Issuu on Google+

Genomics in Breast Cancer 15

|

Adjuvant Treatment of Melanoma 40

|

VOLUME 3, ISSUE 4

Multiple Myeloma 41, 46

MARCH 1, 2012

ASCOPost.com

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

Inefficient Markets Impede Cancer Pain Relief

2012 Genitourinary Cancers Symposium

Two Novel Agents Prolong Survival in Advanced Prostate Cancer By Alice Goodman

T

wo novel agents with distinct mechanisms of action join ranks of treatments that extend survival for patients with castration-resistant prostate cancer: MDV3100 and radium-223. Both drugs achieved a survival advantage compared with Howard I. Scher, MD placebo, with relatively benign side-effect profiles, according to results of two international phase  III trials reported at the 2012 Genitourinary Cancers Symposium, held recently in San Francisco. The first interim analysis of AFFIRM was presented by Howard I. Scher, MD, Memorial SloanKettering Cancer Center, New York. Updated results of the effect of radium-223 on skeletal-related events in the ALSYMPCA trial were presented by Chris

Parker, MD, Consultant Clinical Oncologist at the Royal Marsden Hospital, London. Survival results of ALSYMPCA were previously reported at the European Multidisciplinary Cancer Congress last fall (see The ASCO Post, October 15, 2011).

AFFIRM Analysis “MDV3100 is a first-in-class androgen receptor signaling inhibitor. The oral investigational drug was rationally designed to inhibit androgen receptor signaling, which is a key SEE PAGE 55 driver of prostate growth,” Dr. Scher told listeners (Fig. 1 on page 10). At the first planned interim analysis of the randomized, placebo-controlled AFFIRM trial, MDV3100 reduced the risk of death by 37% in men with castrationresistant prostate cancer for whom docetaxel treatment had failed. At that time, an independent data monitoring continued on page 9

A Visionary Call for the ‘Creative Destruction’ of Medicine

Opinion

thoughts with The ASCO Post on an unprecedented transformation in medicine, as described in his recently published book, The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care (see book review on page 33). Here he discusses issues of value and cost in health care, the problems inherent in mass screening efforts, “individualized” vs “personalized” medicine, and how future innovations may be When you introduce new introduced to our healthtechnology into health care, it is care system.

ccording to nationally regarded cardiologist and geneticist Eric Topol, MD, Chief Academic Officer of Scripps Health, the next frontier of the digital revolution can create exponentially better health care. Dr. Topol, who is also Director of the Scripps Translational Science Institute and Professor of Genomics, The Scripps Research Institute, recently shared his

—Eric Topol, MD

he potent analgesic property of morphine was first isolated in 1804, and after more than 2 centuries morphine is still the gold standard for moderate to severe pain. It is relatively easy to produce, and compared to most pharmaceuticals, morphine is dirt-cheap. Therein lies the cruel conundrum: Morphine is widely available in Western, developed nations, but in resource-constrained countries, comprising about 80% of the world’s population, market conditions have grossly inflated the drug’s price, leaving the majority of the world’s poorer cancer patients suffering in severe pain because they can’t afford analgesic relief.

The Cost Barrier When governments scale up health-care delivery services in the public sector of a lower-income country, they naturally want a lowDr. O’Brien is Director, Global Access to Pain Relief Initiative, a joint program of the Union for International Cancer Control and the American Cancer Society.

By Ronald Piana

invariably coupled with increased costs. But we have an opportunity to turn that model around.

T

continued on page 8

A Conversation with Eric Topol, MD

A

By Meg O’Brien, PhD

Radical Innovation

MORE IN THIS ISSUE Oncology Meetings Coverage Gastrointestinal Cancers Symposium�������� 3 San Antonio Breast Cancer Symposium���������������������������� 14, 15, 21 ASH Annual Meeting�������������������� 41, 44 FDA Update�������������������������������������������������� 25 Direct from ASCO��������������������������������������� 26 Conversation with Marshall R. Posner, MD������������������������������ 35

Congratulations on your new book. It’s quite a provocative title; what was the inspiration? continued on page 22

March Is Colorectal Cancer Awareness Month

A Harborside Press® Publication


The ASCO Post  |   MARCH 1, 2012

PAGE 2

News

Lung Cancer Alliance Announces National Framework for Lung Cancer Screening Excellence

Editorial Board  James  O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

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

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

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

Robert W. Carlson, MD Stanford University Medical Center

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado 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 John A. Fracchia, MD New York Urological Associates 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

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

Barely Changed Survival Rate By announcing the first-of-its-kind national framework for lung cancer screening, the Lung Cancer Alliance is breaking through the status quo on lung cancer, whose 15% survival rate has barely changed in 40 years. More people die of lung cancer than the next four leading causes of cancer death— breast, prostate, colon, and pancreatic cancers—combined.

“If properly implemented, lung cancer screening has the potential to save more lives than anything we have done since the War on Cancer began,” said James L. Mulshine, MD, Associate Provost for Research and Director of the Translational Sciences Consortium at Rush Medical College.

Guiding Principles The National Framework states that the public has a right to know if they are at risk, that low-dose CT screening can save their lives, and that they should only go to sites that follow certain Guiding Principles, which are listed at www.screenforlungcancer.org/ national-framework/. “Proper implementation must include a comprehensive Continuum of Care that includes a team of clinical specialists with expertise in pulmonary disease, thoracic surgery, radiology, and oncology,” said William R. Mayfield, MD, Chief Surgical Officer for WellStar Health Systems, whose group developed the well-designed protocol included in the SEE PAGE 55 Framework.

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) 692-0805. Copyright ©2012 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.

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

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.

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

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: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

Harborside Press® Publishing Staff  Conor Lynch, Executive Editor Conor@harborsidepress.com

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

Michael Buckley, Graphic Designer Michael@harborsidepress.com

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan

London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

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

T

he Lung Cancer Alliance (LCA) moved lung cancer screening to a national platform by announcing a Framework for Lung Cancer Screening Excellence, which includes a bill of rights for the at-risk public and guiding principles for lung cancer screening sites. “The science is indisputable: Screening those at high risk for lung cancer with low-dose CT scans can save tens of thousands of lives each year,” said LCA President and CEO Laurie Fenton Ambrose. “We are moving forward now with thoughtful and responsible leaders to bring this benefit of screening to those at high risk for lung cancer safely, efficiently, and effectively,” she said.

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; e-mail: 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.


ASCOPost.com  |   MARCH 1, 2012

PAGE 3

2012 Gastrointestinal Cancers Symposium What Were the Take-home Messages from the 2012 Gastrointestinal Cancers Symposium? By Richard M. Goldberg, MD

R

ichard M. Goldberg, MD, of The Ohio State University Medical Center, chaired the steering committee of the 2012 Gastrointestinal Cancers Symposium in San Francisco, which attracted approximately 4,000 registrants who viewed data from some 700 scientific abstracts. The ASCO Post asked Dr. Goldberg to describe his “take-aways” from the meeting, and how the data fit with the emerging landscape of GI cancer.

Richard M. Goldberg, MD

It is becoming clear from recent studies, such as those presented at the 2012 Gastrointestinal Cancers Symposium, that gastrointestinal tumors we call one entity (based on the organ in which they originate) are actually very heterogeneous. Our understanding of GI cancers will probably become as complicated as our taxonomy in lymphoma. Tumors will be described by their behavior, which will be predicted by molecular markers and not just by the classical anatomic markers like grade and stage. Markers such as KRAS probably will be joined by dozens of other factors that will help us choose drugs.

Genetic Advances I believe in the next 10 to 15 years we will be referring to tumor subtypes differentiated by their genetic profiles. At that point, our strategies may become more effective, with one strategy good for one subtype and a different strategy for another. We are already seeing this, for instance, in neuroendocrine tumors. Everolimus (Afinitor) and sunitinib (Sutent) are effective in pancreatic neuroendocrine tumors, but there is no evidence

of an effect in carcinoid tumors, and all are called neuroendocrine tumors. We heard at this meeting, in a study by Yao et al,1 that certain carcinoid subsets might benefit from these agents, and this has relevance to our therapeutic approach, especially when we use a drug that has significant toxicity. In keeping with these genetic advances, we are seeing new genetic tests to assess colorectal cancer recurrence risk. The ColoPrint test, with data presented by Tabernero et al,2 is the next step in what I think is a refinement of these decision-making tools. They are “on the verge” of becoming useful, and this will grow over time. We also heard from Dr. David Ahlquist about a stool test that evaluates fecal DNA for a marker of a precancerous or cancerous condition.3 The idea behind this—that polyps and tumors are constantly exfoliating cells—is fascinating. This technique does not depend on bleeding and does not involve bowel prep, appears to be much more sensitive than the current fecal occult blood test, and detects low-profile serrated polyps, which can be problematic to identify with colonoscopy. If we could use serial stool DNA testing like serial Pap smears instead of colonoscopy, the cost savings would be tremendous. From all these perspectives, this technology would be welcomed. The data presented by Dr. Ahlquist was very impressive, and this is a very exciting development.

New Drugs: Some Wins, Some Disappointments We also heard encouraging data for the new multitargeted tyrosine kinase inhibitor regorafenib.4 This is a very interesting compound that has the potential to affect a number of pathways in colon cancer. The data presented by Grothey et al showed an overall survival difference with regorafenib as a single agent in very heavily pretreated patients. The data look very similar to the initial data in the third-line setting for cetuximab (Erbitux) and panitumumab

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

Important News Briefs: New Data Reported in Gastric, Colorectal, and Hepatocellular Cancers By Caroline Helwick

F

indings presented at the 2012 Gastrointestinal Cancers Symposium will impact the future care of patients with these malignancies. The ASCO Post has summarized some of the most newsworthy data in the following briefs. In the phase III GRANITE-1 trial (n = 656), single-agent SEE PAGE 55 treatment with everolimus (Afinitor) in previously treated patients with advanced gastric cancer did not significantly improve overall survival, vs best supportive care. Overall survival was 5.4 months with everolimus and 4.3 months with best supportive care (P = .1244). Everolimus did, however, reduce the risk of progression by 34% (P < .0001), although the median progression-free survival was 1.68 vs 1.41 months, respectively.1 In the phase III NCIC CTG/AGITG CO.20 trial (n = 750) in metastatic chemotherapy-refractory KRAS wild-type colorectal cancer, the addition of the novel multitargeted tyrosine kinase inhibitor brivanib to cetuximab (Erbitux) did not improve overall survival, the primary endpoint, though it did improve progression-free survival. Median overall survival was 8.8 months with brivanib/cetuximab vs 8.1 months with cetuximab alone (P = .12). Median progression-free survival was 5.0 vs 3.4 months, respectively (P < .0001), a 28% reduction in risk.2 The Korean AMC 0101 trial (n = 640) aimed to determine if adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer could be improved with four strategies: (1) adding cisplatin, (2) prolonging the administration of low-dose oral fluoropyrimidine, (3) starting chemotherapy early, and (4) giving it intraperitoneally. Postoperative intraperitoneal cisplatin and early mitomycin plus long-term doxifluridine plus cisplatin, compared to mitomycin plus short-term doxifluridine, significantly improved relapsefree survival (HR = 0.729; P = .0092) and overall survival (HR = 0.768; P = .0365) in the study’s long-term (median of 6.6 years) follow-up.3 The randomized double-blinded placebo-controlled phase II global SPACE trial (n = 307) evaluated the efficacy of sorafenib (Nexavar) in combination with transarterial chemoembolization using doxorubicin-eluting continued on page 7

(Vectibix), before we identified the subset of patients (with KRAS wildtype) who actually benefit. Regorafenib is a drug worthy of additional testing, though we need to find biomarkers that will help us discern what subset of patients are most likely to gain from this agent. The 1.4 months of overall survival difference was modest, but it’s a signal. By refining how we use this agent we will likely be able to exploit it to greater benefit. Two other studies, however, were disappointing. In advanced gastric cancer, the GRANITE-1 study found no overall survival benefit for

everolimus as a single agent.5 While the shape of the progression-free survival curve suggested there may be a responsive subset, my thought is we should focus on other targeted agents rather than developing iterative studies of agents for whom the trial endpoints are negative. The other novel tyrosine kinase inhibitor, brivanib, also failed to improve overall survival in combination with cetuximab, vs cetuximab alone, in advanced colorectal cancer.6 But should we conclude that brivanib is a useless drug? I hope we don’t. Perhaps, we should instead try to narrow down and continued on page 7

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.


ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 2/12 08A11090CR1


ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

ORAL THERAPY

Mechanism of action Abiraterone is an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17-hydroxylase/C17,20-lyase) — Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue Androgen biosynthesis inhibition with ZYTIGA® results in decreased levels of serum testosterone and other androgens At the interim analysis of the pivotal phase 3 study, ZYTIGA® + prednisone showed a statistically significant improvement in median overall survival (OS) compared with the control arm* — Median OS: 14.8 months vs 10.9 months (hazard ratio = 0.646; 95% confidence interval: 0.543, 0.768, P < 0.0001)

Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring.

If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®. *Study Design: ZY TIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropinreleasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL). 1 The primary efficacy endpoint was overall survival.

Reference: 1. de Bono JS, Logothetis CJ, Molina A , et al. Abiraterone and increased sur vival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

08Z11121R3

Important Safety Information


ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. 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 clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders 7.2 1.1 4.6 1.0 Arrhythmia6 3.8 0.5 2.8 0 Chest pain or chest discomfort 7 2.3 1.9 1.0 0.3 Cardiac failure8 1

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. 2 3


ASCOPost.com  |   MARCH 1, 2012

PAGE 7

2012 Gastrointestinal Cancers Symposium ZYTIGA® (abiraterone acetate) Tablets acetate) Tablets ZYTIGA® (abiraterone Table 2: Laboratory Table 2: Laboratory Abnormalities Abnormalities of Interest in of aInterest Phase in 3 Placebo-Controlled a Phase 3 Placebo-Controlled Clinical Clinical Trial Trial AbirateroneAbiraterone (N=791) (N=791) Placebo (N=394) Placebo (N=394) All Grades All Grades Grade 3-4 GradeAll3-4 Grades All Grades Grade 3-4 Grade 3-4 Laboratory Laboratory AbnormalityAbnormality(%) (%)(%) (%) (%) (%)(%) (%) High Triglyceride High Triglyceride 62.5 62.50.4 0.4 53.0 53.0 0 0 High AST High AST 30.6 30.62.1 2.1 36.3 36.31.5 1.5 Low Potassium Low Potassium 28.3 28.35.3 5.3 19.8 19.81.0 1.0 Low Phosphorus Low Phosphorus 23.8 23.87.2 7.2 15.7 15.75.8 5.8 High ALT High ALT 11.1 11.11.4 1.4 10.4 10.40.8 0.8 High Total Bilirubin High Total Bilirubin 6.6 6.6 0.1 0.1 4.6 4.6 0 0 DRUG INTERACTIONS DRUG INTERACTIONS Effects of Abiraterone Effects of Abiraterone on Drug Metabolizing on Drug Metabolizing Enzymes: ZYTIGA Enzymes: is an ZYTIGA inhibitor is an of inhibitor the of the hepatic drug-metabolizing hepatic drug-metabolizing enzyme CYP2D6. enzyme In CYP2D6. a CYP2D6Indrug-drug a CYP2D6interaction drug-drug interaction trial, the trial, the Cmax and AUC Cmax of and dextromethorphan AUC of dextromethorphan (CYP2D6 substrate) (CYP2D6were substrate) increased were2.8increased and 2.9-fold, 2.8- and 2.9-fold, respectively, respectively, when dextromethorphan when dextromethorphan was given with wasabiraterone given with abiraterone acetate 1,000 acetate mg daily 1,000 mg daily and prednisone and prednisone 5 mg twice 5daily. mg twice Avoiddaily. co-administration Avoid co-administration of abiraterone of abiraterone acetate with acetate with substrates of substrates CYP2D6 with of CYP2D6 a narrow withtherapeutic a narrow therapeutic index (e.g., index thioridazine). (e.g., thioridazine). If alternative If alternative treatments treatments cannot be cannot used, exercise andcaution consider dose reduction the be used,caution exercise anda consider a dose ofreduction of the concomitantconcomitant CYP2D6 substrate [see Clinical Pharmacology (12.3) in full (12.3) Prescribing CYP2D6drug substrate drug [see Clinical Pharmacology in full Prescribing Information]. Information]. Drugs that Drugs Inhibitthat or Induce Inhibit CYP3A4 or Induce Enzymes: CYP3A4Based Enzymes: on in Based vitro on data, in vitro ZYTIGA data, is aZYTIGA is a substrate of substrate CYP3A4.ofThe CYP3A4. effectsThe of effects strong CYP3A4 of stronginhibitors CYP3A4 (e.g., inhibitors ketoconazole, (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, ritonavir, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, indinavir, nelfinavir, or inducersor (e.g., phenytoin, rifampin, rifampin, indinavir,voriconazole) nelfinavir, voriconazole) inducers (e.g., carbamazepine, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not have not rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone been evaluated, vivo. Avoid or use withorcaution, strong inhibitors inducers been in evaluated, in vivo. Avoid use with caution, strongand inhibitors andofinducers of CYP3A4 during ZYTIGA treatment Clinical[see Pharmacology (12.3) in full(12.3) Prescribing CYP3A4 during ZYTIGA[see treatment Clinical Pharmacology in full Prescribing Information]. Information]. USE IN SPECIFIC USE INPOPULATIONS SPECIFIC POPULATIONS Pregnancy:Pregnancy: Pregnancy Pregnancy Category X Category [see Contraindications]. ZYTIGA is contraindicated X [see Contraindications]. ZYTIGA is contraindicated in women who are orwho mayare become pregnant receiving drug. Ifthe thisdrug. drugIfisthis drug is in women or may becomewhile pregnant whilethe receiving used duringused pregnancy, or if the patient becomes takingwhile this drug, during pregnancy, or if the patientpregnant becomeswhile pregnant takingthe this drug, the patient should be apprised ofapprised the potential hazard to the fetusto and potential risk for patient should be of the potential hazard thethe fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment ZYTIGA. pregnant duringwith treatment with ZYTIGA. ZYTIGA is not indicated use in women. not known abiraterone Nursing Mothers: Nursing Mothers: ZYTIGA is notforindicated for useItiniswomen. It isifnot known if abiraterone acetate is excreted in excreted human milk. Because many drugsmany are excreted in excreted human milk, and milk, and acetate is in human milk. Because drugs are in human because of because the potential serious for adverse reactions nursing infants frominfants ZYTIGA, of theforpotential serious adverseinreactions in nursing from ZYTIGA, a decision should be made to be either discontinue nursing, or discontinue the drug taking a decision should made to either discontinue nursing, or discontinue the drug taking into accountinto theaccount importance of the drug of to the drug mother. the importance to the mother. Pediatric Use: ZYTIGAUse: is not indicated children. in children. Pediatric ZYTIGA is notinindicated Geriatric Use: Of the total of patients phase 3intrial of ZYTIGA, of patients Geriatric Use: number Of the total numberin ofapatients a phase 3 trial71% of ZYTIGA, 71% of patients were 65 years and65over and 28% were years and75over. Noand overall in safety in safety were years and over and7528% were years over.differences No overall differences or effectiveness were observed these elderly patients andpatients youngerand patients. or effectiveness werebetween observed between these elderly younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects inwith baseline (n = 8)mild or moderate = 8) hepatic (Childsubjects withmild baseline (n = 8) or(nmoderate (n = impairment 8) hepatic impairment (ChildPugh Class Pugh A andClass B, respectively) and in 8 healthy subjects with normalwith hepatic A and B, respectively) and incontrol 8 healthy control subjects normal hepatic function. The systemic of abiraterone after a single orala 1,000 dose function. Theexposure systemic(AUC) exposure (AUC) of abiraterone after singlemg oral 1,000 mg dose of ZYTIGA increased approximately 1.1-fold and1.1-fold 3.6-foldand in subjects mild and of ZYTIGA by increased by approximately 3.6-fold inwith subjects with mild and moderate baseline hepatic impairment, respectivelyrespectively compared to subjects to with normalwith normal moderate baseline hepatic impairment, compared subjects hepatic function. hepatic function. No dosage No adjustment is necessary patientsfor with baseline mild hepaticmild impairment. dosage adjustment is for necessary patients with baseline hepatic impairment. In patients In with baseline impairment (Child-Pugh(Child-Pugh Class B), reduce patients withmoderate baselinehepatic moderate hepatic impairment Class B), reduce the recommended dose of ZYTIGA mg once If elevations ALT or AST the recommended dose to of 250 ZYTIGA to 250daily. mg once daily. If in elevations in ALT or AST >5X ULN or>5X totalULN bilirubin >3X ULN occur in patients with baseline or total bilirubin >3X ULN occur in patients withmoderate baselinehepatic moderate hepatic impairment,impairment, discontinuediscontinue ZYTIGA treatment Dosage andDosage Administration (2.1) and (2.1) and ZYTIGA [see treatment [see and Administration Clinical Pharmacology (12.3) in full (12.3) Prescribing Information]. Clinical Pharmacology in full Prescribing Information]. The safety of ZYTIGA baseline severe hepatic impairment has not been The safetyinofpatients ZYTIGA with in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. studied. These patients should not receive ZYTIGA. For patientsForwho develop hepatotoxicity during treatment, of treatment patients who develop hepatotoxicity during interruption treatment, interruption of treatment and dosageand adjustment may be required Dosage andDosage Administration (2.2) in full (2.2) in full dosage adjustment may be[see required [see and Administration PrescribingPrescribing Information,Information, Warnings and Precautions, and Clinicaland Pharmacology (12.3) in (12.3) in Warnings and Precautions, Clinical Pharmacology full Prescribing Information]. full Prescribing Information]. Patients with Renalwith Impairment: In a dedicated impairment trial, the mean Patients Renal Impairment: In a renal dedicated renal impairment trial, PK the mean PK parametersparameters were comparable between healthy subjects normalwith renal function were comparable between healthywith subjects normal renal function (N=8) and those end stage disease (ESRD) on hemodialysis (N=8) after (N=8) a (N=8) with and those with renal end stage renal disease (ESRD) on hemodialysis after a single oral single 1,000 mg ZYTIGA. NoZYTIGA. dosage No adjustment is necessary patientsfor patients oraldose 1,000ofmg dose of dosage adjustment is for necessary with renal impairment [see Dosage[see andDosage Administration (2.1) and Clinical Pharmacology with renal impairment and Administration (2.1) and Clinical Pharmacology (12.3) in full (12.3) Prescribing Information]. in full Prescribing Information]. OVERDOSAGE: OVERDOSAGE: have beenofnooverdose reports ofofoverdose of ZYTIGA during clinical studies. There have There been no reports ZYTIGA during clinical studies. is no specificInantidote. In of theanevent of an stop overdose, stop ZYTIGA, undertake There is noThere specific antidote. the event overdose, ZYTIGA, undertake general measures, supportive including measures,monitoring including monitoring for arrhythmias cardiac failure general supportive for arrhythmias and cardiacand failure liver function. and assess and liverassess function. andStore Handling: Store at 20°C toto 25°C (68°F to 77°F); excursions to 15°C Storage andStorage Handling: at 20°C to 25°C (68°F 77°F); excursions permitted topermitted 15°C to to 30°C (59°F 86°F)controlled [see USProom controlled room temperature]. on its mechanism to 30°C (59°F 86°F) [seetoUSP temperature]. Based on itsBased mechanism of action, harm a developing fetus. women Therefore, who areorpregnant or of action, ZYTIGA mayZYTIGA harm amay developing fetus. Therefore, whowomen are pregnant may beshould pregnant should ZYTIGA not handle ZYTIGA without protection, women whowomen may bewho pregnant not handle without protection, e.g., gloves e.g., gloves Use Populations]. in Specific Populations]. [see Use in [see Specific Manufactured by: Manufactured by: Patheon Inc. Patheon Inc. Mississauga, Mississauga, Canada Canada Manufactured for: Manufactured for: Janssen Biotech, Inc. Janssen Biotech, Inc. Horsham, Horsham, PA 19044 PA 19044 Issued: 2011 December 2011 Issued: December

08Z11205B 08Z11205B

Take-home Messages continued from page 3

enrich the population to increase the likelihood of a response in future trials, in other words, restrict the drug to patients most likely to benefit. Biomarker studies must also inform us on this.

