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ASCO Plenary Reports 1, 24

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Novel agents in ovarian cancer 10

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VOLUME 2, ISSUE 10

Lifestyle and cancer 11

JULY 1, 2011 ASCOPost.com

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

2011 ASCO Plenary Report

Novel Agents Improve Survival in Patients with Metastatic Melanoma

On William Osler: the Old Art and the New Science

Melanoma studies were the newsmakers at ASCO 2011. By Caroline Helwick

By Marvin J. Stone, MD, MACP

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ovel treatments for metastatic melanoma dominated the buzz at the 2011 ASCO Annual Meeting and across the major news outlets, with reports that two agents with entirely different mechanisms of action could extend survival. The studies’ inclusion in the ASCO Plenary Session attested to the significance of the findings, which clearly could alter the care of patients who historically had poor survival.

ease “is really a huge step toward personalized care in melanoma,” said Dr. Chapman. Marc S. Ernstoff, MD, of Dartmouth-Hitchcock Medical Center in New Hampshire, commented in an editorial accompanying the publication, “The results…represent a major shift in the way we think about and treat melanoma…For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an imporBRAF Inhibitor Hits the Mark tant effect on survival and quality of life.”3 In an international phase III trial, The open-label BRAF Inhibitor in targeting of the BRAF V600E mutation Melanoma (BRIM-3) trial evaluated vePaul Chapman, MD murafenib compared to standard treatwith the orally administered agent vemurafenib (PLX4032) led to a 63% reducment with dacarbazine in 675 patients tion in the risk of dying of melanoma, reported Paul with inoperable, previously treated stage IIIC or IV Chapman, MD, of Memorial Sloan-Kettering Cancer metastatic melanoma harboring a V600E mutation. Center in New York.1 The study was published online This abnormality in the BRAF gene is present in concurrently in The New England Journal of Medicine.2 about half of all melanoma patients. continued on page 2 An improvement in the survival of advanced dis2011 ASCO Plenary Report

Longer Imatinib Treatment Is Better in High-risk GIST By Caroline Helwick

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phase III trial presented at the ASCO 2011 Plenary SesAdjuvant Imatinib in Resected High-risk GIST sion could change the duration of adjuvant therapy for some patients ■■ Giving 3 years of adjuvant imatinib improved outcomes over 1 year of the drug in patients with operable high-risk GIST. with resected gastrointestinal stromal tumors (GIST). ■■ Recurrence-free survival at 5 years was 65.6% with 3 years of When imatinib treatment was treatment, compared to 47.9% with 1 year of imatinib. extended to 3 years, compared ■■ Risk of death was reduced by 55% with 3 years of treatment. with the standard 1 year, patients with high-risk GIST were 54% dard will be 3 years of adjuvant imatinib in the near less likely to have a recurrence and 55% less likely to future.” die within 5 years, according to results presented by Mark G. Kris, MD, Chair of the ASCO Cancer Heikki Joensuu, MD, of Helsinki University Central 1 Communications Committee, agreed. Moderating a Hospital in Finland. press briefing, Dr. Kris said, “I think the entire oncol‘Compelling’ Data ogy community was extremely excited when we saw “These data are pretty compelthat survival curve and those numbers at 5 years. It’s ling,” Dr. Joensuu commented. “I one of the amazing stories in oncology…. This is the SEE PAGE 39 continued on page 8 would not be surprised if the stan-

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illiam Osler (1849–1919) is one of the most revered physicians in the history of medicine. He was an outstanding clinician who emphasized bedside teaching, hard work, medical history, and lifelong learning.1 As Professor of Medicine at four institutions in three countries, he exerted a profound influence on medical education. A prolific writer, his textbook became the most popular and widely read treatise on medicine in the world. Osler blended the art and science of medicine perhaps as well as anyone and remains a valuable role model for students and physicians. Osler’s career had an impact on many branches of medicine, including the fields of hematology and oncology. Osler learned to use the microscope as a schoolboy. His first publication, entitled Christmas and the Microscope, appeared in continued on page 4

Dr. Stone is Director of Oncology Medical Education, Quality & Safety and Associate Director of the Baylor Charles A. Sammons Cancer Center, Dallas.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 ASCO Annual Meeting �������������1, 5, 10, 11, 24, 35, 37 11th International Conference on Malignant Lymphoma����������������������� 12 Direct from ASCO��������������������������������������� 16 Cardio-oncology������������������������������������������ 28 Investigational Agents��������������������������������� 33 FDA Update�������������������������������������������������� 36 Patient’s Corner�������������������������������������������� 39

A Harborside Press® Publication


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News

Metastatic Melanoma continued from page 1

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

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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

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

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Contributing Writers: Charlotte Bath, Jo Cavallo, Margot J. Fromer, Alice Goodman,

Caroline Helwick, Ronald Piana, Larry J. Rosenberg, PhD, Matthew Stenger, Marian Wiseman

