TAP Vol 2 Issue 8 by Harborside Press LLC

Electronic health records 4

Abiraterone in prostate cancer 18

VOLUME 2, ISSUE 8

Oncology drug shortage 29

MAY 15, 2011 ASCOPost.com

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

Patients, Pathways, Progress

Targeted Therapy

Lung Cancer Mutation Consortium Investigates Genetic Changes, Seeking to Reduce Associated Mortality

By George W. Sledge, Jr, MD ASCO President, 2010–2011

By Paul A. Bunn, Jr, MD

e have entered a new era in the management of patients with non–small cell lung cancer (NSCLC). To select the optimal therapy we must now distinguish between the histologic subtypes of NSCLC and we must know the gePaul A. Bunn, Jr, MD netic alterations in these cancers. Adequate biopsies are now required to ensure the right histologic diagnosis and to have sufficient DNA for genetic testing.

Activating Mutations, Corresponding Inhibitors As outlined in the accompanying TAP on Technology article that begins on page 6, patients with activating EGFR mutations fare better on an EGFR tyrosine kinase inhibitor such as erlotinib (Tarceva) or gefitinib (Iressa) compared with combination platinum-based therapy

in the first-line setting. In contrast, NSCLC patients without these mutations fare better on first-line chemotherapy—hence, the need for testing. For patients with activating mutations, erlotinib or gefitinib can be expected to produce response rates of about 70%, with median progression-free survival of about a year or more and median surSEE PAGE 23 vival times exceeding 2 years. Patients with an EML4/ALK fusion gene treated with the ALK inhibitor crizotinib in any line of therapy also have a response rate of about 70% and a median progression-free survival approaching 1 year. Although crizotinib is not yet approved by the FDA, clinical trials are widely available and FDA approval will hopefully come soon. Thus, advanced NSCLC patients should have their tumors tested for the EML4/ALK fusion as well as EGFR mutations. Genetic studies have informed us that up to 50% of lung adenocarcinomas may harbor an activating continued on page 6

Association of Community Cancer Centers

11 Critical Issues Facing Oncology Today By Al B. Benson III, MD, FACP

uring the recent 37th Annual National Meeting 1. The contentious health-care debate demands of the Association of Community Cancer Cenan informed oncology community to provide feedters (ACCC) held in Washington, DC (see coverage back to both state governments that are tackling reon page 13), a grassroots advocacy effort was reiniticord deficits and our national leadership, in particular ated with ACCC members to prevent decreased servisiting their state-specific vices and access to highcongressional offices to quality cancer care. Coming together is a address, among other 2. The rising cost of beginning. Teaching together concerns, the national oncancer care is clearly recology drug shortage and lated to the health-care is progress. Working together the importance of nursdebate, with projections of is success. ing education to patient significant increases in the —Henry Ford care. More than ever, oncost of cancer care over the cology leadership will be next few years. Also linked required at both the local to our aging population, and national levels. The complexity of these issues will which is most at risk, cost increases are worrisome mandate unity among stakeholders to address longnot only because of the impact of affordability of care and short-term solutions to the challenges, which are but also given potential negative effects on delivery of continued on page 13 listed in part as follows:

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chose “Patients, Pathways, Progress” as the theme for my term as President of the American Society of Clinical Oncology because it symbolizes what I believe the Society stands for and serves. It is also a theme that embraces my own personal relationship with the Society and its continuing work in the cancer community at large.

Patients Patients always come first. ASCO is a 28,000-member strong international society that cares for patients with cancer. All of our research and policy efforts are dedicated with laser-like attention to the core issues that concern our patients. No other cancer society is as focused on the complete array of therapies, education, and research that affects the lives of people living with cancer. Nor is any other cancer society as concerned with the intimate relationship between a cancer doctor and pacontinued on page 2

Dr. Sledge is the Ballve-Lantero Professor of Oncology and Professor of Medicine and Pathology at Indiana University Simon Cancer Center, Indianapolis.

MORE IN THIS ISSUE ASCO through the Years �� 3, 19, 42, 43 Genetic Profiling in Non–Small Cell Lung Cancer �� 6 FDA Update �� 18, 36–40 National Cancer Policy Forum ��20 Direct from ASCO ��24 Stem-cell Transplant in Multiple Myeloma ��32

A Harborside Press® Publication

The ASCO Post | MAY 15, 2011

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Perspective

Patients, Pathways, Progress continued from page 1

tient. It is a special relationship built on honesty and mutual respect.

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

Mary McCabe, RN Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology 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 Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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 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

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Ronald Piana, Matthew Stenger, Marian Wiseman

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Pathways The term “pathways” has several different meanings. First, it refers to the great scientific revolution that has occurred over the past 2 decades, during which we came to recognize that cancer cells arise from distinct pathways driving growth, invasion, and metastases. Interrupting those pathways is an enormously effective way of tackling the cancer problem in the clinic and the laboratory. But in addition to these exciting new molecular pathways, ASCO is involved in the pathways that lead new drugs to the laboratory and ultimately to our patients by way of the clinical trials system. And finally, it connotes decisions about the clinical pathway that begin when a patient is diagnosed with cancer. What is the path of care for that patient? As oncologists, we need to find a pathway that is safe, relatively pleasant, and has a positive outcome. In addition, our patients need a pathway that enables them to optimally navigate their way through the health-care system.

Progress Hopefully, progress flows from our focus on patients and the pathways that generate the best-proven care for them. From the perspective of an ASCO member, progress can be placed in the context of the advances we have made—but with an eye on the potential for losing those advances. Our health-care system is undergoing a rapid evolution, much of which will bring positive change by providing greater access to care for many of our nation’s uninsured, who in the past have been left out of the system. At the same time, the changes in the healthcare system will require exceptional attention if progress is to be maintained. To that end, ASCO is concerned about continuing our progress on the research front. Funding for the NCI and support for the clinical trials system are threatened because of budget cuts. As an organization that values progress for its patient population, ASCO needs to take a stance that fa-

On Being an Oncologist

ike many cancer care professionals, I entered the field of oncology because of specific clinical moments between doctor and patient. For me, these were experiences I had as a house officer, an intern, and a resident. In fact, I can actually point to the patient who made me a medical oncologist. She was a woman in her early 20s with leukemia. She had a couple of kids, and she died within a few weeks after her diagnosis. I was actually the one who told her that she had leukemia. After a second of stunned silence, the first words out her mouth were, “Who will take care of my children?” I was an intern at the time and had never done anything like this before. After speaking to her, I went into the stairwell and cried. Over the years, I have thought about her words. Naturally, as an oncologist I’ve accepted this very difficult part of the discipline as a responsibility and a challenge— not just for myself, but for our Society. The answer to her question, presumably, is those of us who are involved in cancer research and cancer care. We have a responsibility, both to the individual patients and to the society they live in, to develop treatments and cures for cancer. This is true not only for those of us fortunate enough to live in prosperous areas like the United States and Western Europe, but also for those in places around the world without adequate resources. “Who will take care of my children?” has remained the driving challenge throughout my career.

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—George W. Sledge, Jr, MD

vors sensible reform of the health-care system. That means we must support our national clinical trials system and even more deeply support the cancer research enterprise via the NCI. Future progress depends on continued commitment, from both ASCO and the larger medical community.

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For reflections from past ASCO Presidents, see our special feature, “ASCO through the Years,” on pages 3, 42, and 43.

ASCOPost.com | MAY 15, 2011

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Leadership

ASCO through the Years: Pearls from Past Presidents A Common Concern for Quality Care and the Patient with Cancer By Ronald Piana

On April 9, 1964, ASCO’s original founding committee met in a small room in the Edgewater Beach Hotel in Chicago. The minutes of that meeting indicate they were united by “their common concern for the patient with cancer.” ASCO’s first meeting in 1964 had slightly more than 70 attendees. This month, an estimated 30,000 people from across the globe will gather in Chicago to attend the 47th Annual Meeting of American Society of Clinical Oncology. The size and scope of ASCO today might have seemed unimaginable to the Society’s founders; however, they would be proud that the central core of ASCO’s mission has remained unchanged. To commemorate ASCO’s 47th Annual Meeting, The ASCO Post presents reflections from some of the Society’s past Presidents. For a complete list of past ASCO Presidents, see page 19.

Personalizing Cancer Care Richard Schilsky, MD ASCO President, 2008–2009

uring my Presidency we completely revamped the way the ASCO Board of Directors works by creating various subcommittees and a much more deliberate strategic planning process. In effect, the Board members took more ownership of ASCO’s agenda, planning the future of the Society rather than dealing with its multiple operational aspects. It was an important change for ASCO. My theme was Personalizing Cancer Care and I was pleased that my Presidential speech was enthusiastically received. However, as I was leaving the “Sometimes in our desire to hall a patient advocate stopped me and reach a scientific understanding said that she was very disappointed with of cancer, we forget that our my speech. I asked why? She said all I main objective is to connect talked about was molecular pathology with and care for the patient.” and genotyping. To her, personalized medicine meant that the doctor gets to know each patient as an individual and delivers the kind of personalized care they need. As physicians, our goal is to understand the needs of each patient and then provide a treatment plan built around a set of personalized needs and goals. The patient advocate’s comment made me remember that sometimes in our desire to reach a scientific understanding of cancer, we forget that our main objective is to connect with and care for the patient. I’ll never forget that encounter.

One Community

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Nancy E. Davidson, MD ASCO President, 2007–2008

y Presidential theme was One Community. I think that theme continues to express much of our goal in oncology, which is to make sure that all members of the cancer care team work together—oncologists, nurses, scientists, nutritionists, psychologists, social workers, administrators, and others. I also had the privilege to be the first President to work an entire term with “As health-care providers it is our CEO, Dr. Allen Lichter. Allen and our obligation to talk about I talked a lot about the likelihood that costs with our patients.” cost was going to be ever more important

in the overall discussion of how we deliver health care in this country. Some ASCO members felt that doctors and patients shouldn’t talk about money; they should only focus on care. However, we decided that it was unrealistic to avoid that conversation. So we launched the Cost of Care Task Force, and its first challenge was to tackle something I brought up, which was that cost is a side effect, just like losing your hair or having low blood cell counts, and as health-care providers it is our obligation to talk about costs with our patients. I’m proud of the role that ASCO is continuing to play in advocating ways to provide the highest quality of oncology care in the most cost-effective manner.

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Multidisciplinary Interactions Gabriel N. Hortobagyi, MD, FACP ASCO President, 2006–2007

s my Presidency gradually fades into the past, it is sobering to reminisce on how exciting it was. ASCO is a great organization with an amazing staff and a solid mission. Chairing the Board meetings was clearly a highlight of my Presidency because of the vast talent and collective wisdom that is brought to bear with each issue under discussion. Recruiting Allen Lichter, MD, as CEO was a thrill. In partnership with Allen, we took the first steps to make ASCO less dependent on Pharma support. Future ASCO Presidents should continue to seek alternative sources of revenue for our Society, to avoid the appearance of any conflict of interest. My theme was multidisciplinary interactions and the emphasis on serving all ASCO constituencies, especially the international membership, which “Today, thanks to a vigorous had been an “orphan” contingent for International Affairs many years. Today, thanks to a vigorous Committee, ASCO influences International Affairs Committee, ASCO oncology services on all four influences oncology services on all four corners of the world.” corners of the world, and partners with multiple regional societies in educational conferences, and the training of young oncologists. Looking forward, ASCO Presidents should use their bully pulpit to emphasize issues of quality of care, rapid translation of research into practice, championing the rights of cancer patients, and partnering with patient advocates to positively influence the political process. Despite the regulatory maze and increased bureaucracy, oncology continues to be the greatest of professions, enormously rewarding for those who practice for the right reasons—combining patient care, research, and the training of our next generation of cancer care providers.

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continued on page 42

The ASCO Post | MAY 15, 2011

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Expert’s Corner Health Information Technology

Electronic Health Records: A View from the Top By Lawrence N. Shulman, MD As told to Ronald Piana

Integrating an EHR

Lawrence N. Shulman, MD

ll parties in today’s spirited healthcare debate agree on two things: Transitioning from a paper-based system to electronic health records (EHRs) is inevitable, and the road ahead will be bumpy. The landmark 2009 American Recovery and Reinvestment Act (ARRA) laid the groundwork with massive national investment in EHRs. However, confusion over selection and implementation of these expensive systems has somewhat tempered the pace of adoption—the complexity of cancer care and a relatively limited number of oncology-specific vendors makes EHR implementation even more challenging for the oncology community. In addition, many hospitals are using general EHR systems with limited oncology functionality. In this installment of Expert’s Corner, ASCO Health Information Technology (HIT) Workgroup member Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute offers the insight of an early adopter of electronic health information systems.

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In 1992, my colleagues and I at Brigham and Women’s Hospital developed a computerized chemotherapy order entry system, which we initiated because chemotherapy ordering, preparation, and administration are highrisk procedures in oncology, an area where small mistakes can have dire consequences. In 1997, the system was brought to Dana-Farber Cancer Institute. Several years later, we designed an EHR and interconnected it with the chemotherapy order entry system. Most current EHRs supplied by vendors have both electronic medical record and order entry functionalities built in. But because we began so

ure the system to reduce the likelihood of future errors.

Vendor Option Usually Best Despite our success, I would not advise an institution to take on the challenge of organically developing its own EHR systems. Most hospitals simply do not have the wherewithal (staff, infrastructure, knowledge, and capital) to successfully accomplish such an ambitious project. A vendor option with support is usually the best option. At Dana-Farber and the Partners Healthcare System (we share our clinical information system infrastructure with them), we applied, and continue to apply, the same innovative approaches in developing our EHR

This paradigm shift in the way we gather, analyze, share, and store clinical outcomes data will eventually make our health-care system better and more cost-effective. long ago, our systems were engineered in sequence, as part of an organic, “homegrown” process. It was a laborintensive effort that required a devoted team, but in the long run it was worthwhile because during the process, we became intimately involved with the system’s multiple functionalities. Continuous learning also occurs from “near misses”—episodes where an error was made and caught somewhere in the system, and we were able to reconfig-

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 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 wendy@harborsidepress.com or fax (631) 692-0905. Copyright ©2011 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. 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 26,000 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: $225; Individual International: $275; Institutional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

systems that we do with our cancer research—we dedicate human and financial resources to be a leader in the field, continually developing new functionality, testing and analyzing, and developing anew. Even large health-care networks like Geisinger Health System or Kaiser Permanente have chosen not to develop their own systems. Implementing an EHR is a transformative journey, and for most institutions it is better to

take that journey with an accredited vendor. An exception is US Oncology, which has developed their own robust oncology EHR.

Meshing Clinical and Technologic Advances Advances in oncology disease management happen at a rapid pace; therefore, health information systems cannot be static. Our systems at Dana-Farber are analyzed and revised regularly. The chemotherapy order entry component is updated every other week. On alternate Tuesday mornings at 7:00 AM, we input new functionalities; we’ve been following this procedure for many years. The EHR component is only updated twice a year, simply because it is complex and widely deployed. The upgrades are a major undertaking, carried out under careful scrutiny, but these upgrades are critical for us to maintain a state-of-the-art system. We have dedicated committees that meet on a regular basis to prioritize what upgrades should be made. We then develop them and make sure that the functionalities are adequate. However, every time you upgrade software, despite strict safety protocols, you’re at risk of disabling or altering a function somewhere in the system. These mishaps usually happen during testing. Most are trivial, but major unwanted system changes—such as corrupting dosing formulas for chemotherapy—have occurred. A value-added benefit of our EHR process is the close and equal relationship established between physician

Correspondence: Address general inquiries to Harborside Press®, 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. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; email: leslie@harborsidepress.com. 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.” 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. 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.

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.