In Conclusion So my take-home lessons from this meeting are that we must return to our laboratories to sequence DNA and RNA and must exploit other analytic techniques to get a firmer grasp of tumor biology. This, in turn, will permit us to optimize drug development with the ultimate and attainable goal of improv-

Important News Briefs continued from page 3

beads in patients with intermediatestage hepatocellular carcinoma. The study met its primary endpoint of improvement in time to progression, with a hazard ratio of 0.797 (P  = .072). Time to vascular invasion/ extrahepatic spread was reduced by 28% (P  = .076), but median overall survival had not been reached in either arm and was not significantly different between arms. A higher number of early transarterial chemoembolization discontinuations were seen in the sorafenib arm in non-Asian regions, and the duration of sorafenib treatment was longer in Asian regions, associated with greater efficacy.4 Stereotactic body radiation therapy as an alternative to radiofrequency ablation, achieved excellent local control, with low toxicity, for the treatment of primary and metastatic liver tumors in a study from the University of Michigan. Stereotactic body radiation therapy allows conformal delivery of ablative doses while sparing normal liver tissue. In a retrospective comparison with radiofrequency ablation in 189 patients, freedom from local progression was observed in 93% of the stereotactic body radiation therapy group and 86% of the radiofrequency ablation group at 1 year, and in 84% and 83%, respectively, at 2 years. With radiofrequency ablation, tumor size ≥ 3 cm had worse outcomes, whereas neither tumor size nor treatment dose predicted for outcomes with stereotactic body radiation therapy. In particular, stereotactic body radiation therapy may be more effective than radiofrequency ablation

ing patient outcomes. Studies from this meeting point to looming discoveries toward incremental progress.

Disclosure: Dr. Goldberg has received research funding from Abbott, Genentech, Bayer, Myriad, and sanofi-aventis. He has been an unpaid consultant to Bayer, Myriad, and sanofi-aventis, and has been paid as a consultant by Genomic Health, Genentech, and Lilly.

References 1. Yao J, Hainsworth JD, Wolin EM, et al: Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus or placebo among patients with advanced neuroendocrine tumors. 2012 Gastrocontinued on page 8

for the local control of large liver tumors, in whom it reduced recurrences by 69% (P = .03).5

References 1. Van Cutsem E, Yah KH, Bang YJ, et al: Phase 3 trial of everolimus in previously treated patients with advanced gastric cancer: GRANITE-1. 2012 Gastrointestinal Cancers Symposium. Abstract LBA3. Presented January 19, 2012. 2. Siu LL, Shapiro JD, Jonker DJ, et al: Phase III randomized trial of cetuximab plus either brivanib alaninate or placebo in patients with metastatic chemotherapy refractory K-RAS wild-type colorectal carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 trial. 2012 Gastrointestinal Cancers Symposium. Abstract 386. Presented January 21, 2012. 3. Kang Y-K, Ryoo B-Y, Chang H-M, et al: Update of AMC 0101 study: A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluoridine plus cisplatin versus mitomycin-C plus short-term doxifluridine as postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer. 2012 Gastrointestinal Cancers Symposium. Abstract 4. Presented January 18, 2012. 4. Lencioni R, Llovet JM, Hang G, et al: Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediatestage hepatocellular carcinoma: phase II randomized, double-blind, placebocontrolled SPACE trial. 2012 Gastrointestinal Cancers Symposium. Abstract LBA154. Presented January 20, 2012. 5. Liu E, Stenmark MH, Lee OE, et al: Stereotactic body radiation therapy as an alternative to radiofrequency ablation for the treatment of primary and metastatic liver tumors. 2012 Gastrointestinal Cancers Symposium. Abstract 158. Presented January 20, 2012.


The ASCO Post  |   MARCH 1, 2012

PAGE 8

Issues in Oncology

Cancer Pain Relief continued from page 1

cost product. Ironically, even though morphine is a very inexpensive drug, its cost is a major barrier to access in regions such as sub-Saharan Africa, Latin America, and Eastern Europe. However, when we scale up a treatment that’s not in wide use, such as morphine, there is actually a downside. When sale volumes are low and per-dose profits are similarly low, especially in off-patent drugs like morphine, the potential for profit is harder to realize. Naturally, this scenario chills a supplier’s incentive to enter the new drug markets. Moreover, if a drug supplier does want to sell its product in a new market, it has to pay several thousand dollars in product registration fees. Given the regulatory complexity of many developing nations, that process can take a couple of years. Also, because opioids are regulated products, there is an additional layer of onerous compliance work. Further complicating the process is that in developing nations there is generally no guaranteed demand for suppliers. Unlike the past 10 years in HIV/AIDS treatment, we actually had guaranteed market demand driven by The Global Fund and The U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), so producers knew that certain countries would order therapies for 5 years or more, which was a significant incentive for suppliers to enter the market. In regions like sub-Saharan Africa we don’t have a set market demand for pain products even though the need for them is great. In order to hedge their investment in an uncertain market, drug suppliers mark up their prices. More importantly, the lack of competition in developing markets is a disincentive for lowering prices. These

Take-home Messages continued from page 7

intestinal Cancers Symposium. Abstract 157. Presented January 20, 2012. 2. Tabernero J, Moreno V, Rosenberg R, et al: Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of stage II colon cancer patients. 2012 Gastrointestinal Cancers Symposium. Abstract 384. Presented January 21, 2012. 3. Ahlquist DA: Stool DNA testing: A step closer to eradicating colorectal cancer. Invited presentation at the 2012 Gastro-

market inefficiencies have often made morphine more expensive in sub-Saharan African, Eastern European, and Latin American markets than in the United States. Seeking to maximize their profit, distributors also block certain products. For instance, the fentanyl transdermal patch, a very effective longacting analgesic, is about 30 times more expensive than morphine. We’ve found that in some developing markets distributors will bring in fentanyl, but not low-cost morphine, simply because fentanyl has a higher profit margin. When you aggregate all these factors, the end result is low market penetration and a more expensive, often cost-prohibitive supply of morphine.

Relief Initiative (GAPRI) has been working with the Ugandan Ministry of Health and local palliative care stakeholders in Uganda (including the Palliative Care Association of Uganda and the African Palliative Care Association) to scale up Hospice Africa Uganda’s production and certify them as a drug manufacturer. The hospice now sells morphine solution to the government at a cost 40% less than the cost of importing the drug from an international supplier. This process also makes the local market more efficient. Since Hospice Africa Uganda produces its own liquid morphine, they actually manufacture on demand, taking only a week to fill an order. They are able to produce

It is important to distinguish between cost and price. The cost of morphine is pennies per dose; the inefficiencies within the market drive the exorbitant prices. — Meg O’Brien, PhD

A Ugandan Model It is important to distinguish between cost and price. The cost of morphine is pennies per dose; the inefficiencies within the market drive the exorbitant prices. In Uganda, what we needed was a way to bypass many of the supply and demand issues that created access barriers to pain medication and left the country without any morphine for more than 6 months in 2010. For years, a nongovernmental hospice in Uganda, Hospice Africa Uganda, has been producing its own liquid solution morphine. Over the past year, the Global Access to Pain intestinal Cancers Symposium. Presented January 21, 2012. 4. Grothey A, Sobrero A, Siena S, et al: Results of a phase III randomized, doubleblind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care versus placebo plus BSC in patients with metastatic colorectal cancer who have progressed after standard therapies. 2012 Gastrointestinal Cancers Symposium. Abstract LBA385. Presented January 21, 2012. 5. Van Cutsem E, Yah KH, Bang YJ, et al: Phase 3 trial of everolimus in previously

three different incremental dosages in real time; the expiration clock starts ticking at the time they mix it so they can hold the raw powder for much longer, giving more shelf life than an imported finished product. Most importantly, the raw powder does not need to be registered, meaning that they can procure the raw ingredient from the supplier that gives them the best price.

Win-Win Situation This is one of the newer approaches that can actually produce and deliver morphine to cancer patients in pain for literally pennies a day. The pain treatment costs in the Ugandan modtreated patients with advanced gastric cancer: GRANITE-1. 2012 Gastrointestinal Cancers Symposium. Abstract LBA3. Presented January 19, 2012. 6. Siu LL, Shapiro JD, Jonker DJ, et al: Phase III randomized trial of cetuximab plus either brivanib alaninate or placebo in patients with metastatic chemotherapy refractory K-RAS wild-type colorectal carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 trial. 2012 Gastrointestinal Cancers Symposium. Abstract 386. Presented January 21, 2012.

el are about $1 per week. And because it resulted in the government getting heavily discounted morphine, in turn, the Ugandan government has agreed to pay for annual orders up front, allowing the hospice to better plan procurements. The government also pays for morphine for all pain patients in the country for free. That includes thousands of patients being treated by hospice programs across the country that previously had to purchase their own morphine out of pocket—an untenable expense for most. Hospice Africa Uganda used to spend over $40,000 per year on morphine; now they’re making a small profit on every bottle they sell to the government. And all their patients get treated for free. It is a win-win situation—the overall price has gone down across the board, the efficiencies are up, we’re wasting less product, we’re not having to toss expired product, and all the patients are getting their pain medications when they need it. This is an example of a creative, cooperative approach by a hospice that was willing to take on a risky endeavor for their patients, local partners who supported them, a proactive government that believed in and invested in local solutions, and a small international organization that is helping them both to cut through bureaucratic hurdles. This collaboration is circumventing the challenging market inefficiencies endemic in much of the world’s poorer regions, and by doing so, we have helped relieve unnecessary pain and suffering. Addressing the global tragedy of needless pain is a continued work in progress, and the Ugandan model is continuing to be refined, but it represents a point of light on the horizon—hope for affordable, government-led solutions to unnecessary suffering.

Disclosure: Dr. O’Brien reported no potential conflicts of interest.

The ASCO Post Watch future issues for important news from key oncology meetings.

Visit www.ASCOPost.com


ASCOPost.com  |   MARCH 1, 2012

PAGE 9

2012 Genitourinary Cancers Symposium Novel Agents in Prostate Cancer continued from page 1

committee recommended that the trial be halted and patients in the placebo arm offered treatment with MDV3100. “The survival advantage coupled with the favorable side-effect profile positions MDV3100 as a potential frontline treatment in the postdocetaxel setting,” Dr. Scher said. The drug is currently under review at the FDA. AFFIRM enrolled 1,199 men with castration-resistant prostate cancer in whom docetaxel treatment failed and randomly assigned them 2:1 to oral MDV3100 or matched placebo. Median overall survival was 18.4 months in the MDV3100 arm vs 13.6 months in the placebo arm (P  < .0001). Median radiographic progression-free survival was also significantly superior for MDV3100 (8.3 vs 2.9 months; P  < .0001). The survival benefit of MD3100 was significant across all prespecified subgroups.

survival benefit,” Dr. Scher said. The adverse event profile of MDV3100 was similar to that of placebo. More serious adverse events were reported in the placebo arm (38.6%) than in the MDV3100 arm (33.5%). More grade 3 or higher adverse events were also reported in the placebo arm (53.1% vs 45.3%). Adverse events

of interest included a slightly higher percentage of patients with low-grade fatigue on the MDV3100 arm as well as a small number of seizures (0.6%). During the discussion following the presentation, Dr. Scher said that all five cases of seizures were reviewed thoroughly, and two of the cases were due to brain metastases. “The rare event of

seizure is unlikely to deter physicians from prescribing MDV3100 given the robust survival benefit and the overal safety profile,” he commented.

Updated ALSYMPCA Results Radium-223 is a first-in-class alphaemitting radiopharmaceutical that continued on page 10

Imaging and PSA A significantly higher proportion of patients treated with MDV3100 showed tumor shrinkage on imaging (30% of patients had complete or partial responses to MDV3100 on imaging vs a 1.3% tumor shrinkage rate in the placebo group; P < .0001). In addition, a greater percentage of MDV3100-treated patients had at least a 50% or greater decline in PSA level (54% vs 1.5%; P < .0001). “These favorable changes [in imaging and PSA] are consistent with the

Advances in Castration-resistant Prostate Cancer ■■ The androgen receptor signaling inhibitor MDV3100 and the alpha-emitting radiopharmaceutical radium-223 prolonged survival in patients with castration-resistant prostate cancer in two large phase III trials.

■■ Both drugs have favorable side-effect profiles.

■■ The best use of these drugs

may prove to be in sequence or in combination, and they may have synergy, extending survival beyond additive effects.

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

■■ Both drugs have been given fast-track status by the FDA.

©2011 AVEO Pharmaceuticals, Inc. and Astellas Pharma US, Inc.

011L-073-4740

12/11

Printed in the USA


The ASCO Post  |   MARCH 1, 2012

PAGE 10

2012 Genitourinary Cancers Symposium Novel Agents in Prostate Cancer continued from page 9

mimics calcium and targets bone metastases with high-energy, very shortrange alpha particles. These particles are more penetrant than gamma or beta particles. Radium-223 potentially spares healthy tissue, thereby limiting side effects. ALSYMPCA enrolled 922 men with progressive, symptomatic metastatic castration-resistant prostate cancer with two or more known bone metastases but no visceral metastases. They were randomly assigned to radium-223 vs placebo in a 2:1 ratio. As reported previously, radium-223 significantly improved overall survival compared with placebo in the ALSYMPCA trial. Median overall survival was 14 months for radium-223 vs 11.2 months for placebo (P = .00185). The trial was halted early due to the benefit in overall survival.

Skeletal-related Events At the Genitourinary Cancers Symposium, Dr. Parker presented the first analysis of skeletal-related events. Median time to first skeletalrelated event was significantly delayed in the radium-223 group (13.6

vs 8.4 months; P = .00046). Looking at the individual components of skeletal-related events, radium-223 exerted a preventive effect on pathologic bone fracture (4% vs 7%; P  = .013), spinal cord compression (3% vs 6%; P  = .016), and need for external-beam radiation (23% vs 27%; P  = .0038). No difference between treatment arms was seen in terms of need for surgical intervention (2% in both arms).

Tumor Death

A

MDV3100

cell nucleus

A 2

MDV3100

AR

First to Prevent Spinal Cord Compression

1

Inhibits nuclear translocation of AR

Inhibits binding of androgens to AR

“To our knowledge, radium-223 is the first drug ever shown to be effective in the prevention of spinal cord compression. This is an important observation, because this is a devastating complication of bone metastases,” Dr. Parker stated. Safety and tolerability of radium-223 was extremely favorable, with a low incidence of myelosuppression: Incidence of grade 3/4 neutropenia was 1.8% for radium-223 vs 0.8% for placebo, and of grade 3/4 thrombocytopenia, 4% vs 2%, respectively. A lower percentage of patients in the radium-223 group reported adverse events: 88% vs 94% for adverse events of any grade, and

MDV3100 3 Inhibits association of AR with DNA

Fig. 1: MDV3100 inhibits multiple steps in the androgen receptor signaling pathway. A = androgens; AR = androgen receptor. Reprinted with permission from Scher HI, et al.1

51% vs 59% reporting grade 3/4 adverse events.

Disclosure: Dr. Parker has received honoraria from Bayer for serving on advisory boards. Dr. Scher has been a consultant or advisor for and has received research funding from Medivation.

References 1. Scher HI, Fizazi K, Saad F, et al: Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI) on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AF-

FIRM study. 2012 Genitourinary Cancers Symposium. Abstract LBA1. Presented February 2, 2012. 2. Parker C, Heinrich D, O’Sullivan JM, et al: Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. 2012 Genitourinary Cancers Symposium. Abstract 8. Presented February 2, 2012.

EXPERT POINT OF VIEW

“M

y comment on the AFFIRM trial is ‘wow, very impressive.’ The median survival and the declines in PSA levels are impressive, and this is going to change the way we care for patients in our practices,” said Nicholas Vogelzang, MD, medical oncologist with Comprehensive Cancer Centers of Nevada and Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology. Dr. Vogelzang moderated a press briefing on the AFFIRM and ALSYMPCA trials at the 2012 Genitourinary Cancers Symposium. Since the drugs studied in these two trials—MDV3100 and radium-223—have different mechanisms of action, they will probably be used in sequence or combination. “We would expect survival to be dramatically pushed forward [with use of both drugs]. Thus far, these drugs haven’t been given in sequence, but using them both should bump up

gelzang said. Both MDV3100 and radium-223 have received fast-track designation from the FDA.

‘Incredible Achievement’

Nicholas Vogelzang, MD

Oliver Sartor, MD

survival in the next 2 to 3 years,” Dr. Vogelzang predicted.

No Regulatory Hurdles Foreseen “These mechanistically different agents will be combined. We need to see if they have synergy. This is an important step to be taken,” stated Oliver Sartor, MD, Medical Director of the Tulane Cancer Center, New Orleans, and lead investigator for the ALSYMPCA trial in the United States. Both Dr. Vogelzang and Dr. Sar-

Adam S. Kibel, MD

tor said that they foresee no major regulatory hurdles for MDV3100 and radium-223. Neither leukemia nor bone marrow failure (events of concern) has been observed with radium-223, and the seizures in five patients treated with MDV3100 are not perceived as an obstacle to approval. “With both drugs, adverse events are actually less than with placebo. With this kind of survival benefit and safety profile, both drugs should be approved relatively quickly, Dr. Vo-

Adam S. Kibel, MD, Chief of Urology at Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, called MDV3100 “an incredible achievement in rational drug design by Drs. Charles Sawyers and Howard Scher.” Dr. Kibel continued, “Both of these drugs are advances. We will end up using them extensively, probably earlier in the disease process. There is no reason why we couldn’t use them together, in sequence or in combination, and with other drugs. There is great potential here.”

Disclosure: Dr. Vogelzang was an investigator on the radium-223 trial. Dr. Sartor has been a consultant to Medivation, Algeta, and Bayer, and also an investigator for Algeta and Bayer. Dr. Kibel reported no potential conflicts of interest.


Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

1


The first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation, then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.


EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9 mo) for ZELBORAF patients vs 4.5 months (95% CI, <0.1-11.7 mo) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of analysis.

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 months vs 1.6-1.7 months) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%)3 There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

0.294 inrash, alopecia, fatigue, photosensitivity The most common adverse reactions of any grade (≥30%) reported were arthralgia, reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

© 2012 Genentech USA, Inc. All rights reserved. BRF0000653201 Printed in USA.

zelboraf.com


The ASCO Post  |   MARCH 1, 2012

PAGE 14

34th Annual San Antonio Breast Cancer Symposium Atypical Breast Lesions: How High Is the Cancer Risk? By Caroline Helwick

W

omen with atypical breast lesions have approximately a 5% to 11% risk of developing breast cancer within 5 years, depending on histology, and this risk can be reduced

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

lesions treated at Boston area hospitals. The study was led by Suzanne B. Coopey, MD, a surgical oncologist at Massachusetts General Hospital, Boston, and was presented by senior inves-

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were  ≥ 65 years. Elderly disorders patients (≥  65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 †# pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. 8

-

-

7

-

-

12

-

-

10

-

-

-

-

-

14

-

-

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

Kevin S. Hughes, MD

-

Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

disorders Cough Injury, poisoning and procedural complications Sunburn

tigator Kevin S. Hughes, MD, also a surgical oncologist at Massachusetts General. “While all types of atypical lesions are known to increase the risk of breast cancer, it is not clear from the medical literature just how much they increase risk, because there are conflicting data,” Dr. Hughes noted. “Also, the effect of chemoprevention in the clinical setting needs to be clarified.”

BRF0000422001 Initial U.S. Approval: August 2011 © 2012 Genentech, Inc

Large Population Analyzed Dr. Coopey and colleagues reviewed 76,333 pathology reports for 42,950 individuals and identified 2,942 women (mean age 51) diagnosed with atypical breast lesions between 1987 and 2010. This included 1,199 (40.8%) with atypical ductal hyperplasia, 828 (28.1%) with atypical lobular hyperplasia, 570 (19.4%) with lobular carcinoma in situ, and 345 (11.7%) with borderline ducSEE PAGE 55 tal carcinoma in situ/ severe atypical ductal hyperplasia. The effect of chemoprevention was analyzed from 1999 forward. After an overall follow-up of 67 months, breast cancer was diagnosed in 7.1% of women with atypical ductal hyperplasia, 10.9% with atypical lobular hyperplasia, 11.1% with lobular carcinoma in situ, and 8.4% with borderline ductal carcinoma in situ/severe atypical ductal hyperplasia. Median time to breast cancer diagnosis was 48 months, 50 months, 47 months, and 60 months, respectively. There were significantly more ipsilateral cancers for all atypical types combined (P  < .005), and bilateral cancers were rare, Dr. Hughes reported. “The different diagnoses did not carry different levels of cancer risk,” he observed. “This is not what we expected when we started the study.” The Safety:10"

ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced  >  1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc  >  500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both  >  500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

with chemoprevention, according to a presentation at the 2011 San Antonio Breast Cancer Symposium.1 Investigators tracked the outcomes of 2,942 women Safety:7"with atypical breast

continued on page 15


ASCOPost.com  |   MARCH 1, 2012

PAGE 15

34th Annual San Antonio Breast Cancer Symposium Genomics Projects Plumb Breast Cancer’s Inner Workings By Susan London

T

wo large collaborative genomics projects are producing new and sometimes surprising findings about what makes breast cancers tick—information that may ultimately be applied to improve clinical outcomes. In a special session titled “Genome Data for the Masses: Presentation of TCGA and ICGC Breast Tumor Data,” speakers at the San Antonio Breast Cancer Symposium offered overviews of these ongoing projects.

Comprehensive Approach The Cancer Genome Atlas (TCGA) project (http://cancergenome.nih.gov), a joint effort of about 20 U.S. institutions, is exhaustively characterizing 1,000 breast cancers.1 Various labs prepare specimens, perform assays, generate genomic data, and analyze results, and clinical experts help to integrate and interpret the findings. “TCGA provides a really comprehensive approach to the disease,” commented Elaine R. Mardis, PhD, of the Washington University School of Medicine in St. Louis. “The comprehensive nature of the data provides for a much richer final product, if you will, because of that

EXPERT POINT OF VIEW

Charles M. Perou, PhD

C

harles M. Perou, PhD, the May Goldman Shaw Distinguished Professor of Molecular Oncology at the University of North Carolina, Chapel Hill, commented on the research being conducted by The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). “The TCGA and ICGC efforts are providing the blueprint for what can be tested as possible biomarkers in the current, and next, generation of clinical trials. These projects are also showing us how common pathways are differentially altered in given tumor types vs others, and we are seeing tumor subtype–specific alterations that could have clinical relevance,” he told The ASCO Post.

“These broad and in-depth genomic my hope that in the future, the TCGA characterizations of most common tu- and ICGC will directly study tumor samples from mor types will soon randomized clinireveal the frequent This is a resource cal trials that are somatically mutated evaluating current genes, and all the for the community. and promising commonly deleted You can go to these new therapeutics, and amplified rewebsites and access thus making the gions of the cancer translational imgenome.… In most the data as we are pact even greater cases, the tumors going along through than it is today.” examined by the The TCGA TCGA and ICGC these studies. and ICGC findare being used as the ings are intended discovery engine to —Charles M. Perou, PhD to be shared refind the set of ‘gesources for the netic players’ for a given tumor type, which can then be used breast cancer research community, Dr. Perou added. “An important aspect of in future clinical trials,” Dr. Perou said. both of these studies is that the data comTranslational Impact ing from these studies is to be made pub“These projects are also discover- licly available in … near real time,” he ing new cancer-causing genes, or more explained. “So this is not a resource for commonly, finding that cancer-causing those of us generating the data—this is a genes identified in one tumor type are resource for the community. You can go also present in a tumor type not previ- to these websites and access the data as we ously known to be influenced by this are going along through these studies.” Disclosure: Dr. Perou reported no given gene. Some of these may also have potential conflicts of interest. clinical relevance,” he commented. “It is

continued on page 18

Atypical Breast Lesions continued from page 14

breast cancer risks by type of atypia are shown in Table 1. Invasive cancers were significantly more common than noninvasive cancers among patients with lobular carcinoma in situ (71.1%) and atypical lobular hyperplasia (68.9%) (P  < .001) but were not more frequent for the other types of lesions (47.4% in atypical ductal hyperplasia and 57.1% in patients with borderline lesions), he said.