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

Immunotherapy Drug Also Improved Survival

In the first interim analysis, progresThe immune-stimulating monosion-free survival was 5.3 months with clonal antibody ipilimumab (Yervoy) vemurafenib vs 1.6 months with dacaralso produced solid results indicative bazine, for a 74% reduced risk of proof benefit in the first-line metastatic gression. Estimated overall survival at setting.4 Ipilimumab blocks CTLA‑4 and thus augments T-cell activation. 6 months was 84% vs 64%, respectiveThe drug was approved by the FDA in ly (Fig. 1), and the risk of dying was March 2011 for the second-line treatreduced by 63%, which was highly sigment of metastatic melanoma. The nificant. Overall and progression-free current study confirmed its activity as survival benefits were observed across a first-line agent for metastatic disease. all subgroups, Dr. Chapman reported. Study 024 includVemurafenib also ed 502 patients with led to a significantly Vemurafenib is untreated metastatic higher response rate melanoma randomly than dacarbazine: the first single drug assigned to dacarba48.4% vs 5.5%. for melanoma to zine (8 cycles) plus The study was ipilimumab (every halted very early to improve response 3 weeks for 4 cycles, allow the control rate, progressionthen every 12 weeks) arm to immediately or dacarbazine cross over to active free survival, and alone. Median overtherapy. Median overall survival all survival was 11.2 follow-up was only months with ipilim3 months at the compared to standard umab/dacarbazine time of the analysis, chemotherapy. vs 9.1 months with and median overdacarbazine alone, all survival has not which was a highly been reached in the significant 28% reduction in the risk vemurafenib arm, he added. of dying of melanoma (P = .0009), re“Vemurafenib is the first single ported Jedd Wolchok, MD, of Memodrug for melanoma to improve rerial Sloan-Kettering Cancer Center, New sponse rate, progression-free survivYork. Like the BRIM‑3 trial, this study al, and overall survival compared to was also published concurrently online.5 standard chemotherapy,” he noted. At 1 year, 47.3% of the ipilimumab/ “It is a promising new therapy for padacarbazine group was alive, compared tients with metastatic BRAF V600E– with 36.3% of the control group. The mutated melanoma and a foundation survival rate at 2 years was 28.5% vs upon which to build combination 17.9%, and at 3 years was 20.8% vs therapies.” 12.2%, respectively (Fig. 2). He added that many patients have Many responses are durable, he durable remissions while on vemuadded. Median duration of response rafenib, and the hope is that these will was 19.3 months with ipilimumab/ translate into long-term survival. dacarbazine compared to 8.1 months Although adverse events were genwith dacarbazine. erally mild (approximately 10% grade “This is the second randomized ipili3+ toxicity), dose interruption or mumab phase III trial to show a signifimodification was required in 38% of cant survival improvement in metastatic patients. Vemurafenib is now available melanoma,” Dr. Wolchok noted. Further in an expanded access program, and development is ongoing in the adjuvant FDA approval is expected for patients setting, with alternative combination with BRAF mutations.

Novel Agents in Melanoma ■■ In the first-line metastatic melanoma with mutated BRAF setting, the BRAF inhibitor vemurafenib reduced risk of death by 63% and risk of disease progression by 74%.

■■ Also as a first-line treatment, ipilimumab and dacarbazine reduced risk of

death by 28% with mature follow-up (3 years) and durable responses (19.3 vs 8.1 months).

■■ Both regimens were compared with dacarbazine. ■■ The drugs work by different mechanisms and have different toxicity profiles.


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2011 ASCO Annual Meeting Fig. 1: Overall survival in BRIM-3 trial. Reprinted with permission from Chapman PB, et al.2 Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Fig. 2: Overall survival in Study 024. Reprinted with permission from Robert C, et al.5 Copyright © 2011 Massachusetts Medical Society. All rights reserved.

regimens, in different doses and schedules, and in different cancer types.

Financial Disclosure: Dr. Wolchok serves as a consultant for Bristol-Myers Squibb. Dr. Chapman has received consultation fees from Roche/Genentech and GlaxoSmithKline. Dr. Ernstoff reported institutional grants open or pending from Roche and GlaxoSmithKline.

References 1. Chapman PB, Hauschild A, Robert C, et al: Phase III randomized, open-label multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAFmutated melanoma. 2011 ASCO Annual Meeting. Abstract LBA4. Presented June 5, 2001. 2. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. June 5, 2011 (early release online). 3. Ernstoff MS: Been there, not done that—melanoma in the age of molecular therapy. N Engl J Med. June 5, 2011 (early release online). 4. Wolchok JD. Thomas L, Bondarenko I, et al: Phase III randomized study of ipilimumab plus dacarbazine vs DTIC alone as first-line treatment in patient with unresectable stage III or IV melanoma. 2011 ASCO Annual Meeting. Abstract LBA5. Presented June 5, 2011. 5. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. June 5, 2011 (early release online).

