proceedings From a Roundtable Discussion, January 25, 2014, St. Petersburg, Florida

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

Wendy H. Vogel, MSN, FNP, AOCNP速 Wellmont Cancer Institute, Kingsport, Tennessee

Christopher J. Campen, PharmD, BCPS

The University of Arizona Cancer Center, Tucson, Arizona

Mailing with the May 1st Issue of The ASCO Post

ASCOPost.com | APRIL 15, 2014

PAGE 135

In the Literature Emerging Clinical Data continued from page 134

was at the 100 mg once daily dose.

The researchers concluded: This analysis represents the longest reported follow-up of patients with [chronic-phase] CML treated with a secondgeneration BCR-ABL inhibitor. Findings indicate that a consistent subgroup of [chronic phase] CML patients resistant or intolerant to imatinib can have a longterm benefit from dasatinib therapy. In particular, those with faster and deeper responses to dasatinib (BCR-ABL ≤ 10% at 3 months) are more likely to have better long-term outcomes.

“For the substantial proportion of patients who respond well to dasatinib,” they added, the risk of progression to accelerated- or blast-phase disease is low.

The study has been registered at ClinicalTrials.gov, with the identifier NCT00123474.

Shah NP, et al: Blood. February 25, 2014 (early release online).

Adding Idelalisib to Rituximab Improved Survival in Patients With Relapsed CLL Receiving rituximab (Rituxan) with idelalisib, rather than rituximab with placebo, “significantly improved progression-free survival, response rate, and overall survival” among patients with relapsed chronic lymphocytic leukemia (CLL) who were less able to undergo chemotherapy because of clinically significant coexisting medical conditions, according to results of a phase III study.

“On the basis of response rates and progression-free survival results, the combination of idelalisib and rituximab may be a treatment option for these patients,” researchers reported in The New England Journal of Medicine.

The multicenter double-blind, placebo-controlled trial randomly assigned 220 patients with decreased renal function, previous therapyinduced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. Idelalisib (formerly called GS-1101 and CAL-101) is an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K-delta). The activation of PI3K, in part, mediates signaling through the B-cell receptor, which plays a key role in the pathogenesis of CLL, the investigators explained.

In phase I studies, idelalisib either alone or combined with other agents (including rituximab) “had clinically significant activity with an acceptable

profile in patients with relapsed or refractory CLL,” they wrote. This led to the current phase III study, which at the first prespecified interim analysis, “was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy,” the researchers stated. Because of this, the duration of treatment was short—a median of 3.8 months.

The median age of patients was 71.

Nearly two-thirds had advanced-stage disease. “Patients in the two study groups had received a median of three previous agents, including regimens containing rituximab, cyclophosphamide, fludarabine, and bendamustine” (Treanda), the researchers noted.

isib group,” the authors commented.

Contributing equally to the study were Richard R. Furman, MD, of Weill Cornell Medical College in New York, Jeff P. Sharman, MD, of U.S. Oncology Research in Springfield, Oregon, and Steven E. Coutre, MD, of Stanford University School of Medicine in California. The study was funded by Gilead Sciences of Foster City, California. Its ClinicalTrials.gov identifier is NCT01539512.

Furman RR, et al: N Engl J Med 370:997-1007, 2014.

NON-HODGKIN LYMPHOMA

Bendamustine/Rituximab May Be Important Alternative for Median progression-free survival Indolent NHL or MCL

Key Findings

was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group = 0.15, P < .001), the researchers reported.

“Improvement in progression-free survival was observed not only in the overall study population but also in all subgroups examined, including patients with poor prognostic features, such as 17p deletion or TP53 mutations and unmutated immunoglobulin heavy-chain variable region.”

Patients receiving idelalisib also had superior overall survival rates: 92% at 12 months vs 80% for those receiving placebo (hazard ratio for death = 0.28, P = .02). “Sixteen patients died while participating in the study: 4 patients (4%) in the idelalisib group and 12 patients (11%) in the placebo group,” according to the study report. The overall response rate, evaluated for 88 patients in each group who had at least one postbaseline assessment or discontinued the study before the first assessment at the time of the analysis was 81% in the idelalisib vs 13% for those receiving placebo (P < .001).