Outcomes with Chemoprevention Among the 2,460 patients diagnosed since 1999, chemoprevention with tamoxifen, raloxifene (Evista), and/or exemestane (for any duration) was received by 466 (18.9%), whereas 1,472 (59.8%) received no treatment. (Data were not available for 21.2% of patients.) “Chemoprevention had a clear effect, significantly decreasing the risk of

cancer occurrence for all atypia types,” Dr. Hughes reported. “But only 20% of patients took these medications, which certainly leaves room for improvement.” At 5 years, cancer occurred in only 4.1% receiving some type of chemopreventive agent, vs 8.3% of patients left untreated. At 10 years, the difference widened, with cancer diagnosed in 7.5% vs 21.3% (P < .05). By atypia type, for chemoprevention vs no treatment, the 10-year cancer risks were 8.5% vs 19.9% for atypical ductal hyperplasia, 8.5% vs 18.7% for atypical lobular hyperplasia, 2.1% vs 14.7% for borderline lesions, and 10.3% vs 32.4% for lobular carcinoma in situ. All were statistically significant (P < .05), he said.

Interest Sparked Discussion Several questions from attendees followed the presentation, and discussion was lively. Dr. Hughes said his group hopes to mine the data to determine risk according to age, benefit of

chemoprevention Table 1: Breast Cancer Risk by Atypia Type (without by duration of treat- Chemoprevention) ment, risk accord5-yr Risk 10-yr Risk ing to amount or Lesion Type magnitude of atyp- ADH 4.5%a 17.3% ia, and other factors ALH 10.9% 20.7% that might further 10.5% 23.7% delineate cancer LCIS risk and the value of Borderline DCIS/ADH 9.7% 26.0% chemoprevention. Elaborating on a Cancer risk for ADH at 5 years was the only significantly different finding the high incidence among the lesion types. ADH = atypical ductal hyperplasia; ALH = atypical lobular hyperplasia; of noninvasive duc- DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. tal carcinoma in Courtesy of Kevin S. Hughes, MD, and Suzanne Brooks Coopey, MD. situ (approximately 40%) diagnosed over time, Dr. Hughes ty of chemopreventive agents in panoted that patients were closely foltients with certain risk factors. Disclosure: Drs. Hughes and Coopey lowed with yearly mammograms. “The reported no potential conflicts of interest. high rate of screening might explain this high rate,” he said. Reference When asked which patients should 1. Coopey SB, Mazzola E, Buckley JM, receive chemoprevention, he said, “I et al: Clarifying the risk of breast cancer in tend to use chemoprevention for any women with atypical breast lesions. 2011 patient with atypia, though we need San Antonio Breast Cancer Symposium. to decide if we can exclude patients Abstract S4-4. Presented December 7, age 70 and older.” He added that more 2011. needs to be learned regarding the safe-


In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of

electrolytes within the normal range should be performed. • Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. • Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. • Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. • Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite


Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology . These Guidelines also include therapies other than VOTRIENT as first-line treatment options

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

VOTRIENT: Safety Profile Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. • Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. • CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. • CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

• Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). • Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); and leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). • VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2012. © National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed November 17, 2011. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com


The ASCO Post  |   MARCH 1, 2012

PAGE 18

34th Annual San Antonio Breast Cancer Symposium Genomics Project continued from page 15

expertise across the genomic spectrum.” In analyses of the first 507 breast cancers, sequencing of the exome (the exons of the most annotated human genes) has identified significant

mutations in dozens of genes, Dr. Mardis reported. Some of the most commonly mutated ones—PIK3CA, TP53, and GATA3—have previously been implicated in breast cancer. But there are also a host of new ones, such as MAP3K1. Additionally, analyses are suggest-

ing correlations between mutations and clinical phenotypes that may have relevance for treatment. For instance, several dozen significantly mutated genes have been identified in luminal A cancers; in contrast, only a handful have been identified in basal-like cancers, with mutations

BRIEF SUMMARY VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

of TP53 predominating. “I think this reflects the clinical situation when looking for targeted therapies in basal subtype disease. There aren’t a lot of therapeutic options that are being identified for patients” having those tumors, Dr. Mardis said.

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension : In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and


ASCOPost.com  |   MARCH 1, 2012

PAGE 19

Photo courtesy © SABCS/ Todd Buchanan 2011

34th Annual San Antonio Breast Cancer Symposium

Michael Stratton, FRCPath, FMCDSCI, FRS

Elaine R. Mardis, PhD

vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebocontrolled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

41

<1

0

33

1

0

36

3

<1

10

1

<1

34

4

0

11

0

0

31

4

1

24

4

0

26

<1

1

14

0

0

17

0

<1

3

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Vast Heterogeneity Discovered The International Cancer Genome Consortium (ICGC) project (http://www.icgc.org), a collaborative effort of about 40 laboratories

worldwide, is performing detailed analysis of 1,500 breast cancers.2 Results for the first 69 cancers are providing a wealth of information about driving mutations, according to investigator Michael Stratton, FRCPath, FMCDSCI, FRS, of the Wellcome Trust Sanger Institute,

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of full prescribing information and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)].

Hinxton, Cambridge, the United Kingdom. Exome sequencing here has likewise identified a variety of mutated genes not previously recognized to have a role in the disease. “The majority of new genes that are becontinued on page 20


The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MARCH 1, 2012

PAGE 20

34th Annual San Antonio Breast Cancer Symposium Genomics Project continued from page 19

ing discovered are recessive cancer genes, tumor suppressor genes,â&#x20AC;? he noted. In total, 34 genes (old and new) have been found to have driving mutations, a list that is likely to get

even longer, according to Dr. Stratton. The most commonly mutated genesâ&#x20AC;&#x201D;typically the most attractive as drug targetsâ&#x20AC;&#x201D;are PIK3CA and TP53. However, when combined, less commonly mutated genes make up about half of the total. â&#x20AC;&#x153;So we cannot ignore these infrequently

mutated cancer genes: They are collectively contributing substantially,â&#x20AC;? he commented. â&#x20AC;&#x153;The disease is proving to be extremely heterogeneous,â&#x20AC;? Dr. Stratton further noted, showing examples of three cancers to demonstrate the point. Although all of the cancers had

Understanding Genomics in Breast Cancer â&#x2013; â&#x2013;  The Cancer Genome Atlas

(TCGA) project is a joint effort of about 20 institutions in the United States that is analyzing genomic data for 1,000 breast cancers.

â&#x2013; â&#x2013;  The International Cancer

7.2 Effects of Pazopanib on CYP Substrates Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/ kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged â&#x2030;Ľ65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/ min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/ day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t5IFSBQZXJUI7053*&/5NBZSFTVMUJOIFQBUPCJMJBSZMBCPSBUPSZ abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. tZFMMPXJOHPGUIFTLJOPSUIFXIJUFTPGUIFFZFT KBVOEJDF tVOVTVBMEBSLFOJOHPGUIFVSJOF tVOVTVBMUJSFEOFTT tSJHIUVQQFSTUPNBDIBSFBQBJO t(BTUSPJOUFTUJOBMBEWFSTFSFBDUJPOTTVDIBTEJBSSIFB OBVTFB BOEWPNJUJOH have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. t8PNFOPGDIJMECFBSJOHQPUFOUJBMTIPVMECFBEWJTFEPGUIFQPUFOUJBMIB[BSE to the fetus and to avoid becoming pregnant. t1BUJFOUTTIPVMECFBEWJTFEUPJOGPSNUIFJSIFBMUIDBSFQSPWJEFSTPGBMM concomitant medications, vitamins, or dietary and herbal supplements. t1BUJFOUTTIPVMECFBEWJTFEUIBUEFQJHNFOUBUJPOPGUIFIBJSPSTLJONBZ occur during treatment with VOTRIENT. t1BUJFOUTTIPVMECFBEWJTFEUPUBLF7053*&/5XJUIPVUGPPE BUMFBTUIPVS before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

Genome Consortium (ICGC) project, a collaboration of about 40 laboratories worldwide, is compiling genomic descriptions of 1,500 breast cancers.

â&#x2013; â&#x2013;  Findings of these two

projects may have many implications for targeted treatment of breast cancer, ultimately improving clinical outcomes.

driving mutations in four genes, they did not share a single mutated gene in common. â&#x20AC;&#x153;Nevertheless, for the pathologist and for the clinician, these would be called ductal carcinoma of the breast, they would be ER-positive and HER2-negative. Despite all having that same description on which treatment would be based, they are genetically completely different animals,â&#x20AC;? he said. Whether this is important clinically is not yet clear. However, â&#x20AC;&#x153;it would be extremely surprising to me if this diversity of genetic drive to these cancers did not have some sort of phenotypic effect on their biology, their behavior, and their response to treatment,â&#x20AC;? Dr. Stratton concluded.

â&#x2013; 

Disclosure: Drs. Mardis and Stratton reported no potential conflicts of interest.

References 1. Mardis ER: TCGA breast cancer sequencing: Results and interpretation. San Antonio Breast Cancer Symposium. Special Report. Presented December 10, 2011. 2. Stratton M: Diverse patterns of mutation in breast cancer genomes. San Antonio Breast Cancer Symposium. Special Report. Presented December 10, 2011.

Send Us Your News Š2011, GlaxoSmithKline. All rights reserved. Revised 10/2011 VTR:4BRS Š2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT274R0 November 2011

Write to editor@ASCOPost.com. All submissions will be considered for publication.


ASCOPost.com  |   MARCH 1, 2012

PAGE 21

34th Annual San Antonio Breast Cancer Symposium SWOG S0226 Findings Revive Interest in Combination Hormonal Therapy By Susan London

T

wo hormonal therapies combined are more efficacious than one when used as first-line treatment for hormone receptor–positive metastatic breast cancer in postmenopausal women, finds Southwest Oncology Group trial S0226. Results of the phase III trial, reported at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium,1 showed that progression-free and overall survival among the 694 patients studied were 1.5 and 6.4 months longer, respectively, for those randomly assigned to anastrozole (Arimidex) plus fulvestrant (Faslodex) than for those given anastrozole alone. However, unplanned subgroup analyses suggested that these benefits were largely restricted to women who had not received adjuvant tamoxifen, according to first author Rita S. Mehta, MD, of the University of California, Irvine Medical Center. The positive findings of the trial overall are noteworthy in that they contrast with the negative findings of the FACT trial, a smaller trial where 32% of patients were ineligible, which tested the same combination and found no improvement in either outcome.2 “We think our patient population was a more endocrine-sensitive population,” Dr. Mehta speculated. Also, “our trial was not confounded by patients crossing over to combination therapy because patients only crossed over to fulvestrant.”

Differing Patient Populations Kathy Pritchard, MD, of the NCIC Clinical Trials Group and the University of Toronto noted that the group had canceled a planned adjuvant trial of the combination based on the earlier negative trial. “Do you think there is enough evidence here [in S0226]— that it’s clear enough that this relates to previous nontreatment with endocrine therapy—that you might suggest this combination should still be taken into the adjuvant setting?” she asked. “It’s actually [due to] multiple factors. We think that it’s probably that this was a relatively nontreated patient population…, [and] we think we may have picked out an endocrine-sensitive population,” Dr. Mehta replied, which would indeed make the findings applicable to the adjuvant SEE PAGE 55 population.

Discussant James N. Ingle, MD, of the Mayo Clinic in Rochester, Minnesota, agreed that differing patient populations between trials may have played some role. He warned against putting too much emphasis on a negative unplanned subgroup analysis in an otherwise positive trial. “The unplanned subset analysis finding of no benefit in prior tamoxifen patients should be interpreted with caution,” he maintained. “If confirmed, it would suggest that the combination is of value only in endocrine therapy– naive women with metastatic disease. These are uncommon today, and the only place you could probably find these women is in the adjuvant or neoadjuvant setting.” In sum, Dr. Ingle said, the field now has two randomized trials with conflicting findings. “The combination of anastrozole plus fulvestrant cannot be recommended as a new standard in women with metastatic breast cancer,” he concluded.

Rita Mehta, MD

Kathy Pritchard, MD

anastrozole-only arm were strongly encouraged to switch to fulvestrant at progression, and ultimately 41% did. The patients had a median age of 65 years. Only a minority had received adjuvant tamoxifen (40%), chemotherapy (33%), and aromatase inhibitors (2%). Trial results showed that patients in the anastrozole/fulvestrant arm had significantly better progression-free survival than their counterparts in the anastrozole arm (15.0 vs 13.5 months; HR  = 0.80; P = .007). In subgroup analyses, the difference was significant among those who had not received

Anastrozole/Fulvestrant for Hormone-sensitive Breast Cancer ■■ Anastrozole plus fulvestrant extended median survival of women with

hormone receptor–positive metastatic breast cancer, compared to those receiving standard treatment with anastrozole alone (47.7 vs 41.3 months).

■■ The combination lengthened median time to disease progression

(15 vs 13.5 months), but the progression-free survival difference was only significant among those who had not received adjuvant tamoxifen.

■■ These findings contrast with the negative findings of the earlier FACT

trial, which found no improvement using the same combination therapy.

Study Details Explaining the trial’s rationale, Dr. Mehta noted that the combination of anastrozole (which lowers estrogen levels) and fulvestrant (which downregulates the estrogen receptor) may have additive effects and has been shown to downregulate several resistance proteins in a preclinical model. The postmenopausal women studied had hormone receptor–positive breast cancer and had not received therapy for metastases. Prior adjuvant tamoxifen was allowed, and prior adjuvant aromatase inhibitor therapy was allowed if completed at least a year earlier. After stratification by adjuvant tamoxifen receipt, patients were randomly assigned in balanced fashion to treatment with anastrozole with or without fulvestrant. Those in the

adjuvant tamoxifen (17.0 vs 12.6 months; HR  = 0.74) but not among those who had. Patients in the anastrozole/fulvestrant arm also had significantly better overall survival (47.7 vs 41.3 months; HR = 0.81; P = .049). This benefit likewise appeared to be restricted to those who had not received adjuvant tamoxifen (47.7 vs 39.7 months; HR = 0.74).

Predictive Factors Sorting out whether adjuvant tamoxifen is a predictive factor is not straightforward, according to Dr. Mehta. “Prior tamoxifen use is confounded with time between adjuvant diagnosis and metastatic diagnosis,” she explained. “We really need to better understand other possible predictive factors since prior adjuvant tamoxifen could be a false

James N. Ingle, MD

lead from an unplanned analysis.” Benefit was generally similar in subgroups stratified according to a variety of other factors, including age, HER2 positivity, visceral disease, measurable disease, prior chemotherapy, and time since diagnosis. She added, “If we look at the forest plot, the most benefit was in patients who were diagnosed with breast cancer more than 10 years prior (which included patients who were treated or untreated with tamoxifen). Therefore, the important take-home point is that the trial was powered for all eligible patients, and the progression-free survival and overall survival benefit was significant for all patients in the intent-to-treat analysis who qualified to go on the study.” “The toxicity of the combination was comparable to single-agent treatment, although grade 5 toxicity was seen only with the combination,” Dr. Mehta reported. Specifically, there were three deaths with the combination, due to pulmonary emboli and cerebrovascular ischemia. Only 1% of patients in the anastrozole group and 3% of patients in the anastrozole/fulvestrant group stopped treatment early because of adverse effects.

Disclosure: Drs. Ingle and Pritchard reported no potential conflicts of interest. Dr. Mehta has received research support for a study at UCI by AstraZeneca.

References 1. Mehta RS, Barlow WE, Albain KS, et al: A phase III randomized trial of anastrozole versus anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: SWOG S0226. 2011 San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 7, 2011. 2. Bergh J, Jönsson PE, Lidbrink E, et al: First results from FACT—an open-label randomized phase III study investigating loading dose of fulvestrant combined with anastrozole at first relapse in hormone receptor-positive breast cancer. 2009 San Antonio Breast Cancer Symposium. Abstract 23. Presented December 10, 2009.


The ASCO Post  |   MARCH 1, 2012

PAGE 22

Opinion Health-care Technology

‘Creative Destruction’ of Medicine

Screening and Individualized Medicine

continued from page 1

Many in the oncology community believe that if we could replicate the mass screening efforts that are routine in breast and prostate cancer for application in other cancers, it would have a large impact on cancer mortality. What are your thoughts on screening? The problem is that we don’t recognize the primacy and uniqueness of each individual. To date, the judgments we make and things we do in medicine—the old rules, whether it’s screening or therapy—are related to large populations, not individuals. Previously, we didn’t have the digital tools to do otherwise. But now we’re at this exciting inflection point, where we are able to zoom in on individual patient characteristics.

The title simply captures the extraordinary opportunity we have to vastly improve the way we think about and practice medicine. The term “creative destruction” denotes a transformation that accompanies radical innovation. But this transformation is not likely to emanate from the medical community, the traditional way innovation jumps forward. In the current era of social networking, the transformation will likely come from a convergence of technology and consumerism, especially in the cancer space, which offers the most near-term opportunity for positive change. As one example, when we have a tumor biopsy or tissue sample, it solely gets put in formalin, then fixed in paraffin, which is completely unacceptable. We need frozen tissue so we can rapidly conduct exome or whole-genome sequencing and use it to customize the right care for the individual’s driver mutations of a particular cancer. We have this technology; however, we have a challenge getting surgeons, pathologists—basically the whole oncology community—to switch to frozen samples. Of course, this is just one of many “rules” that need to be broken in the oncology sector.

Value and Cost The health-care debate seems to get mired in issues of value and cost. How can we make systemic improvements given our limited resources? One of the steadfast rules is that when you introduce new technology into health care, it is invariably coupled with increased costs. But we have an opportunity to turn that model around by being able to track physiologic metrics, genomic sequences, and advanced imaging modalities. By making medicine more precise, these advances can markedly reduce costs while improving care. The convergence of digital technology and consumerism will provide real, actionable data attached to specific health needs, which will in turn drive costs down by eliminating the waste involved in population-based medicine.

Further, once we have a diagnosis, with few exceptions we don’t screen that person to see what drug will work; we give the same drug to all people with that diagnosis. In diabetes, everybody gets metformin even though metformin doesn’t have any beneficial effect in 25% of those patients. However, in today’s medical mindset, we don’t take the patient off metformin; we simply add another drug, without screening to see if the drug is going to work. There are almost 400  million diabetics worldwide, so it’s a huge issue of wasteful medical resources. Again, that’s just one example of many.

Introducing Innovations Considering that we have the tools to create “homo digitus” patients, how can

We have already seen the profound impact of social networking in the health space, and it’s just the tip of the iceberg. When people have their personal physiologic metrics and genomics on handheld devices, they’ll band together, and you’ll see a movement that will change medicine. —Eric Topol, MD

I never use the popular term personalized medicine, which to me denotes a concierge-style model. Instead, individualized medicine can define a patient biologically, physiologically, and anatomically, aggregating into what I call homo digitus—in effect, digitizing a human being for all the essential characteristics that make that person tick. That approach will lead to far better outcomes going forward. For instance, we won’t have to have all women undergo routine mammograms after age 40 or 50, because a substantial proportion of women have no risk of developing breast cancer. We will ultimately identify that no-risk or extremely lowrisk population, thus eliminating falsepositives, biopsies, and the associated anxiety and attendant costs. In this case, mass screening disregards individual variability and promotes unnecessary medical procedures.

we organize those tools to really make an impact on our vastly complicated system? By self-organization—there are groups out there already taking the lead with online patient empowerment communities. The people in these communities trust their peers more than their doctors, for one reason, because their peers have like conditions that are discussed freely. We have already seen the profound impact of social networking in the health space, and it’s just the tip of the iceberg. When people have their personal physiologic metrics and genomics on handheld devices, they’ll band together, and you’ll see a movement that will change medicine. Does a digital landscape fit into the strictures imposed by our limited financial resources? Innovations moving forward can-

not induce added cost pressures on the system. That would be untenable. We have a dual challenge with technologic innovation; it must improve health outcomes and significantly reduce expenditures. With creative destruction, you destroy very expensive methods with marginal benefit. In the United States, we spend $350 billion per year for prescription dugs, and we know at least one-third of that is total waste, offering no benefit or, even worse, inducing serious side effects. Pharmacogenomics is a perfect way to destroy the old wasteful model of prescribing drugs. It’s very inexpensive to run genotypes, once we have basically cracked the code—knowing the specific variant allele(s)—for each drug. We have inexpensive ways to drill down to the things that produce good outcomes. For instance, I’m a cardiologist and I don’t have to send a significant proportion of patients to a facility to have a formal echocardiogram, because I have a handheld high-resolution device that’s just as good as the hospital laboratory. Why do we send people to facilities for sleep studies that reimburse at $3,000 per night when the same study could be done in the person’s home for less than $100 and get the same data?

Closing Thoughts Any last thoughts you would like to share? I would like to see a transformation in which the medical community engages in the health-care revolution that will ultimately be consumer driven. We have a remarkable digital infrastructure including social networking that complements new opportunities to change the course of medicine, such as advances in genomics, biosensors, and imaging. There will be a superconvergence of human data capture that will give us the ability to digitally define the essential characteristics of each individual, not heterogeneous populations. I hope that my colleagues in medicine will acknowledge and embrace this unique opportunity to reboot medicine.

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


In combination with IV 5-FU–containing chemotherapy in first- and second-line MCRC…

Think Avastin

Because overall survival matters The only FDA-approved biologic with significant overall survival (OS) benefits in first- and second-line MCRC1-4 4.7-month increase in median OS with Avastin plus IFL in pivotal first-line Study 21071,2,4

Percentage Surviving

100

First-line median OS:

20.3 vs 15.6 months

80

(HR=0.66 [95% CI, 0.54–0.81], P<0.001)

60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

18 12 OS (Months)

24

30

OS in second-line Study E3200: IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; IFL=5-FU/leucovorin (LV)/ irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indication

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.

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

©2011 Genentech USA, Inc. 

13.0 months with Avastin plus FOLFOX4 vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)1,3

All rights reserved. 

AVA0000402601 

Printed in USA. 

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother 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%) 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 accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 4. Data on file. Genentech, Inc.

(11/11)

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), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 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 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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).]

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).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate >  10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60  days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer MBC, an indication for which Avastin is not approved, the incidence of Grade 3–4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

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

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

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

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade  3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥  2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

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

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

55% 55% 19%

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

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 );


ASCOPost.com  |   MARCH 1, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

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

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

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

way, biological products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biological product that is already approved by the FDA, which is called a reference product. The following three guidance documents provide the FDA’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency: ■■ Scientific Considerations in Demonstrating Biosimilarity to a Reference Product ■■ Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product ■■ Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 All three documents are available at www.fda.gov. FDA is seeking public comment on the guidance documents, and instructions on how to submit comments will be announced in a Federal Register notice. In finalizing the guidance documents, the agency will consider the information received from the public.

Pertuzumab Gets Priority Review for Metastatic Breast Cancer

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

T

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

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

FDA Issues Draft Guidance on Biosimilar Product Development he FDA recently issued three draft guidance documents on biosimilar product development to assist industry in developing such products in the United States. “When it comes to getting new biosimilar products on the market, FDA has taken an innovative approach to supporting their development at every step of the process,” said Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research. “These draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers.” The Patient Protection and Affordable Care Act, signed into law by President Obama on March 23, 2010, amended the Public Health Service Act to create an abbreviated approval pathway—under section 351(k)— for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product. Through this new approval path-

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

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

FDA Update

T

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis,Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

PAGE 25

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

01/12 AVA0000764001 10127309 Initial U.S.Approval: February 2004 Code Revision Date: December 2011 Avastin® is a registered trademark of Genentech, Inc. ©2012 Genentech, Inc.

he FDA has accepted Roche’s Biologics License Application for pertuzumab (Omnitarg) and granted Priority Review. The proposed indication is pertuzumab in combination with trastuzumab (Herceptin) and docetaxel chemotherapy for people with HER2-positive metastatic or locally recurrent, unresectable breast cancer, who have not received previous treatment or whose disease has relapsed after adjuvant therapy. The FDA confirmed the action date is June 8, 2012. The pertuzumab application is based on results from the pivotal phase  III CLEOPATRA study. The study demonstrated a 6.1-month improvement in median progressionfree survival for people who received a pertuzumab-based regimen (pertuzumab combined with trastuzumab and docetaxel) compared to those who received trastuzumab and chemother-

apy alone (median progression-free survival = 18.5 vs 12.4 months).