Expert Point of View

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iscussing the melanoma studies at the Plenary Session, Kim Margolin, MD, of the University of Washington Fred Hutchinson Cancer Research Center in Seattle, noted that while the new therapies are welcomed, they are not without their challenges. “Ipilimumab now shows a survival benefit in first-line therapy, compared with [dacarbazine]… Checkpoint blockade—ie, enhancement of autologous antitumor immune responses— works!” she noted. “And vemurafenib, which is a transformation advance based on a rational approach to melanoma molecular biology, showed a survival benefit in the first-line setting as well,” she said. “Regression was seen in over 80% of patients. There was rapid relief of symptoms, median progression-free survival of 7 months, and an early survival benefit.” She added that in other studies, for

peutic advantage to the chemotherapy component, there is no reason to use these drugs together,” she noted. With vemurafenib the problems include cutaneous toxicity, gastrointestinal upset, and arthralgias. Skin toxicities include hyperkeratotic follicular Notable Toxicities eruption, extreme sun These treatments were sensitivity, tender calluses Kim Margolin, MD of the extremities, squanot without side effects, however. Notable adverse mous cancers, and keratoevents with ipilimumab are hepato- acanthomas. toxicity, endocrine abnormalities, and immune-mediated adverse reactions, Optimizing Clinical Use The issue in the clinic is how to for which ipilimumab already carries a “black box” warning. Grade 3/4 in- best use these new agents, Dr. Margocreases in liver enzymes were observed lin said. The BRAF inhibitor might be prescribed for immediate cytoreducin approximately 20% of patients. “In view of the increased hepatotox- tion and symptom relief, or possibly icity with ipilimumab and dacarbazine as a bridge to other therapies, ie, surin combination, and the lack of thera- gery or radiotherapy, she suggested. In

a subset of patients with progressive disease in limited sites, continuation of vemurafenib treatment beyond progression was shown to be potentially beneficial after local therapy.1 Relapse may be different than in other therapies, she said.

contrast, ipilimumab works at a slower pace and might be the first option for a patient with less tumor burden and fewer symptoms. “The goal is durable benefit,” she said. “Definitive progression would trigger a switch to vemurafenib.” “Both agents require experience and commitment by the physician and patient to manage these unique toxicities,” she added. Future investigations will evaluate the combination of vemurafenib and ipilimumab.

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

Reference 1. Kim KB, Flaherty KT, Chapman PB, et al: Pattern and outcome of disease progression in phase I study of vemurafenib (RG7204) in patients with metastatic melanoma. 2011 ASCO Annual Meeting. Abstract 8519. Presented June 6, 2011.


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Perspective

On William Osler continued from page 1

1869. While still a medical student, his first clinical paper described the gross and microscopic findings in a patient with breast cancer. By the time he received his MD degree from McGill University, Osler was an accomplished microscopist. He used this skill to great advantage in postgraduate studies and became a staunch advocate of the value of the microscope

William Osler in Montreal, 1909.

in medicine. Osler taught microscopy to medical students at McGill, brought the first microscope to the University of Pennsylvania Hospital, and established the Clinical Microscopy Laboratory at Johns Hopkins.

Achievements in Hematology and Oncology Osler’s contributions to hematology and oncology, although only a small portion of his massive legacy, were indeed substantial.2 He was among the first to recognize platelets as the third formed element in the blood and

identified their role in thrombosis. He made important contributions to the study of pernicious anemia including observations on gastric atrophy and description of characteristic red cell morphologic changes in peripheral blood and bone marrow. Osler’s description of polycythemia vera in 1903 was a landmark report that led to an increased diagnosis of this entity. The same was true of his clinical description of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). After some missteps, Osler confirmed Laveran’s description of organisms in the blood of patients with malaria and helped convince the medical community of their diagnostic importance. Moreover, in Philadelphia and later in Baltimore, blood films were examined in all cases of fever and then routinely. Osler performed over 1,000 autopsies. His knowledge of gross and microscopic pathology provided him with broad understanding of the natural history of disease. Osler’s monographs on abdominal tumors and cancer of the stomach were key clinical contributions to the literature.3,4 His lectures on abdominal tumors, delivered in 1893, summarized 67 cases with extensive clinical as well as surgical and autopsy findings. Osler and Thomas McCrae reviewed 150 cases of cancer of the stomach seen at Johns Hopkins in an encyclopedic fashion. Surgery was often recommended for definitive diagnosis and early treatment. The close interaction between Osler and William Halsted at Johns Hopkins was perhaps one of the earliest examples of multidisciplinary management, which has proved to be such a valuable approach in oncology. “To attain the best possible results the physician and surgeon

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0905. Copyright ©2011 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $225; Individual International: $275; Institutional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

must cooperate.”4 Osler made another contribution that surely surpassed all of his others: Ever the clinician microscopist, he introduced diagnostic microscopy into North American medicine. Laboratory observations were an extension of those made at the bedside. Proficiency with the microscope was considered as important as accurate auscultation. Osler brought the microscope to the clinic, enabling physicians to arrive at precise diagnoses and rational therapy for patients. The impact of clinical microscopy had an important role in defining etiology and pathogenesis of blood disorders and solid tumors.

Closing Thoughts What if Osler were alive today? He would no doubt continue to underscore the importance of hard work, close observation, a practical approach to the day’s activities, and ongoing education. Osler welcomed advances in medicine and quickly

applied them to the care of his patients—whether it was the use of newly described stains in interpretation of blood smears or urging the Johns Hopkins Board to acquire an x-ray machine within a few months of Roentgen’s discovery. It seems likely Osler would be squarely in the forefront of today’s progress in scientific medicine. But he would constantly remind us that “the old art cannot possibly be replaced by, but must be absorbed in, the new science.”

References 1. Bliss M: William Osler: A Life in Medicine. New York, Oxford University Press, 1999. 2. Stone MJ: William Osler’s legacy and his contribution to haematology. Brit J Haematol 123:3-18, 2003. 3. Osler W: Lectures on the Diagnosis of Abdominal Tumors. New York, D. Appleton & Co, 1899. 4. Osler W, McCrae T: Cancer of the Stomach. Philadelphia, Blakiston, 1900.