More than 90% of patients had at least one adverse event. The most common adverse events in the idelalisib group were pyrexia, fatigue, nausea, chills, and diarrhea. The most common adverse events in the placebo group were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

Serious adverse events occurred in 40% of patients receiving idelalisib and 35% of those receiving placebo, with the most frequent in both groups being pneumonia, pyrexia, and febrile neutropenia. “A surprising finding was a reduction in rates of infusion-related toxicity from rituximab in the idelal-

Results from the BRIGHT study combined with long-term safety data from other studies suggest that bendamustine (Treanda) plus rituximab (Rituxan) “may be an important alternative treatment option” for the initial treatment of patients with low-grade non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL), researchers reported in Blood.

This randomized, noninferiority, phase III study evaluated the efficacy and safety of bendamustine plus rituximab vs a standard rituximabchemotherapy regimen (R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] or R-CVP [rituximab plus cyclophosphamide, vincristine, and prednisone]) for treatment-naive patients with indolent NHL or MCL. Participating centers were located in the United States, Canada, Brazil, Peru, Mexico, Australia, and New Zealand. The lead author was Ian W. Flinn, MD, of the Sarah Cannon Research Institute in Nashville.

Eligible patients were at least 18 years old and had CD20-positive indolent NHL or MCL. “Patients were required to be treatment-naive with a need for treatment as indicated by the presence of ≥ 1 of the following: B symptoms, large tumor mass (characterized by lymph node with a diameter > 3 cm in 3 or more regions or by a lymph node with a diameter > 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy,” the investigators explained.

“During screening, the investigators preassigned patients to the most appropriate standard treatment (RCHOP/R-CVP) based on their per-

formance status, comorbidities, and general health. After confirmation that patients met the eligibility criteria for the study, the preassigned patients were then randomized to open-label treatment with either [bendamustine/ rituximab] or the standard therapy at a 1:1 ratio,” the authors wrote.

Six cycles were planned and two additional cycles were permitted at investigator discretion. Among those treated with standard therapy, 104 received R-CHOP and 119 got R-CVP.

Major Results Assessed by the primary endpoint of complete response rate, bendamustine/rituximab was noninferior to R-CHOP/R-CVP (31% vs 25%, P = .0225 for noninferiority). The complete response rate for bendamustine/ rituximab was greater than the 22% threshold for noniferiority, ie, more than 88% of the complete response rate for standard therapy.

The higher complete response rate with bendamustine/rituximab therapy was not statistically superior to standard therapy (P = .1269), the researchers noted. “Overall response rates were 97% for the [bendamustine/rituximab] treatment group and 91% for the standard-therapy treatment group, which was statistically superior for the [bendamustine/ rituximab] treatment group [complete response rate ratio = 1.04, 95% CI = 0.99-1.09, P = .0102].”

The safety profiles of the regimens differed. “Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with [bendamustine/rituximab] (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05),” the investigators reported.

By the data cutoff point in March 2012, 21 patients had died, 12 in the bendamustine/rituximab treatment group and 9 in the standard-therapy group. The deaths of three patients in the bendamustine/rituximab] treatment group “were possibly related to treatment (pneumonia, chronic obstructive pulmonary disease, and sepsis),” the authors wrote. “Follow-up is continuing for [progression-free and overall survival], and a new study will provide further data on long-term toxicities,” the researchers added.

This trial was registered at ClinicalTrials.gov as NCT00877006. n Flinn IW, et al: Blood. March 3, 2014 (early release online).

The ASCO Post | APRIL 15, 2014

PAGE 136

Perspective Outlook on Cancer Research

Impact of Sequestration

continued from page 1

How will cancer research have to be prioritized to meet current budget limitations, and what research will have to be eliminated or never launched?

We will try to fund the most meritorious research and be responsible stewards of appropriated funds. Of necessity, we will fund less research.

presequester spending levels. In addition, the budget represents $3 billion, or about 10%, less purchasing power in current dollars compared to FY2007.

The ASCO Post talked with Dr. Lowy about how the new budget will impact cancer research at the NCI.