Underlying Mechanisms Pertuzumab, a humanized monoclonal antibody, is unique in that it is designed specifically to prevent the HER2 receptor from pairing with other HER receptors, a process that is believed to play a critical role in the growth and formation of several different cancer types. By preventing receptor pairing, pertuzumab is thought to block cell signalling, which may inhibit cancer cell growth or lead to the death of the cancer cell. Binding of pertuzumab to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of pertuzumab and trastuzumab are believed to complement each other, as both bind to the HER2 receptor but on different regions.


The ASCO Post  |   MARCH 1, 2012

PAGE 26

Direct from ASCO

Philanthropy Spotlight

Career Development Award Recipient Susan K. Parsons, MD, Supports Next Generation of Researchers

Susan K. Parsons, MD, MRP

L

ike all pediatric oncologists, Susan K. Parsons, MD, MRP, knows that when a child is diagnosed with cancer, it happens to the whole family. Siblings must cope with everything from disruption of routine to reduced parental attention, to the often-new possibility of

mortality. Parents must navigate a complex health-care system while providing emotional support for their children, managing their own emotions, and juggling career responsibilities and family finances. The clinical and whole-life impact of treatment of cancer in children—from outcomes of bone marrow transplantation to the impact of high-tech medical interventions on children and families— has been the focus of Dr. Parsons’ work, first at the Harvard-affiliated Dana-Farber Cancer Institute and Children’s Hospital in Boston, and now at Tufts University School of Medicine/Tufts Medical Center, where Dr. Parsons is Professor of Medicine and Director of The Health Institute at the Institute for Clinical Research and Health Poli-

Career Development Award The Career Development Award (CDA) is a 3-year grant totaling $200,000 to provide funding to clinical investigators who have received their initial faculty appointment, to establish an independent clinical cancer research program. This research must have a patient-oriented focus, including a clinical research study and/or translational research involving human subjects. The grant was first awarded in 1992. © 2012. American Society of Clinical Oncology. All Rights Reserved.

cy Studies. She is currently analyzing the results of a 5-year study that offered an integrated Web-platform tool to 200 families with children treated at six transplant centers nationwide, following each of the families for a year. “The tool provided a wealth of self-directed resources for families—covering everything from coordinating your child’s medi-

cal care, to issues associated with re-entry to life post-treatment, to how to talk to your employer when your child is in treatment, to stress reduction techniques, to how to manage your bills,” said Dr. Parsons. “We found incredible variability in how often people used it and which resources they accessed. We’re now tweaking the model and hope to make it avail-

James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology The Conquer Cancer Foundation is honored to announce the creation of the James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology. Established by Dr. Nachman’s friends and colleagues in remembrance and celebration of his incredible legacy as an internationally renowned pediatric cancer expert, the award will be granted annually, beginning at the 2012 Annual Meeting to a junior faculty member who submits the highest-scoring abstract in pediatric oncology. We gratefully thank our donors for their support and generosity.

For more information about the James B. Nachman ASCO Junior Faculty Award, including a listing of donors, please visit www.conquercancerfoundation.org/merit

Photo courtesy of the University of Chicago Medical Center.


ASCOPost.com  |   MARCH 1, 2012

PAGE 27

Direct from ASCO

able to families in the future.” Doing this work is the reason Dr. Parsons chose oncology. And it’s the reason she supports the Conquer Cancer Foundation of the American Society of Clinical Oncology.

The Power of Mentoring Last fall, Dr. Parsons made a generous donation to the Conquer Cancer Foundation’s Leadership to Legacy campaign, which allows ASCO members to direct their annual contributions to the support of cancer research. “I wish I could do more,” Dr. Parsons said. “It is impossible to overstate the value of these earlycareer awards. They are pivotal in the lives of each researcher and in the broader context of cancer research,” she added. “ASCO and the Conquer Cancer Foundation awards give people the money they need to fund their research, conduct early studies, and forge key collaborations. You can’t be competitive right now without having this kind of preliminary data, without having a track record of publications.” Dr. Parsons still remembers the specific date in February when she received the advice that launched her oncology career. “After earning my Master’s degree in health economics at Cornell, I worked as a management consultant in Manhattan and on other cost-containment projects. I was working on a project analyzing the cost-benefit ratio of second surgical opinions—which required interviewing approximate-

ly 600 patients about the impact of their illness on their ability to work, their functional limitation, and their follow-up—and I found that I was fascinated by their stories. Even among patients with the same medical conditions, I was struck by the differences in their experiences with

is the norm in oncology.” In 1993, during her third fellowship year, Dr. Parsons received an ASCO Career Development Award (CDA) supporting her outcomes research in pediatric hematopoietic stem cell transplantation. “It was a total career-starter,” she said. “It al-

It is impossible to overstate the value of these early-career awards. They are pivotal in the lives of each researcher and in the broader context of cancer research. —Susan K. Parsons, MD, MRP

their illnesses and with the healthcare system. My department head, who happened to be a former pediatric oncologist, said, ‘You don’t sound like an economist. Have you ever considered becoming a physician?’ And that was it. I couldn’t stop thinking about becoming a physician.”

lowed me to begin this investigation, which is still a focus of my research nearly 20 years later. It allowed me to form my first research team. And it was the first signal that what I wanted to do in outcomes research was possible. Beyond the funding, it was an incredibly important objective, external validation.”

Dual Focus on Clinical Care and Research

Paying It Forward

In oncology, Dr. Parsons found herself among kindred spirits— colleagues who were interested in the full context of the clinical experience and who integrated research and clinical care into their professional lives. “If they weren’t thinking about the disease, the treatment, and the side effects, they were thinking about their next clinical trial or experiment. A dual focus on clinical care and research

Leadership to Legacy Through the Conquer Cancer Foundation Leadership to Legacy campaign, ASCO members and other field leaders have the opportunity to personally invest in the future of oncology by supporting the work of its most talented young researchers. Contributions to the Leadership to Legacy campaign not only fuel clinical projects of superlative quality, but also provide critical, early-career support for the next generation of oncology research leaders. An annual donation to the Leadership to Legacy campaign is a commitment to the cultivation of excellence in the field of oncology for the ultimate benefit of patients with cancer now and far into the future. Together, we are fostering the investigations that will build our legacy and shape the future of cancer care. To learn more about how to support the Leadership to Legacy campaign please visit www.ConquerCancerFoundation.org/Legacy, e-mail info@ conquercancerfoundation.org, or call (571) 483-1700 to speak with Foundation staff.

In the years since she received her own CDA, Dr. Parsons has paid it forward by mentoring the rising generation of cancer researchers—

she proudly reports that David Buchbinder, MD, one of her mentees, received both a Young Investigator Award and later a CDA—and, ultimately, by making a philanthropic gift to strengthen the Conquer Cancer Foundation’s support of the next generation. “I’m very hands-on with junior faculty,” Dr. Parsons said. “It’s great to be able to help them get established, and help them to be strategic about knowing which project might lead to another. It’s also incredibly gratifying to help fund the future of cancer research by contributing to the Conquer Cancer Foundation,” she commented. “I can’t imagine why any oncologist wouldn’t want to support the Foundation’s work,” Dr. Parsons added. “Research is at the core of oncology. It’s how our field developed and grew, and it’s the basis of every new discovery and every new therapy. It’s essential that we invest in the development of new therapies, and also in research to evaluate those therapies. It’s so very important that we keep that work going by investing in the work of young investigators.”

© 2012. American Society of Clinical Oncology. All Rights Reserved.

Save the Date ASCO’12 Annual Meeting

Best of ASCO® Chicago

June 1-5, 2012

July 12-13, 2012

McCormick Place

Hyatt Regency Chicago

Chicago, Illinois

Chicago, Illinois

Best of ASCO® Boston August 3-4, 2012 Renaissance Boston Waterfront Hotel Boston, Massachusetts

Best of ASCO® San Diego August 10-11, 2012 Manchester Grand Hyatt San Diego, California


The ASCO Post  |   MARCH 1, 2012

PAGE 28

Direct from ASCO

ASCO Seeks Better Access to Clinical Trials for Patients with Cancer

A

SCO and other organizations submitted recommendations to the Centers for Medicare & Medicaid Services to influence

development of a clinical trials coverage regulation of the Patient Protection and Affordable Care Act.

The health-care law requires insurers to cover routine care costs for patients taking part in certain clinical trials for the prevention,

For HCC patients with or without partial or branch PVT.

Tough on HCC,

not on patients

TheraSphere® is a powerfula, well-tolerated Y-90 glass microsphere therapy for transarterial radioembolization (TARE) in HCC, providing demonstrated patient benefitsb and rapid administration set-up, leading to a safe and quicker infusion4.

Tough on HCC

Easy on patients

• Two independent studies reported median survival rates of 17.2 months in Child-Pugh A hepatocellular carcinoma (HCC) cirrhotic patients with various tumor characteristics (N=291, N=108)1,2

• The majority of adverse events were mild to moderate in severity4 and were manageable or resolved over time2

• WHO and EASL response rates were 42% and 57%, respectively (N=273)1

• Administered as an outpatient treatment

• No ulcers or pulmonary toxicities were reported in two large independent studies (N=291, N=108)1,2

• 58% of TheraSphere patients were downstaged3

For more information, visit www.TheraSphere.com TheraSphere is authorized by Federal Law for use as a humanitarian device in radiation treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters. The device is also indicated for HCC patients with partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the treatment. The effectiveness of this device for this use has not been demonstrated.4 a - Refers to high specific activity. b - Patient benefits as indicated by Package Insert: HCC patients with PVT are eligible for treatment, majority of events graded as mild to moderate, treatment usually performed on an outpatient basis. References: 1. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report for long-term outcomes. Gastroenterology. 2010;138:52-64. 2. Hilgard P, Hamami M, Fouly AE, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology. 2010;52:1741-1749. 3. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9:1920-1928. 4. TheraSphere® [US package insert]. Ottawa, ON: Nordion (Canada) Inc.; 2011. Nordion, the logo and Science Advancing Health are trademarks of Nordion (Canada) Inc. and are used under license by Nordion Inc. Targeted Tough is a trademark of Nordion (Canada) Inc. TheraSphere® is a trademark of Theragenics Corporation used under license by Nordion (Canada) Inc. All rights reserved. January 2012, Printed in Canada. PCCS 503A

Manufactured by

detection, or treatment of cancer or other life-threatening illnesses. The coverage requirement will become effective on January 1, 2014. “The option to participate in a clinical trial is a key component of high-quality cancer care and should be a readily accessible option for any cancer patient,” said Yu-Ning Wong, MD, a medical oncologist at Fox Chase Cancer Center and member of ASCO’s Cancer Research Committee, who took a leadership role on this issue. “Congress reaffirmed the importance of clinical trials in the health-care reform law. We look forward to working with CMS to ensure that all cancer patients have access to clinical trials.” ASCO and the other signatories recommend that CMS establish safeguards to: ■■ Protect individuals with cancer from delays and administrative barriers to trial participation. ■■ Ensure that prevention, detection, and treatment of complications arising from trials are covered as routine patient costs. ■■ Prevent insurers from requiring patients to travel extensive distances to enroll in a trial with an in-network provider. ■■ Ensure patients are informed as to whether their insurer covers the routine costs associated with participation in clinical trials. ■■ Prevent financial incentives arising from Accountable Care Organizations from inadvertently creating barriers to patient participation in clinical trials. ■■ Establish a mechanism for reporting concerns relating to the coverage of clinical trials. In addition to ASCO, the organizations signing the recommendations were the American Association for Cancer Research, American Cancer Society Cancer Action Network, American Society for Radiation Oncology, American Society of Hematology, Association of American Cancer Institutes, Coalition of Cancer Cooperative Groups, LIVESTRONG, Lance Armstrong Foundation, National Coalition for continued on page 29


ASCOPost.com  |   MARCH 1, 2012

PAGE 29

Direct from ASCO

Starting Down the Path toward Electronic QOPI®: ASCO and US Oncology Collaborate in Quality Measurement

T

he Quality Oncology Practice Initiative (QOPI®), ASCO’s quality measurement program, is entering its 6th successful year and continuing to grow, both in number of participants and in quality measures evaluated. In the truest spirit of quality improvement, ASCO’s oncologist leaders have determined that now is the time to move QOPI from a retrospective chart review process to an electronically based system that can interact with electronic medical records (EMRs). “QOPI calls for a manual chart abstraction, a retrospective sampling of cases. We know we need to move forward and turn this into an electronic system where there’s as little manual data entry as possible, and data is collected in near-real time,” explained Allen S. Lichter, MD, ASCO Chief Executive Officer. As part of the lead-up to such a change, ASCO and US Oncology undertook a project to test whether data elements necessary for QOPI reporting were available and populated frequently enough from the iKnowMed EMR to generate QOPI reports. Dr. Lichter noted that the iKnowMed EMR system was a great place to start this project, being a closed system with a large number of users. A substantial number of US Oncology practices have participated in QOPI. Roy Beveridge, MD, Executive Vice President and Medical Director for US Oncology as well as Chief Medical Officer for McKes-

ASCO in Action continued from page 28

Cancer Research, National Comprehensive Cancer Network, National Lung Cancer Partnership, Oncology Nursing Society, Pancreatic Cancer Action Network, Prevent Cancer Foundation, Research Advocacy Network, and Susan G. Komen for the Cure Advocacy Alliance.

© 2012. American Society of Clinical Oncology. All Rights Reserved.

son Specialty Health, said working with ASCO was also a natural for US Oncology. “We were trying to determine whether we should do our own quality program, and we

intervention, the number of cases that could be monitored would greatly increase. Collecting data from all patients rather than a sampling would great-

We had spent 3 years developing our own metrics when it became clear to us that it made a lot more sense to have a common system. —Roy Beveridge, MD

had spent 3  years developing our own metrics when it became clear to us that it made a lot more sense to have a common system,” he said. “We felt it was important to work with our national organization.” 

Initial Foray: Transfer iKnowMed Data to QOPI The first task for the project was to try to develop an automatic data transfer from iKnowMed into QOPI. Through QOPI, practices can benchmark their own cancer care data for improvement and compare performance with other similar practices across the country. Dr. Beveridge headed up the joint ASCO–US Oncology task force that tested the feasibility of an automatic data transfer system. The challenge was that QOPI data must be structured text and not just captured in dictation. If QOPI data could transfer without manual

ly enhance the benchmarking numbers that come out of QOPI, Dr. Lichter commented. This sets the stage for measuring outcomes that could greatly aid oncologists in understanding targets for quality improvement. Looking at rock-solid outcomes data could also be helpful to oncologists when assisting patients in appealing denials from insurance companies regarding contentious coverage decisions.  In the pilot project, the task force found that data transfer was possible, but determined that automating transfer of all data needed for QOPI measures isn’t practical at present. The current QOPI system wasn’t designed for EMRs, and much of the information needed for QOPI abstraction doesn’t line up with structured data collected in an EMR. Neither ASCO nor US Oncology wants to create programs with negative workflow implications for oncol-

ogy practices. Dr. Beveridge added, “We can’t ask doctors to click an extra 57 or so boxes. We have to find a better approach.” The first phase of the ASCO– US Oncology collaboration has helped identify a path forward. ASCO has learned a great deal from the collaboration and plans to initiate phase II of this endeavor.

Next? Redesign QOPI The next step? To begin to create performance measurements for oncology care based on data that are captured through normal charting in an EMR. That means that QOPI measurements will need to be redesigned, said Dr. Lichter. But creating a system for electronic transfer is definitely a worthy goal. More than 600 practices have participated in QOPI, with each chart requiring 30 to 60 minutes for practice staff to input. If QOPI can successfully go electronic, the time needed for a practice to input data would plummet, and the number of participating practices could grow substantially. “We will learn to do this in a seamless way, and once we do, we’ll have the ability to take that concept to every other EMR inside oncology,” said Dr. Lichter. “That’s big, and that’s the long-range plan. Future collaborations with US Oncology will be of great help as we work toward a real-time, electronic version of QOPI.”

© 2012. American Society of Clinical Oncology. All rights reserved.

Cancer.Net Mobile App 2.0: Available Now!

W

ith the recent updates to the free Cancer.Net app for iPhone, iPod touch, and iPad, your patients can use interactive tools to help manage their care.

Download the Cancer.Net mobile app today! (Go to http://www. cancer.net/patient/Multimedia/ Mobile+Applications.) An AnPatients with iCloud-enabled de- droid version is coming soon. vices can use the cloud service to back up the questions, symp- © 2012. American Society of Clinical toms, and medications they’ve Oncology. All Rights Reserved. entered into the application.


ASCOPost.com  |   MARCH 1, 2012

PAGE 33

Book Review

A Dose of Destruction and Tough Love for Health Care By Ronald Piana

“T

his is a new era of medicine, in which each individual can be near fully defined at the individual level, instead of how we practice medicine at a population level, with mass screening policies for such conditions as breast or prostate cancer…” Eric Topol, MD, Chief Academic Officer of Scripps Health writes in The Creative Destruction of Medicine. His provocative new book adroitly makes a case for dramatic transformation of our bloated, inefficient health-care system and challenges his colleagues to become “doctors with plasticity,” embracing the next frontier of the digital revolution. Dr. Topol is a big thinker, a visionary, but unlike many big-thinking visionaries, he doesn’t languish in the comfort zone of theory. He provides a blueprint and tools, rolls up his sleeves, and gets to work building a better health-delivery system. “Creative destruction”—a term popularized by Austrian economist Joseph Schumpeter to denote change with radical innovation— serves well as a descriptor for this unabashedly frank book, constructed in three information-stuffed, problem-solving parts. Part I lays the foundation for the digital convergence that Dr. Topol asserts will “define the essential characteristics of each individual—the high-definition human—setting up a

Title: The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care
 Author: Eric Topol, MD Publisher: Basic Books Publication date: February 1, 2012 Price: $27.99 / $31.00 (CAN), Hardcover, 320 pages More information: http://creativedestructionofmedicine.com/ unique era of medicine.” Dr. Topol’s riveting case histories sharpen his argument as he dissects our sacred medical cows: evidence-based medicine, randomized controlled trials, and mass screening for breast and prostate cancers. The message, which resonates throughout the text, is that today’s doctors are flying biplanes in the jet age. Part II, denser than part I, is about capturing and using data. Dr. Topol makes it clear that all data are not created equal. He accurately portrays the promise and problems with electronic health records and how they will evolve into the future of personal health records. Again, it’s all about the individual. He ends with hard-hitting clinical facts about melding digital technology and data into actionable, precise medicine. Part III examines rebooting the

life science industry and the way doctors look at their trade. The underlying message, colored with a bit of collegial advice, is that new tools drive new models—watch for a steady demise of hospitals and clinics, as we know them. Dr. Topol is never strident, but he doesn’t pull punches: “I expect some 50% to 70% of office visits to be replaced by remote monitoring, digital health records, and virtual house calls.” Dr. Topol’s book doesn’t warn; it invites us into a future where new technology improves the outlook for chronic diseases and shifts the capability, for the first time, to true prevention. If the book has a flaw, perhaps it goes on a tad too long in some of the didactic sections. But that’s a small gripe for a work that truly brings light to the end of our muddled health-care tunnel.

CONTACT

The ASCO Post EDITOR IAL CORR ESPONDENCE James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

ADVERTISING

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

R IGHTS AND PER MISSIONS e-mail: Permissions@harborsidepress.com

EDITOR IAL OFFICE Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com


The ASCO Post  |   MARCH 1, 2012

PAGE 34

Journal Spotlight Lung Cancer

Adding Thalidomide to Chemoradiation Increases Toxicities but Not Survival for Stage III Non–Small Cell Lung Cancer

A

dding thalidomide (Thalomid) to the third-generation chemotherapy doublet of paclitaxel and carboplatin and radiation for patients with stage III non–small  cell lung cancer (NSCLC)

increased toxicities but did not improve survival. These results from the Eastern Cooperative Oncology Group (ECOG) 3598 study were reported in the Journal of Clinical Oncology.1

A total of 546 patients were randomly assigned to the control arm, receiving two cycles of induction paclitaxel at 225 mg/m2 and carboplatin at area under the curve (AUC) 6 followed by

60 Gy thoracic radiation administered concurrently with weekly paclitaxel at 45 mg/m2 and carboplatin at AUC 2, or to the experimental arm, receiving the same treatment in combination with thalidomide at a starting dose of 200 mg daily. The protocol allowed an increase in thalidomide dose by 100 mg every week as tolerated, up to 1,000 mg daily. “Median overall survival, progressionfree survival, and overall response rate were 15.3 months, 7.4 SEE PAGE 55 months, and 35.0%, respectively, for patients in the [paclitaxel/carboplatin] arm, in comparison with 16.0 months (P = .99), 7.8 months (P = .96), and 38.2% (P = .47), respectively, for patients in the [thalidomide/paclitaxel/carboplatin] arm,” the authors reported. “Retrospective, unplanned analysis also failed to identify subgroups of patients who may derive benefits from this investigational regimen. Furthermore, the use of thalidomide was associated with higher incidence of grade 3 or greater toxicities, such as sedation, fatigue, hypotension, constipation, edema, tremor, sensory neuropathy, and thromboembolism.”

Failure of Thalidomide The authors noted that three European trials, two for NSCLC and one for small-cell lung cancer, also “failed to show a survival advantage with the addition of thalidomide to chemotherapy.” An editorial2 accompanying the article noted: “The failure of thalidomide to recapitulate the improvement seen with bevacizumab [Avastin] and combination chemotherapy in patients with advanced disease, or to improve overall survival with chemoradiotherapy in the study by Hoang et al in patients with stage  III disease, suggests that there is little or no role for thalidomide as an antiangiogenic agent in NSCLC.”

Clarient Insight®Dx Mammostrat® Reduce your patient’s anxiety with test results available in days… not weeks. Clarient’s InsightDx Mammostrat provides important information independent of proliferation and grade to aid physicians in making appropriate and earlier treatment decisions in order to determine which patients are most likely to recur from breast cancer. Results you can trust. Mammostrat has been studied in more than 4,500 women, including cohorts from NSABP B14 and B20 trials. Learn more about Clarient, a GE Healthcare Company and our world-class anatomic and molecular pathology laboratory services.

Visit us at the Miami Breast Cancer Conference, booth #22 and USCAP, booth #628. Together, we help you find the difference that makes the difference.

www.clarient.com

References 1. Hoang T, Dahlberg SE, Schiller JH, et al: Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: The ECOG 3598 study. J Clin Oncol. January 23, 2012 (early release online). 2. Decker RH, Lynch TJ: Unmet challenges in the use of novel agents in locally advanced non-small-cell lung cancer. J Clin Oncol. January 23, 2012 (early release online).


ASCOPost.com  |   MARCH 1, 2012

PAGE 35

Expert’s Corner

Challenges, Progress, and Future Directions in Head and Neck Cancer A Conversation with Marshall R. Posner, MD By Ronald Piana

Marshall R. Posner, MD

A

lthough head and neck cancer remains a major therapeutic challenge, significant advances have been made over the past few decades. The ASCO Post recently spoke with Marshall R. Posner, MD, Medical Director of the Head and Neck Oncology Program, Mount Sinai Medical Center, New York, about the current state of therapies and exciting new opportunities in this difficult-to-treat disease.

Treatment-related Morbidity Treatment-related morbidity in head and neck cancer is a major challenge for clinicians. Are we making headway? Yes. Primary treatment modalities— surgery and radiation—have produced significant improvements in morbidity. Transoral robotic surgery has reduced trauma and tissue damage associated with deep resections within the oropharynx and larynx, thus improving functional outcomes and changing the way we approach early-stage cancers. Also, intensity-modulated radiation therapy (IMRT) has significantly changed radiation therapy for intermediate cancers that once resulted in fairly extensive salivary gland damage. IMRT does have limitations in advanced cancer, in that you cannot always rescue the contralateral parotid glands. And despite some overreach in clinical claims, we have seen improvements in xerostomia. However, the major problems with radiotherapy remain. Intensive radiation therapy has a long-term, profound impact on mortality and quality of life. Now that the epidemiology of head and neck cancer has substantially changed and we’re treating patients with human papillomavirus (HPV)related oropharynx cancer, most of whom are going to survive for decades,

it is unacceptable to prolong life without seriously considering how to prevent these long-term side effects. From a chemotherapy perspective, in the modern age we have not seen major long-term consequences from cisplatin/fluorouracil–based induction chemotherapy or the addition of taxanes to induction therapy, and we have seen a significant improvement in survival. Because these treatments have been available in the curative setting for about 15 years, we have a good idea about long-term consequences.