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PAGE 5

Expert’s Corner

end-users, oncologists, nurses, pharmacists, and the IT staff. I’ve seen other scenarios in which there hasn’t been adequate partnership between these separate but intertwined entities, resulting in suboptimal or failed efforts. To maximize success, the clinical end-users need to be fully engaged in the development and implementation processes involved.

but the hospital has its own EHR vendor system. The patients move back and forth between both care facilities, and we’ve developed significant interoperability between those systems. So, if a cancer patient is in an inpatient unit in the hospital, all of the patient’s essential medical information

from the ambulatory cancer clinic can be accessed in the hospital system, and vice versa. In effect, we have a working microsystem of what can be accomplished on a national scale. This successful venture cost several million dollars and required a lot of hard work and expertise. But it can be

done. And unless we move toward this type of nimble interoperability, our health-care system will be unable to deliver the type of high-quality, costeffective medical and cancer care that our patients deserve.

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Financial Disclosure: Dr. Shulman reported no potential conflicts of interest.

Data Outcomes Are Critical EHRs are key to monitoring outcomes and performance measurements. Dana-Farber uses EHRs to assess quality standards for our clinical practice. The chemotherapy ordering, for example, is guideline-driven, with acceptable regimens defined by disease and requiring literature support. At Dana-Farber, we also have very detailed contact with Blue Cross Blue Shield of Massachusetts that is framed around quality initiatives based on data collected monthly from our information systems. ASCO’s Quality Oncology Practice Initiative (QOPI) has made great strides in creating a culture of quality measurement and improvement. ASCO’s leadership is now working to build on this effort, moving away from manual chart extraction and retrospective reviews toward real-time data capture. The ASCO HIT Workgroup that sits under the ASCO Quality of Care Committee has been running vendor labs at the ASCO Annual Meeting and EHR symposiums for a few years. We’re encouraging the vendors to develop oncology-specific EHR systems that can be used to extract quality data.

NOW APPROVED

Interoperability A big challenge will be the development of interoperability—the ability of EHRs from different systems to communicate with each other. This paradigm shift in the way we gather, analyze, share, and store clinical outcomes data will eventually make our health-care system better and more cost-effective. In particular, an oncology office practice EHR should be able to bilaterally communicate with its hospital EHR. Dana-Farber is working on interoperability. We have established several ambulatory cancer centers in the northeast. Some of these ambulatory cancer centers sit next to community hospitals—partnerships, if you will. For instance, we have an ambulatory cancer clinic next to South Shore Hospital in southeastern Massachusetts. The ambulatory cancer center utilizes the EHR we use at Dana-Farber’s main campus,

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TAP on Technology Targeted Therapy

Genetic Profiling in Non–Small Cell Lung Cancer By Matthew Stenger

pproximately 2% to 7% of paGrowing List of Genetic observed in 47 (57%) of 82 patients, As noted by the authors, the rate Alterations tients with non–small cell lung with partial response in 46 and comand speed of response observed with ALK rearrangements join a growcancer (NSCLC) have tumors with plete response in 1, and stable disease crizotinib were similar to those with ing list of genetic abnormalities incoroncogenic fusion genes consisting of was observed in 27 additional patients EGFR (epidermal growth factor reporated into analysis for oncogenes in portions of the echinoderm microtu(33%). These outcomes compare very ceptor) tyrosine kinase inhibitors in NSCLC tumors. A currently available bule-associated protein-like 4 (EML4) favorably with an estimated response EGFR-mutant NSCLC, indicating lung cancer mutation panel tests for gene and the anaplastic lymphoma kirate of 10% associated with secondthat ALK-positive tumors are a secEGFR, KRAS, and ALK mutations that nase (ALK) gene (EML4-ALK). In a line chemotherapy in such patients. ond genetically defined subgroup of predict response and study recently reportlack of response to ed by Kwak et al in The targeted therapies in New England Journal of NSCLC. The presMedicine, the oral ALK ence of each of these tyrosine kinase inhibioncogenes is almost tor crizotinib showed always exclusive of remarkable activthe presence of the ity in patients who had other two within an NSCLC with these individual tumor. ALK gene rearrangeActivation of ments. Screening of the EGFR tyrosine nearly 1,500 NSCLC kinase (via ligand patients identified 82 binding of EGFR) patients (5.5%) with results in activation advanced ALK-posof signaling pathways itive disease, 96% of Fig. 1: Schematic illustration showing how the aberrant fusion gene EML4-ALK encoding a cytoplasmic chimeric protein is formed through break points on the EML4 and ALK genes. Horizontal arrows show the direction of transcription. for cell growth and whom had received survival. EGFR tyroprior treatment. ALK sine kinase inhibitors such as erlotinib rearrangements tended to occur in tuEstimated probability of progressiononcogene-driven lung cancer that is (Tarceva) and gefitinib (Iressa) block mors of younger patients, with most free survival at 6 months was 72%, highly susceptible to targeted therapy. activation of the signaling pathways. having little or no exposure to tobacco with median survival not yet reached If it is assumed that 5% of patients with EGFR mutations (eg, exon 19 dele(never = 76%, ≤ 10 pack-years = 18%, at the time of analysis. The most comNSCLC have tumors that harbor ALK tions, L858R, L861Q, and G719A/ > 10 pack-years = 6%) and most havmon adverse events were grade 1 or 2 rearrangements, it can be estimated C/S) activate the EGFR in the absence ing adenocarcinoma (96%). gastrointestinal side effects and mild that approximately 8,800 patients per of ligand and confer greater likelihood After a mean treatment duration of vision disturbance. Grade 3/4 ALT year in the United States alone would of response to these kinase inhibitors. 6.4 months at a crizotinib dose of 250 and AST elevations each occurred in be eligible for crizotinib or other ALK continued on page 8 mg twice daily, confirmed response was 6% of patients. kinase inhibitor therapy.

Lung Cancer Mutation Consortium

features and to one another, and to place patients harboring these genetic changes on clinical trials of specific in-

a Grand Opportunities grant mechanism. The members of the consortium are listed in the sidebar on page 8. A

shown in Fig. 1 below. To date, more than 900 of the expected 1,000 cases continued from page 1 have been enrolled, and more than mutation driving the 50% of these have a tumor for which there genetic alteration in are known specific inone of the genes tested. Mutated Drug Classes KRAS mutations Frequency Gene Under Study hibitors. Among these There will be presentaare KRAS, NRAS, tions of the data at the KRAS/ 25% ARQ197+erlotinib EGFR mutations NRAS 1% GSK MEKi BRAF, HER2, MEK1, ASCO Annual Meeting BRAF mutations PIK3CA, and AKT1 in Chicago in June and OSI906+erlotinib EGFR 23% MM121+erlotinib in addition to EGFR. at the World ConferEML4-ALK translocation Non–small cell lung ence on Lung Cancer in NRAS 1% GSK MEKi cancers may also be Amsterdam in July. MEK mutated GSK BIBW 2992 HER2 2% driven by amplificaWith the finding FGFR4 mutated PF-02341066 tion of MET as well that lung cancer morEML4/ALK 7% (crizotinib) PIK3CA as fusion of ALK, with tality can be reduced GSK1026 for V660E BRAF 6% both being assessable by 20% or more by anGSK MEKi for HER2 mutations by fluorescence in situ nual spiral CT scans PI3K/AKT 5% BIM120 Pending hybridization (FISH). in high-risk subjects as Crizotinib MET ampl 5% well as these improveConsortium ments in therapy, we Fig. 1: Molecular subtypes of lung adenocarcinoma being tested by the Lung Cancer Mutation Consortium. Source: Ding L, et al: Protocols can expect a continued Nature 455:1069-1075, 2008; Yamamoto H, et al: Cancer Res 68:6913-6921, 2008. Courtesy of Paul A. Bunn, Jr, MD. To determine the reduction in lung canprecise frequency of these genetic hibitors, the NCI has funded the Lung summary of the genetic testing and cer mortality—a tribute to scientific alterations, their relation to clinical Cancer Mutation Consortium through some of the activated protocols are advances.

■

The case for Vectibix® Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION: Vectibix® is indicated as a single agent for the treatment of occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus

epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical irinotecan-containing chemotherapy regimens. studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing pulmonary fibrosis and resulted in death. The second patient had symptoms of mCRC is based on progression-free survival. Currently, no data demonstrate an pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently improvement in disease-related symptoms or increased survival with Vectibix®. discontinue Vectibix® therapy in patients developing interstitial lung disease, Retrospective subset analyses of metastatic colorectal cancer trials have not shown pneumonitis, or lung infiltrates. a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in In a randomized, controlled clinical trial, median magnesium levels decreased by codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring cancer with these mutations. oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred Important Safety Information, including Boxed WARNINGS: 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and treatment (eg, oral or intravenous electrolyte repletion) as needed. were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months (5.1), and Adverse Reactions (6.1)]. after the last dose. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have patients. Fatal infusion reactions occurred in postmarketing experience. [See been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Interrupt or discontinue Vectibix® for acute or worsening keratitis. Reactions (6.1, 6.3)]. Adequate contraception in both males and females must be used while receiving In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to transmitted from the mother to the developing fetus and has the potential to cause the development of severe dermatologic toxicities, infectious complications, including fetal harm when administered to pregnant women. sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and Discontinue nursing or discontinue drug, taking into account the importance of the drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening drug to the mother. If nursing is interrupted, it should not be resumed earlier than dermatologic toxicity and monitor for inflammatory or infectious sequelae. 2 months following the last dose of Vectibix®. Terminate the infusion for severe infusion reactions. The most common adverse events of Vectibix® are skin rash with variable presentations, Vectibix® is not indicated for use in combination with chemotherapy. In an interim hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including analysis of a randomized clinical trial, the addition of Vectibix® to the combination of diarrhea resulting in dehydration. ® bevacizumab and chemotherapy resulted in decreased overall survival and increased The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion adverse reactions occurring at a higher rate in patients treated with Vectibix® included reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration Please see brief summary of Prescribing Information on next page. (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Reference: 1. Vectibix® (panitumumab) stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade prescribing information, Amgen. 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®. In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

The ASCO Post | MAY 15, 2011

PAGE 8

TAP on Technology Targeted Therapy

Genetic Profiling of NSCLC continued from page 6

Other rare mutations (eg, T790M and exon 20 insertion) are associated with resistance to these agents. Activating mutations are found in approximately 40% of East Asian patients and 10% to 15% of Caucasian patients. These muta-

tions are more common in patients with no smoking history (although they are also found in smokers), females, and adenocarcinomas (although they are also found in squamous cell tumors). Patients with these mutations have a greater than 70% of response Trim:likelihood 7.875” to erlotinib or gefitinib. Live: 7”

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

In NSCLC, EML4-ALK is an aberrant fusion gene (see Fig. 1) encoding a cytoplasmic chimeric protein with constitutive kinase activity. Several distinct EML4-ALK chimeric variants have been identified (representing breakpoints within different EML4 exons), with all of

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations]. Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v11, 3/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-E

these variants found to be transforming in vitro. As noted, EML4-ALK is more common in patients with no/light smoking history and in adenocarcinomas. In the study by Kwak et al, none of the 82 patients with ALK rearrangement had activating EGFR mutations. In addition to EML4, other fusion partners for ALK (eg, KIF5B and TFG) have been identified in NSCLC, suggesting that ALK rearrangements may constitute a molecular subgroup of tumors susceptible to ALK kinase inhibition. It should be noted that mutations in EML4ALK that confer resistance to crizotinib (C1156Y and L1196M) have already been identified in a patient with NSCLC with a strong initial response to the agent.

Conclusions Mutations in EGFR and EML4-ALK fusions are important determinants of response to targeted treatments in continued on page 10

Lung Cancer Mutation Consortium Sites and Primary Investigators* Dana-Farber Cancer Institute Bruce E. Johnson, MD Winship Cancer Institute of Emory University Fadlo Khuri, MD H. Lee Moffitt Cancer Center Eric Huara, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Stephan Baylin, MD Trim: 10.75” Live: 10”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information]. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information]. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression 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 specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Predictive/Prognostic Value

MD Anderson Cancer Center/ Ignacio Wistuba, MD Massachusetts General Hospital Cancer Center Jeffrey Engleman, MD Memorial Sloan-Kettering Cancer Center Mark G. Kris, MD

National Cancer Institute–Intramural Activities Giuseppe Giaccone, MD UCLA/Jonsson Comprehensive Cancer Center Steven Dubinett, MD University of Colorado Cancer Center Paul Bunn, MD University of Pittsburgh Cancer Institute Jill Siegfried, MD UT Southwestern Simmons Comprehensive Cancer Center Joan Schiller, MD Vanderbilt-Ingram Cancer Center William Pao, MD, PhD Medical University of South Carolina George Simon, MD *See related story on page 6.

ALOXI provides powerful CINV prevention that can’t be ignored. ®

Proven CINV prevention in a single IV dose • Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy 1,2 • Lasts long against nausea following moderately emetogenic chemotherapy 3 • Powerful acute CINV prevention following highly emetogenic chemotherapy 4 • Eisai offers a variety of support programs and resources

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083A 08/10

The ASCO Post | MAY 15, 2011

PAGE 10

TAP on Technology

Genetic Profiling of NSCLC continued from page 8

NSCLC. Genetic tests to identify the presence of all of these alterations will greatly aid in selecting appropriate therapy, avoiding unnecessary use of treatments in significant segments of the

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists. 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 reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=194) (N=633) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and ﬂatulence.

population. The use of genotyping to detect these alterations is likely to become standard practice in this setting. Work is ongoing to identify other genetic drivers of NSCLC tumorigenesis and to bring us another step closer to personalized treatment of this disease.

■

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron 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 and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, 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.

Resources Choi YL, Soda M, Yamashita Y, et al: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734-1739, 2010. Hallberg B, Palmer RH: Crizotinib— latest champion in the cancer wars? N Engl

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert.

J Med 363:1760-1762, 2010. Jackman DM, Miller VA, Cioffredi L-A, et al: Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated nonsmall cell lung cancer patients: Results of an online tumor registry of clinical trials. Clin Cancer Res 15:5267-5273, 2009. Kwak EL, Bang Y-J, Camidge R, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010. Massachusetts General Hospital Cancer Center: Tumor genotyping brings personalized, targeted therapies to patients. In: Advances at the Mass General Cancer Center, Summer 2010. Available at http:// www.massgeneral.org/cancer/assets/ pdfs/Advances_TRL.pdf. Massarelli E, Varella-Garcia M, Tang X, et al: KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 13:2890-2896, 2007. Quest Diagnostics: Lung cancer mutation panel (EGFR, KRAS, ALK). Available at http://www.questdiagnostics.com/hcp/ intguide/jsp/showintguidepage.jsp?fn=TS_ LungCancerMutation_Panel.htm. Sasaki T, Rodig SJ, Chirieac LR, et al: The biology and treatment of EML4-ALK nonsmall cell lung cancer. Eur J Cancer 46:17731780, 2010. Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with non-small–cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009.

Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

Bernard Fisher, MD, was up to his neck in information sent to him by the ASCO headquarters during his tenure as the 29th President of the American Society of Clinical Oncology, 1992–1993. For recollections from other past ASCO Presidents, see pages 3, 42, and 43 in this issue of The ASCO Post.