NCI’s FY2014 budget is a bit under $5 billion a year, which is the largest single funding amount for any institute at NIH. This is a substantial amount of money and NCI will focus on using it to fund the very best science. We are trimming some programs, and looking for and launching new efforts, including the RAS project [a $10 million

per year program to find therapies for patients with RAS mutations], to find drugs to target a family of mutated proteins that could be an Achilles’ heel of many tumor types.

The NCI continues to fund a wide range of outstanding research, from basic to applied….

Five billion dollars is still a significant amount of money, and if spent wisely, it can fund significant research.

—Douglas R. Lowy, MD

Also, in 2012 to 2013 the NCI went to great lengths to maintain the number of grants we funded in the past.

Future of Cancer Research Is the NIH experiencing a loss in cancer researchers?

There are plenty of people doing cancer research. However, some excellent researchers may be dropping out of the system due to low success rates. In addition, those low success rates in cancer research risk having the best young people taking their talents to other areas.

What are you optimistic about in terms of NCI-sponsored research?

The NCI continues to fund a wide range of outstanding research, from basic to applied. NCI-supported investigators have made great strides in the past, and this progress will continue. Five billion dollars is still a significant amount of money, and if spent wisely, it can fund significant research. n Disclosure: Dr. Lowy reported potential conflicts of interest.

no

ASCOPost.com | APRIL 15, 2014

PAGE 137

Perspective

Transition From Busy Oncologist to Retiree: Challenges and Opportunities A Conversation With Mark J. Clemons, FRCP

By Ronald Piana

O

ncology is a demanding field that requires special qualities to care for very sick patients, many of whom will die prematurely of their disease.

Research indicates that years of facing life-and-death decisions in the clinic can be associated with oncology burnout syndrome, which effects physician quality of life in a number of ways.

Over the past 2 decades, there has been increasing focus on the causes and consequences of oncology burnout; however, there has been relatively little in the literature about how oncologists adjust from a busy practice into retirement. To gain insight into this inevitable but tricky transition, The ASCO Post recently spoke with Mark J. Clemons, FRCP, Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada, who has investigated and published on the topic.1

Starting the Discussion Why did you and your colleagues begin examining oncology retirement?

In oncology, we have laser-like focus on delivering personalized medicine for our patients, and I think we sometimes forget the personalized aspects of ourselves as cancer providers.

And thinking about aging and retirement is part of that process.

A lot of colleagues wondered why I was looking at this issue and asked me who I’d spoken to. It’s sort of a hushhush subject, which is part of the problem. Although we may have informal “corridor discussions” about retirement, usually with older colleagues, there is little practical guidance for a successful transition into retirement.

As a very intense oncology career begins to wind down, there are stresses in planning for the future. We should all plan for a future beyond full-time oncology, so we thought we’d start the discussion.

Timing of Retirement When do most oncologists retire?

That’s an important question to answer when planning retirement, because if you have an estimate of when most of your colleagues retire, it helps gauge the likely duration of your own career. That said, it’s difficult to gather up-to-date data on oncologists’ retirement ages. Interestingly, we found that in the United States and Canada, most oncologists are aiming to retire at

about 64 or 65, but the majority transition into retirement in the few years after 65.

A quote I paraphrased during my research into oncology retirement was, “No one ever said on his deathbed, ‘I wish I’d spent more time at the office.’”

The relevance of that quote is simple: If we knew when oncologists tend to die, maybe we could make better choices about when we choose to retire. Although we were unable to obtain data on the average age of death for oncolo-

lenges from their counterparts in private practice. Again, a good financial advisor will be able to match investment and savings plans to your specific salary and lifestyle needs.

Sense of Loss How do oncologists generally approach the actual process of retirement?

It varies. Some of our colleagues have retired “cold turkey,” and that approach worked for them. But we also found that certain oncologists who

By 2020, 50% of the oncology workforce in the United States and Canada will be aged 65 years or older.

So on a practical level, proper planning will help our younger colleagues plan for better resource allocation as we retire. Planning ahead has benefits for the individual oncologist’s quality of life, as well as for the system overall.

—Mark J. Clemons, FRCP

gists, we know that the average age of doctors dying in the past 20 years is 77 years for all specialties; this average age is likely to increase in the future.