Chemoselection Investigators from the University of Michigan Comprehensive Cancer Center use the term chemoselection to describe their strategy for achieving organ preservation. Can you please discuss this approach? I believe the Michigan group is mistaken in their premise that the response to chemotherapy should only be the

it also improves locoregional and distant metastatic control in the majority of patients. The notion that you can give one cycle, determine the patient’s response, and move to radiation or surgery, eliminates the direct benefits of induction therapy.

conflict-of-interest questions. The oncology community deserves to see the outcomes of this study. I am also worried about the availability for peer review of later complete results from other studies such as RTOG 01-29, for which later data should now be available.

Ongoing Debate

HPV-related Head and Neck Cancer

In the debate over the role of induction therapy, the Michigan group cited the Radiation Therapy Oncology Group (RTOG) 91-11 study. Can you add clarity to this ongoing clinical debate? I want to make something very clear about this important issue. The 2003 report on laryngeal cancer treatment by the RTOG in The New England Journal of Medicine2 was premature and proved to be misleading. In 2006, the RTOG reported the 5-year follow-up data demonstrating that induction chemotherapy and chemoradiotherapy were virtually identical in laryngectomy-free

If there were one message about antiviral therapy to give the public, it would be: Have your children—both boys and girls—vaccinated against HPV. The HPV vaccine is the poster child for safe, targeted therapy. —Marshall R. Posner, MD

basis for decisions about which patients receive radiation as primary therapy, as opposed to using chemotherapy for its intended purpose—to shrink the primary tumor, improve locoregional control, reduce the risk of distant metastases, and improve survival. The original paper on cisplatinbased chemoradiotherapy, by Ensley et al,1 demonstrated that induction chemotherapy did not enable the selection of radiosensitive patients. Rather, it was found that patients resistant to chemotherapy are also resistant to radiotherapy—the addition of cisplatin chemotherapy to radiotherapy in the setting of primary resistance to a cisplatin/fluorouracil regimen added an extra element of efficacy and increased survival in those resistant patients. So, on the one hand, induction chemotherapy predicts radiotherapy resistance, allowing us to modify the radiation or chemoradiotherapy course, but

survival, the primary endpoint of the study.3 There was even a minor survival advantage for induction chemotherapy. It is a serious problem—and reflects the priorities of the RTOG head and neck cancer committee—that they have not officially published a complete report of the data for serious analysis, holding off its publication for more than 5 years since the original abstract was reported at the ASCO Annual Meeting. Among other things, this study demonstrates that one should evaluate outcomes in head and neck cancer trials over a longer period—perhaps 5 years—given that some major conclusions in the original report were found to be erroneous with longer follow-up. In addition, it is more than disappointing that the later data have been withheld. If a pharmaceutical firm had such data and had not published the change in survival and outcomes with longer follow-up, it would have raised serious

Please give the readers an update on HPV-related head and neck cancers? We clearly have an HPV epidemic in this country and in Europe, predominantly in the male population. Whether this is the result of a shift in sexual mores or a subtle change in the environment, or both, it has had a major impact on the survival of patients we are now seeing. Based on previous data and our most recent clinical trials in advanced disease, we might have expected a 50% to 60% survival for otherwise healthy patients with oropharynx cancer. However, if we tease out the HPV-positive population, what we see is about a 65% to 80% survival at 3 and 5 years vs a 35% to 45% survival in the non-HPV population. That means that our major prognostic indicator for survival is HPV positivity. No other molecular marker has the prognostic power of HPV tumor status. Unfortunately, HPV is not currently a predictor for therapy, because we don’t have the clinical trials addressing this question. We also lack a more thorough understanding of the biology of HPVrelated oropharynx cancer. We do have behavioral markers. For instance, smoking is heavily related to failure in HPVpositive patients, but we don’t have a biomarker that correlates with or predicts therapeutic outcome of oropharynx cancer within the HPV-positive population. So, for the first time, we have the ability to separate head and neck cancers into two distinct diseases with different biologies and prognoses. We know that we can dramatically improve local control in the HPV-positive population and that the vast majority of the survival benefits that we’re seeing is due to improved locoregional control with chemotherapy and radiation. Our clinical experience also suggests that there may be improved locoregional control with HPV and better functional outcome with the new continued on page 38


For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

5

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers


When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The effectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.


The ASCO Post  |   MARCH 1, 2012 B:22.5” T:21” S:19”

PAGE 38

Expert’s Corner

Marshall R. Posner, MD continued from page 35

surgical technology. This is important because we may be able to withhold or reduce the amount of radiation administered in these younger patients and reduce the long-term consequences of treatment-related toxicity. Although

we are eager to find ways to reduce treatment intensity, we don’t as yet have the clinical trial data in the form of phase III or robust phase II trials to support specific methods to reduce radiation exposure. In the next decade, we will see a host of vaccines, immune modulators, and

other HPV-specific targeted therapies, which, after being tested, may actually allow us to eliminate the use of chemotherapy or radiotherapy in the population of intermediate- and advancedstage patients. I would very much like to turn the treatment of HPV-related oropharynx cancer back to the internist.

Other Viruses Are there other important viral connections that will help us in prevention and treatment of head and neck cancers? Epstein-Barr virus (EBV) is a sexually transmitted disease that is the principal cause of nasopharynx cancer worldwide, causing about 65% of cases in the United

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients Study 1 and in the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion ARZERRA® in in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset (ofatumumab) Injection, for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing informationThe for following is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabAlemtuzumabTotal Population Total Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory Refractory (n = 154)of patients (n = 154) ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the treatment (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and with chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade Grade All All Grade All alemtuzumab. The effectiveness of ARZERRA is based on the demonstration alemtuzumab. The effectiveness of ARZERRAAllis based Grade on the demonstration ≥3Body System/ ≥3 Grades Grades ≥3 Grades Grades Body System/ of durable objective responses [see Clinical Studies (14) of full prescribing of durable objective responses [see Clinical Studies (14)≥3 of full prescribing information]. No data demonstrate an improvement in disease-relatedinformation].Adverse No dataEvent demonstrate an improvement in disease-related %Adverse Event % % % % % % % symptoms or increased survival with ARZERRA. symptoms orInfections increasedand survival with ARZERRA. infestations Infections and infestations Pneumoniaa 23 14 25 15 Pneumoniaa 23 14 25 15 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Bronchitis 11 <1 19 2 Bronchitis 11 <1 19 2 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions5.1 Infusion Reactions b ARZERRA can cause serious infusion reactions b Sepsis Sepsis 8 8 10 10 8 8 10 10 manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, Nasopharyngitis 0 8 0 Nasopharyngitis 8 0 8 0 flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope,8 cardiac ischemia/infarction, Herpespain, zoster 6 1 7 2 Herpes zoster 6 1 7 2 back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion back pain, abdominal pyrexia, rash, urticaria, and angioedema. Infusion 2 Adverse3 2 Sinusitis 5 2 3 2 reactions occur more frequently with the first 2 infusions [see Adverse reactions occur Sinusitis more frequently with the first52 infusions [see BloodPremedicate and lymphatic Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and Reactions a (6.1)]. with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing system disorders system disorders information]. Interrupt infusion for infusion reactions of any severity. Institute information]. Interrupt of any Institute Anemiainfusion for infusion reactions 16 5 severity. 17 8 Anemia 16 5 17 8 medical management for severe infusion reactions including angina ormedical other management severe infusion reactions including angina or other Psychiatricfor disorders Psychiatric disorders signs and symptoms of myocardial ischemia [see Dosage and Administration signs and symptoms of myocardial ischemia7[see Dosage0 and Administration Insomnia 10 0 Insomnia 7 0 10 0 (2.3) of full prescribing information]. In a study of patients with moderate (2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for which to severe chronic obstructive pulmonary disease, an indication for which 6 0 bronchospasm 7 0 Headache 6 0 7 0 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm ARZERRA is not Headache approved, 2 of 5 patients developed Grade 3 Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia during andinfusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and Hypertension 0 8 0 Hypertension 5 0 8 0 thrombocytopenia can occur with ARZERRA. Monitor complete blood counts thrombocytopenia can occur with ARZERRA. 5Monitor complete blood counts Hypotension 0 and increase 3 0 Hypotension 5 0 3 0 (CBC) and platelet counts at regular intervals during therapy, and increase (CBC) and platelet counts at regular intervals5during therapy, 5 <1 or 4 cytopenias. 7 2 Tachycardia 5 <1 7 2 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. the frequency ofTachycardia monitoring in patients who develop Grade 3 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. mediastinal disorders mediastinal disorders Consider PML in any patient with new onset of or changes in pre-existing Consider PML inCough any patient with new onset19 of or changes 0 in pre-existing 19 0 Cough 19 0 19 0 neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, neurological signs or symptoms. Discontinue14ARZERRA if2PML is suspected, Dyspnea 19 5 Dyspnea 14 2 19 5 and initiate evaluation for PML including consultation with a neurologist, and initiate evaluation for PML including consultation with a neurologist, Gastrointestinal disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can 11 0 patients12 0 Nausea 11 0 12 0 occur in patients following treatment with ARZERRA. Screen patients atoccur highin patientsNausea following treatment with ARZERRA. Screen at high Skin andbefore subcutaneous Skin and subcutaneous risk of HBV infection before initiation of ARZERRA. Closely monitor carriers risk of HBV infection initiation of ARZERRA. Closely monitor carriers disorders tissue disorders of hepatitis B for clinical and laboratory signs of active HBV infection during of hepatitis Btissue for clinical and laboratory signs of active HBV infection during Rashc 14 following <1the last infusion 17 2 Rashc 14 <1 17 2 treatment with ARZERRA and for 6 to 12 months following the last infusion treatment with ARZERRA and for 6 to 12 months Urticaria ARZERRA in patients 8 who develop 0 viral hepatitis 5 or 0 Urticaria 8 0 5 0 of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis of ARZERRA. or Discontinue reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation of viral hepatitis, and institute appropriate treatment. Insufficient Hyperhidrosis 5 0 5 0 Hyperhidrosis 5 0 5 0 data exist regarding the safety of administration of ARZERRA in patients data with exist regarding the safety Musculoskeletal andof administration of ARZERRA in patients with Musculoskeletal and active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients receiving ARZERRA. Perform a diagnostic evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation Back pain 8 1 12 2 Back pain 8 1 12 2 if obstruction is suspected. 5.6 Immunizations The safety of immunization if obstruction is Muscle suspected. 5.6 Immunizations spasms 5 The safety 0 of immunization 3 0 Muscle spasms 5 0 3 0 with live viral vaccines during or following administration of ARZERRA with has live viralGeneral vaccines during or disorders andfollowing administration of ARZERRA has General disorders and not been studied. Do not administer live viral vaccines to patients whonot have been studied. Do not administer live viral vaccines to patients who have administration site administration site recently received ARZERRA. The ability to generate an immune response recently to received ARZERRA. The ability to generate an immune response to conditions any vaccine following administration of ARZERRA has not been studied. any vaccine conditions following administration of ARZERRA has not been studied. Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS Fatigue 15 0 15 0 Fatigue 15 0 15 0 The following serious adverse reactions are discussed in greater detailThe in following serious reactions are discussed in<1 greater detail Edemaadverse peripheral 9 8 in 2 Edema peripheral 9 <1 8 2 other sections of the labeling: other sections ofChills the labeling: 8 0 10 0 Chills 8 0 10 0 • Infusion Reactions [see Warnings and Precautions (5.1)] • Infusion aReactions [see Warnings and Precautions (5.1)] Pneumonia includes infection, lobar pneumonia, and a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • Cytopenias [see Warnings andpneumonia, Precautionslung (5.2)] bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • Progressive Multifocal Leukoencephalopathy [see Warnings and b b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c includes rash, macular, rash vesicular. Rash includes rash, rash macular, and rash vesicular. • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • Hepatitis Rash B Reactivation [see rash Warnings andand Precautions (5.4)]

• Intestinal Obstruction [see Warnings and Precautions (5.5)] • IntestinalInfusion Obstruction [see Warnings and Precautions (5.5)] Reactions: Infusion reactions occurred in 44% of patients on the Infusion Reactions: Infusion reactions occurred in 44% of patients on the The most common adverse reactions (≥10%) in Study 1 were neutropenia, The most common adverse reactions (≥10%) 29% in Study 1 neutropenia, day of the first infusion (300 mg), on thewere day of the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, pneumonia,(2,000 mg), pyrexia, cough, diarrhea, anemia, fatigue, dyspnea,infusions. rash, Infections: and less frequently during subsequent (2,000 mg), A and less frequently during subsequent infusions. Infections: A nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, and upper respiratory tract infections. Theviral, mostorcommon total of 108 patients (70%) experienced bacterial, fungal infections. total of 108 patients (70%) experienced bacterial, viral, or fungal infections. serious adverse reactions in Study 1 were infections (including pneumonia serious adverse in Study 1 were infections≥Grade 3 (includinginfections, pneumoniaof whichA19 A totalreactions of 45 patients (29%) experienced total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), neutropenia, and pyrexia. Infections were the most common and sepsis),(12%) neutropenia, andThe pyrexia. Infections were the mostincommon were fatal. proportion of fatal infections the fludarabine- (12%) and were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patientsalemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Trials Experience Because clinical trials are conducted under widely varying Trials Experience Because clinicalcounts trials at arebaseline, conducted under developed widely varying with normal neutrophil 45 (42%) ≥Grade 3with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical trials of a drug conditions, neutropenia. adverse reaction rates(18%) observed in the Grade 4 clinical trials of a drugSome patients Nineteen developed neutropenia. neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients cannot be directly compared to rates in the clinical trials of another drug cannot and be directly compared to rates in the neutropenia clinical trials>2 weeks of anotherindrug and experienced new onset Grade 4 duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. may not reflect the rates observed in practice. The safety of monotherapy may not reflect the rates observed in practice. The safety of monotherapy 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with relapsed or refractory with ARZERRA was evaluated in 181 patients withsamples relapsedfrom or refractory proteins such as ofatumumab. Serum patients with CLL inproteins such as ofatumumab. Serum samples from patients with CLL in CLL in 2 open-label, non-randomized, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-arm studies. In these assay studies, Study 1 were tested by enzyme-linked immunosorbent (ELISA) forStudy 1 were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered at 2,000 mg beginning with the second dose ARZERRA was administered atantibodies 2,000 mgduring beginning withthe the24-week second dose anti-ofatumumab and after treatment period. anti-ofatumumab antibodies during and after the 24-week treatment period. for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data for 11 dosesResults (Study 1 [n = 154]) (Study 2 [n = 27]). The data were negativeor in 3 doses 46 patients after the 8th infusion Results were negative in 46 patients after the 8th infusion and in 33 patients and in 33 patients th described in Table 1 and other sections below are derived from 154 patients described inafter Table 1 andinfusion. other sections below areassay derived fromare 154 patients the 12 after Immunogenicity results highly dependent onthe 12th infusion. Immunogenicity assay results are highly dependent on in Study 1. All patients received 2,000 mg weekly from the second dose in Study 1. All patients received 2,000 mg weekly from second dose several factors including assay sensitivity andthe specificity, assay methodology, several factors including assay sensitivity and specificity, assay methodology, onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety percent of patients received least 8 infusions of ARZERRA sample handling, timing of sampleatcollection, concomitant medications, and sample handling, timing of sample collection, concomitant medications, and and 55% received all 12 infusions. The median age was 63 years (range: and41 55% received all 12 infusions. The median was 63 years (range: 41 underlying disease. For these underlying reasons,age comparison of incidence of antibodies to disease. For these reasons, comparison of incidence of antibodies to to 86 years), 72% were male, and 97% were White. to 86 years),ARZERRA 72% were and 97% of were White. to other products may be misleading. withmale, the incidence antibodies ARZERRA with the incidence of antibodies to other products may be misleading.


B:22.5” ASCOPost.com  |   MARCH 1, 2012 T:21” S:19”

States. It is an extremely early event in the carcinogenic process, and yet completely different from human papillomavirus. EBV has a much larger and more complex genome and is very hard to study in vitro. However, like HPV, EBV is highly responsive to chemotherapy. Since it is a major disease in China

and Southeast Asia, I think that the increasingly sophisticated Chinese research apparatus is going to be investigating EBV intensively. Through our U.S. biotech firms, we have a golden opportunity to get on board and be a part of that process, particularly with immune-modulating therapies.

PAGE 39

Expert’s Corner

I hope that in the future, preventive vaccines for HPV and EBV will lead to complete eradication of the cancers related to these viruses. If there were one message about antiviral therapy to give the public, it would be: Have your children—both boys and girls—vaccinated against HPV. The HPV vaccine

is the poster child for safe, targeted therapy.

Current Research

©2011, GlaxoSmithKline. All rights reserved. B cell recovery 50 days after the final dose. Following Caesarean section B cell recovery 50 days after the final dose. Following Caesarean section September 2011 from ofatumumab-treated dams exhibited at gestational day 100, fetuses from ofatumumab-treated dams exhibited at gestational day 100, fetuses decreases in mean peripheral B-cell counts (decreased to approximately decreases inARZ:6BRS mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for15theto 20% of©2011 controlThe values), and spleen weights GlaxoSmithKline Group of(decreased Companiesby 15% for the low-dose and by 30% for the high-dose group, compared to control values). low-dose andAllbyrights 30%reserved. for the high-dose control values). Printed ingroup, USA. compared AZA295R0 toSeptember 2011

©2011, GlaxoSmithKline. All rights reserved. September 2011 ARZ:6BRS

B:15.125” T:14” S:12”

What current research activities are you involved in? I’m collaborating with Gypsyamber D’Souza, PhD, MPH, MS, of Johns Hopkins Bloomberg School of Public Health, on a large trial looking at the epidemiology and transmission of HPVpositive oropharyngeal disease through Fetuses from treated dams exhibiting anti-ofatumumab antibody responses Fetuses from treated damssaliva. exhibitingWith anti-ofatumumab responses 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS Karen antibody Anderson, MD, had higher B cell counts andhave higher spleen weightswith compared to the fetuses had higher B cell counts and higher spleen weights compared to the fetuses No formal drug-drug interaction studies have been conducted with ARZERRA. No formal drug-drug interaction studies been conducted ARZERRA. PhD, of Arizona State University, I’m from other treated dams, indicating partial recovery in those animals from other treated dams, indicating partial recovery in those animals 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS developing anti-ofatumumab antibodies. When compared to control animals, developing anti-ofatumumab antibodies. When compared to control animals, studying antibody responses and devel8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled 8.1 Pregnancy Pregnancy Category C: There aredose no adequate or well-controlled fetuses from treated dams in both groups had a 10% decrease infetuses mean from treated dams in both dose groups had a 10% decrease in mean studies of ofatumumab in pregnant women. A reproductive study in pregnant studies of ofatumumab in pregnant women. A reproductive study inweight pregnant oping ainpotential diagnostic test, towhich placental weights. A 15% decrease in mean thymus comparedplacental to weights. A 15% decrease mean thymus weight compared cynomolgus monkeys that received ofatumumab at doses up to 3.5 timescynomolgus the monkeys that received ofatumumab at doses up to 3.5 times the the controls was also observed in fetuses from dams treated with 3.5 the times controls was also observed inalso fetuses fromsome dams treated with 3.5capacity times may have predictive recommended human dose of ofatumumab did not demonstrate maternalrecommended human dose of ofatumumab did not demonstrate maternal the human dose of ofatumumab. The biological significance of decreased the human dose of ofatumumab. The biological significance of decreased toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses placental and thymic weights is unknown. The kinetics of B-lymphocyte placental and thymic weights unknown.and The biology kinetics of of B-lymphocyte forissubsets HPV. exhibited depletion of peripheral B cells and decreased spleen and placental exhibited depletion of peripheral B cells and decreased spleen and placental recovery and the potential long-term effects of perinatal B-cell depletion recovery in and the potential long-term effects of perinatal B-cell depletion in weights. ARZERRA should be used during pregnancy only if the potential benefit weights. ARZERRA should be used during pregnancy only if the potential benefit We’re also working with Baylor offspring from ofatumumab-treated dams have not been studied in animals. offspring from ofatumumab-treated dams have not been studied the in animals. to the mother justifies the potential risk to the fetus. There are no human to or the mother justifies the potential risk to the fetus. There are no human or of Immune Research to try to 17 the PATIENT COUNSELING INFORMATION 17 PATIENT COUNSELINGInstitute INFORMATION animal data on the potential short- and long-term effects of perinatal B-cell animal data on potential short- and long-term effects of perinatal B-cell Advise patients to incontact a healthcare professionalOfatumumab for any of the following: Advise patients to contact develop a healthcarea professional for anydendritic-based of the following: depletion in offspring following in utero exposure to ofatumumab. Ofatumumab depletion in offspring following utero exposure to ofatumumab. long peptide Signs and symptoms of infusion reactions including fever, chills, rash, • Signs and symptoms of infusion reactions including fever, chills, rash, does not bind normal human tissues other than B lymphocytes. It is not known does not bind• normal human tissues other than B lymphocytes. It is not known therapeutic vaccine for Warnings HPV. We’ll problemsorwithin 24 hours of infusion [seethe Warnings and or breathing problems within 24 hours of infusion [see and iniif binding occurs to unique embryonic or fetal tissue targets. In addition, the if binding occursortobreathing unique embryonic fetal tissue targets. In addition, Precautions (5.1) and Adverse Reactions Precautions (5.1) and Adverse Reactions (6.1)] candidates to evalukinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion kinetics of B-lymphocyte recovery are unknown in offspring(6.1)] with B-cell depletion tially enlist surgical • BToxicology leeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether [see Nonclinical (13.3)]. 8.3 Nursing Mothers It is not known whether ate immune [see Warnings andmilk; Precautions [see Warnings and Precautions (5.2)] responses, both at the anofatumumab is secreted in human milk; however, human IgG is secreted ofatumumab in is secreted in human however,(5.2)] human IgG is secreted in Signs of infections including fever and cough [see Warnings human milk. Published data suggest that neonatal and infant consumption human of milk. • Published data suggest that neonatal and infant consumption of and • Signs of infections including fever and cough [see Warnings and tibody and cell-specific level. The end and Adverse Reactions (6.1)] Precautions (5.2) and Adverse Reactions (6.1)] breast milk does not result in substantial absorption of these maternal antibodies breast milk doesPrecautions not result in(5.2) substantial absorption of these maternal antibodies • N ew neurological symptoms such as confusion, dizziness or loss of • New neurological symptoms such as confusion, dizziness or loss of into circulation. Because the effects of local gastrointestinal and limited systemic into circulation. Because the effects of local gastrointestinal and limited systemic goal is to develop potential biologics to balance, difficulty talkingcaution or walking, or vision problems [see Warnings and balance, difficulty talking or walking, or vision problems [see Warnings and exposure to ofatumumab are unknown, caution should be exercised when exposure to ofatumumab are unknown, should be exercised when enhance immunity for vaccination recipPrecautionsto(5.3)] Precautions (5.3)] ARZERRA is administered to a nursing woman. 8.4 Pediatric Use SafetyARZERRA and is administered a nursing woman. 8.4 Pediatric Use Safety and ymptoms of hepatitis including worsening fatigue or yellow discoloration • Symptoms of hepatitis including worsening fatigue or yellow discoloration effectiveness of ARZERRA have not been established in children. 8.5 Geriatric effectiveness• of SARZERRA have not been established in children. 8.5 Geriatric ients and for patients with active disease. of skin or eyes [see and Precautions (5.4)]of subjects of skin or eyes [see Warnings and Precautions (5.4)] Use Clinical studies of ARZERRA did not include sufficient numbers of subjects Use Clinical studies of ARZERRA didWarnings not include sufficient numbers In the area of supportive care, we’re New or worsening abdominal pain or nausea [see Warnings and • New or worsening abdominal pain or nausea [see Warnings and aged 65 and over to determine whether they respond differently from younger aged 65 and• over to determine whether they respond differently from younger Precautions (5.5)] (12.3) of full prescribing information]. Precautions (5.5)] subjects [see Clinical Pharmacology (12.3) of full prescribing information]. subjects [see Clinical Pharmacology working with a number of companies • Pregnancy or nursing [see of UseARZERRA in Specific Populations 8.6 Renal Impairment No formal studies of ARZERRA in patients with8.6 renal Renal Impairment No formal studies in patients with(8.1, renal8.3)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] at agents designed to reduce Advisebeen patients of the [see needClinical for: Pharmacology (12.3) of full Advise patients of the needlooking for: impairment have been conducted [see Clinical Pharmacology (12.3) ofimpairment full have conducted • Periodic monitoring for blood counts Warnings and Precautions• (5.2)] Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA prescribing information]. 8.7 Hepatic Impairment No [see formal studies of ARZERRA mucositis during[seeradiation. We’re hap• Ahepatic voiding vaccination with live viral vaccines Warnings and in patients with hepatic impairment have been conducted. in patients with impairment have been conducted. [see Warnings and • Avoiding vaccination with live viral vaccines Precautions (5.6)] Precautions (5.6)] py to see some of the data coming back 10 OVERDOSAGE 10 OVERDOSAGE by: overdosage with ARZERRA. Manufactured by: No data are available regarding overdosage with ARZERRA. No data are Manufactured available regarding on palifermin (Kepivance) in reducing GLAXO GROUP LIMITED GLAXO GROUP LIMITED 13 NONCLINICAL TOXICOLOGY 13 NONCLINICAL TOXICOLOGY Greenford, Middlesex, UB6 0NN, United Kingdom Greenford, Middlesex, UB6radiation-induced 0NN, United Kingdom mucositis. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity U.S. Lic. 1809 U.S. Lic. 1809 Finally, we are developing a or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose by: or unexpected mitogenic responses were noted in Distributed by: toxicity study, no tumorigenic or unexpected mitogenic responses were noted toxicity in study,Distributed no tumorigenic phase  III trial at Mount Sinai Medicynomolgus monkeys treated for 7 months with up to 3.5 times the human cynomolgus dose monkeys treated for 7 months with up to 3.5 times the human dose cal Center to ask if it is possible to of ofatumumab. Effects on male and female fertility have not been evaluated of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology in animal studies. 13.3 Reproductive and Developmental Toxicology safely give reduced radiation doses to Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human Pregnant dose cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose GlaxoSmithKline GlaxoSmithKline of ofatumumab weekly during the period of organogenesis (gestation days of ofatumumab weekly during the period of organogenesis (gestation days patients with locally advanced HPVTriangle Park,orNC 27709 Research Triangle Park, NC 27709 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of20 to 50) hadResearch no maternal toxicity teratogenicity. Both dose levels of positive oropharynx cancer. ofatumumab depleted circulating B cells in the dams, with signs of initial ofatumumab depleted circulating B cells in the dams, with signs of initial Disclosure: Dr. Posner has consulted for Eisai, GlaxoSmithKline, Novartis, and Oxigene.