Lessons for Today

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any of Osler’s precepts and teachings are as applicable today as they were a century ago. Their universality and timeless relevance are guideposts. Some of his frequently cited aphorisms include: ■■ “In the physician or surgeon no quality takes rank with imperturbability.” ■■ “Care more particularly for the individual patient than for the special features of the disease.” ■■ “Now the way of life that I preach is a habit to be acquired gradually by long and steady repetition. It is the practice of living for the day only, and for the day’s work. Life in day-tight compartments.” ■■ “The best doctor, like the successful general, is the one who makes the fewest mistakes.” ■■ “To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease—these are our ambitions.”

Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; email: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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


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2011 ASCO Annual Meeting Investigational Agents

Iniparib Fails to Improve Outcomes in Triple-negative Breast Cancer Results are at odds with earlier positive findings. By Caroline Helwick

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s reported in the March 15 issue of The ASCO Post, a phase III trial of the novel agent iniparib failed to demonstrate a significant improvement in survival for women with metastatic triple-negative breast cancer. The “top-line” results were communicated in the spring via press releases from Sanofi-aventis and BiPar Sciences, but the full results were withheld until the ASCO Annual Meeting.

boplatin to 12.3 months with the addition of iniparib. The blockbuster-level findings fueled anticipation over the results of

the phase III trial presented by Joyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center, Texas Oncology, and US Oncology in Dallas.2

Study Data The study randomly assigned 519 women with stage IV triple-negative continued on page 6

NOW APPROVED PREPARE FOR A NEW OPTION

Joyce O’Shaughnessy, MD

Iniparib provokes cell-cycle arrest in the G2/M phase and induces double-strand DNA damage but does not inhibit poly (ADP-ribose) polymerase (PARP) 1 and 2 at physiologic drug concentrations—though it is often referred to as a PARP inhibitor. In the previous randomized phase II study,1 the addition of iniparib to gemcitabine/ carboplatin therapy improved response rates, progression-free survival, and overall survival in 123 women with metastatic triple-negative breast cancer. Overall survival, in fact, nearly doubled, from 7.7 months with gemcitabine/car-

Iniparib in Metastatic Triple-negative Breast Cancer ■■ Randomized open-label

phase III trial failed to uphold the benefits seen in the previous phase II study.

■■ Iniparib combined with

gemcitabine/carboplatin numerically improved progression-free and overall survival, but the differences were not statistically significant.

■■ Patients treated in the second or third line appeared to obtain the most benefit from iniparib, in an exploratory analysis.

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.

Important Safety Information Contraindications ZYTIGA™ may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Warnings and Precautions 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. Safety has not been established in patients with LVEF < 50% or NYHA Class III or IV heart failure. 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) has been reported in clinical trials 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 or if the patient experiences unusual stress. 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). 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. Adverse Reactions The most common adverse reactions (≥ 5%) reported in clinical trials were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia 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.

Please see adjacent page for Brief Summary of full Prescribing Information. Contact your Centocor Ortho Biotech Sales Representative for more information.

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2011 ASCO Annual Meeting Triple-negative Breast Cancer continued from page 5

breast cancer to gemcitabine/carboplatin or to gemcitabine/carboplatin/ iniparib. The coprimary endpoints were progression-free and overall survival, and the study was considered positive if either endpoint was met.

Due to the use of two primary endpoints, P values of .04 for overall survival and .01 for progression-free survival were required to prove statistical significance. The arms were well balanced except for a shorter disease-free interval after first-line treatment

in the three-drug arm (9.5 vs 15.9 months), but the difference in disease-free interval between the two arms in the overall population was not significant. At the time of the primary analysis, 96% of the gemcitabine/carboplatin arm had crossed over to receive iniparib.

ZYTIGA™ (abiraterone acetate) 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 Y3294ALT_Island_7x10_v1 2

In the intent-to-treat population, median progression-free survival was 5.1 months in the gemcitabine/carboplatin/iniparib arm vs 4.1 months with gemcitabine/carboplatin (P = .027), which was a 21% reduction in risk that did not meet the prespecified continued on page 8

ZYTIGA™ (abiraterone acetate) 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, 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]. 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 4.2 23.4 4.1 Joint swelling/discomfort2 29.5 26.2 3.0 23.1 2.3 Muscle discomfort3 General disorders 26.7 1.9 18.3 0.8 Edema4 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 Cardiac disorders 7.2 1.1 4.6 1.0 Arrhythmia5 Chest pain or 3.8 0.5 2.8 0 chest discomfort 6 2.3 1.9 1.0 0.3 Cardiac failure7 1 2 3 4 5

6

7

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 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 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). Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 5/20/11 11:13 AM


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2011 ASCO Annual Meeting Expert Point of View

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he discussant of the iniparib data (abstract 1007), Lisa A. Carey, MD, Medical Director of the University of North Carolina Breast Center, noted that the phase  II results pro-

voked “great enthusiasm and high expectations from doctors and patients” but the primary statistical endpoint was not met. “There was a numerical signal in favor of iniparib, but the ef-

fect size was small,” she noted. “Even if it is real, is a 1-month advantage in progression-free survival and less than 1 month in overall survival clinically meaningful?”