ASCOPost.com | MAY 15, 2011

PAGE 11

OncologyWorldwide Renowned International Oncologist Once Served as a Flying Doctor in Africa By Ronald Piana

Volker Diehl, MD

The worldwide oncology community possesses a common language based on evidence, clinical trials, and shared anecdotal results of the day-to-day care of patients with cancer. However, diverse political, economic, and cultural issues in different geographic regions present varying challenges to the delivery of oncology services. Oncology Worldwide explores those similarities and differences on an occasional basis.

olker Diehl, MD, Professor of Medicine, Emeritus, University of Cologne, Germany, recently shared a snapshot of his oncologic journey with The ASCO Post.

the United States to work in the laboratory of Drs. Werner and Brigitte Henle in Philadelphia. There, I succeeded in transforming the first lymphocytes in vitro with the Epstein-Barr Virus (EBV); and by serendipity, once again, I discovered that EBV causes infectious mononucleosis. An exciting first step—what followed? I was fortunate to receive a grant to work in East Africa, flying around Kenya, Tanzania, Uganda, and Sudan with the great Dr. Denis Burkitt in the Flying Doctor Service, an air ambulance enterprise established in 1957 as part of the African Medical and Research Foundation. Our mission was to study whether infectious mononucleosis also occurs in children with Burkitt lymphoma, a disease found

medical oncologist, getting involved in clinical and basic research in Hodgkin lymphoma in Sweden, a well-to-do country in which there is an abundance of this disease. When I started my clinical work at the Radiumhemmet, Karolinska University Hospital in Stockholm, I got very mad at Hodgkin lymphoma. Remember, in 1969 it still killed 70% to 80% of the young patients with advanced stages of “Hodgkin’s disease,” as it was called at that time.

Next Steps Where did your anger at Hodgkin lymphoma lead? In 1969, we did not know whether it was a real tumor, an inflammatory process, or an aggressive infectious

It is a breakthrough that we can cure about 90% of patients with Hodgkin lymphoma and are able to give patients with high-grade non-Hodgkin lymphoma a 50% to 60% chance of being cured, which was not imaginable 10 to 20 years ago. —Volker Diehl, MD

Career Beginnings What inspired you to become an oncologist? I became an oncologist by serendipity. I did my thesis on tissue culture work with monkey kidney cells in an attempt to disprove Warburg’s theory that cancer cells continue to use glycolysis in the presence of oxygen for their energy supply. While culturing cancer cells in vitro, I started research in virology. In 1966, I was invited to

frequently in East Africa. While there, I got involved in treating children with Burkitt lymphoma in the radiotherapy department at the Kenyatta Hospital in Nairobi, Kenya. Following my year in East Africa (the most exciting time of my life) I went to Stockholm, Sweden, and began work at the Karolinska University Hospital, primarily as a radiotherapist. Afterward, I started my training as a

Clinical Milestones Recalled by Volker Diehl ■■ Recruitment of patients with cancer into clinical trials and the operational institution of comprehensive cancer centers across Germany, similar to the structure of U.S. comprehensive centers

■■ The advent of personalized therapy with molecular compounds such as

HDAC inhibitors, mTOR inhibitors, and target-specific antibodies such as rituximab (Rituxan), bevacizumab (Avastin), brentuximab vedotin, and others

■■ The development of more precise molecular/genetic diagnostic tools and imaging procedures for metabolic and morphologic diagnostics

disease. We discovered that EBV was indeed involved in the pathogenesis of Hodgkin lymphoma, but its role was still blurry at this time—the clinical picture of drenching night sweats, fever, lymph node enlargement, itching, and other signs of infectious processes did not necessarily lead us to consider this disease as a true cancer entity. I attempted to culture the tumor cells in vitro; the so-called ReedSternberg cells—at that time, we did not know their origin, clonality, and cellular identity—to get in closer in the fight with Hodgkin disease. It took me 10 years and 427 failed attempts to grow the first in vitro Hodgkin tumor cell line, the famous L428 cell line. It was the first Hodgkin cell line ever grown in vitro, which later became the “in vitro masterpiece” for thousands of laboratories around the world and was used to elucidate the pathogenic mechanisms behind the transformation of a

normal germinal B lymphocyte into a fragile, malignant, monoclonal cell with the capacity to attract “innocent bystander cells” of the innate immunity armamentarium to form its specific protective environment.

German Hodgkin Study Group How did you apply this growing body of scientific knowledge? In 1972 I went back to Germany. In 1978, while doing my medical fellowship at the University in Hannover, I was asked by the German Federal Ministry of Research and Technology to initiate a Clinical Cooperative Trial Group and research program for patients with Hodgkin lymphoma. The overriding purpose was to standardize treatment for patients with this disease. To that end, I founded the German Hodgkin Study Group (GHSG), initially with three centers and only five patients recruited to the study in the first year. Today, the GHSG is the largest and most renowned study group in Hodgkin lymphoma research worldwide. In 2011, about 450 centers all over Europe participate in the 6th generation of GHSG studies, with approximately 20,000 Hodgkin lymphoma patients documented in the computer in Cologne. Of the 2,000 newly diagnosed patients in Germany, about 1,400 to 1,600 per anno are included in the studies; approximately 85% of patients with the diagnosis are treated according to the GHSG protocols every year in Germany, in private hematology practices and in small and large community hospitals.

Research and Health Care in Germany What do you see as differences between the practice landscapes in Germany and the United States? In Germany, the government supports university hospitals. Each director of a university clinic oversees from 20 to 30 doctors, each of whom has a regular salary granted by the state government (16 states in Germany). Research efforts are supported by the Federal Research Foundation continued on page 12

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MAY 15, 2011

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Oncology Worldwide Perspective

Volker Diehl, MD continued from page 11

(Deutsche Forschungsgemeinschaft) and third-party donations from cancer societies, philanthropic foundations, private sponsors, or industry. Every doctor working at an academic institution is expected to engage in basic or

clinical research. There are 260 health insurance companies in Germany; every person must be insured. About 15% of your salary is withdrawn automatically for health insurance and 18% for retirement funds. Only 10% of German citizens are privately insured. There

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are around 250 private hematologyoncology practices in Germany; every large community hospital and university hospital has medical oncology and radiotherapy departments. Most patients with cancer are diagnosed and treated in 1 of 12 comprehensive cancer centers in close coop-

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We need to conduct clinical trials on a global scale, not only in orphan cancers, but also in rare adult tumors. eration with regional referring cancer centers and private hematology-oncology practices. For the hematologic cancers, up to 80% of patients are treated in clinical trials according to protocols. For solid tumors, this number is much lower, about 5% to 20%.

Future of Oncology Do you have any last thoughts about the state of oncology moving forward? Continued progress in oncology is only possible when we join forces globally in health research, health management, and basic and clinical research. We need to conduct clinical trials on a global scale, not only in orphan cancers, like pediatric tumors, but also in rare adult tumors such as Hodgkin lymphoma, myeloma, and others. Breakthroughs in the big killercancers like lung, breast, colorectal, and prostate can only be achieved by an intimate liaison between the pharmaceutical industry, basic biogenetic research labs, bioinformatics institutions, and visionary clinicians who have conquered their egos. And last but not least, we need more patients who are willing to cooperate by enrolling in clinical trials, from phase I to phase III. ASCO and ASH are mediators and the Societies provide wonderful arenas in which to foster and promote these various ideas and endeavors.

â&#x2013;

Visit The ASCO Post at

The ASCO Annual Meeting The ASCO Post Booth 3039 Harborside Press Booth 13068

ASCOPost.com | MAY 15, 2011

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ACCC 37th Annual National Meeting Improving Patient Outcomes in an Era of Declining Reimbursement By Ronald Piana

s few as 5,000 community oncologists care for upward of 80% of the nation’s patients with cancer. According to Chris Beardmore, CEO of Translational Research Management (TRM), this vital group of community practitioners needs to use extreme caution or face an untenable loss of revenue. Speaking at the 37th Association of Community Cancer Centers (ACCC) Annual National Meeting in Washington, DC, Mr. Beardmore said that since the passage of the Medicare Modernization Act of 2003, declining reimbursements began a slow, but ineluctable trend in community cancer care. “If you reimburse oncologists with an average sale price model plus 6%, you need to assume that every practice is on equal footing, which isn’t the case. Larger group purchasing organizations are getting better

11 Critical Issues continued from page 1

Al B. Benson III, MD, FACP

complex integrated oncologic services, access to quality care, and innovation (including research). 3. Oncology drug shortages are now the topic of headline news (see page 29), resulting in suboptimal treatment for some patients. A thorough investigation of these shortages is mandatory and requires a proactive approach to prevent potential harm to our patients. 4. The projected workforce shortages are upon us with no current adequate solution to enhance the required numbers of medical oncologists, radiation oncologists, and nurses, a phenomenon that will have significant consequences in providing access to care and integration of essential oncology services. 5. The clinical trials crisis has resulted in a further decrease in the percentage of patients participating in clinical trials, according to recent reports. Inadequate funding of clinical research, particularly in the public sector, is a worsening phenomenon that continues to be inadequately ad-

pricing, perhaps 1% to 2%. That means that the margin for a midsized or small oncology practice is as little as 3%.” Mr. Beardmore explained that if a practice fails to sufficiently collect from patients and insurance companies to guarantee that they get that needed percentage of markup, the chemotherapy debt incurred has the potential to drive the entire practice underwater. This shaky reimbursement scenario plus a rising competitive bar with the growth and development of “superregional” cancer centers is reshaping much of the community landscape.

Physician-Hospital Relationships

Benefits of a Clinical Trial Site Network ■■ Greater access to clinical trials and novel therapeutics ■■ Nationwide master clinical trial agreements/budgets ■■ Standardization of fees ■■ Use of centralized institutional review boards/independent ethics committees

■■ Operational input on study design ■■ “Just in time” study launcha A “just in time” approach would make a study available to many more sites than are typically involved in a small study. When any site in this contracted network encounters an appropriate patient, that site would be “launched” into the study, getting the regulatory work done, conducting a site-initiation visit, and getting an IRB approval quickly enough to get the patient onto the study (just in time). Particularly for studies of rare malignancies, this approach would likely be faster and more cost-effective than the current way of doing things. a

In the 1990s, community cancer centers experimented with oncology practice acquisitions. While aspects of that trend went quite well (in that they

were certainly better equipped to provide coordinated multifaceted care), for a variety of reasons those relation-

ships began to break apart, and oncologists who were working at community

dressed. In addition, there is the growing need for a new paradigm in clinical trial design that—rather than focusing on an empiric approach—emphasizes strategies to enhance our understanding of tumor biology and patient selection. This ambitious shift in paradigm requires significant resources that can only be obtained by collaboration among all stakeholders, including the pharmaceutical industry, government, academia, patients, community practices, regulatory agencies, and insurers. 6. The U.S. cancer clinical trials enterprise is in further peril, particularly in the public sector. Among the reasons for this threat include the

7. The fusion of evidence-based pathways/guidelines and the art/ practice of medicine must be accepted by all participants, and that merging process will be increasingly scrutinized and linked to reimbursement. Patients, the medical community, and insurers will need to embrace an evidence-based practice model if we intend to offer the highest-quality care with judicious use of resources. This evidence-based medical strategy must include clinical research as a routine component of effective oncologic care. 8. The changing practice environment will require close monitoring. Trends such as corporate acquisition of

and efficiency. Models should also reflect the current importance of palliative and survivorship care. 10. The oncologist’s role in comparative effectiveness research (CER) discussions must be emphasized. Concerns reflect the recognition that an appropriate data infrastructure must be developed that will include the integration of analyses based on molecular profiling to best identify appropriate subpopulations of patients most likely to benefit from a given treatment approach. It is also critical to assess any impact of CER on innovation and practice workload, as well as on guidelines and reimbursement. 11. Finally, it is critical that we readdress the relationships among investigators, practitioners, and the pharmaceutical device/diagnostic industries. We must have a transparent partnership while at the same time strongly discouraging the creation of oncology enterprise silos as a means of preventing conflicts. True scientific partnerships are essential if we are to effectively offer the necessary investigator expertise to industry to develop the most robust publicly and privately supported trials for our patients. CME should be a component of these discussions. The growing complexity of oncologic treatment based on biologic principles will require access to continual education for our workforce. One goal of these discussions should be the development of platforms on which to build collegial partnerships

The entire health-care enterprise must interact as a partnership to develop the necessary strategies, so that we can offer continued patient access to innovative and quality cancer care. movement of clinical trials to other countries, stagnant patient participation, increasing regulatory demands, an increasingly restricted workforce, and a reliance on philanthropy and voluntary efforts that may not be sustainable given our current economic environment. The increasing development of clinical trials away from U.S. shores has critical ramifications such as fewer patient treatment options, stifled innovation, and limited physician experience working with new agents.

practice networks, the loss of smaller community-based practices, and the integration of oncology practices into the hospital setting warrant debate about physician independence and decision-making, economics of treatment delivery, and integration of innovation and clinical trial support in the practice environment. 9. Innovative practice models should be encouraged to better integrate necessary oncology services to all patients with comfort, compassion,

continued on page 14

The ASCO Post | MAY 15, 2011

PAGE 14

News Association of Community Cancer Centers

Improving Patient Outcomes continued from page 13

hospitals went into private practice. The ongoing health-care debate is once again raising the possibility that community oncologists will return to the hospital practice environment. “The current financial pressures they’re feeling, along with perceived opportunities presented by accountable care organizations, are ultimately bringing them back into a position where they may need to develop a relationship with a hospital,” said Mr. Beardmore. He said that in today’s environment it is important to structure novel physicianhospital relationships so that the community oncologist can get the benefits of collaboration. “Moreover, to ensure that patient outcomes are continually improving, participation in complex clinical trials is ever so important,” said Mr. Beardmore. At the same time, Mr. Beardmore cautioned that a physician-hospital relationship does not have to follow an ownership model. “Community oncologists are fiercely independent, and I’m not entirely certain they

want a fixed salary and to be put into a position in which the hospital influences their clinical autonomy,” said Mr. Beardmore. He added that a wellstructured physician-hospital relationship provides clinical and financial value to community-based physicians and improves clinical collaboration,

gram Standards found that only 2% to 4% of adults participate in clinical trials and SEE PAGE 23 a worrisome 84% of patients are unaware of this treatment option. Mr. Beardmore said that phase I and

but does not affect the doctor-patient relationship.

Research Hubs One long-standing issue in oncology is lack of participation in cancer clinical trials. The American College of Surgeons Commission on Cancer Pro-

An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients…

Start With SPRYCEL (dasatinib) SPRYCEL: Superior Response Rates vs Imatinib • Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259) vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519) at a minimum follow-up of 12 months1,2 — Primary endpoint was conﬁrmed complete cytogenetic response (CCyR)† by 12 months

Major Molecular Response (MMR)‡ at Any Time1

11 Critical Issues

■

MMR at Any Time

continued from page 13

while avoiding examples of unacceptable behavior that have promoted the current rhetoric. “Coming together, teaching together, and working together” is the formula for our oncology community to achieve success in addressing the challenges outlined herein. The entire health-care enterprise must interact as a partnership to develop the necessary strategies, so that we can offer continued patient access to innovative and quality cancer care. Our professional societies, including oncology state medical societies, can help provide the tools to address the complexity of issues at both the local and national level. As exemplified by the recent ACCC grassroots advocacy effort, we are back and need to come back again and again as the advocates for our patients and profession.

52% SPRYCEL (95% CI, 46-58)

P<0.0001§

34%

SPRYCEL (n=259) Imatinib (n=260)

Imatinib (95% CI, 28-40)

50 60 MMR (%)

100

• Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1 • Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1 • Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with imatinib (n=177)1

Select Important Safety Information • SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related events; ﬂuid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial infarction; and use in pregnancy

Financial Disclosure: Dr. Benson reported no potential conflicts of interest.

• The most frequently reported serious adverse events in patients with newly diagnosed CP CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%)

Adapted in part from Benson AB: Profile of action. ACCCBuzz. Posted March 18, 2011. Available at acccbuzz.wordpress.com.

• The most frequently reported adverse reactions reported in ≥10% of patients with newly diagnosed CP CML included myelosuppression, ﬂuid retention events (pleural effusion, superﬁcial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash

Dr. Benson is Professor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, and Immediate Past President of the Association of Community Cancer Centers.

• Please see detailed Important Safety Information on adjacent pages

Indication SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome.