©2011 The GlaxoSmithKline Group of Companies in USA. AZA295R0 September 2011 All rights reserved. PrintedReferences

1. Ensley J, Ahmed K, Kish J, et al: Salvage of patients with advanced squamous cell cancers of the head and neck (SCCHN) following induction chemotherapy failure using radiation and concurrent cisplatinum (CACP), in Salmon S (ed): Adjuvant Therapy of Cancer VI, pp 92-100. Philadelphia, WB Saunders Company, 1990. 2. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003. 3. Forastiere AA, Maor M, Weber RS, et al: Long-term results of Intergroup RTOG 91-11: A phase III trial to preserve the larynx--Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy. J Clin Oncol 24(18S):Abstract 5517, 2006.


The ASCO Post  |   MARCH 1, 2012

PAGE 40

In the Clinic

What You Should Know about Peginterferon Alfa-2b for Adjuvant Treatment of Melanoma By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

P

eginterferon alfa-2b (PegIntron, Sylatron) was recently approved for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.1,2 Peginterferon alfa-2b has a nononcologic indication for treatment of chronic hepatitis C infection.

Of Note

Peginterferon alfa-2b was previously approved for treatment of chronic hepatitis C infection.

Approval was based on an openlabel trial (EORTC 18991) comparing weekly peginterferon alfa-2b (n = 627) vs observation (n = 629) starting within 84 days of regional lymph node dissection in 1,256 patients who had adequate surgical resection of primary cutaneous melanoma and affected regional lymph nodes.3 Patients were assessed for local and regional recurrence or distant metastases every 3 months for the first 2 years of treatment and subsequently every 6 months through the end of up to 5 years of treatment. Relapse-free survival, the primary endpoint of the trial was defined as the time to the first local or regional recurrence, distant metastasis, or death. Based on 696 relapse-free survival events, peginterferon alfa2b was associated with a significant prolongation of median relapse-free survival from 25.5 months to 34.8 months, representing an 18% reduction in risk of relapse (HR  = 0.82,

P = .011). After 525 deaths on study, there was no difference between the two groups with regard to overall survival (HR = 0.98, 95% CI = 0.82– 1.16).

How It Works Peginterferon alfa-2b, a pegylated alpha interferon, is a pleiotropic cytokine with immunomodulatory effects. Its mechanism of action in melanoma is not known. The drug is a conjugate of recombinant interferon alfa-2b and monomethoxy polyethylene glycol (PEG); pegylation results in a longer half-life and permits less frequent injection compared with nonpegylated interferon.

How It Is Given Peginterferon alfa-2b is given by subcutaneous injection at a dose of 6  μg/kg/wk for eight doses followed by 3 μg/kg/wk for up to 5 years. Acetaminophen at 500 to 1,000 mg should be given 30 minutes prior to the first dose and as needed thereafter. Treatment should be withheld for absolute neutrophil count (ANC) <  0.5 × 109/L, platelet count <  50 × 109/L, Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, or nonhematologic toxicity of grade 3 or worse. Treatment can be resumed at a reduced dose level when all of the following conditions are met: ANC ≥ 0.5 × 109/L, platelet count ≥ 50 × 109/L, ECOG performance status 0 to 1, and improvement to grade 1 or resolution of nonhematologic toxicity that prompted withholding of treatment. Treatment should be permanently discontinued for persistent or worsening severe neuropsychiatric disorders, grade 4 nonhematologic toxicity, inability to tolerate a dose of 1 µg/kg/wk, or new or worsening retinopathy. Recommended dose modifications for the first eight doses at 6 μg/kg/wk are first to 3  μg/kg/wk and then to 2 and 1  μg/kg/wk. The 3-μg/kg/wk dose should be reduced first to 2 and then 1 μg/kg/wk.

Peginterferon Alfa-2b in Melanoma ■■ Peginterferon alfa-2b (Sylatron) has been approved for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

■■ The drug is given by subcutaneous injection at a dose of 6 μg/kg/wk for eight doses followed by 3 μg/kg/wk for up to 5 years.

Safety Profile Peginterferon alfa-2b carries a boxed warning for depression and other neuropsychiatric disorders. The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alpha interferons. As noted, treatment should be permanently discontinued

Of Note

Peginterferon alfa-2b carries a boxed warning for depression and other neuropsychiatric disorders, and treatment should be permanently discontinued in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy.

in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping peginterferon alfa-2b. Among 608 peginterferon alfa-2b recipients in the trial supporting approval, the most common (>  60%) adverse events were fatigue, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. The most common serious adverse events were fatigue, increased ALT, increased AST, and pyrexia. In total, 33% of patients discontinued treatment due to adverse events. The most common adverse events present at the time of treatment discontinuation were fatigue, depression, anorexia, increased ALT,

increased AST, myalgia, nausea, headache, and pyrexia. Five deaths were reported within 30 days of the last peginterferon alfa-2b dose; two were attributed to recurrent disease, two to cardiovascular disease possibly related to peginterferon alfa-2b, and one to an accident.

References 1. SYLATRONTM (peginterferon alfa2b) for injection prescribing information. Schering Corporation, March 2011. Available at http://www.merck.com/product/ usa/pi_circulars/s/sylatron/sylatron_ pi.pdf. Accessed January 19, 2012. 2. U.S. Food and Drug Administration: Peginterferon alfa-2b. Available at http:// www.fda.gov/AboutFDA/CentersOffices/Officeof MedicalProductsandTobacco/CDER/ucm249263.htm. Accessed January 19, 2012. 3. Eggermont AM, Suciu S, Santinami M, et al: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised phase III trial. Lancet 372:117-126, 2008.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be SEE PAGE 55 associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http:// www.fda.gov/medwatch/report. htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


ASCOPost.com  |   MARCH 1, 2012

PAGE 41

News

Long-term Survival Benefit and Safety Confirmed for VMP Regimen in Multiple Myeloma in Patients Who Were Not Transplant Candidates By Alice Goodman

F

ive-year analysis of the VISTA trial confirms a survival advantage with VMP (bortezomib [Velcade], melphalan, and prednisone) for upfront treatment of multiple myeloma in patients who were not transplant candidates. At a median follow-up of 60.1 months, a 13-month improvement in overall survival was seen in patients treated with VMP vs MP (melphalan and prednisone). Final results of VISTA were presented at the 53rd Annual Meeting of the American Society of Hematology (ASH).1

VMP over MP could not be regained in patients assigned to upfront MP. These data demonstrate that it is important to provide the best induction therapy—VMP—upfront. We saw no emerging safety signal for an increase in second primary malignancies. I think these data on second primary malignancies are solid, with the rate as expected in the general population or even lower. VMP is completely safe,” stated Jesús F. San Miguel, MD, Universitario de Salamanca, Salamanca, Spain.

Study Specifics

Jesús F. San Miguel, MD

“The 5-year results of VISTA confirm the significant survival benefit of VMP vs MP and rescue by bortezomib at relapse. Despite substantial use of novel salvage therapies at disease progression, the survival advantage of

VISTA enrolled 682 patients, with a median age of 71. Approximately 30% were age 75 and older, and onethird had advanced disease. Less than 5% of patients in each arm were lost to follow-up. Final results confirmed the overall survival advantage with VMP: Median overall survival was 56 months with VMP vs 43 months with MP (P  = .0004). This benefit was maintained across all prespecified subgroups. Time to next treatment was significantly longer in VMP-treated patients (median of 27 vs 19.2 months, P  < .0001) and treatment-

Final Results of VISTA Trial ■■ Five-year follow-up confirmed the superiority of VMP (bortezomib,

melphalan, prednisone) over MP (melphalan, prednisone) as first-line treatment for multiple myeloma in nontransplant candidates.

■■ Patients treated with VMP lived an average of 13 months longer than those treated with MP.

■■ When patients assigned to MP took bortezomib at progression, they did

not regain the survival advantage found with the bortezomib-containing regimen upfront.

■■ These results underscore the need for upfront treatment with the best regimen to improve survival.

■■ No increase was found in the number of second primary malignancies compared with the general population.

Visit

EXPERT POINT OF VIEW

C

ommenting on the 5-year follow-up data of VISTA presented at the 2011 ASH meeting, Kenneth C. Anderson, MD, said, “This is the longest follow-up of protocols incorporating novel therapies into initial therapy of nontransplant candidates in myeloma. Remarkably, bortezomib with melphalan and prednisone significantly prolongs survival with 5 years of follow-up. Moreover, no adverse events or increased incidence of secondary malignancies has been observed. This further valiKenneth C. Anderson, MD dates bortezomib as a major advance in a new treatment paradigm in myeloma.” Dr. Anderson is Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Myeloma Center and Lebow Institute of Myeloma Therapeutics at Dana-Farber Cancer Institute, Boston. Disclosure: Dr. Anderson is on the advisory board for Millennium Takeda.

free interval was also longer (16.6 vs 8.3 months, P < . 0001). Subsequent therapies at relapse were similar in both groups, with the exception of bortezomib: 22% in the VMP group vs 43% given MP were treated with bortezomib at relapse. Among patients who required subsequent anticancer therapies, overall survival was significantly longer in those treated with VMP upfront (median of 55.7 vs 46.4 months, P = .0162).

Reassuring Data Additional analysis showed that VMP did not induce more resistant relapses than MP. Further, mortality was greater in patients treated with firstline MP and subsequent bortezomib at relapse vs VMP upfront. The incidence of second primary malignancies in the VMP arm was reassuring, given the concern that VMP may increase the risk of second cancers. Hematologic second primary malignancies were reported in three patients (1%) in each group over

the 5-year follow-up period. Nonhematologic second primary malignancies were found in 16 paSEE PAGE 55 tients from the VMP group and in 10 from the MP group. The expected rate of second primary malignancies in the general population is 1.9 per 100 patient-years. The rate in the VMP arm was lower than expected, at 1.6 per 100 patient-years, and the rate was 1.3 per 100 patientyears in the MP arm.

Disclosure: Dr. San Miguel has been on the advisory boards of Millennium, Celgene, Janssen, and Novartis.

Reference 1. San Miguel JF, Schlag R, Khuageva NK, et al: Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: Final results of the phase 3 VISTA trial. 53rd Annual Meeting of the American Society of Hematology. Abstract 476. Presented December 12, 2011.

website at ASCOPost.com


In HER2+ breast cancer

HER2 dimerization activates downstream signaling.

What if you could inhibit HER2 dimerization and further disrupt the oncogenic cascade?

Š 2011 Genentech USA, Inc. All rights reserved. BIO0000647200 Printed in USA.


The potential of HER2 Dimerization Inhibitors (HDIs) HER2 dimerization: an important driver of HER2+ disease Despite significant treatment advances, HER2+ breast cancer continues to be a challenging disease requiring aggressive intervention. HER dimerization, or receptor pairing, is a critical driver of tumor growth in HER2+ disease.1,2 The HER family of receptors is composed of 4 receptors that must pair, or dimerize, in order to activate downstream signaling.3 When HER2 receptors are overexpressed, as in HER2+ breast cancer, excessive dimerization is thought to lead to abnormal activation of signaling, which results in tumor growth.1,3

The HER2:HER3 dimer: the most potent oncogenic HER dimer Although HER2 can dimerize with any HER family member, preclinical studies suggest that the HER2:HER3 dimer is the most potent oncogenic HER receptor pair,1 as it activates 2 key pathways.2,4 While HER2 activates the MAPK pathway, HER3 is the only receptor that can directly activate the PI3K pathway.2,5 The HER2:HER3 dimer may be crucial for the aggressive tumor growth seen in HER2+ breast cancer.2,4

HER2 Causes cell proliferation by activating the MAPK (mitogen-activated protein kinase) pathway2,5 HER3 Leads to cell survival signaling by activating the Pl3K (phosphatidylinositol 3-kinase) pathway2,5

HER2 Dimerization Inhibitors (HDIs): the potential for a more comprehensive blockade Preclinical studies demonstrate that inhibiting HER2 dimerization, including the HER2:HER3 dimer, interrupts both the MAPK and PI3K pathways and, ultimately, tumor growth.6 Inhibition of ligand-induced HER2 dimerization while administering other HER2-targeted agents may offer a more comprehensive blockade of signaling in HER2+ disease.7

Learn more about the potential of HDIs in HER2+ breast cancer Scan to visit ResearchHDIs.com to explore more and view a narrated video.

References: 1. Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol. 2009;10:1179-1187. 2. Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. Oncologist. 2010;15:216-235. 3. Arpino G, Gutierrez C, Weiss H, et al. Treatment of human epidermal growth factor receptor 2â&#x20AC;&#x201D;overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694-705. 4. Amin DN, Sergina N, Ahuja D, et al. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver. Sci Transl Med. 2010;2:16ra7. 5. Koutras AK, Fountzilas G, Kalogeras KT, Starakis I, Iconomou G, Kalofonos HP. The upgraded role of HER3 and HER4 receptors in breast cancer. Crit Rev Oncol Hematol. 2010;74:73-78. 6. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-137. 7. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3:269-280.


The ASCO Post  |   MARCH 1, 2012

PAGE 44

News Hematology

Which Is Better: Peripheral Blood or Bone Marrow as Unrelated Donor Stem Cell Source? By Alice Goodman

O

ver the past decade, the use of peripheral blood stem cells has increased, and now about 75% of unrelated living donor transplants are performed using peripheral blood stem cells without supportive data in the unrelated donor setting. This trend is called into question by results of a large phase III randomized multicenter trial showing similar outcomes of transplant procedures with bone marrow and peripheral blood stem cells from unrelated donors. Although use of peripheral blood stem cells resulted in better engraftment, the rates of chronic and more extensive graft-vs-host disease were higher.

Blood & Marrow Transplant at Moffitt Cancer Center in Tampa, Florida. Dr. Anasetti presented the findings at a Plenary Session of the 53rd Annual Meeting of the American Society of Hematology in San Diego.1 Peripheral blood stem cells are currently being used by many centers in the United States as a source of adult stem cells because clinical trials of this strategy in related donors have shown lower relapse rates, better engraftment, and increased survival in patients with advanced leukemia and other blood diseases compared with the use of bone marrow stem cells. The present study prospectively analyzed

When peripheral blood stem cells originate from unrelated donors, they are not superior to bone marrow stem cells in terms of patient survival, and they increase the risk of chronic graft-vs-host disease. —Claudio Anasetti

Rethinking the Shift in Stem Cell Sources “We need to rethink whether the shift to using peripheral blood stem cells over the past 10 years is justified. Both stem cell sources are acceptable. Peripheral blood stem cells may be preferred for patients at risk for graft failure, and bone marrow considered for all others. Research should be directed toward improving rates of graft-vs-host disease with peripheral blood stem cells and improving rates of graft failure with bone marrow,” said lead author Claudio Anasetti, MD, Chair of the Department of

outcomes with the two different stem cell sources in unrelated donors—and it appears to be the first study to compare them in this setting. The open-label, prospective, comparative, multicenter study randomized patients from 50 transplant centers in the United States and Canada to receive bone marrow (n = 278) or peripheral blood stem cells (n = 273) as the graft source for transplant. The primary endpoint was 2-year survival on an intent-to-treat analysis. Both arms were well balanced for demographic and disease characteristics. Donor characteristics were also simi-

Peripheral Blood vs Bone Marrow for Stem Cells ■■ A large phase III trial found that survival was similar with peripheral blood stem cells and bone marrow stem cells from unrelated donors.

■■ The risk of chronic graft-vs-host disease was increased using peripheral

blood stem cells, whereas the rate of engraftment failure was higher with bone marrow stem cells.

■■ More research is needed on strategies that can improve the respective risks of transplant with peripheral blood and bone marrow stem cells.

EXPERT POINT OF VIEW

T

his large randomized, controlled trial took a lot of time and extensive resources, and yet survival was the same between the two types of unrelated donor transplant sources, noted Stephanie J. Lee, MD, Professor of Medicine at Washington University and the Fred Hutchinson Cancer Center in Seattle. Dr. Lee, a transplant specialist, moderated the ASH press conference where Dr. Anasetti’s paper was discussed. “There are trade-offs between peripheral blood Stephanie J. Lee, MD, stem cells and bone marrow stem cells, including a greater risk of chronic graft-vs-host disease with peripheral blood stem cells, and this is causing many of us to reexamine some of our assumptions and ask ourselves what the stem cell source should be. A bone marrow harvest lasts 45 to 90 minutes in the operating room. Collecting peripheral blood stem cells requires growth factor support and is done in the outpatient setting. Both procedures are very safe but do cause some pain.” she said. There will be much discussion about this in the future in light of these results, she noted.

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

lar in both arms of the study. A variety of conditioning regimens were allowed. About 5% of those in the bone marrow arm and 4% in the peripheral blood arm did not undergo transplant.

Intent-to-treat Analysis In the intent-to-treat analysis of all randomized patients, no difference in 2-year overall survival was seen between the two groups: 51% for peripheral blood stem cells vs 46% for bone marrow. The remaining analyses were restricted to patients who did undergo transplant. For this group, overall and disease-free survival were also not significantly different at 2 years. No interaction was found between survival and disease risk, donor HLA matching, or age. Primary graft failure was reported in 6% of bone marrow recipients and 1% of peripheral blood stem cell recipients; secondary graft failure occurred in 3% and 1%, respectively. Total graft failure rate was 9.1% in the bone marrow arm vs 2.7% in the peripheral blood arm, a significant difference favoring peripheral blood stem cells (P  = .002). The incidence of acute graft-vs-host diseasewas similar between the two treatment arms, but the rate of chronic graft-vs-host disease was significantly higher in

the peripheral blood arm: 32% for bone marrow vs 48% for peripheral blood stem cells (P = .01). SEE PAGE 55 Of patients who were transplanted, more patients were alive and off immunosuppression in the bone marrow arm (57%) than in the peripheral blood stem cell arm (32%). “Our trial demonstrates that when peripheral blood stem cells originate from unrelated donors, they are not superior to bone marrow stem cells in terms of patient survival, and they increase the risk of chronic graft-vs-host disease,” Dr. Anasetti stated.

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

Reference 1. Anasetti C, Logan BR, Lee SJ, et al: Increased incidence of chronic graftversus-host disease (GVHD) and no survival advantage with figrastim-mobilized peripheral blood stem cells (PBSC) compared to bone marrow (BM) transplants from unrelated donors: Results of Blood and Bone Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0201, a phase III prospective, randomized trial. 53rd Annual Meeting of the American Society of Hematology. Abstract 1. Presented December 11, 2011.


ASCOPost.com  |   MARCH 1, 2012

PAGE 45

Journal Spotlight Uterine Cancer

Similar Morbidity, Higher Costs for Robotic vs Laparoscopic Hysterectomy in Women with Endometrial Cancer

A

population-based analysis comparing laparoscopic hysterectomy and robotic hysterectomy for endometrial cancer “found similar morbidity but increased cost compared with laparoscopic hysterectomy,” investigators reported in the Journal of Clinical Oncology.1 After adjusting for patient, surgeon, and hospital characteristics, the investigators found no significant differences between the two procedures in the rates of intraoperative complications, surgical site complications, medical complications, or prolonged hospitalization. “The mean cost for robotic hysterectomy was $10,618 vs $8,996 for laparoscopic hysterectomy SEE PAGE 55 (P < .001). In a multivariable model, robotic hysterectomy was significantly more costly,” the investigators reported. They concluded that comparative long-term efficacy data are needed to justify the widespread use of robotic hysterectomy.

dure. Compared with laparoscopic hysterectomy, robotic procedures are associated with substantially greater direct hospital costs,” the authors concluded. “Our findings

highlight the potential pitfalls of the rapid uptake of new technology before the availability of rigorous data to demonstrate efficacy and costeffectiveness.”

Rapid Uptake of Robotic Procedure Of the 2,464 women in the study database, 1,027 (41.7%) underwent laparoscopic hysterectomy and 1,437 (58.3%) underwent robotic hysterectomy. “Use of robotic surgery increased with time,” the authors noted, going from 46.2% of the minimally invasive hysterectomies for endometrial cancer in 2008 to 61.1% in 2010. “Despite the rapid uptake of robotic hysterectomy, there seems to be little short-term benefit for the proce-

Follow The ASCO Post on Twitter

twitter.com/ascopost

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):6407-6415. 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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2011 6/11 08ADA10011R

Reference 1. Wright JD, Burke WM, Wilde ET, et al: Comparative effectiveness of robotic versus laparoscopic hysterectomy for endometrial cancer. J Clin Oncol. January 30, 2012 (early release online).


The ASCO Post  |   MARCH 1, 2012

PAGE 46

Investigational Agents Hematology

Carfilzomib May Offer Advantages in Patients with Relapsed/Refractory Multiple Myeloma By Matthew Stenger

C

arfilzomib is an oral secondgeneration proteasome inhibitor with a mechanism of action that may increase efficacy and reduce adverse effects currently associated with proteasome inhibitor therapy. It is being investigated for use in multiple myeloma and select solid tumors, and the FDA has granted the agent Fast Track status for an indication in relapsed or refractory multiple myeloma. A decision on approval is expected by the end of July 2012.