ZYTIGA™ (abiraterone acetate)

ZYTIGA™ (abiraterone acetate)

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.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Toronto, Canada

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Y3294ALT_Island_7x10_v1 3

Manufactured for: Centocor Ortho Biotech Inc. Horsham, PA 19044 Issued: April 2011 08Z11008

The exploratory analysis, in which adjustment for baseline differences in disease-free interval marginally improved the P value, is “interesting and hypothesis-generating,” she added. While the two trials and their populations were quite similar, baseline differences may have figured into the inconsistent re-

Lisa A. Carey, MD

sults—for example, the proportions of BRCA-mutated tumors and atypical molecular profiles within the groups are unknown, she said. “Triple-negative eligibility enriches for subtypes of biologic interest but will misclassify some,” she pointed out. “However, we have no reason to think this happened in a differential manner across the two trials,” she added. Importantly, gemcitabine/ carboplatin is probably not the preferred backbone regimen for triple-negative breast cancer.

Lessons Learned “We have learned from this study that the role and mechanism of iniparib is still a work in progress, and clinical activity is less than predicted; that triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition; and that gemcitabine/ carboplatin as a chemotherapy backbone has modest activity,” she said. While further study of this interesting and rather nontoxic drug is underway, as is a search for relevant biologic pathways within triple-negative breast cancer, conventional chemotherapy remains the mainstay of treatment, according to Dr. Carey.

Financial Disclosure: Dr. Carey has served as an uncompensated consultant or advisor for Genentech, GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis, ScheringPlough, and Wyeth.

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2011 ASCO Annual Meeting High-risk GIST continued from page 1

kind of data that does change guidelines.” SSGXVIII was an open-label phase III study that evaluated 36 vs 12 months of adjuvant imatinib at 400 mg daily after resection in 400 patients with GIST who were considered at high risk of recurrence by tumor size, mitosis count, or tumor rupture at surgery. The dose could be reduced for toxicity.

Heikki Joensuu, MD

At a median follow-up of 54 months, the intent-to-treat analysis found recurrences or death in 50 (25%) of 198 patients receiving 36 months of imatinib compared to 84 (42%) of 199 patients receiving 12 months of the drug. This yielded a recurrence-free survival rate of 86.6% at 3 years and 65.6% at 5 years, respectively, compared to 60.1% and 47.9% with 12 months of treatment (HR = 0.46; P < .0001), Dr. Joensuu reported. “Resistance was not a big problem

Triple-negative Breast Cancer continued from page 6

alpha (P = .01). Median overall survival was 11.8 vs 11.1 months, for a 12% risk reduction (P = .28). Overall response rates were 34% vs 30%, and clinical benefit rates were 41% and 36%, respectively, Dr. O’Shaughnessy reported. Fifty-one percent of patients received gemcitabine/carboplatin/iniparib treatment in the first-line setting, and an exploratory analysis of this subgroup mirrored the overall results. However, the iniparib-containing triplet given second- or third-line to 43% of patients

in the current study,” he observed. The overall survival rate was 96.3% at 3 years and 92.0% at 5 years with 36 months of treatment, compared to 94.0% and 81.7%, respectively, with 12 months of imatinib (HR  = 0.45; P = .019). “Compared to 1 year of adjuvant imatinib, 3 years improves recurrencefree survival and overall survival as treatment for GIST patients who have a high estimated risk of recurrence after surgery,” he concluded. Grade 3 or 4 adverse events were reported by 33% of the 36-month arm and 20% of the 12-month arm (P = .006); 26% and 13%, respectively, discontinued imatinib prior to GIST recurrence (P = .001). The most common events were anemia, periorbital edema, fatigue, nausea, and muscle cramps, all generally mild.

Financial Disclosure: Dr. Joensuu has received honoraria (paid to the Clinical Research Institute of Helsinki University Central Hospital) from Novartis for speaking and participation in advisory board meetings. Dr. Kris reported no potential conflicts of interest.

Reference 1. Joensuu H, Eriksson M, Hartmann J, et al: Twelve vs 36 months of adjuvant imatinib as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). 2011 ASCO Annual Meeting. Abstract LBA1. Presented June 5, 2011.

reduced mortality risk by 35%, with a median overall survival of 10.8 months, up from 8.1 months with gemcitabine/ carboplatin. Median progression-free survival was 4.2 vs 2.9 months, a 33% risk reduction.

Subgroup Analysis “An exploratory analysis by prior therapy suggests there is a potential efficacy benefit among secondand third-line patients, though a confirmatory study is needed,” Dr. O’Shaughnessy said. By using prespecified baseline factors in the multivariate Cox model,