Planning Retirement When should oncologists begin serious retirement planning?

It’s important to retire at a reasonable age with a solid plan that lets you maintain a good standard of living.

This is especially important in the uncertain economic environment that we face. Over the past 5 years, most of us—even more so in the States—have seen our pension contributions reduced in value.

So it is vital to begin planning early, and the best way to do that is to find a financial advisor with whom you are comfortable, one who understands your particular needs. It’s an important step in developing a personalized and comprehensive financial plan. In order to maintain the lifestyle to which one has become accustomed, a common formula is that one should save enough to be able to draw 70% of preretirement annual earnings.

Naturally, salaried oncologists in academia have different sets of chal-

went the cold-turkey route got this sudden sense of emptiness in their lives.

Even though oncology is a physically and emotionally demanding profession, there’s a great deal of satisfaction and self-worth in caring for sick and vulnerable patients. So there can be sense of loss, which is associated with its own set of problems as you age. Whether to use a cold-turkey or stepwise process depends on the individual.

Are there ways to prevent post-retirement issues such as feeling a sense of loss?

We found that many oncologists try to fill their once incredibly busy lives with substitute activities. For instance, a lot of doctors said that they were going to travel more. However, that’s a bit of a clichéd answer, and if you’re not traveling before you retire, chances are that you’ll not travel after you retire— and if you do, there’s a good chance that traveling won’t fill the void you’re experiencing. But if you had a preretirement avocation such as music or painting, for instance, retirement can be a good time to expand your talents.

In other words, do something that’s re-

warding, not something to fill the time.

Moreover, if you love medicine, you can participate in research committee work or any number of volunteer projects that require medical expertise, such as mentoring younger colleagues.

Some retired oncologists find great reward in working in underserved areas, developing nutrition or pain management programs. There are also numerous study activities—such as learning about a new tumor type—that can keep you intellectually engaged in your retirement. Again, this is all part of the planning that makes for a successful and rewarding retirement.

Closing Thoughts Do you have any last thoughts on retirement after a career in oncology?

It is important not to get lost in the transition. Retirement planning is vital for oncologists to enjoy the remaining years of life. Surveys have shown that the first year is often the most stressful.

Up to 27% of retired physicians exhibit some signs of depression.

This is an incredibly complicated process, and we have no formal teaching or structure to help the retirement transition. By 2020, 50% of the oncology workforce in the United States and Canada will be aged 65 years or older.

So on a practical level, proper planning will help our younger colleagues plan for better resource allocation as we retire. Planning ahead has benefits for the individual oncologist’s quality of life, as well as for the system overall. n

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

Reference 1. Clemons MJ, Vandermeer LA, Gunstone I, et al: Lost in transition? Thoughts on retirement—“Will you still need me, will you still feed me, when I’m sixtyfour?” Oncologist 18:1235-1238, 2013.

How Are You Planning for Retirement?

Share your thoughts and expectations on retiring from a busy oncology career. Or if you already are retired, let us know how you are enjoying this next phase. Write to editor@ASCOPost.com.

T:10.25" S:9.5"

The ASCO Post | APRIL 15, 2014

PAGE 138

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

Health-Care Policy

Greatly Frustrated by Congressional Failure to Act on Sustainable Growth Rate Disappointing 12-Month ‘Patch’ Throws Oncology Practices into One More Year of Instability

T

needs of patients with cancer unless fundamental, systemic change is enacted. Congressional committees agreed on this widely supported legislation, H.R. 4015/S. 2000, which would have repealed the SGR and made meaningful progress toward addressing many of the challenges outlined in ASCO’s recently released State of Cancer Care in America: 2014 report, including disparities in access to care and the closure or consolidation of small practices that serve more than one-

T:13"

ASCO will continue to press Congress to do its job by repealing the SGR formula and replacing it with a more stable and rational system that ensures access to high-quality cancer care for all Medicare beneficiaries.

—Clifford A. Hudis, MD, FACP ASCO President

ment system. We are disappointed that this remarkable progress and hope for real change has been cast aside by partisan politics over paying for the cost of repeal. The failure of Congress to repeal SGR and to instead move forward with yet another SGR patch represents a threat to physician practices and the access of Medicare beneficiaries to high-quality, affordable cancer care. It is not a solution and simply means that we will face this crisis next year for an 18th time.