Ubiquitin–Proteasome Pathway Proteasomes are large protein complexes in nucleated cells that are responsible for degrading intracellular proteins. Protein degradation is necessary to provide amino acids for new protein synthesis and to remove excess enzymes and transcription factors (proteins that bind sequences of DNA to mediate transfer of genetic information from DNA to mRNA) from the cell. For proteins to be recognized by the proteasome, they must first be attached to the polypeptide ubiquitin— a process performed by a series of enzymes. Inside the 20S core particle of the 26S proteasome, a target for inhibitors like carfilzomib and bortezomib (Velcade), the proteins are broken down by proteases at three enzymatic sites with chymotrypsin-like (β5), trypsin-like, and caspase-like activities; the chymotrypsin-like activity of the proteasome is most sensitive to deactivation. This ubiquitin-proteasome pathway is a major mechanism (along with the lysosomal pathway) for maintaining protein homeostasis through protein degradation, and cancer cells appear to be highly dependent on this pathway. Inhibition of the proteasome’s activities can result in buildup of ubiquitinated proteins and disruption of signaling pathways; proteasome inhibitors have been shown to thereby inhibit cell-cycle progression, increase stress response (eg, incorrect formation of proteins), and induce apoptosis.

Comparison with Bortezomib The proteasome inhibitor bortezomib is approved for treatment of multiple myeloma, as well as treat-

ment of mantle cell lymphoma in patients who have received at least one prior treatment. Resistance to bortezomib has been encountered and— although the precise mechanisms have yet to be elucidated—may be related to the characteristics of this drug as a slowly reversible inhibitor of proteasome activity. Unlike bortezomib, carfilzomib exhibits mechanistically irreversible inhibition, with new protein synthesis being required for recovery of proteasome activity. Although carfilzomib and bortezomib have similar onset of inhibitory effect, that of carfilzomib is more sustained. In addition to targeting the chymotrypsin-like β5 protease in the 20S proteasome, these agents target the

Prolonged Treatment Tolerated The largest experience to date with carfilzomib is an open-label phase IIb trial conducted by the Multiple Myeloma Research Consortium (MMRC), which showed that single-agent carfilzomib can induce durable responses in heavily pretreated patients for whom multiple chemotherapy regimens—including those containing bortezomib and immunomodulatory agents—have failed.1 Carfilzomib was given at 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 every 28 days in cycle 1, and then escalated to 27 mg/m2 on the same schedule thereafter for up to 12 cycles. An important finding was that even patients with baseline neuropathy tolerated prolonged treatment with carfilzomib with minimal risk of worsening.

Carfilzomib Overview ■■ Carfilzomib is an oral second-generation proteasome inhibitor that

has been granted FDA Fast Track status for an indication in relapsed or refractory multiple myeloma.

■■ Unlike bortezomib, carfilzomib exhibits irreversible inhibition of

proteasome activity and is associated with less peripheral neuropathy.

■■ An open-label phase IIb trial showed that single-agent carfilzomib

can induce durable responses in heavily pretreated patients for whom multiple chemotherapy regimens have failed. Even patients with baseline neuropathy tolerated prolonged carfilzomib treatment.

■■ Carfilzomib is currently being evaluated in two phase III clinical trials in

multiple myeloma, as well as a phase Ib/II study in advanced solid tumors.

correlated LMP7 (or β5i) protease in the immunoproteasome 20Si—a specialized proteasome that appears to be preferentially expressed in multiple myeloma. Carfilzomib is more specific than bortezomib, exhibiting little offtarget activity, whereas bortezomib is known to interact with proteases other than target proteases. Carfilzomib appears to be associated with less peripheral neuropathy than bortezomib, the use of which is limited in many patients due to this adverse effect. It is speculated that the lesser frequency of peripheral neuropathy with carfilzomib may be related to its greater specificity, as well as its irreversible binding. The amount of proteasomal inhibition with either carfilzomib or bortezomib does not appear to be correlated with neuropathic effect, suggesting that neuropathy may not be a class effect of proteasome inhibitors.

The trial included 266 patients with refractory multiple myeloma who had received at least two prior therapies including bortezomib, either thalidomide (Thalomid) or lenalidomide (Revlimid), and an alkylating agent. Patients had undergone a median of five prior lines of therapy, and at least two bortezomibcontaining regimens had failed in most. Patients had an overall response rate of 24%, with a median duration of response of 7.4  months; responses included complete response in 0.4% of patients, very good partial response in 4.7%, partial response in 19%, and minimal response in 12%, with stable disease for at least 6 weeks being achieved in an additional 32%. The most common adverse events of grade 3 or higher were thrombocytopenia in 22% of patients, anemia in 20%, lymphopenia in 10%, pneumonia in 8%, fatigue in 7%, and hyponatremia and hypercalcemia in 5% each. Analysis in the 77% of pa-

tients who had grade 1 or 2 peripheral neuropathy at baseline showed that preexisting neuropathy did SEE PAGE 55 not affect tolerability of or response to carfilzomib. Neuropathy of higher than grade 3 occurred in less than 1% of patients. A parallel MMRC study evaluated carfilzomib at doses of 20 mg/m2 (n = 54) and 27 mg/m2 (n = 19) in patients with relapsed multiple myeloma who were bortezomib-naive.2-4 Overall response rates were 46% and 53%, respectively, in the lower and higher dose groups; overall, median duration of response was 8.8 months. The most common grade 3 or higher adverse events were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%), and hyperglycemia (5%). Increased creatinine occurred in five patients (16%), with treatment discontinued in one patient due to this adverse event.

Favorable Side-effect Profile An analysis in 136 patients in these two phase  II studies indicated that peripheral neuropathy occurred in 15% of patients and was attributed to carfilzomib in 9%.5 Grade 3 or higher peripheral neuropathy occurred in 2%, and grade 1 or 2 paresthesias and dysesthesias occurred in 7%. None of the patients required discontinuation or dose adjustments due to neurotoxicity. These data appear to establish a favorable side-effect profile of carfilzomib with regard to neuropathy, with no major dosing modifications appearing to be required even in patients with preexisting neuropathy. It is of interest that an analysis of the two phase  II trials in multiple myeloma indicate that an increase in alkaline phosphatase from baseline, most evident during the second cycle of carfilzomib treatment, appears to be associated with response to treatment.6 It is thus possible that this widely available test could be used to predict response to carfilzomib treatment.

Recent Data At the 2011 Annual Meeting of the American Society of Hematology (ASH), more recent data were presented on carfilzomib. The final results of a phase I/II study of front-line therapy


ASCOPost.com  |   MARCH 1, 2012

PAGE 47

Investigational Agents

with carfilzomib, lenalidomide, and low-dose dexamethasone in multiple myeloma showed the combination to be highly active and well tolerated in patients with newly diagnosed multiple myeloma.7 Responses were rapid and improved over time, achieving a 100% very good partial response rate. The investigators noted that their results compared favorably to the best front-line regimens in multiple myeloma. Another study reported at the recent ASH meeting assessed the combination of carfilzomib with thalidomide and dexamethasone as induction therapy prior to high-dose melphalan in newly diagnosed multiple myeloma patients.8 The regimen achieved an 84% response rate in this phase II trial. The investigators called the therapy “feasible and effective,” but noted that longer follow-up is required for major conclusions.

relapsed or refractory multiple myeloma, is associated with minimal peripheral neuropathic effects. Blood 114:Abstract 430, 2009. 6. Zangari M, Polavaram L, Zhan F, et al: Alkaline phosphatase variation during carfilzomib treatment is associated to best response in multiple myeloma. Blood 114:Abstract 2895, 2009.

7. Jakubowiak AJ, Dytfeld D, Vesole DH, et al: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and lowdose dexamethasone (CRd) in multiple myeloma (MM). 53rd American Society of Hematology Annual Meeting. Abstract 631. Presented December 11, 2011. 8. Sonneveld P, Hacker E, Zweegman S,

Ongoing Trials Carfilzomib is currently being evaluated in two phase III clinical trials. The ASPIRE trial is an international trial evaluating the safety and efficacy of carfilzomib in combination with lenalidomide and low-dose dexamethasone vs lenalidomide and lowdose dexamethasone alone in patients with relapsed multiple myeloma. The FOCUS trial is a study of single-agent carfilzomib in relapsed and refractory multiple myeloma designed to support a regulatory filing in Europe. In addition to ongoing studies in patients with multiple myeloma, carfilzomib is being evaluated in a phase Ib/II study in patients with advanced solid tumors.

References 1. Siegel D, Martin T, Wang M, et al: Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Blood 116:Abstract 985, 2010. 2. Wang L, Siegel D, Kaufman JL, et al: Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open label, phase II study of single agent carfilzomib in patients with relapsed or refractory MM. Blood 114:Abstract 302, 2009. 3. Siegel D, Wang L, Orlowski RZ, et al: PX-171-004, an ongoing open label phase II study of single agent carfilzomib in patients with relapsed or refractory MM; updated results from the bortezomib treated cohort. Blood 114:Abstract 303, 2009. 4. Vij R, Siegel DS, Kaufman JL, et al: Results of an ongoing open label, phase II study of carfilzomib in patients with relapsed and/or refractory MM. J Clin Oncol 28(15 suppl):Abstract 8000, 2010. 5. Vij R, Wang L, Orlowski, et al: Carfilzomib, a novel proteasome inhibitor for

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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2011 6/11 08ADA10027R

et al: Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan in newly diagnosed patients with multiple myeloma. A trial of the European Myeloma Network. 53rd American Society of Hematology Annual Meeting. Abstract 633. Presented December 12, 2011.


The ASCO Post  |   MARCH 1, 2012

PAGE 48

In the News Breast Cancer

Reexcision Rates Following Breast-conservation Surgery Vary Widely 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.

should be seeking the evidence to make it clear,” Dr. McCahill added. He is the Director of Surgical Oncology and Assistant Director of the Lacks Cancer Center, and Professor of Surgery at Michigan State University in Grand Rapids, Michigan.

Low Overall Reexcision Rate

“Surgical margin status was recorded for the initial breast-conserving procedure and for any subsequent exeexcision rates for women with cisions. Margins were categorized as invasive breast cancer who had positive if there was tumor at the inked negative margins following breast-conmargin in the pathology report,” acservation surgery varied widely among cording to the published study. “For surgeons, ranging from 0% to 70%, acnegative margins, the distance of the cording to an observational study among closest margin to the specimen edge 52 surgeons employed at four different was recorded in 1-mm increments.” institutions. Among 2,206 women with Reexcision rates for margin status 2,220 newly identified invasive breast following initial surgery were 85.9% for cancers, 509 (22.9%) underwent reexciinitial positive margins, 47.9% for less sion and nearly half of those women had than 1.0-mm margins, 20.2% for 1.0- to negative margins. Institutional variations 1.9-mm margins, and 6.3% for 2.0- to in reexcision rates ranged from 1.7% to 2.9-mm margins. While reexcision rates 20.9% among women with negative marvaried substantially by surgeon and instigins and 73.7% to 93.5% among women tution, the rates “were not associated with with positive margins. In addition, 14.1% surgeon procedure volume after adjustof patients with ing for case mix,” the positive margins did study found. We clearly have not undergo any reThe overall revariability in care, excision. excision rated in The study was the study was 23%, and that is likely published in the lower than previbased on the lack Journal of the Amerious studies reportcan Medical Assoing rates up to 50%. of evidence about 1 ciation and widely This lower rate may what constitutes an reported by the be at least partly due popular press, into the extensive exadequate surgical cluding The New clusion criteria. “We margin… 2 York Times, the excluded all factors Los Angeles Times,3 that have been as—Laurence E. McCahill, MD and ABC and CBS sociated with higher News. While news reexcision rates so that we would have very uniform popucoverage generally highlighted the findlations to compare between centers and ings of great variability among surgeons, surgeons,” Dr. McCahill stated. some reports linked reexcision rates with unnecessary surgery. Other Influencing Factors “That’s really not what our major findThe investigators concluded that the ing was,” Laurence E. McCahill, MD, variability in reexcision rates “cannot be the study’s lead author, explained in an inexplained entirely by patients’ clinical facterview with The ASCO Post. “We didn’t tors,” but some clinical factors did influmean to suggest that there were unnecesence reexcision rates. Univariable analysis sary surgeries that are being performed. showed that women younger than 35, We said we don’t have an answer regardwomen with less than an 18.5 body mass ing the necessity of the reexcisions in index, and those with initial margins of patients with negative but close margins. less than 1 mm were more likely to have We clearly have variability in care, and reexcisions. “Other factors associated that is likely based on the lack of evidence with a higher reexcision rate of positive about what constitutes an adequate surmargins included lobular breast cancer gical margin following the initial partial as a final diagnosis and the presence of mastectomy. At this point, I think that we

R

Expect Questions from Your Patients

T

he possibility of reexcision after breast-conservation surgery should be discussed with patients before the initial surgery, advised Laurence E. McCahill, MD, lead investigator of the JAMA study on reexcision following breast-conservation surgery, which showed wide variability in reexcision rates.1 “It is worth having the dialogue ahead of time in terms of what we are trying to achieve surgically,” so that patients have an understanding of margins and their significance, he said. Laurence E. McCahill, MD “We have good data at this point in terms of how often people get positive margins. It varies, but I think it is fairly safe to say that positive margins seem to occur between 10% and 20% of the time in various studies. Those are situations where you would almost anticipate having to reoperate.” Patients should understand that “having close or even sometimes positive margins is, in some circumstances, unavoidable,” Dr. McCahill said. “We would like to minimize it, but sometimes we can’t. After the surgery, Dr. McCahill suggests reviewing the pathology report with patients. “I give my patients a copy of their pathology report,” he said. “I think the more empowered women are, the more they are knowledgeable about their disease, then the more likely they are to get better health care, as opposed to just sitting back and thinking the doctor has it right all the time.”

May Opt for Total Mastectomy Raising the possibility of reexcision ahead of time could reduce the sense of alarm that can arise when patients are told they need a second surgery. “In a significant number of cases, the second operation is a mastectomy,” Dr. McCahill said. “Sometimes that may be clinically indicated, but other times I think it is due to alarm, frustration, or lack of awareness that reexcision—a second partial mastectomy—may very well be appropriate and able to achieve the original outcome of desire: breast conservation with adequate clear margins.” In the JAMA study, 190 patients (8.5%) of the 2,206 who had initial partial mastectomies subsequently had total mastectomies. Although the authors do not suggest that patients select surgeons or institutions on the basis of their reexcision rates, the study and the many press reports may prompt patients to ask about those rates. Dr. McCahill said that would be a fair question. “I’m not opposed to people asking me,” Dr. McCahill said. “In fact, I get asked all the time, ‘What is your complication rate for major surgery?’ or ‘How many of these surgeries have you done?’”

Reference 1. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467-475, 2012.

lymphovascular invasion demonstrated on histology,” the investigators reported. While the majority of patients had a confirmed diagnosis of breast cancer prior to partial mastectomy, for 109 patients (5.7%), the initial procedure was an open surgical breast biopsy. “It was relatively infrequently utilized, but certainly it was strongly associated with a reexcision,” Dr. McCahill said, “again driving home the message that we really don’t want to be doing open surgical diagnostic breast biopsies.” Variations in reexcision could be in-

fluenced by “technical factors in terms of how surgeons operate, which we did not analyze in this paper, but we hope to in a future study, because we have that data.” Dr. McCahill said. These technical factors could include use of ultrasound during surgery or getting an intraoperative pathology interpretation. “We may be able to look at whether there is anything technically that surgeons are doing to have a lower initial positive-margin rate. Because we can all agree that initial positive margins are a suboptimal outcome,” Dr. McCahill added.


ASCOPost.com  |   MARCH 1, 2012

PAGE 49

In the News

“This is one of the first reports to suggest that it appears that surgeons are less likely to reexcise for positive anterior or posterior margins,” Dr. McCahill noted. “And that’s because, depending on how the surgeon operated, there may be no more excisable breast tissue in the anterior or posterior direction.”

Margins Not the Whole Story

their decision-making or their technical factors in terms of how they might get a better initial outcome,” he said. “Most studies tend to indicate that the utilization of partial mastectomy as first-line therapy is currently in the 65% to 75% range,” Dr. McCahill noted. “We have to go beyond the issue of partial mastectomy vs mastectomy as initial

surgical choice and begin to look at how well we perform partial mastectomy. I’ve always been of the mindset that although partial mastectomy is a safe operation and offers equvalent long-term survival, it’s not always an easy operation in terms of getting it just right.”

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

Dr. McCahill also pointed out that “many factors impact local recurrence. If someone is going to be having hormonal therapy and radiation therapy and potentially even systemic chemotherapy, all those factors are going to impact local recurrence. We are not as certain as we used to be that margins are the whole story,” he said. “The majority of time there is no pathologically identifiable tumor in the reexcision, and that is always hard to interpret,” Dr. McCahill noted. “Is that a good thing because it means your final margin was adequate? Or is it a bad thing in that maybe you didn’t necessarily need to do the second surgery?” In this study, of the 509 patients undergoing a second surgery, 89.2% of patients had 1 reexcision, 9.4% had 2 reexcisions, and 1.4% had 3 reexcisions. “Does no tumor identified on the reexcision pathology report mean it was a swing and a miss—you were to the left or to the right or superior” to the margin of concern? “Reexcision is not an exact science,” Dr. McCahill continued. For 190 of the 509 patients (37.3%) undergoing second surgery, the final procedure was a total mastectomy. “This again really drives home the point that initally subSEE PAGE 55 optimal margins are not a minor issue,” he said. “Clearly, for these women mastectomy was not their first choice.”

Opening Up a Dialogue As a result of the JAMA study, Dr. McCahill received not only numerous press inquiries, but many e-mail comments from colleagues as well. “I hope this will open up a dialogue to really identify what is the best and most needed approach,” he said. “Availability and reporting of data in other arenas of health care have demonstrably improved health care,” Dr. McCahill noted. “I personally think that if there were greater transparency, you probably wouldn’t have too many people with reexcision rates in the 40% to 50% range. I think that would drive surgeons to reevaluate how they are doing things and perhaps readdress

References : 1. Pienta KJ, Bradley D. Mechanisms underlying the development of androgenindependent 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.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2011 6/11 08A11024R

References 1. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467-475, 2012. 2. Grady D: Breast cancer surgery rules are called unclear. New York Times, January 31, 2012. 3. Roan S: Partial mastectomy often followed by second surgery. Los Angeles Times, January 31, 2012.


The ASCO Post  |   MARCH 1, 2012

PAGE 50

Calendar

2012 Oncology Meetings MARCH ACR 5th Annual PET/CT Symposium March 1-4 • Stowe, Vermont For more information: www.acr.org

Society of Interventional Radiology 37th Annual Meeting March 24-29.San Francisco, California For more information: www.sirmeeting.org

4th ESMO Sarcoma and GIST Conference March 9-10 • Milan, Italy For more information: www.esmo.org Society for Thoracic Radiology Thoracic Imaging Meeting March 11-14 • Huntington Beach, California For more information: www.thoracicrad.org ACCC 38th Annual National Meeting March 12–14 • Baltimore, Maryland For more information: http://accc-cancer.org EPI2K12 March 12-14 • Sydney, Australia For more information: http://epi2K12.org 29th Annual Miami Breast Cancer Conference March 14-17 • Miami, Florida For more information: cancerlearning.onclive.com NCCN 17th Annual Conference March 14-18 • Hollywood, Florida  For more information: www.nccn.org

JULY Best of ASCO® Chicago July 12-13 • Chicago, Illinois

MAY

3rd Asian Breast Cancer Congress March 3-4 • Bangalore, India For more information: http://abcconline.net TAT 2012 (International Congress on Targeted AntiCancer Therapies) March 8-10 • Amsterdam, The Netherlands For more information: www.tatcongress.org

American Roentgen Ray Society Annual Meeting April 29-May 4 • Vancouver, Canada For more information: www.arrs.org

4th IMPAKT Breast Cancer Conference May 3-5 • Brussels, Belgium For more information: www.esmo.org

For more information: http://boa2012.asco.org Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information:

9th International Symposium on Ovarian Cancer and Other Gynecologic Malignancies March 30-31 • New York, New York For more information: http:// cancerlearning.onclive.com 5th Annual Interdisciplinary Prostate Cancer Congress March 31 • New York, New York For more information: http:// cancerlearning.onclive.com AACR 103rd Annual Meeting March 31-April 4 • Chicago, Illinois For more information: www.aacr.org

APRIL ASTRO Spring Refresher Course April 13-15 • Chicago, Illinois For more information: www.astro.org 35th National Conference on Breast Cancer April 13-15 • Hollywood, Florida For more information: www.acr.org 3rd European Lung Cancer Conference April 18-21 • Geneva, Switzerland For more information: www.esmo.org

Hematology/Oncology Pharmacy Association 8th Annual Meeting March 21-24 • Orlando, Florida For more information: www.hoparx.org

2nd Annual Stomach Cancer Education Symposium April 21 • Hollywood, Florida For more information: www.cantstomachcancer.org

65th Society of Surgical Oncology Annual Meeting March 21-24 • Orlando, Florida For more information: www.surgonc.org

American Radium Society Annual Meeting April 28-May 2 • Las Vegas, Nevada For more information: www. americanradiumsociety.org

ONS 37th Annual Congress May 3-6 • New Orleans, Louisiana For more information: www.ons.org State of the Art Techniques in IMRT, IGRT, SBRT, Proton and Brachytherapy May 4-6 • Las Vegas, Nevada For more information: www.astro.org

unmc.edu/panpacificlymphoma 13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer

Accelerating Anticancer Agent Development and Validation Workshop May 16-18 • Bethesda, Maryland For more information: www. acceleratingworkshop.org

Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the

AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org

JUNE ASCO Annual ’12 Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

AUGUST Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org 10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com UICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec, Canada For more information: www.worldcancercongress.org


ASCOPost.com  |   MARCH 1, 2012

PAGE 51

Calendar

SEPTEMBER Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org

17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/conference/17th_ICCN 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

OCTOBER ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information:  www.lynnsagebreastcancer

24th EORTC-NCI-AACR

17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com

Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information:

RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/

www.ecco-org.edu 32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org 3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org

Chemotherapy Foundation 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation​ symposium.org

DECEMBER

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology

Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com

Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

Pan Pacific

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com

2012

Lymphoma Conference

Tuesday-Friday

July 17-20, 2012

ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

NOVEMBER 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

Hyatt Regency Maui Resort & Spa Lahaina, Maui, Hawaii

A comprehensive conference by internationally recognized speakers presenting the most recent developments in lymphoma and transplantation.

Conference Directors James O. Armitage, MD

Joe Shapiro Professor of Medicine Division of Oncology and Hematology Department of Internal Medicine University of Nebraska Medical Center

Julie M. Vose, MD, MBA

Chief, Division of Oncology and Hematology Neumann M. and Mildred E. Harris Professor Department of Internal Medicine University of Nebraska Medical Center

CALL FOR ABSTRACTS: April 16, 2012

Scan code with your smartphone to learn more!

unmc.edu/panpacificlymphoma


American Society of Clinical Oncology

2012 Annual Meeting

June 1-5, 2012 | McCormick Place | Chicago, Illinois chicago2012.asco.org

Collaborating to Conquer Cancer

The ASCO Annual Meeting brings together more than 25,000 oncology professionals from a broad range of specialties, making it an excellent venue for exploring the theme of the Meeting — “Collaborating to Conquer Cancer.” Join us June 1-5 in Chicago to discover the latest in translational research and clinical trials, the impact of multidisciplinary care, the possibilities of real-time oncology knowledge, and the power of each and every patient interaction. Register today for the best rates and secure your housing reservation at chicago2012.asco.org.


ASCOPost.com  |   MARCH 1, 2012

PAGE 53

Expert’s Corner Patient–Clinician Relationship

A Patient with Cancer Saw a Need and Left a Living Legacy By Ronald Piana

response was to set up an organization that would advocate for, and advance methods to strengthen, the caregiver-patient relationship. Ironically, that is probably more of a key issue now than it was in 1995, when Kenneth Schwartz died.

Success Story

Richard T. Penson, MD, MRCP

I

t is well documented that the rigors of delivering cancer care can unintentionally supersede valuable doctor-patient communication. Before he died in 1995, Kenneth B. Schwartz, a patient with cancer at Massachusetts General Hospital, recognized this phenomenon and founded the Kenneth B. Schwartz Center, a nonprofit organization that sponsors the Schwartz Center Rounds, a forum dedicated to improving the special relationship between doctors and their patients. To gain insight into the Rounds, The ASCO Post spoke with long-time Rounds participant and advocate, Richard T. Penson, MD, MRCP, Clinical Director of Medical Gynecologic Oncology, Massachusetts General Hospital, Boston.