ASCOPost.com | MAY 15, 2011

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News

II trials have extensive time elements involved in collecting samples (pharmacokinetic, pharmacodynamic, pharmacogenomic), and in some instances they require that the participants be in a health-care facility for up to 10 hours a day. The inherent complexity of these trials and the attendant burdens placed

on the providers and their patients work against the system. “The general idea behind TRM is that we can actually form a novel relationship between a community cancer center and a group of community oncologists, in which complex phase I clinical trials are coordinated and car-

ried out within the ‘hub’ facility,” said Mr. Beardmore. “As trials move to phase II or III—studies that do not involve intensive sample collection— they can be integrated back to the community practices where the patients are ultimately going to be treated.” “What I foresee is a synergistic envi-

for Superior Response vs Imatinib in 1st Line

Start With Convenient Once-Daily Dosing

1 pill 100 mg 1 time per day

One tablet taken consistently, either in the morning or in the evening Tablets should not be crushed or cut; they should be swallowed whole Tablet not actual size.

• In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient1

SPRYCEL Can Be Taken Either With or Without Food1

FASTING

SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with: • No fasting requirements • No need to alter meal schedules • No need to take with food

Important Safety Information About Drug Interactions • Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should be avoided • Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided • Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided • Concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy is needed, the dose should be given 2 hours before or after SPRYCEL *Stratified by Hasford risk score.2 Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1 ‡ MMR (at any time) was defined as BCR-ABL ratios ≤0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples standardized on the International Scale.1 †

Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1

Please see detailed Important Safety Information, including Important Safety Information on Drug Interactions, on adjacent pages.

ronment in which the hospital basically provides the centralized support system for early and complex studies; but when it comes to first- and second-line care of patients or research in the adjuvant setting, the study would be conducted in the community setting, because this is continued on page 16

The ASCO Post | MAY 15, 2011

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News

Improving Patient Outcomes continued from page 15

where most of these patients would prefer to be seen,” said Mr. Beardmore. He stressed that by using this synergistic approach, community practices do not lose valuable revenue stream or the handson continuum of care they would by send-

ing their trial patients to academic centers.

Nationwide Networking “We’re spending a great deal of money to conduct clinical trials, and a lot of those precious research dollars are being wasted on redoing certain activities multiple times. However, we can de-

crease much of that waste by coordinating a nationwide network of our clinical trial sites,” said Mr. Beardmore. “The first step is to establish a master agreement that would cover hundreds if not thousands of study sites. Then we can get rid of the excess time negotiating issues like indemnification

language, which really doesn’t change from trial to trial,” he said. “The second important benefit of the network,” continued Mr. Beardmore, “is that we can begin to identify costs at ancillary service providers, such as the cardiologists doing echocardiograms, radiologists doing CTs, or the labs that

Important Safety Information Myelosuppression: • Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities — Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated — Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation — Hematopoietic growth factor has been used in patients with resistant myelosuppression Bleeding-Related Events: • SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans — In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients • Most bleeding events were associated with severe thrombocytopenia — Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants Fluid Retention: • SPRYCEL is associated with fluid retention — In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported in these trials • Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray • Severe pleural effusion may require thoracentesis and oxygen therapy • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids QT Prolongation: • In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval) • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms • In clinical trials of patients treated with SPRYCEL (n=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL. Nursing Mothers: It is unknown whether SPRYCEL 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 to discontinue SPRYCEL.

ASCOPost.com | MAY 15, 2011

PAGE 17

News

are running specimens. This would give a better estimate of the total cost of the trial prior to design and launch.” According to Mr. Beardmore, a nationwide network would also remove much of the excess time spent on prestudy visits and clinical trial agreements, focusing that energy on what the budget is going

to be for the study, the site initiation visits to train physicians to properly implement the trial, and the quality of forms and systems used to request medical services in support of a clinical trial. “As we move toward comparative effectiveness research and personalized medicine, we are going to see trials that

are incredibly focused, and patients are going to be selected because their cancer expresses certain characteristics. A nationwide network would help accrue large enough numbers of select patients across the system to conduct this vital clinical research within a shorter time period,” concluded Mr. Beardmore.

Drug Interactions: SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4. • Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided • Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL • Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. • In newly diagnosed chronic phase CML patients: — The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) — The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash — Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%) • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML — Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption — Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

Please see brief summary of full Prescribing Information on adjacent pages. References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb. 2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

For more information online, visit www.sprycel.com.

■

Financial Disclosure: Mr. Beardmore is CEO of Translational Research Management, a company interested in creating a nationwide community oncology research network. In addition, TRM supports the conduct of industrysponsored clinical trials at network sites. He has no ownership in the community oncology sites, the biopharmaceutical companies he works with, or the products being tested.

The ASCO Post | MAY 15, 2011

PAGE 18

FDA Update

FDA Approves Abiraterone for Late-stage Prostate Cancer

he FDA has approved abiraterone acetate (Zytiga) in combination with prednisone to treat patients with metastatic castrationresistant prostate cancer who have received prior docetaxel therapy. Abiraterone is an oral agent that targets

cytochrome P450 17A1 (CYP17A1), which plays an important role in the production of testosterone. The drug works by decreasing the production of this hormone that would stimulate cancer cells to continue growing. The application was reviewed un-

der the FDA’s priority review program, which provides for an expedited 6-month review for drugs that may offer major advances in treatment, or provide a treatment when no adequate therapy exists. Abiraterone is being approved ahead of the product’s

SPRYCEL® (dasatinib) Tablet for Oral Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data will be required to determine long-term outcome. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens. Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse Reactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens. QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms. Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Use in Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings and Precautions]. • Bleeding related events [see Warnings and Precautions]. • Fluid retention [see Warnings and Precautions]. • QT prolongation [see Warnings and Precautions]. • Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions]. 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 described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively). The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 1). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML

June 20, 2011 regulatory goal date. Abiraterone’s safety and effectiveness were established in a clinical study of 1,195 patients with latestage castration-resistant prostate cancer who had received prior treatment with docetaxel chemotherapy.

included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and Table 2 for CML patients with resistance or intolerance to prior imatinib therapy. Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 cardiac dysfunctiona Pericardial effusion 2 <1 <1 0 Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 b 11 17 0 1 Rash Nausea 9 21 0 0 Fatigue 8 11 <1 0 Myalgia 6 12 0 0 6 5 1 1 Hemorrhagec Gastrointestinal bleeding 2 <1 1 0 d 5 5 0 1 Other bleeding CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

Table 2:

Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 100 mg Once Daily

Preferred Term

Fluid Retention Superficial localized edema Pleural effusion Generalized edema Pericardial effusion Congestive heart failure/ cardiac dysfunctiona Pulmonary edema Headache Diarrhea Fatigue Dyspnea Musculoskeletal pain Nausea Skin rashb Myalgia Arthralgia Infection (including bacterial, viral, fungal, and non-specified) Abdominal pain Hemorrhage Gastrointestinal bleeding CNS bleeding Vomiting Pyrexia Febrile neutropenia

Chronic (n=165) All Grade Grades 3/4

140 mg Once Daily Myeloid Blast Accelerated (n=74) (n=157) All Grade All Grade Grades 3/4 Grades 3/4 Percent (%) of Patients 35 8 34 7 18 1 14 0

34 18

4 0

18 3 2 0

2 0 1 0

21 1 3 0

7 0 1 0

20 3 0 4

0 33 27 24 20 19 18 17 13 12 12

0 1 2 2 2 2 1 2 0 1 1

1 27 31 19 20 11 19 15 7 10 10

0 1 3 2 3 0 1 0 1 0 6

12 11 2 0 7 5 1

1 1 1 0 1 1 1

6 26 8 1 11 11 4

0 8 6 1 1 2 4

Lymphoid Blast (n=33) All Grade Grades 3/4 21 3

6 0

7 0 0 0

21 0 0 0

6 0 0 0

4 18 20 20 15 8 23 16 7 5 14

3 1 5 1 3 1 1 1 1 1 7

0 15 18 9 3 0 21 21 3 0 9

0 3 0 3 3 0 3 0 0 0 0

8 19 9 0 12 18 12

3 9 7 0 0 3 12

3 24 9 3 15 6 12

0 9 3 3 0 0 12

a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].

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Leadership

Patients received either abiraterone once daily in combination with prednisone two times a day or a placebo twice daily in combination with prednisone. The study was designed to measure overall survival. Patients who received the abiraterone/prednisone combination had a median overall

survival of 14.8 months, compared to 10.9 months for patients receiving the placebo/prednisone combination. The most commonly reported side effects in patients receiving abiraterone included joint swelling or discomfort, low levels of potassium in

the blood, fluid retention, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion, and upper respiratory tract infection.

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ASCO through the Years: Past Presidentsa 2010-2011: George W. Sledge, Jr, MD 2009-2010: Douglas W. Blayney, MD 2008-2009: Richard Schilsky, MD 2007-2008: Nancy E. Davidson, MD 2006-2007: Gabriel N. Hortobagyi, MD 2005-2006: Sandra J. Horning, MD 2004-2005: David H. Johnson, MD

Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL (n=258)

Imatinib (n=258) Percent (%) of Patients

Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0– 1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 4. Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML 100 mg Once Daily (n=165)

Advanced Phase CML 140 mg Once Daily Accelerated Myeloid Phase Blast Phase (n=157) (n=74) Percent (%) of Patients

Lymphoid Blast Phase (n=33)

Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 9 9 10 /L, Grade 4 <25 × 10 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0– 2.5 mmol/L, Grade 4 <2.5 mmol/L). Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia,

depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib). 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. Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial lung disease. DRUG INTERACTIONS Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information]. Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1) in Full Prescribing Information]. Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL. H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy. Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. Nursing Mothers: It is unknown whether SPRYCEL 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 SPRYCEL, 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 SPRYCEL in patients less than 18 years of age have not been established. Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment. Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGE Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse Reactions], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2). Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1284903

DS-B0001A-10-10

Rev October 2010

2003-2004: Margaret A. Tempero, MD 2002-2003: Paul A. Bunn, Jr, MD 2001-2002: Larry Norton, MD 2000-2001: Lawrence H. Einhorn, MD 1999-2000: Joseph S. Bailes, MD 1998-1999: Allen S. Lichter, MD 1997-1998: Robert J. Mayer, MD 1996-1997: James O. Armitage, MD 1995-1996: John H. Glick, MD 1994-1995: Karen H. Antman, MD 1993-1994: George P. Canellos, MD 1992-1993: Bernard Fisher, MD 1991-1992: Martin D. Abeloff, MD 1990-1991: Harvey M. Golomb, MD 1989-1990: Robert C. Young, MD 1985-1986: John R. Durant, MD 1984-1985: Sydney E. Salmon, MD 1982-1983: Saul A. Rosenberg, MD 1981-1982: John E. Ultmann, MD 1980-1981: Emil J. Freireich, MD 1979-1980: Charles G. Moertel, MD 1978-1979: Albert H. Owens, MD 1977-1978: Vincent T. DeVita, Jr, MD 1976-1977: James F. Holland, MD 1975-1976: Joseph Bertino, MD 1974-1975: Rose Ruth Ellison, MD 1973-1974: Bayard Clarkson, MD 1972-1973: Paul P. Carbone, MD 1971-1972: Kenneth B. Olson, MD 1970-1971: Jesse L. Steinfeld, MD 1969-1970: Paul Calabresi, MD 1968-1969: Emil Frei, MD 1967-1968: George C. Escher, MD 1966-1967: Fred J. Ansfield, MD 1965-1966: Michael J. Brennan, MD 1964-1965: Harry F. Bisel, MD See pages 3, 42, and 43 for shared recollections from some of these former ASCO Presidents. The ASCO Post invites all readers to submit recollections or personal stories of your experiences as an ASCO member. Write to editor@ASCOPost.com.

The ASCO Post | MAY 15, 2011

PAGE 20

News Clinical Trials

National Cancer Policy Forum Looks Back at IOM Report to Assess Progress, Needed Improvements By Margot Fromer

n his opening remarks at a workshop, “Implementing a National Cancer Clinical Trials System for the 21st Century,” Richard Schilsky, MD, said, “There is something for everyone to do here to optimize the system.” The goal of the workshop was to examine efforts to implement IOM’s 2010 recommendations on the NCI Cooperative Group Program, which suggested that the program be substantially changed. The meeting was hosted by ASCO and the Institute of Medicine (IOM) National Cancer Policy Forum, and held in Washington, DC. Dr. Schilsky is Professor of Medicine and Deputy Director, University of Chicago Comprehensive Cancer Center and Past President of ASCO.

NCI Claims Changes and Improvements James H. Doroshow, MD, Director, NCI Division of Cancer Treatment and Diagnosis (CTEP), said that as a result of the IOM report, NCI has significantly speeded up the clinical trials process. The agency has made other changes as well (see sidebar below), “But we have to begin thinking seriously about the number of patients we can accrue,” he cautioned.”

Lori Minasian, MD, Acting Director, NCI Division of Cancer Prevention, said that in response to the IOM report, the NCI will reduce the num-

James H. Doroshow, MD

Dr. Minasian also said that they are looking at ways that will enhance CCOP’s abilities to collect biospecimens in conjunction with the clinical trials

Lori Minasian, MD

ber of Cooperative Groups from 10 to 5 (4 adult and 1 pediatric). As a consequence, only those 5 funded Cooperative Groups would be eligible to be Cooperative Group CCOP Research Bases. There will remain Cancer Center CCOP Research Bases. “In addition, because treatment does not always involve drugs, we are encouraging collaborative funding with NIH, the American Cancer Society, and other entities to study quality of life, survivorship, nutrition, and other interventions that have an effect on patients with cancer.”

Richard Schilsky, MD

that are run through the national system. “In addition, we are working to develop additional ways to improve diversity, although the Minority-Based CCOP program already contributes significantly to this effort. And perhaps most important, because many NCI investigators do not accrue patients, we need to improve outreach to our own physicians.”

Cooperative Group Chairs Report Jan C. Buckner, MD, Professor of Oncology, Mayo Clinic College of

Medicine and Chair of the North Central Cancer Treatment Group, said that the Cooperative Groups have been conducting “high-quality, multidisciplinary, practice-changing research for decades and will continue to do so.” The groups have developed biobanking repositories to support translational research, which he said are among the largest and best annotated in the country. “They have driven a number of landmark trials in HER2positive breast cancer, colon cancer, and non-Hodgkin lymphoma. “We also have developed detailed technical specifications for a data capture system, developed plans for complying with new NIH timelines for clinical trial activation, created informatics tools for biospecimens, and developed innovative clinical trial designs and endpoint validation studies.” But unaddressed issues remain: a system for setting research priorities; sufficient funding; scientific collaboration; coordinated review of translational science; and modern informatics. Philip J. DiSaia, MD, Professor, Department of Obstetrics and Gynecontinued on page 23

NCI Responds to IOM’s 2010 Recommendations ■■ Recommendation 1:

Consolidation of Cooperative Group operations NCI is considering merging the Cooperative Groups to four adult and one pediatric division and conducting external peer review of all groups in the same cycle—with new criteria.

■■ Recommendation 2:

Consolidation of administration and data management operations NCI has instituted centralized patient registration, has implemented timelines for trial development and activation, and is working on a single harmonized approach to trial management.

■■ Recommendation 3:

Trans-agency streamlining and harmonization of government oversight and regulation NCI and FDA have established an agreement for early review of approved phase III trials.

■■ Recommendation 4:

More collaboration among stakeholders NCI is facilitating incentives for collaboration and is developing standardized material transfer agreements for industry and academia.

■■ Recommendation 5:

Submission of annotated biospecimens to standardized biorepositories and new funding for use of biospecimens in retrospective studies NCI is revising procedures for collecting, reviewing, and banking biospecimens.

■■ Recommendation 6:

Innovative designs for clinical trials that evaluate therapeutics and biomarkers NCI has initiated the Biomarker, Imaging, and Quality of Life Studies Funding Program to incorporate correlative studies into phase II and III trials.

■■ Recommendation 7:

A consistent, dynamic process to oversee unified oncology research standards SEE PAGE 23 NCI has defined studies for biomarkers, imaging, and quality-of-life investigations.