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Expert Point of View

C

harles D. Blanke, MD, Chief of Medical Oncology at the University of British Columbia in Vancouver, critiqued the SSGXVIII study, noting its “goals were reasonable and the methodologies for primary and secondary objectives were sound. The conclusion regarding recurrence-free survival is valid, as is the conclusion regarding overall survival, with some limitations.” He said that oncologists who typically initiate imatinib upon relapse, based on the lack of survival advanCharles D. Blanke, MD tage otherwise, will need to rethink this strategy, he said. Based on the positive findings, Dr. Blanke advised, “If you have a patient who has a high-risk GIST, at least as defined by the study, giving him or her 3 years of imatinib represents the new gold standard. For now, the overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to ‘catch up’ when a patient has recurrent metastatic disease.” He acknowledged, however, that compliance over 3 years may be unrealistic. In the study, 32% of the 36-month arm discontinued treatment early, compared with 15% of the 12-month arm. Grade 3/4 toxicities were similar in frequency, but twice as many dropped out on the 36-month arm for an adverse event or “other reasons,” he noted. “Were low-grade side effects challenging to tolerate long term? Is it too difficult to take a pill for years with no disease evident? Such difficulties on the 3-year arm of SSGXVIII may bode poorly for therapy lasting even longer.” The optimal duration of treatment remains unknown, though there are reasons to believe that giving imatinib even longer might be better, as disease tends to progress when patients go off drug, he said. “For now, if I were a patient with a resected GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatment to eternity, meaning indefinitely.”

Financial Disclosure: Dr. Blanke served as a compensated advisor for Novartis.

but replacing the time since diagnosis of metastatic disease with the diseasefree interval from primary breast cancer surgery, the investigators found that patients receiving iniparib in the second- or third-line setting had their risk of progression reduced by 29% (P = .05) and mortality risk reduced by 29% (P = .031). Dr. O’Shaughnessy also suggested the drug may work in some molecular subtypes of triple-negative breast cancer but not others. “Metastatic triplenegative breast cancer is highly heterogeneous on intrinsic subtyping. Biomarker analyses are underway to

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evaluate patient populations that may benefit from iniparib,” she said.

Financial Disclosure: Dr. O’Shaughnessy has received honoraria from sanofi-aventis.

References 1. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011. 2. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. 2011 ASCO Annual Meeting. Abstract 1007. Presented June 6, 2011.


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2011 ASCO Annual Meeting Gynecologic Oncology

Novel Agents Prolong Disease-free Survival in Ovarian Cancer Maintenance olaparib added 4 progression-free months. By Caroline Helwick

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ovel agents produced high response rates and prolonged remissions in patients with platinum-sensitive recurrent ovarian cancer, in studies reported at the 2011 ASCO Annual Meeting. In an international randomized phase II trial, maintenance therapy with the oral poly  [ADP-ribose] polymerase (PARP) inhibitor olaparib extended disease-free survival by 4 months, according to Jonathan Ledermann, MD, of University College London in the United Kingdom.1 “Olaparib significantly prolonged progression-free survival by nearly 4 months on average, compared with placebo. This is the first study to demonstrate a statistically significant benefit of maintenance treatment for platinum-sensitive relapsed serous ovarian cancer,” Dr. Ledermann said. “It shows proof of principle for the concept of

maintenance therapy in ovarian cancer using a PARP inhibitor.” At the time of analysis, 50% of the olaparib-treated patients, compared with just 16% of the placebo subjects, were still on treatment.

Underlying Mechanism PARP is a key regulator of DNA damage response and helps repair single-strand breaks. In normal cells, homologous recombination repair is also engaged in repairing damage. Cells with impaired homologous repair cannot repair themselves, which leads to chromosomal instability and cell death. Up to 50% of high-grade serous ovarian cancer patients could be deficient in homologous repair, Dr. Ledermann explained. “We think platinum-sensitive serous ovarian cancer may be a good indicator of homologous repair defi-

Expert Point of View

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tanley B. Kaye, MD, of Royal Marsden Hospital in London, the invited discussant, commented, “The trial of olaparib was important, showing clear superiority of olaparib with an impressive hazard ratio that was not restricted to BRCA-mutated patients.…There is a role for taking this drug forward as potential maintenance.” He noted that homologous repair deficiency is a common molecular defect, and pointed out that olaparib had already been shown in an earlier trial to be acStanley B. Kaye, MD tive in a proportion of patients in whom BRCA status was negative. Therefore, drugs that capitalize on this could be worthy candidates in unselected populations. “The majority of patients in whom BRCA status was unknown or negative responded to olaparib,” he noted. As to whether a single-agent PARP inhibitor or combination approach would be preferable, Dr. Kaye emphasized that a PARP inhibitor/chemotherapy combination, while synergistic, could be myelotoxic.

What We Know and Don’t Know Emphasizing “what we know now” about PARP inhibitors as single agents, he observed that olaparib has significant clinical activity in both BRCA-mutated and sporadic ovarian cancer, with a favorable toxicity profile and the potential as maintenance therapy. As for “what we still need to know,” he named long-term toxicity, impact on subsequent chemotherapy and overall survival, nature of a reliable biomarker, and potential for combination with other maintenance approaches, such as bevacizumab (Avastin). PARP inhibitors and chemotherapy in combination have also proven feasible though this usually increases myelosuppression. The combination may also increase efficacy in platinum-sensitive disease, although the impact on progression-free and overall survival in randomized trials remains unclear. Optimal dose and schedule, biomarkers, and differences in the potential of the different PARP inhibitors should be explored, he said.