Origins of the Organization Can you give the readers some insight into the founder of the Schwartz Center? Kenneth Schwartz was a 40-yearold health advocacy lawyer with a 10-year-old son when he was diagnosed with advanced lung cancer. His journey as a patient with cancer, from diagnosis to death, reinforced his experience as an advocacy lawyer that the central place of compassionate care was being eroded from the medical profession. His

Who participates in the Rounds? Currently, there are about 50,000 clinicians and other medical staff who attend monthly Schwartz Rounds at 240 sites in 35 states— numbers that continue to grow, which is a pretty impressive rate of growth, given the organization’s 16year history. What are the factors that have made the Rounds so successful? A key to success is having effective leadership to rally the medical staff to attend the Rounds. Although there are various people from all spectra of medicine, from research scientists to clergy, much of the group’s initiative comes from clinicians. Hearing clinicians talk openly about caring for

Sample of Discussion Topics during Schwartz Rounds ■■ Caring for colleagues as patients ■■ Working with a difficult patient or family ■■ When is it time to stop palliative chemotherapy? ■■ Effect of culture and race on the patient’s experience ■■ Role of spirituality and miracles ■■ Burnout or compassion fatigue ■■ Medical mistakes care, but how to deliver compassionate care.

Personal Perspective On a personal level, how have the Rounds affected you? When I began my career in medicine, in my naiveté, I thought that everyone loved what he or she did. But as I got older, I noticed more burnout-associated problems. My guess is that all generations of clinicians face the same issues associated with long-term stress. It is very hard to deliver high-quality, cost-effective, and compassionate cancer care

Hearing clinicians talk openly about caring for people with life-threatening diseases ignites discussion about the emotional and social challenges faced by caregivers. —Richard T. Penson, MD, MRCP

people with life-threatening diseases ignites discussion about the emotional and social challenges faced by caregivers. Ultimately, clinicians speak frankly about their frustrations in seeing some of their patients show disease progression and treatment failure, but they also share clinical “pearls”—not just how to give outstanding cancer

Sample of Measured Benefits from Schwartz Rounds ■■ Improved communication with patients and family ■■ Increased insight into difficult social issues ■■ Improved knowledge of needs related to diverse cultures ■■ Greater sense of personal worth ■■ Better sense of belonging to a team with a common goal ■■ Appreciation for alternative approaches to hard psychosocial issues

over a long period without catching some of the emotional flack, or grieving over the losses. That’s a demanding characteristic of the profession. A popular software adage notes, “you can have it quick, cheap, or effective, but you can’t have all three.” And I think that’s also the case with today’s health care, in that we are all very concerned that the mounting pressures of providing cost-effective care will further distance the clinician from the patient. So these topics—being too busy, burnt out, or emotionally bruised—are some of the recurring themes visited during the Rounds.

Burnout in Oncology Burnout is an issue that has gotten better-deserved attention over the past

few years. How has it been addressed in the Rounds? We regularly raise issues surrounding burnout. Staff are a vital but vulnerable resource and can burn out under the incessant pressure of patient care. Sometimes we are overcommitted, overstretched, and just too busy. We often discuss issues that affect the whole care team—for instance, communicating with a team member who aggressively gives ineffective and costly care at the end-of-life. I’d say that burnout comes up as a subject every 3 or 4 months. The truth is that we are often preoccupied with the demanding medical aspects of our patients, their families, and our colleagues, and feelings of frustration, anger, and helplessness too often go unaddressed. I love my job, and it’s a tremendous privilege, but there is a definite human cost in cancer care. Every so often you need to renew the original passion that led you to becoming a doctor who cares for people with life-threatening illnesses, many of whom will die under your care.

Measuring Benefits As one who participates in Rounds, can you quantify any benefits from this model? Yes, in fact there’s been an external audit that found numerous benefits. For example, participants stated that Rounds discussions led to an increased ability to respond to patients’ social and emotional issues, which led to a greater sense of teamwork, more appreciation of their colleagues’ contributions, and a decreased sense of isolation and stress. Moreover, participants reported that Rounds often led to changes in institutional practices or policies. I think continued on page 54


The ASCO Post  |   MARCH 1, 2012

PAGE 54

Expert’s Corner

Schwartz Rounds

Impact on Career

continued from page 53

How have the Rounds affected your career? In medicine, there is the principle of “see one, do one, teach one,” and a recommendation that comes up during Schwartz Rounds can be a useful bit of guidance along those lines. In particular, physicians are often like

there are also measurable and sustained changes in behavior, but these have not been formally evaluated. Ultimately, the Rounds process benefits our patients by making us more aware of key issues, and fostering real support and connection between clinicians and patients.

well-intentioned amateurs when it comes to social, psychological, and spiritual issues. For me, being involved in Schwartz Rounds has served my patients and me by continuing to remind me why I’m doing this difficult but extremely rewarding work. One aspect of the Rounds that I’ve found particularly helpful in terms of

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

37%

inspiration is not so much connecting with patients with whom I already have a good rapport, but dealing with those who have very difficult problems and are hard to like. A couple of years ago during the Rounds, a psychiatrist gave this tip: Look into the difficult patient’s eyes and articulate something that you admire about that person. For instance, you could say, “With all that’s going on in your life, I really admire the way you’re able to…,” then fill in the blank. It works; it’s a small but meaningful way to show that you are giving them your full attention, and that you care. The Rounds have had a profound impact on my career because in solid tumor oncology we only cure a few, but we must care for them all. And to achieve that total care package, day after day, requires a committed self-renewal and reconnection with the patient. That is what Schwartz Rounds is all about.

changed

Disclosure: Dr. Penson has received research funding from Lilly, ImClone, Endocyte, AstraZeneca, Amgen, and Eisai. He has been on scientific advisory boards for Genentech, Biomarin, Lifecore Biomedical, and Clovis.

63% confirmed

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com. Treating pNET 22

|

Biosimilars in cancer treatment 37

|

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

T

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase  III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

T

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States. Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

O

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I thought he had Hodgkin disease, so I arranged a lymph node biopsy. I remember looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematologic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that others could not. To my surprise, he said this pathology was something he’d never seen before.

A small piece of information or a major breakthrough in one scientific discipline can translate valuable information into another scientific area.

—Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ................15, 24, 41, 49 53rd ASTRO Annual Meeting ............................. 8–11, 14, 30 AACR Basic Cancer Research Meeting ..................................... 39 AACR Conference on Cancer Health Disparities ..................................... 52 Direct from ASCO ....................................... 27

continued on page 20

A Harborside Press® Publication

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com


ASCOPost.com  |   MARCH 1, 2012

PAGE 55

Lab Notes

Ongoing Molecular Research in the Science of Oncology DRUG RESISTANCE PI3K Inhibitors May Improve Response to Cancer Immunotherapy The induction of antitumor immunity by vaccines or immunotherapies is inhibited by the immunosuppressive microenvironment of tumors. Toll-like receptor (TLR) agonists have the potential to increase inflammatory antitumor effects in the microenvironment, but these ligands can exert a mixture of both positive and negative effects on inflammation.

Tumor Growth and Survival Marshall and colleagues from Trinity College Dublin, Ireland, and Bioceros, Utrecht, The Netherlands, recently showed that small-molecule inhibitors of phosphoinositide 3-kinase (PI3K) reduce immunosuppression in tumor cells and increase the proinflammatory effects of TLR agonists that support antitumor immunity. In three different mouse models of cancer, the combination of a TLR5 agonist (flagellin) with a class I PI3K inhibitor delayed tumor growth and increased survival, with complete tumor rejection and resistance to secondary challenge being observed in some cases. Tumor growth suppression was associated with accumulation of polyfunctional T cells that produced effector cytokines including interferon (IFN)-α, interleukin (IL)-17, and IL-2. Mice deficient in IL-17 or IFN-α did not exhibit protection from tumor growth. The authors stated “[O]ur results indicate that PI3K inhibition heightens the antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor Tcell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy.”

Marshall NA, et al: Cancer Res 72:581591, 2012.

TARGETED THERAPY Significant Differences in Genetic Characteristics of Primary Colorectal Cancer and Hepatic Metastases Vermaat and colleagues from the University Medical Center Utrecht, Hubrecht Institute, Utrecht, The Netherlands, and Hoffman-La-Roche

Inc./Genentech, Nutley, New Jersey, recently showed that there was significant genetic variation between individual primary colorectal cancer tumors and their subsequent respective hepatic metastases. As stated by the authors, “In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters.” In their study, primary colorectal cancer tumors and their matched hepatic metastases were analyzed by targeted deep-sequencing of DNA isolated from formalinfixed, paraffin-embedded archived material from 22 patients. A total of 817 gene variants that potentially altered protein function were identified. Compared with the individual primary tumors, an average of 83 potentially function-impairing gene variations were gained and 70 variations were lost in the respective metastases.

Implications for Targeting Metastases Identified variations that could potentially influence response to therapy included novel and known variations in such genes as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, as well as aberrations in the upstream and downstream genes of EGFR/PI3K/VEGF pathways and other pathways (eg, mTOR, TGFβ). Samples from 11 patients who received chemotherapy between removal of the primary tumor and metastasis did not exhibit an increase in the amount of genetic variation. As noted by the investigators, the central implication of these findings is that “the choice of treatment in studies investigating targeted therapies [in metastatic disease] should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.”

Vermaat JS, et al: Clin Cancer Res 18:688-699, 2012.

Six1-Eya2 Interaction a Potential Target in Blocking Breast Cancer Metastasis The Six1 gene is a key regulator of embryonic development that requires interaction with the Eya family of proteins (Eya1-4) to activate transcription of genes involved in neurogenesis, myogenesis, and nephrogenesis. Overexpression of Six1 and Eya is observed in a number of cancers. In breast cancer, high levels of Six1 correlate with reduced time to relapse and metastasis and decreased survival only when high levels of Eya2 are also expressed.

Necessary Cofactor In a recent study, Farabaugh and colleagues from the University of Colorado, Aurora, showed that knockdown of Eya2 in MCF7 mammary carcinoma cells reversed the ability of Six1 to induce several pro-metastasis features, including TGF-β signaling and expression of characteristics associated with epithelial-mesenchymal transition (EMT, loss of cell-cell adhesion and an increase in cell mobility) and cancer stem cells. These findings suggest that that Eya2 is a necessary cofactor for the metastasis-promoting activities of Six1 and that targeting these factors may inhibit progression of breast cancer. The investigators noted that “[since] Six1 and Eya2 are not highly expressed in most adult tissues, the Six1-Eya interaction may be a valuable future therapeutic target whose inhibition would be expected to impair breast cancer progression while conferring limited side effects.”

Farabaugh SM, et al: Oncogene 31:552– 562, 2012.

COMBINATION THERAPY

mediated knockdown of DNA repair pathways showed that activated ataxia telangiectasia mutated (ATM), SEE PAGE 55 a kinase that normally repairs DNA breaks, was a crucial mediator of synergy. Activated ATM was relocalized to HSV DNA replication compartments, where it appeared to enhance oncogenic HSV replication and to be prevented from participating in repair of temozolomide-induced DNA damage. The combination of G47Δ and temozolomide prolonged survival of mice with glioblastoma stem cell–derived intracranial tumors, achieving long-term remission in four of eight mice at temozolomide doses attainable in patients. The investigators summarized their findings by stating “The combination of G47Δ and temozolomide acts synergistically in killing [glioblastoma stem cells] through oncogenic HSV-mediated manipulation of DNA damage responses. This strategy is highly efficacious in representative preclinical models and warrants clinical translation.”

Kanai R, et al: J Natl Cancer Inst 104:4255, 2012.

USING QR CODES

Combination of Oncolytic Virus and Chemotherapy Holds Promise in Glioblastoma Glioblastoma remains a uniformly lethal disease. Both the alkylating agent temozolomide and oncolytic viruses (engineered to preferentially infect and kill cancer cells) hold promise in treatment of glioblastoma. The effects of combining the two and the mechanisms of their interaction on cancer stem cells were recently investigated by Kanai and colleagues from Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Transgene, Strasbourg, France, and Fujita Health University, Toyoake, Japan. In their study, athymic mice with glioblastoma stem cell–derived glioblastoma tumors were treated with the oncolytic herpes simplex virus (HSV) G47Δ and temozolomide. The combination showed synergistic effects in killing glioblastoma stem cells, but not neurons, in association with robust induction of DNA damage.

Mediator of Synergy Studies with pharmacologic inhibitors and short-hairpin RNA (shRNA)–

1

2

3

4

When you see a code that you would like to scan, start your code-reading application.

Position your device in front of the code so that it fills about half your screen.

The code will scan automatically.

If the scan is successful, you will be rerouted to the targeted link.


ASCOPost.com  |   MARCH 1, 2012

PAGE 57

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Addition of Bevacizumab to Neoadjuvant Chemotherapy Increases Pathologic Complete Response Rate in HER2-negative Disease Two studies reported in The New England Journal of Medicine showed that the addition of bevacizumab (Avastin) to neoadjuvant chemotherapy significantly increased the pathologic complete response rate in women with HER2-negative breast cancer. In one study, from the German Breast Group, the benefit was restricted primarily to patients with triple-negative tumors (estrogen receptor–negative, progesterone receptor–negative, and HER2-negative). The other study, from the National Surgical Adjuvant Breast and Bowel Project (NSABP), however, found that the greatest benefit was in patients with hormone receptor–positive disease.

German Breast Group Study The German Breast Group reported the results from 1,948 patients with previously untreated primary invasive breast cancer enrolled in the HER2-negative components of the larger GeparQuinto phase  III study. The patients were randomly assigned to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. “All patients who re-

ceived at least one cycle of epirubicin and cyclophosphamide were included in the efficacy and safety analyses,” the authors noted. Overall, the rates of pathologic complete response were 14.9% without and 18.4% with bevacizumab (P = .04), but among the 663 patients women with triple-negative disease, the corresponding rates of pathologic complete response were 27.9% without and 39.3% with bevacizumab (P = .003). For the 1,262 patients with hormone receptor–positive tumors, the rates of pathologic complete response were 7.8% without and 7.7% with bevacizumab (P = 1.0). “Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand–foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications,” the investigators reported. “Because of the short follow-up period, we cannot confirm that the observed increases in the rate of pathological complete response translate into a survival advantage. However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effect will be sustained,” the investigators said.

NSABP B-40 Study NSABP B-40 found that among women with operable HER2-negative breast cancer receiving neoadjuvant chemotherapy, the addition of bevacizumab to treatment significantly increased the rate of pathologic complete response (28.2% without bevacizumab vs 34.5% with bevacizumab, P = .02). The patients, totaling 1,206, had been randomly assigned to receive neoadjuvant therapy with either docetaxel, docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine, with all regimens followed by treatment with doxorubicin/cyclophosphamide. One-half of patients were also randomly assigned to receive bevacizumab at a dose of 15 mg/kg for the first six cycles of chemotherapy. “The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs 32.7%; P = .69),” the authors reported. Both capecitabine and gemcitabine were associated with hand–foot syndrome, mucositis, and neutropenia, while “bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis,” the authors wrote. When the pathologic complete response rate was examined according to hormone-receptor status, “the effect of bevacizumab was more pronounced in the hormone-receptor–positive subset (15.1% without bevacizumab vs 23.2% with bevacizumab, P = .007), with a weaker effect in the hormone receptor–negative subset (47.1% without bevacizumab vs 51.5% with bevacizumab, P = .34),” the researchers reported.

Disparity between Trials

© Michael Crawford / The New Yorker Collection / www.cartoonbank.com

“It is unclear why the greatest benefit from adding an antiangiogenic agent was seen in patients with hormone receptor–positive tumors, in contrast to the findings” from the German Breast Group trial, where “the benefit was confined to patients with hormone receptor–negative tumors,” the NSABP investigators stated. “The disparity in the results of the two trials may be related to differences in the inclusion criteria and the study design, particularly the inclusion in the GeparQuinto trial

of patients with more advanced disease, a different sequencing of drug regimens in the GeparQuinto SEE PAGE 55 trial than that in our trial, and the withdrawal from the GeparQuinto study of patients who did not have a response to the initial four cycles of treatment.” The German investigators generally concurred that these differences could have contributed to the divergent results despite many similarities in the NSABP B-40 and GeparQuinto trials, “including the fact that the median tumor size at baseline was similar in the two trials.”

von Minckwitz G, et al: N Engl J Med 366:299-309, 2012. Bear HD, et al: N Engl J Med 366:310320, 2012.

UTERINE CANCER Nearly Identical Survival for Laparoscopy vs Laparatomy in Patients with Stage I/IIA Disease Building on previously reported results that laparoscopic surgical management of uterine cancer is superior for short-term safety and length-of-stay endpoints, the Gynecologic Oncology Group reported small and lower than anticipated potential for increase risk of cancer recurrence with laparoscopy vs laparotomy. The estimated 3-year recurrence rate was 11.4% with laparoscopy vs 10.2% with laparotomy, a difference of 1.14% for patients with clinical stages I to IIA disease enrolled in the Laparoscopic Surgery or Standard Surgery in Treating Patients with Endometrial Cancer or Cancer of the Uterus (LAP 2) study. The results were reported in the Journal of Clinical Oncology. Patients in the study were randomly allocated 2:1 to laparoscopy (n = 1,696) or laparotomy (n = 920) for hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The primary study endpoint was “noninferiority of recurrence-free interval defined as no more than a 40% increase in the risk of recurrence with laparoscopy compared with laparotomy,” the authors explained. At a median follow-up of 59 continued on page 58


The ASCO Post  |   MARCH 1, 2012

PAGE 58

In the Literature

Emerging Clinical Data continued from page 57

months, there were 210 recurrences and 229 deaths in the laparoscopy group, compared with 99 recurrences and 121 deaths in the laparotomy group. “The estimated 5-year overall survival was almost identical in

both arms at 89.8%,” the authors reported.

Implications of Results “These results do not demonstrate a survival decrement from laparoscopy, which allows patients and surgeons comfort in choosing the

less morbid procedure. The conversion to laparotomy when adequate surgical staging cannot be completed laparoscopically allows for completion of surgical staging without compromising the patient,” the authors concluded. “The results of this trial cannot be generalized to the use of

laparoscopic hysterectomy without lymphadenectomy, because thorough surgical staging was required in both arms of this trial, and conversion was required when lymphadenectomy could not be completed using laparoscopy,” they added. “On the basis of the LAP2 study one can reasonably conclude that there is not a substantial increase in recurrence rates with laparoscopic surgery. However, because the study did not achieve noninferiority, it is important to not dismiss the possibility that a small difference may actually exist,” according to an editorial accompanying the article. “Other trials of minimally invasive surgery are ongoing, and although they are not identical in study design to LAP2, it is hoped that these will provide additional reassurance.” The authors continued, “gynecologic oncologists should continue to consider ways in which minimally invasive surgery for endometrial cancer can be conducted to minimize the potential for dissemination of disease.”

Ongoing Debate

CONQUERING

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s pre-eminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

ConquerCancerFoundation.org

The editorial also pointed out that robotic surgery for endometrial cancer “may be easier to master, is less dependent on the availability of a trained assistant, and has ergonomic advantages for the surgeon” compared to laparoscopic surgery. “Those who are facile with both approaches say that the robot is particularly helpful in morbidly obese patients, in whom exposure and the facility of laparoscopic instruments are compromised. Conversely, robotic surgery typically takes longer than laparoscopy, and expense is also increased by the high cost of the robot, its maintenance, and disposable instruments,” the editorialists wrote. “The debate regarding the appropriate roles of laparoscopy and robotics in training programs and in practice is ongoing. Both confer major advantages relative to open surgery, and minimally invasive surgical approaches are still evolving and can be expected to continue to improve in the future,” the authors concluded. (See page 45 for more on robotic surgery.)

Walker JL, et al: J Clin Oncol. January 30, 2012 (early release online). Berchuck AB, et al: J Clin Oncol. January 30, 2012 (early release online).


ASCOPost.com  |   MARCH 1, 2012

PAGE 59

Patient’s Corner

Facing the Future without Fear of Breast Cancer Recurrence Faith in God and my doctors keeps me positive about what may lie ahead. By Sonia Ray, as told to Jo Cavallo

A

year ago, I was living my dream. Married to a wonderful man, Danny, and with two young children to raise, Karl, 7, and Marcus, 4, I had given up a career in accounting to be a stay-at-home mom. At age 34, I was enjoying life, helping my children with their homework and going to their soccer and baseball games. I wasn’t expecting to have to face a life-threatening illness. But when I felt a lump in my left breast, I knew instinctively that something was wrong. Although there’s no history of breast cancer in my immediate family, I have always had fibrocystic breasts and was diligent about performing regular breast self-exams. This time the lump felt different and it hurt. Because of my age and picture-perfect good health, my gynecologist initially dismissed my concern, saying that he didn’t think the lump was anything to worry about and that he would check it again in a year. But as another 4 weeks passed and the pain in my breast persisted, I decided to take control and insisted that I have a mammogram.

test results, the news wasn’t going to be good. He said that I had a 5-cm mass in my left breast and that he was sure it was cancer. A subsequent biopsy confirmed that I had stage III, grade 3, HER2-positive infilitrating ductal carcinoma. After allowing myself to feel all the emotions brought on by this diagnosis, I was ready to fight the cancer head on. I was given four rounds of a cocktail of doxorubicin and cyclophosphamide, plus 12 courses of a combination of trastuzumab (Herceptin) and paclitaxel to shrink my tumor, and then I had a lumpectomy. Unfortunately, the pathology report showed cancer cells

without breasts, I was still the same person. I still had a life I loved and young children to raise, and I wanted to do whatever was necessary to get back to good health.

Importance of Faith From the moment of my diagnosis and throughout my treatment, I explained everything that was happening to my children so they wouldn’t be afraid. I told them the medication I had to take to kill the bad cells in my body would make my hair fall out, and even let Karl shave my head to take away the seriousness of the situation.

I let myself grieve over the loss of my breasts, and then I decided that with or without hair and with or without breasts, I was still the same person. —Sonia Ray

present around the tissue margins, so I decided to have a mastectomy and a contralateral prophylactic mastectomy, plus 33 doses of adjuvant radiation to get rid of any errant malignant cells. Before going through with the treatment, I let myself grieve over the loss of my breasts, and then I decided that with or without hair and with or

Ready to Fight Having accompanied my mother to her mammogram screenings, I knew that when the radiologist came into the exam room after looking over my

Although the pathology report from my double mastectomy showed that this time the margins around the tissue were clear, there was rapid cell growth in the blood vessels of the specimen. Despite this setback, and throughout the whole cancer journey, I’ve never lost faith in God or in my doctors,

Sonia Ray

confident that I am completely healed. I’ve been blessed to have a wonderful family that encourages me, and a terrific team of physicians and nurses who treat me like a member of their family and not just another “chart.” Having that level of personalized care has made a huge difference in how I perceive my cancer and my prospects for the future because I can sense their passion in wanting to keep me well, and I’m grateful. I know my future holds great things for me, and rather than get stuck in the now, I’m planning this year’s summer vacation and my children’s ongoing school curriculum. I refuse to let the fear of a cancer recurrence take over my life.

Sonia Ray lives in Rex, Georgia.

Coming in Future Issues of The ASCO Post Treating pNET 22

|

Biosimilars in cancer treatment 37

|

VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

Important Oncology News from:

■■ National Comprehensive Cancer Network 17th Annual Conference

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

T

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase  III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

T

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States. Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

O

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I thought he had Hodgkin disease, so I arranged a lymph node biopsy. I remember looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematologic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that others could not. To my surprise, he said this pathology was something he’d never seen before.

A small piece of information or a major breakthrough in one scientific discipline can translate valuable information into another scientific area.

—Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ................15, 24, 41, 49 53rd ASTRO Annual Meeting ............................. 8–11, 14, 30 AACR Basic Cancer Research Meeting ..................................... 39 AACR Conference on Cancer Health Disparities ..................................... 52 Direct from ASCO ....................................... 27

continued on page 20

A Harborside Press® Publication

■■ 2012 Gastrointestinal Cancers Symposium ■■ 2012 Genitourinary Cancers Symposium Plus:

■■ Original Columns and Perspectives from Oncology Leaders ■■ Conversations with Experts About Important Issues in Cancer Care ■■ Special Features on Cost of Cancer Care and Personalized Medicine

Visit The ASCO Post online at ASCOPost.com.


Approved in 3 indications

2.5mg 5mg 10mg

Š2011 Novartis

09/11

AFI-1031818


TAP Vol 3 Issue 4