■■ Recommendation 8:

NCI should reevaluate its role in the clinical trials system NCI has established the Clinical Trials and Translational Research Advisory Committee and has revamped the prioritization process for large phase II and III trials.

■■ Recommendation 9:

Increase the speed, volume, and diversity of patient accrual Clinical trials have a data management system that can be used across groups. Diversity in trial participation has been enhanced.

■■ Recommendation 10:

Allocation of a larger portion of the NCI portfolio to the Cooperative Group program NCI increased reimbursement from $2,000 to $5,000 per patient for large phase II studies, as well as additional funding for certain phase III trials and for biomarker and quality-of-life studies.

■■ Recommendation 11:

Clinical investigators should have adequate training and mentoring, paid research time, necessary resources, and recognition NCI created the Clinical Investigator Team Leadership Award.

■■ Recommendation 12:

Patients in clinical trials should be adequately compensated NCI and CMS have a history of collaboration to support Medicare payment for diagnostc and therapeutic items and services furnished in clinical trials.

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information 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 dehiscence 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 and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and 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 The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were 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 In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

9146401

(01/10)

Printed in USA.

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE 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), and Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 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).] 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 2661 patients with mCRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21‑88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first‑ and second‑line mCRC patients who received a median of 11 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 7, 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 incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. 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. 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. 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, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound 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 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, 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 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. 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.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2‑negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 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).] 1.5 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).] 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).] 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 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI‑CTC Grade 3−4 Adverse Events in Study 1 appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. IFL + Placebo IFL + 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 (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).] NCI‑CTC Grade 3‑4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra‑Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).] Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy. 14% 21% Neutropeniaa 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 aCentral 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. dipstick reading should undergo further assessment with a 24‑hour urine collection.

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AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. NCI‑CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI‑CTC Grade 1‑4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% 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) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second‑line mCRC The following adverse reactions have been identified during post‑approval use of Avastin. Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under‑estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) 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 Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine 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 Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated 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 with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one 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 neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 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 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma). 1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus South San Francisco, CA 94080‑4990 ©2011 Genentech, Inc. Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

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cology, University of California, Irvine, and Chair of the Gynecologic Oncology Group (GOG), wants to keep his group intact. “It is unclear how the recommended consolidations would improve outcomes.” He said that GOG is the only group that conducts trials in gynecologic cancers. It has established

have direct access to a heterogeneous patient population, as well as multispecialty group practices that include oncologists. We also have a substantial investment in the clinical trials infrastructure,” said Dr. Levine. Louis Jacques, MD, Director of the Center for Medicare & Medicaid Services (CMS) Coverage and Analysis Group talked about the methodology the agency uses to determine reimbursement and noted that the major focus is on clinical utility.

Third and fourth, “Goals must be defined at the outset. Sponsors have to be upfront about their ultimate intentions, and it is they who determine the elements of group responsibilities.”

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Financial Disclosure: Dr. Cross is National Medical Director, Aetna. Dr. Gray is a member of the Eastern Cooperaive Oncology Group. Dr.

Using 2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Interaction between Industry and FDA

Philip J. DiSaia, MD

worldwide standards of staging and treatment and has conducted more phase I and II studies than any other group. “GOG’s research has provided the basis for molecular approaches to gynecologic cancers, and our translational research teams have created the single largest tissue bank of gynecologic cancers in the world.” Robert Gray, PhD, Professor of Biostatistics, Dana-Farber Cancer Institute, and a member of the Eastern Cooperative Oncology Group (ECOG), described his vision of a cooperative group system: one that facilitates participation in studies led by any of the groups, avoids duplication, and conducts studies to evaluate molecular and imaging markers. “We also need common information statistical systems, as well as standardization of data collection and management. The current system is too competitive and multiple groups often develop separate systems to perform similar work,” he said.

Paying for Clinical Trials Sharon Levine, MD, Associate Executive Director of Kaiser Permanente, described her organization’s reimbursement policies with regard to clinical trials: coverage for routine care and investigational drugs with therapeutic value. James D. Cross, MD, National Medical Director, Aetna, echoed Kaiser’s reimbursement policies and said the company encourages patients to enter trials. “As a care delivery system of 15,000 physicians, we can accrue patients for clinical trials—and conduct them. We

Ira B. Steinberg, MD, Associate Vice President for Global Medical Affairs, sanofi-aventis, said that industry generally likes working with Cooperative Groups because they provide access to large numbers of patients, accrue quickly, and work with world-class institutions and physicians. But there are problems. “It takes ages to initiate and open trials, data are too variable, and contracts are problematic because of the multiplicity of institutions and languages.” He proposed a solution: Standard Terms of Agreement for Research Trial (START), which consists of a series of

Levine is Associate Executive Director of Kaiser Permanente. Dr. Schilsky is a compensated member of the Scientific Advisory Board of Foundation Medicine, Inc. Dr. Steinberg is Associate Vice President for Global Medical Affairs, sanofi-aventis. Dr. Buckner, Dr. DiSaia, Dr. Doroshow, Dr. Jacques, Dr. Minasian, and Dr. Pazdur reported no potential conflicts of interest.

Getting the Application There are three ways to download the ScanLife application:

1 2

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

Florida Hospital Cancer Institute 2011 ASCO Update American Society of Clinical Oncology

Ira B. Steinberg, MD

standard clauses designed to simplify and streamline the contracting process. Richard Pazdur, MD, Director of the Oncology Program, FDA Center for Drug Evaluation and Research, said, “All companies conduct trials all over the world. The United States is not the sole player, and FDA is not the sole regulator.” When FDA and the pharmaceutical industry cooperate, four principles are paramount, he said. First, responsibility for accurate data rests solely with the drug sponsor. Second, when a trial is conducted by a Cooperative Group, there must be clear communication about criteria, safety, and data distribution among all participants right from the beginning. This is best accomplished by joint meetings at all stages of the trial process.

Saturday, June 25, and Sunday, June 26, 2011 LOCATION AND ACCOMMODATIONS: Buena Vista Palace Hotel 1900 East Buena Vista Drive Lake Buena Vista, Florida 32830 | (866) 397-6516 For more information, call (407) 303-1945 or (800) 375-7761 or email FHCI.Registration@flhosp.org. Florida Hospital Designates this live activity for a maximum of 9.5 AMA PRA Category 1 Credits. Each physician should claim only those hours of credit commensurate with the extent of their participation in the activity.

Sponsored By:

Presented By:

The ASCO Post | MAY 15, 2011

PAGE 24

Direct from ASCO

Chair of the Conquer Cancer Foundation Leads with Exuberance and Meaningful Philanthropy

25-year ASCO member Martin J. Murphy, Jr, PhD, DMedSc, assumed Chair in January 2010

he Chair of ASCO’s Conquer Cancer Foundation speaks with eloquence, authority, and passion when he talks about the Foundation’s role in defeating cancer, and about the honor and responsibility he feels as its Chair. Martin J. Murphy, Jr, PhD, DMedSc, comes by these qualities honestly. Chalk up his eloquence to the Irish in him. His authority is firmly anchored by a lifetime of major accomplishments as a researcher, entrepreneur, and executive, but equally by his legacy as a philanthropist. His passion no doubt hearkens back to the Irish again, but, in addition, he has a wealth of both passion and compassion as a cancer survivor.

The Chance of a Lifetime: Conquering Cancer A top donor to the Conquer Cancer Foundation (formerly The ASCO Cancer Foundation), Dr. Murphy sees the opportunity to donate as a chance of a lifetime. “If you are passionate about what the Foundation does and look to the future, you see there is an opportunity to conquer cancer. If I don’t do my part, it will be left undone or have to be done by someone else,

leaving me unfulfilled.” He believes that contributing to the Foundation also gives oncologists and other caregivers the chance of a lifetime. The Foundation is changing the future of patients with cancer by providing the financial underpinning for many ASCO programs. “The treatment of patients in the United States and in many parts of the world is being impacted daily by ASCO because of education provided at the ASCO Annual Meeting and disease-specific symposia. They are the quintessential educational meetings of every calendar year.” Dr. Murphy points to Cancer.Net, ASCO’s patient information website, as another example of how the Foundation directly supports patient care and the oncology community’s professional milieu. “It’s the Foundation that is enabling these major ASCO programs to go on.”

Embracing Opportunity with Passion Dr. Murphy tells a story about how his own cancer diagnosis led to his passion for embracing opportunity. While he was awaking after

Martin J. Murphy, Jr, PhD, DMedSc

emergency surgery, surrounded by his wife and five children, his brother telephoned. His wife placed the phone on his pillow, and he heard his brother’s voice: “Marty, do you know that the Chinese symbol for ‘crisis’ or ‘catastrophe’ can also be translated as ‘opportunity’?” Dr. Murphy continues, “After initially thinking my brother had gone ’round the bend, the anesthesia fog lifted and I began to understand what he was saying. The crisis that had entered my life with this diagnosis could be a chance of a lifetime—an opportunity for personal and family growth, if I were able to embrace it in the right way.” He emphasizes that embracing this new opportunity is a daily exercise, not a single event or change. “It

is so intimate that it becomes a part of your being—it becomes part of you.” Dr. Murphy sees contributing to the Foundation as an opportunity for the oncology community to make a commitment to their profession and to participate in the renaissance of ASCO’s 11-year-old Foundation, which this year reaffirmed its mission and vision. “The renaissance of the Conquer Cancer Foundation is building on the proud heritage of The ASCO Cancer Foundation and on all that ASCO has done. The Foundation is seeking more than contributions. It is inviting partnership— exuberant support for its vision of a world free from the fear of cancer. This is the opportunity to say ‘I am taking a stand that in my lifetime, I’m going to do all that I can to conquer cancer—in my profession, from my own personal treasury, and from my heart. Most of all, from my heart.’” To contribute to a world free from the fear of cancer and to learn about the Foundation’s programs, visit ConquerCancerFoundation.org.

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QOPI Certification Recognizes Outstanding Performance by Oncology Practices QOPI Certification earned by 65 practices so far

or a private practice like six-physician New England Hematology Associates, garnering Quality Oncology Practice Initiative (QOPI®) Certification can really signal to patients that the care provided there is among the best available—not just in the local market, but nationwide, said Deborah Davis, RN, MS, the practice’s clinical nursing leader. “Achieving certification says your practice was evaluated against extremely high standards and we met them all,” she explained. “It signals our strong commitment of quality to patients, referring physicians, and the community.” Davis added that this is especially

important when competing with large academic medical centers and hospitalbased programs, which Newton, Massachusetts–based New England Hematology Associates does. It’s one of few private practices in the area with an infusion clinic. After starting the process in September of last year, New England Hematology got its QOPI Certification in February.

Rigorous Standards Apply The first program of its kind in the United States, the QOPI Certification program, launched in January 2010, gives oncology practices the opportunity to go a step beyond ASCO’s QOPI program. In the QOPI

program, practices submit data that lets them compare performance with other practices across the country. Certification recognizes outpatient oncology practices that consistently provide the very highest standards of care. Of the more than 650 practices participating in QOPI, 110 have applied to go through the months-long process to gain certification, and 65 have made it through and received the coveted certification plaque. The certification lasts for 3 years and indicates that the practice scored above expected levels in treatment planning, staff training and education, chemotherapy orders and drug preparation, patient consent and education, safe chemotherapy ad-

Deborah Davis, RN, MS

ministration, and monitoring and assessment of patient well-being. The process starts with QOPI data collection. If a practice gets the required scores on QOPI quality measures and believes it can demonstrate compliance with chemocontinued on page 25

ASCOPost.com | MAY 15, 2011

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Direct from ASCO

QOPI Certification continued from page 24

therapy safety standards, it can then apply for certification. The practice submits a Site Assessment Questionnaire, supportive documentation for five randomly selected chemotherapy safety standards, and three randomly selected medical records. QOPI Certification staff and QOPI Steering Group reviewers evaluate the submitted materials. A random selection of applicants receives an onsite audit. If a practice is selected, an advanced practice oncology nurse makes a day-long visit to the practice, reviewing charts and following two patients through their entire visit that day. These are some of the aspects of care reviewed on site: ■■ Written policies, procedures, or guidelines for verification of training and continuing education for clinical staff ■■ Orders for parenteral and oral chemotherapy that are written and signed by licensed indepen-

■■

dent practitioners who are determined to be qualified by the practice according to the practice’s written policies Preparation of chemotherapy drugs (oral or parenteral) by a pharmacist, pharmacy technician, or nurse who is qualified according to the practice’s policies Chemotherapy administration only by qualified physicians, physician assistants, advanced practices nurses, or registered nurses A comprehensive education program for new staff administering chemotherapy, including a competency assessment—or the use of an off-site educational program regarding chemotherapy administration that includes competency assessment Chemotherapy administration education that includes all routes of administration used in the practice site, such as parenteral, oral, intrathecal, intraperitoneal, and intravesicular A standard mechanism for monitor-

ing chemotherapy administration competency at specified intervals ■■ Maintenance of basic life support certification by all clinical staff

very positive, and allowed us to improve the way we work together.”

Certification Process Also Benefits Practice Staff Jockeying to attain the certification can be a rigorous undertaking, but the process itself can have significant upsides, said Kathleen A. Cooney, MD, Frances and Victor Ginsberg Professor of Hematology/ Oncology, Chief of the Division of Hematology, and Interim Director at University of Michigan Cancer Center, which has 180 physicians who handle 100,000 clinic visits and 45,000 infusion visits per year. “In big organizations like ours, you can prioritize activities you think might be important, but you may be overlooking things,” said Cooney. “The certification process provided a really nice opportunity to have external reviews of our own procedures, along with getting all of our staff members on the same page. That was

Kathleen A. Cooney, MD

Once certification is attained, practices can include their certification status in marketing materials to show that their organization is among the upper echelon of outpatient oncology practices. But it’s not just for marketing; QOPI Certification is also beginning to be recognized by major national insurers as a reliable way to identify and compensate high-performing practices.

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ASCO and CollabRx Partner to Develop Online Apps for Planning Treatment Melanoma targeted therapy finder now available

hrough a new partnership, ASCO is working to provide its members with expanding technologic resources to help them deliver high-quality and personalized care. ASCO and CollabRx, an organization that leverages information technology to personalize cancer treatments, recently agreed to develop innovative, Web-based decision support tools that enable physicians and their patients to better understand emerging cancer therapies and the specific genetic profiles of patients’ tumors that these drugs target. This knowledge will empower oncologists to consider all possible options in the course of devising a patient’s targeted therapy plan. The partnership initially focuses on melanoma in the context of CollabRx’s Targeted Therapy Finder – Melanoma, which is an online application or “app” that enables physicians and patients to identify diagnostic tests, treatments, and clinical trials associated with unique molecular profiles of patients’ tumors. By providing access to its extensive knowledge base, ASCO is helping

users of the app receive the most upto-date and comprehensive information pertaining to the clinical testing of novel cancer drugs. ASCO is providing CollabRx with access to all of its published melanoma content, including data presented in abstract format at the Annual Meeting as well as study results described in the Journal of Clinical Oncology. In addition, Cancer.Net Melanoma Associate Editor Lynn M. Schuchter, MD, will assist in providing content curation by identifying the most relevant tests, treatments, and clinical trials for each molecular subtype, based on the best current knowledge.

with ASCO to make the Targeted Therapy Finder – Melanoma app the preeminent source of personalized information for melanoma patients and physicians,” said Jay M. (Marty) Tenenbaum, PhD, CEO of CollabRx. “We are looking forward to leveraging the unique insight of ASCO to help translate the latest scientific findings into actionable results.”

Oncology professionals can access the free Targeted Therapy Finder – Melanoma app via the Society’s website at www.asco.org/therapyfinder. This tool is also available to patients through Cancer.Net at www. cancer.net/targetedtherapyfinder.