Financial Disclosure: Dr. Kaye is a member of advisory boards for AstraZeneca and Merck.

ciency, and we tested this,” he said. The phase II trial randomly assigned 265 patients with platinum-sensitive relapsed serous ovarian cancer to daily oral olaparib as maintenance or to placebo; all patients had responded to at least two previous platinum regimens for recurrence. Disease progression was observed in 44% of the olaparib arm vs 72% of the placebo arm; median progressionfree survival was 8.4 vs 4.8 months, respectively, for a relative risk reduction of 65% that was highly significant (P < .00001) and that was consistent across all subgroups, Dr. Ledermann reported. “Our progression-free survival difference was very impressive and better than we anticipated,” he commented. Outcomes within the BRCA-mutated subset (22% with known mutations) were similar to those for the entire group, he added. The overall survival analysis is not yet mature. “Olaparib was well tolerated, though there was an increase in three side effects,” he acknowledged. These included nausea (68% vs 35%), fatigue (49% vs 38%), and vomiting (32% vs 14%). “In a population enriched for homologous recombination repair deficiency, our results suggest that olaparib may have an important role to play in the future management of serous ovarian cancer,” Dr. Ledermann concluded.

Iniparib Shows Strong Activity Two studies evaluating iniparib in combination with gemcitabine/ carboplatin were promising as well. Iniparib induces cell-cycle arrest as a single agent and potentiates cell-cycle arrest by DNA-damaging agents but is a weak inhibitor of PARP. Richard Penson, MD, of Massachusetts General Hospital, Boston, presented the phase  II trial of iniparib in 41 platinum-sensitive patients without prior treatment for recurrence.2

The overall response rate was 65%, and responses were seen in both the BRCA mutant (approximately 50% of the population) and wildtype cohorts. Median progression-free survival was 9.5 months. SEE PAGE 39 As of May 2011, 17 of 41 patients remained on treatment without progression, he reported. In a separate phase II study of firstline therapy in platinum-resistant patients, 8 of 32 patients responded (25%), and 26 (81%) derived clinical benefit from iniparib, according to Michael Birrer, MD, PhD, also of Massachusetts General Hospital.3 Serious adverse events believed to be related to iniparib were noted in 12% of the first-line patients and 26% of the second-line patients, most commonly thrombocytopenia, neutropenia, anemia, nausea, vomiting, small intestinal obstruction, fatigue, dehydration, and hypokalemia.

Financial Disclosure: Drs. Birrer, Benson, and Ledermann reported no potential conflicts of interest.

References 1. Ledermann JA, Harter P, Gourley C, et al: Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer. 2011 ASCO Annual Meeting. Abstract 5003. Presented June 4, 2011. 2. Penson RT, Whalen C, Lasonde B, et al: A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin in patients with platinum—sensitive recurrent ovarian cancer. 2011 ASCO Annual Meeting. Abstract 5004. Presented June 4, 2011. 3. Birrer MJ, Konstantinopoulos P, Penson RT, et al: A phase II trial of iniparib in combination with gemcitabine/carboplatin in patients with platinum-resistant recurrent ovarian cancer. 2011 ASCO Annual Meeting. Abstract 5005. Presented June 4, 2011.

PARP Inhibitors in Platinum-sensitive Recurrent Ovarian Cancer ■■ Olaparib as maintenance prolonged remission to 8.4 months, compared with 4.8 months on placebo.

■■ Iniparib in the first- and second-line settings produced high response rates and median progression-free survival of over 9 months in treatment-naive patients.

■■ In combination with chemotherapy, toxicity could be problematic.


ASCOPost.com  |   JULY 1, 2011

PAGE 11

2011 ASCO Annual Meeting Smoking and Lack of Exercise Increase Risk of Some Cancers, but Moderate Alcohol Consumption Reduces Colon Cancer Risk By Alice Goodman

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substudy of the large prospective National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial revealed both expected and surprising findings related to the association between lifestyle factors (cigarette smoking, alcohol, and exercise) and cancer risk. As might be expected, long-term cigarette smoking increased the risks of invasive cancers of the breast, lung, and colon. Low levels of physical activity increased the risk of endometrial cancer. Alcohol use did not increase the risk of any invasive cancer, and somewhat surprisingly, moderate alcohol consumption of up to one drink per day actually decreased the risk of colon cancer. “We know that smoking is a risk factor for some cancers, and it appears to be even more risky for women who are at high risk of breast cancer due to family history and other factors. These findings suggest that healthy lifestyle choices give women a way to reduce their risk of invasive cancers,” said lead author Stephanie R. Land, PhD, Research Associate Professor, Graduate

School of Public Health, University of Pittsburgh, who presented the results at the ASCO Annual Meeting.1

Study Details The NSABP Breast Cancer Prevention Trial included more than 13,000 healthy women at increased risk of breast cancer due to age, a diagnosis of lobular carcinoma in situ, family history, or other risk factors. The main study compared 5 years of tamoxifen vs placebo and was unblinded early when it was evident that tamoxifen reduced the risk of breast cancer by 50%. The study presented at the 2011 ASCO Annual Meeting was designed to assess the risk of several common cancers based on self-reports at baseline about alcohol, cigarettes, and exercise. Median follow-up was 7 years. The risk of invasive breast cancer was higher in smokers than in nonsmokers, and increased with longer exposure to cigarettes. Women who smoked for 35 years or more had a 60% higher risk of invasive breast cancer, and those who smoked between

Expert Point of View

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t a press conference where results of the study by Land and colleagues were released, George W. Sledge, Jr, MD, said, “This study highlights the importance of lifestyle factors. We need to think about encouraging women who engage in unhealthy behaviors that place them at risk for cancer to change their lifestyles. Quitting smoking is a women’s health issue [ie, not just a consideration for men], and exercising may prevent uterine carcinoma,” he noted. “The outcomes related to alcohol are interesting, George W. Sledge, Jr, MD but we don’t have a final answer,” added Dr. Sledge, who is Ballve-Lantero Professor of Oncology at the Indiana University School of Medicine, Indianapolis, and Immediate Past President of ASCO. “It’s not clear why alcohol did not increase the risk of breast cancer in this study, and we learned that moderate alcohol intake lowered the risk of colon cancer. We still have more to learn, but this study confirms the importance of lifestyle choices.”