The U.S. cancer system simply cannot continue to meet the growing

The ASCO Post Wants to Hear from You

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

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

Statement by ASCO President Clifford A. Hudis, MD, FACP he American Society of Clinical Oncology (ASCO) is deeply frustrated by the failure of Congress to permanently repeal the flawed sustainable growth rate (SGR) formula used to set Medicare physician payments and passage of the 17th patch to the system.

ASCO and the entire physician community worked closely with House and Senate committees to successfully develop and pass an unprecedented bipartisan, bicameral policy to reform the broken Medicare physician pay-

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

third of cancer patients throughout the United States.

Although we are dismayed that elected leaders threw away an unprecedented opportunity to resolve a longstanding problem, ASCO will continue to press Congress to do its job by repealing the SGR formula and replacing it with a more stable and rational system that ensures access to high-quality cancer care for all Medicare beneficiaries.

For the latest developments, please visit ASCO’s SGR Web page at www .asco.org/advocacy/repeal-sgr-formula -now n

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

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

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

Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

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

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

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

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

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

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

AVASTIN® (bevacizumab) 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

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

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies.

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

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

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

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

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).]

Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

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

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

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

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

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

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

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

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

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

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

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

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

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

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

The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin.

[See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

T:10.25" S:9.5"

AVASTIN® (bevacizumab) 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

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

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

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

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

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of

a

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

AVASTIN® (bevacizumab) In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

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

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

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

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

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

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

Adverse events were encoded using MedDRA, Version 10.1.

a

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs.

5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs.

1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs.

13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs.

3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs.

2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.

Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

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

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

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

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

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

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

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

AVASTIN® (bevacizumab) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

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

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

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

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

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

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

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

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

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

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

01/14 AVA0000765906 Initial U.S. Approval: February 2004 Code Revision Date: January 2014 Avastin® is a registered trademark of Genentech, Inc. © 2014 Genentech, Inc.

S:12.5"

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

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

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

T:13"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).

In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

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

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

AVASTIN® (bevacizumab) 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

In combination with IV 5-FU–based chemotherapy in first- or second-line MCRC or fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival Avastin is the only FDA-approved biologic proven to increase OS in 3 large Phase III trials in first- and second-line MCRC

4.7 4.7

2.2 2.2

months months months

months months

Median OS Median MedianOS OS improvement* improvement* improvement*

Median MedianOS OS improvement improvement† †

1.4 1.4 months months

months

Median MedianOS OS OS ‡‡ ‡ improvement improvement improvement

First-line Study 2107:

Second-line Study E3200:

The TML study§:

A double-blind, controlled clinical trial in patients with previously untreated MCRC1,2

An open-label, controlled clinical trial in Avastin-naive MCRC patients1

An open-label, controlled clinical trial in patients who progressed on an Avastincontaining regimen1,3

*20.3 months with Avastin plus IFL (n=402) vs 15.6 months with placebo plus IFL (n=411) (HR=0.66 [95% CI, 0.54–0.81], P<0.001).1,4 13.0 months with Avastin plus FOLFOX4 (n=286) vs 10.8 months with FOLFOX4 alone (n=291) (HR=0.75 [95% CI, 0.63–0.89], P=0.001).1,4 ‡ 11.2 months with Avastin plus fluoropyrimidine-based chemotherapy|| (n=409) vs 9.8 months with fluoropyrimidine-based chemotherapy|| alone (n=411) (HR=0.81 [95% CI, 0.69–0.94], P=0.0057).1 § TML=Treatment through Multiple Lines (first and second line). || Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin → irinotecan or irinotecan → oxaliplatin.1 †

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; OS=overall survival; IFL=5-FU/leucovorin (LV)/irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indications

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

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

©2013 Genentech USA, Inc.

All rights reserved.

AVA0001557002

Printed in USA.

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

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

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

Indication-specific adverse events

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

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

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2013. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol.

2013;14:29-37. 4. Data on file. Genentech, Inc.

(10/13)

www.avastin-hcp.com