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Visit ASCO Central at the Annual Meeting for Patient Education Resources

Overarching Goal “One of ASCO’s overarching goals is to provide quality and timely information to our members to help them deliver the highest quality of care to their patients,” said Allen S. Lichter, MD, CEO of ASCO. “We’re pleased to partner with CollabRx to leverage the Internet and social media to improve cancer treatment planning in melanoma and beyond.” “We are honored to be working

f you are attending ASCO’s Annual Meeting, visit the Cancer.Net section of ASCO Central, booth #7004, in the Exhibit Hall to learn more about Cancer.Net’s patient education resources. You will find free printed materials—including the ASCO Answers Fact Sheets, Guides to Cancer,

and booklets on topics such as advanced cancer care planning and managing the cost of cancer care—and information about Cancer.Net’s online offerings. In addition, staff will be available to answer any questions you may have about how Cancer.Net can support your practice.

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The ASCO Post | MAY 15, 2011

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Direct from ASCO

Highlights of a Decade: Daniel G. Haller and Journal of Clinical Oncology

t the Annual Meeting in June, Daniel G. Haller, MD, will step down from his post as Editorin-Chief of Journal of Clinical Oncology, a role he has held for the past 10

years. Over the course of that decade, Dr. Haller has helped guide JCO through some of its most significant changes since the journal began publishing in 1983.

Under Dr. Haller’s leadership, JCO established an online manuscript submission system and began publishing articles online before they are assigned to a print issue, essential

components to decreasing the time between submission and publication. Dr. Haller also created the Special Series Review, entire issues dedicated to the hottest topics pertaining to a specific disease site, and oversaw the attendant increase in publication frequency, from 24 to 36 issues per year.

Daniel G. Haller, MD

When considering such a wide array of initiatives, it is difficult to say which innovation has had the most significant impact on JCO. Nicholas Petrelli, MD, Associate Editor (2000–2010), believes that Dr. Haller’s greatest achievement as Editor-in-Chief was “his ability to capture high-quality, practice-changing manuscripts along with cutting-edge translational research. This led to a dramatic improvement of the journal’s impact factor during his tenure and the fact that JCO is now the premiere oncology journal.” The impact factor is a widely used tool that measures the average number of citations received per paper published in the previous 2 years. Under Dr. Haller’s aegis, JCO’s impact factor increased from 8.773 in 2001 to 17.793 in 2010.

Emerging Fields One way Dr. Haller encouraged the growth of JCO’s impact was to expand into specialty areas that had been overlooked previously. Patricia Ganz, MD, Associate Editor (1998– 2009), was charged with improving the peer-review process for the emerging fields of quality of life and psychosocial oncology. “Under Dr. Haller’s leadership and support, I was able to build this area of research content, along with an outstanding editorial board and peer-review database, such that JCO is now the premiere journal for papers in these fields,” she said. continued on page 27

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Direct from ASCO

A Clarification and Reminder about ASCO/CAP Guidelines on HER2 Testing in Breast Cancer

joint letter to the editor¹ to the Journal of Clinical Oncology provides an important reminder of the intent of the ASCO/College of American Pathologists (CAP) guideline panel on human epidermal growth factor receptor 2 (HER2)² and a reconciliation of some pathology technical aspects. The topic of establishing equivocal categories for prognostic and predictive markers in breast cancer has generated frequent discussion. The letter by Elizabeth Hammond, MD, Daniel F. Hayes, MD, and Antonio Wolff, MD, Co-chairs of the ASCO/ CAP guideline panels on HER2 testing and immunohistochemistry (IHC) testing of estrogen receptor/progesterone receptor testing, states: In particular, the equivocal categories for HER2 were meant to trigger HER2 reflex testing using another validated assay if the first test is equivocal (IHC if an equivocal fluorescent in situ hybridization [FISH] test or FISH if an equivocal IHC test). The

Highlights of a Decade continued from page 26

Dr. Haller also influenced changes that cannot necessarily be seen in the journal pages. “[His] enthusiasm for new knowledge is infectious, and he motivates the staff and editors to think about the journal as much as he does. Being able to engage all who are involved in the process of publishing JCO and truly creating a united team has made the journal what it is today,” commented Mary L. Disis, MD,

Panel felt this approach would provide clinicians and their patients with additional information for clinical decision-making. Figure 2 of the January 2007 HER2 Guideline clearly stated that patients with a HER2/ CEP17 (chromosome enumeration probe 17) FISH amplification ratio ≥ 2.0 were eligible for the trastuzumab adjuvant trials, including those with a ratio between 2.0 and 2.2. In a subsequent letter³ to Journal of Clinical Oncology in September 2007, we then revised Figure 1 of the guideline document to state that patients with a HER2 2+ equivocal IHC test who had tumors with uniform intense membrane staining in more than 10% and less than 30% of cells were also eligible for the trastuzumab trials. Most critical to this discussion, we then stated that “Available data from the adjuvant trials at present are insufficient to reliably exclude these patients from therapy with trastuzumab….” The Panel did not

Deputy Editor (2006–present). In the eyes of the Editors he oversaw, Dr. Haller’s was more than an Editor-in-Chief—he was a mentor. “Dan enhanced my experience as an Associate Editor by being an outstanding mentor; not only during my tenure but throughout my career,” said Dr. Petrelli. “He is bright, compassionate, and someone you can trust.”

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SAVE THE DATE Breast Cancer Symposium 2011 September 8-10, 2011 San Francisco Marriott Marquis San Francisco, California

recommend withholding anti-HER2 treatment in those patients with an equivocal HER2 test (or tests) whose results fell within ranges that would have allowed them to be treated in the first generation of adjuvant HER2-targeted trials.

The full letter¹ to JCO can be accessed at http://jco.ascopubs. org/content/early/2011/04/18/ JCO.2011.35.2245.full.pdf+html.

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References 1. Hammond ME, Hayes DF, Wolff AC, et al: Clinical notice for American

Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

www.jco.org

Society of Clinical Oncology–College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol. April 18, 2011 (early release online). 2. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007. 3. Wolff AC, Hammond ME, Schwartz JN, et al: Correspondence: In reply. J Clin Oncol 25:4021-4023, 2007.

What’s Hot in

JCO

Top 10 most-accessed articles recently published in Journal of Clinical Oncology

JCO.org 1. Bevacizumab for Advanced Breast Cancer: All Tied Up With a RIBBON? Harold J. Burstein 29(10): 1232 2. Clinical Research: Show Us the Data Alberto Ocana, et al 29(9): 1099 3. Is It Good or Bad to Find a BRAF Mutation? Keith T. Flaherty 29(10): 1229 4. Biology-Driven Phase II Trials: What Is the Optimal Model for Molecular Selection? Fabrice Andre, et al 29(10): 1236 5. Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value Howard West 29(9): 1095

6. Big Costs for Little Gain in Ovarian Cancer Martee L. Hensley 29(10): 1230 7. Life After Adjuvant Chemotherapy for Breast Cancer: The News Is Mostly Good Belinda E. Kiely, et al 29(9): 1092 8. Providing Protocol Information for Journal of Clinical Oncology Readers: What Practicing Clinicians Need to Know Daniel G. Haller, et al 29(9): 1091 9. “And What Other Medications Are You Taking?” John D. Gordan, et al 29(11): e288 10. How Patients Add Life to Their Days Evan J. Lipson 29(10): 1392

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E AR S UR V IVAL R ATE I S 17 % F O R PATIENTS W ITH M E TAS TATIC S OF T TIS S UE SA RC OMA , YE T S I G N I F ICANT THER APEUTIC A D VAN CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

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In the News Cancer Drugs

Coping Strategies during the Oncology Drug Shortage 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.

by professional groups such as ASCO and the American Society of Hematology (ASH). Reasons cited for the shortage include the consolidation and structure of the pharmaceutical

industry, expiration of patents, scarcity of raw materials, and inability of the FDA to take action. Some reports have noted that generic drugs, with their lower profit margins, are partic-

ularly affected by the oncology drug shortage. Among the oncology drugs acknowledged to be in short supply are cytarabine, leucovorin, thiotepa, continued on page 30

etting priorities for the use of oncology drugs and closely monitoring their use, adjusting the dispensing and workflow patterns, and working closely in a collegial relationship are some of the strategies that Rowena N. Schwartz, PharmD, Director of Oncology Pharmacy at Johns Hopkins Hospital in Baltimore, and her colleagues use to cope with the continuing shortage of oncology drugs. “This is not simply a pharmacy problem,” Dr. Schwartz told The ASCO Post. “This is a problem for providing care to patients, and working together helps us to come up with better ways to make sure care can happen.” The widespread shortage of oncology drugs has received national media coverage, including articles in The Wall Street Journal1 and the Los Angeles Times,2 and prompted actions

Expect Questions from Your Patients

n oncology drug shortage with no end in sight and no good alternatives to many drugs makes it difficult to provide satisfactory answers to patients who are directly affected by the shortage or worried about future repercussions. “There has to be a frank discussion of what is going on, what other options may be used, and whether the provider feels particular options are good or not,” Rowena N. Schwartz, PharmD, advised. Physicians as well as patients can check the status of particular drugs by going to the FDA drug shortage website at www.fda.gov/ Drugs/DrugSafety/DrugShortages.

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Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11): 4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):64076415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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In the News

Oncology Drug Shortage continued from page 29

etoposide, bleomycin, doxorubicin, and cisplatin.

Inadequate Alternatives “For some of these drugs, there are alternatives,” Dr. Schwartz said, “but the alternatives are not always equal in efficacy or they may have toxicity that

Rowena N. Schwartz, PharmD

makes them not your first-line choice, depending on the agent and the disease.” A statement from ASH3 acknowledged “there are no evidence-based clinical guidelines or protocols for specific drug therapy in times of drug shortage,” but added that ASH “is working with clinical experts to try to offer ‘clinical guidance’ to our members on alternative treatment protocols, including alternative drugs that may be substituted, in the face of shortages.” At Johns Hopkins, “we have a group within the pharmacy that goes over shortages every week,” Dr. Schwartz explained. If a drug supply gets to a critical level based on factors such as inventory and pattern of use, the group devises a plan to deal with

the anticipated need. “Then we usually pull together an ad hoc group of providers,” Dr. Schwartz said. That group would include the institution’s oncology leadership as well as frontline physicians who use the drug, pharmacy leadership, clinical pharmacists, and representatives from nursing and Johns Hopkins’s inpatient and outpatient affiliates. “One of the first conversations that we usually have addresses the diseases in which these drugs are critical.” The discussion about possible alternative drugs, Dr. Schwartz said, should be taken in the context of what you use in your institution. “You look at the breadth of the drug’s use in your institution and say, ‘Where will omitting this not be harmful to a patient? Where can we replace this and save it for patients for whom there is no good alternative? That is actually what we tend to do more often—prioritizing rather than restricting.” In general, dose reduction is not one of the strategies used to cope with the drug shortage. “We would not cut back the dose unless the regimen is such that it has been shown to be helpful. For a particular drug, it may be a viable option, but there would have to be data for that,” Dr. Schwartz said. “Communication makes this workable. It has been a real challenge to provide care, but without that collaborative communication among members of the health-care team, I think it would be even worse,” Dr. Schwartz noted.

Cytarabine Rationing “Shortages of drugs used to treat

Sharing Information

hile working to provide the most current information on oncology drug shortages and progress toward potential solutions, ASCO has issued an appeal to find out how these shortages are affecting physician practices. “I would encourage oncology professionals to please report the shortages they are experiencing to ASCO, the FDA, or the American Society of Health-System Pharmacists (ASHP),” said ASCO President-Elect Michael P. Link, MD. “The more physicians reMichael P. Link, MD port, the better idea the FDA has of the current scope of the shortages.” To report information on how oncology drug shortages are affecting your practices, contact: ■■ ASCO at publicpolicy@asco.org or 571-483-1368. ■■ FDA at drugshortages@fda.hhs.gov. ■■ ASHP at http://www.ashp.org/DrugShortages/Report/.

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Summit on Drug Shortages

n November 2010, ASCO co-convened a summit on drug shortages with the American Society of Health-System Pharmacists, the American Society of Anesthesiologists, and the Institute for Safe Medication Practices. The summit also included key stakeholders from pharmaceutical manufacturers, supply chain entities, and the FDA. Although summit participants concluded that there is no single reason for or solution to the shortages, they developed several recommendations, including the following: 1. Improve rapid communication between the pharmaceutical supply chain and providers, so providers have more advanced notice to better anticipate and manage shortages. 2. Remove the barriers faced by drug manufacturers and the FDA to minimize the impact of drug shortages, such as establishing processes for potentially extending the expiration date of a drug in short supply if it still meets safety requirements. 3. Clarify the definition of “medically necessary,” which is the term that prompts notifications to the FDA related to drug shortages, to ensure the FDA is aware of shortages in a more timely manner.

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patients with hematologic malignancies, including leukemia and lymphoma, have become critical and life-threatening,” according to the ASH statement.3 “An increasing number of physicians have been forced to take their patients off therapies midtreatment, delay treatment, choose alternative therapies that are less effective, and ration their remaining supplies of these therapies.” Among the drugs cited was cytarabine. The three companies that manufacture generic cytarabine “have all suffered production difficulties in the past year,” according to the article in The Wall Street Journal,1 and only one company “is currently shipping the drug, but only in limited quantities that are not nearly enough to meet demand.” As of late April, the FDA website on drug shortages (www.fda.gov/ Drugs/DrugSafety/DrugShortages) was reporting that two of the companies were expected to begin shipping by the end of the month.4 Because dates of expected supply “are often not accurate,” it is best not to consider an issue with a particular drug to be resolved “until it is physically in hand,” Dr. Schwartz cautioned. “If there has been a shortage, you don’t know how many people are waiting for it. So when new supplies become available, you don’t know when you will get more. Cytarabine is a great example. When the shortage occurred, we did get some additional drug, but that was not by any means a sign that we would continue to get it. We have been very cautious about the priorities that we’ve set up. We are not going to withdraw

those protocols until we know our supply is relatively solid.”

Lack of Leucovorin The article in the Los Angeles Times2 quoted Dwight Kloth, Director of Pharmacy at Fox Chase Cancer Center in Philadelphia, as commenting that leucovorin has been in a “chronic, lingering, malignant, festering shortage” for a few years. A resulting challenge arises from the inclusion of leucovorin in the FOLFOX regimen (leucovorin, fluorouracil, oxaliplatin) for colon cancer. “There would be a potential issue if you needed to change that therapy,” Dr. Schwartz said. “There are other options, but there would need to be a discussion about when to change it. For example, should you keep enough for one patient to complete X amount of courses and then have new patients starting another regimen like CAPOX [capecitabine (Xeloda), oxaliplatin]?”

Inventory and Workflow “In oncology, the majority, if not all of the drugs are processed in the pharmacy in per-patient dosing,” Dr. Schwartz explained. “We may prepare certain low-cost drugs before the patient comes to the clinic, to facilitate patients getting treated in a timely fashion.” When these drugs are in short supply, per-patient dosing is not done ahead of time with those drugs, “because if the patient doesn’t come or can’t get treated for some reason, we don’t want to waste the drug,” she said. “These are workflow issues, and nurses need to be aware that this drug that you used to get ahead of

ASCOPost.com | MAY 15, 2011

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In the News

time may not be available as quickly because there is a shortage.” As an example, she cited bleomycin. “We currently will not prepare bleomycin doses until the patient is physically there,” she said. “Oncology drugs are expensive, and people don’t like to keep a huge inventory,” Dr. Schwartz notSEE PAGE 23 ed. “But even when there is just the possibility of a shortage, people will increase their inventories. Some people call that hoarding; I think it is just looking at the situation realistically,” Dr. Schwartz said. “What always concerns me is not knowing ahead of time that this could be a problem,” she added. “When these shortages hit without time to prepare, decisions have to be made relatively fast and there is the potential for disruption in care or decisions not being made by the collaborative team. So the more notice that is given, the better.” Dr. Schwartz said that the Johns Hopkins pharmacist in charge of purchasing drugs maintains a good working relationship and communication with the pharmaceutical representatives to keep current on drug supplies. “We work very closely with the pharmacies in the area, and we do borrow and share. People have been very generous about that,” Dr. Schwartz added. “Through our national organization, the Hematology/Oncology Pharmacy Association (HOPA), we

know other people and can contact them to find out what they are doing.” In addition, she said, “with list servers, there is a lot of information out there now, so you can get an idea if a problem is brewing.”

■

Financial Disclosure: Dr. Schwartz reported no potential conflicts of interest.

References 1. Dooren JC: Shortage worsens of leukemia drug. Wall Street Journal, April 14, 2011. Available at online.wsj.com. 2. Hiltzik M: FDA needs teeth to avert drug shortages. Los Angeles Times, April 19, 2011. Available at www. latimes.com.

3. American Society of Hematology: Drug shortages rise to crisis level (updated). April 12, 2001. Available at www. hematology.org. 4. Food and Drug Administration: Current drug shortages. Available at www.fda.gov/Drugs/DrugSafety/DrugShortages. Accessed April 25, 2011.

Contact

The ASCO Post Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 email: Editor@ASCOPost.com ASCOPost.com HarborsidePress.com References : 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

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TAP Caucus Pro/Con

Should All Eligible Patients with Multiple Myeloma Receive Autologous Stem-cell Transplant as Part of Initial Treatment? By Philippe Moreau, MD, and S. Vincent Rajkumar, MD

PRO

Multiple myeloma is the number one indication for autologous stem cell transplantation (ASCT) in Europe and North America, and the majority of myeloma experts in the European Union favor this strategy as part of frontline therapy in eligible, symptomatic patients. This therapeutic choice is supported by the results of seven randomized trials performed in the 1990s, all of which showed response and progression-free survival (PFS) Philippe Moreau, MD rates in favor of ASCT. Additionally, a survival advantage for ASCT was seen in three of the seven studies.1 Indeed, ASCT is a well-established, routine procedure with a mortality rate of less than 2%. This is lower than that reported for treatment approaches utilizing continuous upfront therapy without ASCT—for example, the lenalidomide (Revlimid)/dexamethasone combination.

Treatment Improvements A second argument strongly supporting the use of ASCT upfront is the multitude of improvements in this strategy since the early reports mentioned above. These have resulted in a marked increase in very good partial response (VGPR) rates, from 15% to more than 50% over the past decade. This im-

ASCT is a cost-effective procedure associated with a low mortality rate, and will remain the standard of care in the 2010s; future studies should be focused on defining the groups of patients who will benefit most from this procedure. provement has significant implications, as the achievement of high-quality responses is a significant prognostic factor for outcome. Importantly, we are now able to incorporate novel agents into induction treatments prior to ASCT, and triplet combinations consisting of bortezomib (Velcade), dexamethasone, plus an immunomodulatory drug, such as thalidomide (Thalomid) or lenalidomide, yield VGPR rates of 50% to 60%, which are further upgraded with melphalan at 200 mg/m2 as conditioning treatment prior to ASCT.1 In addition, results of recent studies support the systematic use of consolidation therapy incorporating novel agents after ASCT. The Italian group reported molecular complete responses following consolidation treatment with a novel agent combination.2 Some patients remain free of disease, with a tumor-specific PCR-negative status consistent with a cure. Such unprecedented results were previously only achievable with allogeneic transplantation, which is not recommended in multiple myeloma because of excessive transplant-related mortality. Moreover, early results of ongoing studies indicate that maintenance therapy with novel agents is able to increase the duration of response substantially.3 Overall, the “optimal strategy” of a triplet combination induction regimen followed by ASCT, consolidation, and maintenance, with the incorporation of novel agents in all stages, may result in a VGPR rate of 90%, with an expected median PFS of 4 to 5 years and cure in a subset of patients with good prognostic features at the time of diagnosis.

CON

Multiple myeloma is the number one indication for autologous stem cell transplantation (ASCT) in the United States. Although ASCT has an important role in the overall treatment strategy, I would argue that it is not needed as part of initial therapy for all eligible patients with myeloma. In fact, ASCT is just one of many good options, and the decision on the need for ASCT and its timing must be tailored to meet S. Vincent Rajkumar, MD the needs of the patient. A one-size-fits-all approach is no longer applicable in the disease. To address this further, let us examine the reason ASCT enjoys its current status in the field: Two randomized trials showed a median survival prolongation with high-dose therapy followed by ASCT of approximately 12 to 18 months.1,2 These two trials are the principal sources of randomized data supporting early ASCT. The problem is that there are several other conflicting pieces of randomized trial data that one needs to consider.

Five Considerations First, there were other trials that tested the value of ASCT that failed to show a similar survival benefit. Thus, there is controversy about the true clinical benefit of ASCT. Second, three randomized trials addressed the question of whether ASCT should be done as part of initial therapy or delayed until relapse.3-5 None of these trials showed a survival benefit with early ASCT. Those who support ASCT are not greatly perturbed by these results, but I am. In fact, not a single randomized trial shows that ASCT results in better survival when done as part of initial therapy, rather than later on at the time of relapse. Some argue that “time without therapy” (a presumed surrogate for quality of life) is longer with early ASCT. That may have been true prior to 2011, but not anymore. With many investigators promoting post-transplant maintenance therapy for all patients, it is no longer possible to argue that “time without therapy”

Many patients wish to have a choice of early vs delayed ASCT based on their life situation. They need to know that there are no data on overall survival to support one approach over the other.

It could be argued that similar VGPR rates may be achieved with combinations that include novel agents but do not incorporate ASCT upfront, and that patients may choose to delay ASCT to the time of relapse, preferring oral therapies to be able to enjoy a more “normal” life. However, patients should be informed that very

is longer with early ASCT. We need true quality-of-life comparison studies. Third, a randomized trial that specifically looked at patients responding well to their induction therapy found no benefit when such patients were randomly assigned to ASCT vs continuing standard chemotherapy.6 With modern treatment regimens, excellent response is the rule, and true nonresponders to initial therapy are uncommon. There are no randomized data suggesting that patients who achieve an excellent response to induction derive any survival benefit with early ASCT. Rather, survival improvements with early ASCT come from trials conducted in an era where initial medical therapy of myeloma was much less effective. Fourth, the randomized trials of ASCT that showed survival benefit were done in patients less than 65 years old. Therefore, in Europe, the role of ASCT is largely restricted to this population, especially following the observation that oral therapy with MPT (melphalan, prednisone, and thalidomide [Thalomid]) handily beat tandem ASCT with an intermediate dose of melphalan in terms of overall survival in patients over 65. In the United States, however,

continued on page 33

continued on page 35

Role of Novel Agents

ASCOPost.com | MAY 15, 2011

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TAP Caucus

PRO: ASCT Is the Best Strategy for Eligible Patients continued from page 32

few oral combinations achieve VGPR rates of 70% to 80%. For example, continuous treatment with lenalidomide plus dexamethasone yields only a 45% VGPR rate, and a median PFS of 25 months, which is not optimal.4 In order to reach a VGPR rate of 70% to 80% without the use of ASCT, patients will need to receive combinations that include bortezomib, dexamethasone, plus immunomodulatory drugs or cyclophosphamide.5,6 Such regimens require frequent outpatient hospital visits for at least 6 to 10 months, resulting in a duration of therapy similar to that seen with strategies involving induction, ASCT, and consolidation. It is conceivable that the use of highly effective novel agent combinations upfront, with ASCT delayed to relapse, may challenge the role of frontline ASCT.5 Currently, at least two prospective randomized international phase III trials are enrolling patients to address this unresolved question. However, even if overall survival is expected to be similar in the two arms, the primary hypothesis is that PFS will be superior in the arm receiving upfront intensive treatment, indicating that front-line ASCT may remain the standard of care in the future. Outside the clinical trial setting, patients should also be made aware that the choice of delaying ASCT may have other implications. For example, despite the availability of a frozen graft, there is the risk that high-dose therapy may not be feasible due to the occurrence of refractory disease, a deterioration in performance status, or the development of comorbidities. While upfront ASCT is typically feasible in more than 80% to 90% of cases, this rate is significantly reduced in the relapse setting.

algorithm, patients are categorized into risk groups based primarily on cytogenetic features. In the good-risk subgroup, ASCT is excluded as front-line treatment, although in my view it represents the optimal option for the majority of these patients. For the intermediate-risk group, characterized by the presence of t(4;14), the Mayo Clinic algorithm ad-

vocates bortezomib-based therapy plus ASCT. In the presence of poor-risk disease, the systematic use of ASCT is recommended, although the procedure is known to be associated with a poor outcome in this group of patients. In my view, the optimal approach to the treatment of multiple myeloma may be to propose the most effective

treatment for all patients, regardless of risk status and including the so-called “good-risk” patients, and this most effective treatment should involve the use of ASCT. Another risk-adapted strategy, based on genome analysis, is being proposed by the Arkansas group. However, this complex procedure cancontinued on page 35

Risk-adapted Strategies Finally, I will offer a few thoughts on the topic of risk-adapted strategies and the possibility of restricting ASCT to particular subgroups of patients, which is an issue of major importance. The implementation of such a tailored approach must be the future goal of myeloma therapy, in the same way as it has become standard in the treatment of acute leukemias. To date, regrettably, we have not reached that point in treating myeloma, and I would argue that the M-smart algorithm proposed by the Mayo Clinic group is not optimal. According to this

References: 1. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6): 1665-1671. 2. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-39.

Y2410ALT_ASize_Sm_v2 1

3/16/11 4:41 PM

R e g i s t e R n ow & s av e

Breast Cancer Symposium 2011 The ConT inuum of B r easT Ca r e: sCie n Ce To s u rv ivo r shi p

September 8-10, 2011 San FranciSco marriott marquiS San FranciSco, caLiFornia

Cosponsored By

every member of the breast cancer care team is encouraged to attend this multidisciplinary meeting. this year’s Symposium will be two and a half days of challenging, debate-filled discussions on breast cancer research and treatment. Focusing on the theme of “the continuum of breast care: Science to Survivorship,” the Symposium will foster dialogue between investigators and clinicians to translate research directly into practice.

Join us in San Francisco. Register by August 3, 2011 to secure housing and the best registration rates: www.breastcasym.org.

Housing and Early Registration Deadline: August 3, 2011 at 11:59 PM (EDT) This live activity has been approved for AMA PRA Category 1 Credit™.

Primary Supporter

TARG E T I NG

C A NC E R

C A RE

ASCOPost.com | MAY 15, 2011

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TAP Caucus

PRO: ASCT Is the Best Strategy for Eligible Patients continued from page 33

not easily be carried out by many treating centers. In order to be feasible and routinely applicable, assessment of risk (with the aim of tailoring treatment) should be easy to perform and should consequently not be based on geneexpression profiling or determination of labeling index.

Conclusions In summary, the last decade has seen significant advances in the setting of ASCT, which have resulted in substantial improvements in survival. My personal opinion is that ASCT, which is a cost-effective procedure and is associated with a low mortality rate, will remain the standard of care in the 2010s. Future studies should be focused on defining the groups of patients who will benefit most from this procedure.

■

eloma. J Clin Oncol 28:2077-2084, 2010. 3. Attal M, Cristini C, Marit G, et al: Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol 28(15 suppl):abstract 8018, 2010. 4. Rajkumar SV, Jacobus S, Callander N, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy

for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol 11:29-37, 2010. 5. Richardson P, Weller E, Lonial S, et al: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679-686, 2010 6. Reeder CB, Reece DE, Kukreti V, et

al: Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia 23:1337-1341, 2009. Dr. Moreau is Professor of Medicine, Hematology Department, University Hospital Hôtel-Dieu, Nantes, France.

ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN) in Combination With RT in Locoregionally Advanced Disease

EGFR-Expressing Recurrent Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure as a Single Agent

Financial Disclosure: Dr. Moreau reported no potential conflicts of interest

References 1. Moreau P, Avet-Loiseau H, Harousseau JL, et al: Current trends in transplant for myeloma in the era of novel therapies. J Clin Oncol. April 11, 2011 (early release online). 2. Ladetto M, Pagliano G, Ferrero S, et al: Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografter my-

CON: ASCT Not Necessary for All Eligible Patients continued from page 31

we have included nonrandomized data to support the use of ASCT in patients well past the age of 70. While I do support this for various reasons, it is important to recognize that this approach is not based on randomized data. Finally, and most importantly, we now know that myeloma consists of many cytogenetic types with differing outcomes. Treating all cytogenetic categories in the exact same manner is no longer acceptable. How can we possibly say that subsets of patients with a median survival of 2 to 3 years despite not just one, but two back-toback ASCTs are to be approached in the same way as those in whom the expected median survival is in excess of 10 years?

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.

Risk-adapted Therapy Our approach at Mayo Clinic follows a risk-adapted strategy (as decontinued on page 41

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

The ASCO Post | MAY 15, 2011

PAGE 36

FDA Update

INNO-206 Receives Orphan Drug Designation for Pancreatic Cancer

ytRx Corporation announced that its tumor-targeting prodrug candidate INNO-206 has been approved for orphan drug designation for the treatment of patients with pancreatic cancer by the Office of Orphan

Products Development of the FDA. CytRx holds the exclusive worldwide development and commercialization rights to INNO-206. INNO-206 is designed to control the release of the commonly prescribed

chemotherapeutic doxorubicin and to preferentially target tumors, which may make it more effective and less toxic in patients with cancer than doxorubicin. Objective clinical re-

sponses have been reported in patients with sarcoma, breast, and small cell lung cancers. C ytRx anticipates moving into phase II clinical testing in soft-tissue sarcoma later this year.

■

ERBITUX Significantly Increased SCCHN

in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

RT alone (n=213)

29.3 months

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7

month improvement

P=0.05 RT=radiation therapy; HR=hazard ratio; CI=confidence interval. multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

ASCOPost.com | MAY 15, 2011

PAGE 37

FDA Update

HPV Test Approved for Identifying Cervical Cancer Risk

oche announced that the FDA has approved the cobas Human Papillomavirus (HPV) Test, which identifies women at highest risk for developing cervical cancer. The cobas HPV Test is the only

FDA-approved cervical cancer screening test that allows HPV 16 and 18 genotyping concurrently with high-risk HPV testing. It individually identifies genotypes 16 and 18, the two highestrisk HPV genotypes responsible for

more than 70% of cervical cancer c ases, while simultaneously detecting 12 other high-risk HPV genotypes. The approval was based on data from the ATHENA study involving more than 47,000 women in the United States.

Overall Survival in Both: EGFR-Expressing Recurrent mCRC after Irinotecan and Oxaliplatin Failure as a Single Agent

Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

4.57 months BSC alone (n=285)

34%

improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

† NCIC

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

Results demonstrated that 1 in 10 women, age 30 and older, who tested positive for HPV 16 and/or 18 by the cobas HPV Test actually had cervical precancer even though they showed normal results with the Pap test.

■

The ASCO Post | MAY 15, 2011

PAGE 38

FDA Update

Patient Advocates File Freedom of Information Act Request on Bevacizumab

eaders in the campaign to retain metastatic breast cancer as an indication for the drug bevacizumab (Avastin) recently filed a Freedom of Information Act (FOIA) request with the FDA. The filers include attorney David Rivkin, part-

ner at the law firm Baker Hostetler, Frank Burroughs and Steven Walker on behalf of the Abigail Alliance for Better Access to Developmental Drugs, campaigners for increased access to experimental drugs, and Terrence Kalley on behalf of Free-

dom of Access to Medicines, an organization dedicated to the right of women to retain bevacizumab as a medical option for metastatic breast cancer. The filers are troubled by many of the FDA’s actions in its review

of bevacizumab, a drug that is prescribed annually to an estimated 17,500 women with late-stage breast cancer. Many women and their oncologists report success with the drug, but the FDA will nevertheless be removing the indication for

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

ASCOPost.com | MAY 15, 2011

PAGE 39

FDA Update

metastatic breast cancer, subject to a final appeal by the drug’s manufacturer in June. The FOIA request includes documents regarding the nominations, appointment, actions, and communications of the Oncologic Drugs Advisory Committee (ODAC) that will hear the appeal. No patients or

their advocates will be allowed to speak, and many may not be able to attend due to space limitations at the meeting. The FOIA request also seeks documents regarding the processes by which the FDA reached its conclusions regarding bevacizumab, the communications between the FDA

and various outside parties, any discussions related to the costs of bevacizumab in the FDA review process, conflicts of interest by those party to the bevacizumab decision, and other relevant issues. In addition, the filers are seeking the scientific basis for the FDA’s decision with document requests re-

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB12708

12/10

lated to risk and benefit evaluation of bevacizumab, comparison of the risk/benefit of bevacizumab vs current approved drugs, the use of progression-free survival as a primary endpoint in cancer drug evaluation, and the FDA’s criteria for evaluation of toxicity under its accelerated approval process.

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The ASCO Post | MAY 15, 2011

PAGE 40

FDA Update

Everolimus Approved for Pancreatic Neuroendocrine Tumors

he FDA has approved everolimus (Afinitor), for the treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of

everolimus in the treatment of patients with carcinoid tumors have not been established. The approval was based on a randomized, controlled trial of everolimus 10 mg/d (n = 207) vs placebo (n = 203) in patients with unresectable,

locally advanced or metastatic pancreatic neuroendocrine tumors. The median progression-free survival was 11.0 and 4.6 months in the everolimus and placebo arms, respectively (HR = 0.35; 95% CI = 0.27–0.45; P < .001).

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONs None. WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

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Erratum: In the May 1 print issue of The ASCO Post (2[7]:1, 2011), an Editor’s note states that ODAC recommended Afinitor and Zortress (everolimus) be approved to treat advanced pancreatic neuroendocrine tumors. Only Afinitor, not Zortress, was being considered for approval in this patient population.

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. 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 practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages Acneiform Rash4 87 17 10 1 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

ASCOPost.com | MAY 15, 2011

PAGE 41

TAP Caucus

CON: ASCT Not Necessary for All Eligible Patients

requires that stem cells be collected and cryopreserved early in the disease course. Many patients wish to have a choice of early vs delayed ASCT based on their life situation. They need to know that there are no data on overall survival to support one approach over the other. My rough esti-

continued from page 35

scribed on the website msmart.org). In standard-risk patients (~75% of myeloma cases), the timing of ASCT (early vs delayed) is guided by patient choice (and other factors). This

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

mate is that approximately 50% of eligible patients in the United States are currently deciding to adopt a delayed ASCT strategy. For intermediate-risk patients (~10% of those with myeloma, characterized primarily by the t[4;14] translocation), induction with bort-

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

ER-B0001A-03-11

Rev March 2011

ezomib-based regimen, early ASCT, and routine bortezomib (Velcade)based maintenance is our preference and is supported by data from the Arkansas group. I am ambivalent about the role of ASCT in high-risk patients (~15% of myeloma cases defined either by gene expression profiling or the presence of t[14;16], t[14;20], or 17p-). High-risk patients appear to have a median survival of 2 to 3 years despite tandem ASCT. Our preference is that these patients are treated on clinical trials as much as possible. Selected highrisk patients may wish to consider allogeneic approaches.

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Financial Disclosure: Dr. Rajkumar reported no potential conflicts of interest.

References 1. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996. 2. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003. 3. Barlogie B, Kyle RA, Anderson KC, et al: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321. J Clin Oncol 24:929-936, 2006. 4. Facon T, Mary JY, Harousseau JL, et al: Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM). Preliminary results of a prospective randomized trial (CIAM) protocol (abstract 2729). Blood 88(suppl 1):685a, 1996. 5. Fermand JP, Ravaud P, Chevret S, et al: High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131-3136, 1998. 6. Blade J, Sureda A, Ribera JM, et al: High-dose therapy autotransplantation/intensification versus continued conventional chemotherapy in multiple myeloma patients responding to initial chemotherapy. Definitive results from PETHEMA after a median follow-up of 66 months (abstract 137). Blood 102:42a, 2003. Dr. Rajkumar is Professor of Medicine in the Department of Hematology and the Department of Laboratory Medicine and Pathology at the Mayo Clinic, Rochester, Minnesota.

The ASCO Post | MAY 15, 2011

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Leadership continued from page 3

Medicare Modernization Act Margaret A. Tempero, MD ASCO President, 2003–2004

eing an ASCO President is one of the best experiences anyone in our field can have. There’s a sense that you can really make a difference in the world, and it was truly a privilege. However, I had sort of a Jekyll and Hyde experience during my Presidency in that my original agenda was sideswiped by the passage of the Medicare Modernization Act (MMA), which produced a time of sudden turmoil within ASCO. We understood that the bill, as it was originally written, threatened access to care by putting undo stress on the existing financial models of many community practices— it needed an immediate response from the Society. I was fortunate to have strong in“Being an ASCO President is one dividuals to rely on, Drs. Jack Keech and of the best experiences anyone Joe Bailes. Through long and hard work, in our field can have. There’s a we were able to have a provision added to sense that you can really make a MMA that offered adequate financial prodifference in the world.” tection to community practices. It was a tough time, but a period that showcased the brilliance of the ASCO staff and the resoluteness of the membership in ensuring that our patients could continue to receive high-quality care in their community doctors’ offices. At the time, many people didn’t see the relationship between MMA and access to care. However, it was not about money, it was about community practices retaining enough fiscal integrity to be able to serve their cancer patients. Working through this crucial issue was a powerful experience during my Presidency.

Cancer Prevention

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Paul A. Bunn, Jr, MD ASCO President, 2002–2003

III colorectal cancer. We identified areas “The reason that ASCO continues in need of improvement and suggested to grow is that we are viewed as follow-up efforts to target and improve an evidence-based international the quality of cancer care. Supported organization that puts the largely by Susan G. Komen for the Cure, patient with cancer first.” the study was a major undertaking that actually became the springboard for ASCO into cancer care quality research and education. Now, the Society is globally recognized as the leader in cancer care quality. If I reflect back on my Presidency, I think my part in launching NICCQ was the highlight of an extremely rewarding year. And the reason that ASCO continues to grow is that we are viewed as an evidence-based international organization that puts the patient with cancer first.

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International Affairs Karen H. Antman, MD ASCO President, 1994–1995

ancer is a global problem. One advantage of academic medicine is that faculty get to travel to various universities internationally and see a country though the eyes of their colleagues, and not as a tourist. Therefore, during my Presidency, I established the ad hoc International Affairs Committee which evolved into the standing com“It was very important to get our mittee that has become a vital part of the international colleagues invested organization. At the time, attendance at in ASCO so that we could increase our Annual Meeting was already about the organization’s global status. 50% international. I felt that including And we have.” our international colleagues in ASCO was important so we could communicate and collaborate globally and increase the organization’s global presence. And we have.

AACR–ASCO Transition

ne highlight of serving as ASCO President is working with the outstanding staff—to name just a few, Executive Vice President Charles M. Balch, MD; Chief Operating Officer Ron Beller, PhD; Jean Colvard; Roseanna Thoman; and all the Department heads. During my Presidency, we undertook some very exciting initiatives. One was the elevation of the Cancer Prevention Task Force to full committee status, which allows the Society to focus more effectively on the creation of cancer education and prevention initiatives. Part of ASCO’s strategic planning was to become the authoritative resource for cancer. Since lung cancer is the number one cancer killer worldwide, I thought that we “We set about revising the should lead in prevention initiatives. So we ASCO tobacco control policy; set about revising the ASCO tobacco control the ultimate goal was the policy; the ultimate goal was the global elimiglobal elimination of nation of tobacco products. In part, the policy tobacco products.” called for efforts to increase tobacco taxes, expand prevention programs, limit promotions, and impose trade restrictions. It was a bold move, and one that I am proud of.

Quality of Cancer Care Joseph S. Bailes, MD ASCO President, 1999–2000

nder my leadership as President, ASCO initiated the largest quality of cancer care study ever done. Called the National Initiative for Cancer Care Quality (NICCQ), we looked at more than 60 quality measures for stage I to III breast cancer and stage II to

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George P. Canellos, MD ASCO President, 1993–1994

y Presidency was a transitional year; it was the first time that ASCO had a meeting separate from the American Association for Cancer Research. Since ASCO was thought to be simply a science-light organization that focused solely on clinical trials, the pressure was on to establish an independent scientific presence. I planned for our Annual Meeting to have more science than usual, and ASCO has continued to maintain that solid scientific presence. A contract group was managing ASCO at the time, and it became apparent that we needed to take a permanent role in the organization’s continuous activities. So we offered Dr. John Durant the position of Executive Vice President, and he was later “Since ASCO was thought to be confirmed in the position by my successimply a science-light organization sor. ASCO’s road to independence and that focused solely on clinical trials, eventually to self-publishing the Journal the pressure was on to establish an of Clinical Oncology had begun. independent scientific presence.” Also during my term, Dr. Bernard Fisher was wrongly accused of running an organization that had some problems with its data. Breast cancer advocates were up in arms; the NCI was upset—a real mess. Dr. Fisher was subsequently vindicated. At the ASCO Annual Meeting that I chaired, there were inquiries about having him speak at the Plenary Session. Naturally the presentations were already booked, but we altered the session, eliminating certain talks to make room for Dr. Fisher. I gave him a big hug when he stepped to the lectern, and it set off a roaring ovation from the packed hall. He did a marvelous job.

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Leadership

Science vs Practice

Bernard Fisher, MD ASCO President, 1992-1993

y year as President was a busy one. Aside from continuing my research and directing the activities of the National Surgical Adjuvant Breast and Bowel Project, I was drowned by the vast amount of information that was sent to me by ASCO headquarters (see page 10). At the onset of my Presidency, I discovered that a crisis was brewing regarding ASCO’s mission. Since subsequent Annual Meetings of the Society were no longer to be held in conjunction with the American Association for Cancer Research, many members felt that ASCO was abandoning its scientific objec“ASCO members must base tives and directing its course toward pritherapeutic decision-making vate-practice issues. On the other hand, prion information obtained using vate-practice oncologists were concerned scientific methodology.” that ASCO was not providing them with a platform for discussing their problems related to reimbursement, government affairs, and education of oncologists. During my tenure, I was more concerned with ASCO’s relation with research. I firmly believed that the future vitality, integrity, and justification for the Society would depend on how well research enveloped its membership. I thought that a widening gap between physicians and investigators could not only threaten the welfare of patients, but as clinicians got further away from science, the hope for progress in curing and preventing cancer would diminish. In my Presidential address, I noted a statement by Nobel Laureate Sir Peter Medewar, indicating that to deride any aspect of science, be it fundamental, basic, or clinical, is the ultimate foolishness, the last word in poverty of spirit and meanness of mind. While I was less than enthusiastic about ASCO’s role in the public issues arena, I did believe that ASCO should be used as a bully pulpit to express its positions on selected public issues related to its major goal, ie, promoting medical care based on science. Two decades later, I still maintain that all members of ASCO must have the same objectives relating to the prevention and cure of cancer: They must base therapeutic decision-making on information obtained using scientific methodology rather than empiricism, anecdotalism, and inductivism, which, unfortunately, continue to be used by too many physicians.

The Past Quarter Century

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Journal of Clinical Oncology Emil J. Freireich, MD ASCO President, 1980–1981

uring my Presidency, we decided to increase ASCO’s size to give clinical investigators a better position in the medical world. To that end, I decided that the Society needed its own journal. At that time, we sent our papers to Blood or Cancer Research, where, in my estimation, they received poor treatment. I charged the Science and Publications Committee to develop a plan for the new journal. Led by Emil Frei III, MD, the committee worked long and hard to design guidelines for the journal and to select its first editor, Joseph R. Bertino, MD. The Journal of Clinical Oncology was born, and its continued success as one of the nation’s top-ranked journals is very satisfying. I also felt that ASCO needed to generate more income than it was getting from mem“My advice to young bership dues. I decided to bring in commeroncologists coming into cial exhibits, which helped transform the Sothis great field is to retain a ciety. For one, we now had enough money to sense of urgency!” support our publication and help us initiate grants and educational programs. Unlike other scientific societies, ASCO focused on patient-oriented studies. It’s great to cure mice and treat cell lines and isolate genes, but if we’re going to cure cancer, it is going to take talented physicians working at the bedside and in clinical trials. All of our patients are battling a lethal disease, and my advice to young oncologists coming into this great field is to retain a sense of urgency!

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The Consequence Is Cure

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Philip Schein, MD ASCO President, 1983–1984

quarter century, current survival statistics for most common forms of cancer and the success rate in developmental therapeutics demonstrate that there is much work to be done and no justification for self-congratulatory complacency. Instead we should be encouraged by our successes and intensify our efforts. ASCO, in fulfillment of its commitments to patients with cancer and their families, is well positioned to assume a leadership role in this endeavor.

eflecting on the years since my Presidency, I have been deeply impressed with the advances that have been made in our fundamental understanding of cancer biology and in our capacity to translate discoveries into new, mechanism-based therapeutics. A much broader range of therapeutic tools has emerged than was available to investigators in the past, and prospective patient selection is becoming a reality. The result has been a significant improved outcome for patients with specific tumor types. However, the past decades of research have also brought a humbling appreciation of the continuing challenge: a bewildering array of molecular expressions of tumor heterogeneity and the barriers posed by complex mechanisms of resistance. A significant upward revision in the es“We should be encouraged by timate of the number and quality of new our successes and intensify therapeutics will be required to match our efforts. ” the growing catalog of tumor subtypes. We must also face the reality that a disappointingly low number of new molecular entities survive the development and regulatory processes, and reach the public in form of FDA-approved products. So while there have been unquestioned and important advances over the past

Vincent T. DeVita, Jr, MD ASCO President, 1977–1978

y Presidency was the first year that the Annual Meeting hit 10,000 attendees, which at the time we thought was a huge number—it seemed that we’d hit the ceiling. It was about 9 years after we published the results from our study of combination chemotherapy (MOPP) in the treatment of advanced Hodgkin’s disease, which was the first example of the ability to cure advanced cancer in adults with drugs. So I titled my Presidential speech “The Consequences of the Chemotherapy of Hodgkin’s Disease.” “The most important Given the use of the word “consequencconsequence of using es,” everyone in the audience assumed chemotherapy for Hodgkin’s that I was going to speak about the bad efdisease was its cure.” fects of the chemotherapy. Remember, at that time most people were still skeptical about the curative value of chemotherapy. The title turned out to be an interesting play on words, because the central point of the speech was that the most important consequence of using chemotherapy for Hodgkin’s disease was its cure. To give the speech’s meaning historical perspective, the original paper we published in 1970 on MOPP was the most cited paper in the history of the Annals of Internal Medicine. It took another 11 years for MOPP to fully diffuse into the practice of oncology, so when I gave my Presidential speech it was not fully out there. Nevertheless, it remained the standard of care for 25 years.

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Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates (ADCs) ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-4

Monoclonal antibody

Stable linker

Cytotoxic

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer activities1,3,5-7

conjugates cytotoxic to monoclonal antibody and is designed to allow ADC to remain inactive while in circulation1,2,7,8

incorporated into an ADC can be up to 1000-fold more potent than currently used chemotherapies2,5,7

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibodyâ&#x20AC;&#x201C;mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic.5-7 Preclinical studies show that these anticancer activities may include prevention of signaling, antibody-dependent cellular cytotoxicity, and induction of apoptosis.3,5,6

To learn more, visit the new ADC resource at www.ResearchADCs.com References: 1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 6. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.