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

Lifestyle and Cancer ■■ Smoking cigarettes increased the risk of invasive cancers of the breast, lung, and colon.

■■ Low levels of exercise increased the risk of endometrial cancer. ■■ Drinking one glass of alcohol per day decreased the risk of colon cancer. 15 and 35 years had a 34% higher risk, compared with those who never smoked. Women with a smoking history of less than 15 years did not have an increased risk of breast cancer.

controvert previous studies, Dr. Land pointed out several factors that might

Earlier Findings Confirmed “This is the third large prospective study to show a strong association between smoking cigarettes and breast cancer, and it is the first to show further elevation of cancer risk in women at already high risk of breast cancer,” Dr. Land stated. The risk of colon cancer was also higher for women with longer smoking histories compared to neversmokers. Women who smoked cigarettes for more than 35 years had more than a fivefold higher risk of colon cancer vs those who never smoked. These findings confirm previous studies in women at high risk of breast cancer, and the increase in risk was even higher than in previous studies, Dr. Land noted. As would be expected, smoking cigarettes increased the risk of lung cancer, and longer cigarette exposure increased the risk further. Women who smoked more than one pack per day for more than 35 years had a 30 times higher risk of lung cancer compared with those who never smoked. Those who smoked less than one pack per day for fewer than 35 years had a 13 times higher lung cancer risk.

Other Risk Factors Moderate alcohol consumption (≤ 1 drink per day) was associated with a 65% decreased risk of colon cancer compared to those who did not drink. Although this finding seems to

Stephanie R. Land, PhD

explain this. Fewer heavy drinkers were enrolled in the NSABP study than in the studies that found an association with alcohol and colon cancer, and the findings are based on a single self-report of alcohol drinking habits. In addition, past studies have generally found alcohol to be a stronger risk factor for men than for women, and for rectal rather than colon cancer. About 54% of subjects reported low levels of physical activity at baseline; among these women, the risk of endometrial cancer was increased by 70%. This finding may be related to obesity in these women, Dr. Land speculated.

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

Reference 1. Land SR, Christian N, Wickerham D, et al: Cigarette smoking, fitness, and alcohol use as predictors of outcomes among women in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial. 2011 ASCO Annual Meeting. Abstract  1505. Presented June 6, 2011.


The ASCO Post  |   JULY 1, 2011

PAGE 12

11th International Conference on Malignant Lymphoma Important Briefs: Lymphoma Research on Improved Chemotherapy, Biomarker Associations, and Stem Cell Transplant Approaches By Matthew Stenger

The 11th International Conference on Malignant Lymphoma was held June 15–18 in Lugano, Switzerland. More than 3,000 hematologists, clinical oncologists, pathologists, and researchers attended the meeting, which was first convened in 1981. Topics of discussion included lymphoma staging in the new millennium, lymphoma and its microenvironment, and lymphoma cure vs control. The ASCO Post has selected several key presentations for summary in the following roundup.

DA-EPOCH-R in c-MYC–positive Aggressive B-cell Lymphomas

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he c-MYC–positive aggressive B-cell lymphomas—eg, Burkitt lymphoma and c-MYC–positive diffuse large B-cell lymphoma—are characterized by high proliferation and poor outcomes with CHOP-based regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone). Multiagent intensive chemotherapy is effective in Burkitt lymphoma, but is associated with significant toxicity and mortality. Some 10% of diffuse large B-cell lymphoma cases are c-MYC–positive and exhibit poor outcome with Kieron Dunleavy, MD R-CHOP (rituximab [Rituxan] plus CHOP). In a prospective trial in 31 adult patients with untreated Burkitt lymphoma performed by Kieron Dunleavy, MD, and colleagues at NCI, treatment with DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) resulted in event-free and overall survival rates of 97% and 100%, respectively, at a median follow up of 57 months. Analysis for c-MYC in 108 previously untreated patients with diffuse large Bcell lymphoma who had received DA-EPOCH-R at NCI or in a multicenter Cancer and Leukemia Group B study showed that 9 (8%) were c-MYC–positive. At a median follow-up of 48 months, event-free survival was 83% in c-MYC–positive cases and 76% in c-MYC–negative cases (P = NS), suggesting that DA-EPOCH-R treatment is not associated with worse outcome in c-MYC–positive cases. Notable toxicities in the NCI prospective Burkitt lymphoma study consisted of tumor lysis syndrome in one patient and fever/neutropenia in 16% of treatment cycles. A confirmatory multicenter study of risk-adapted DA-EPOCH-R is underway in Burkitt lymphoma and c-MYC–positive diffuse large B-cell lymphoma. “Our study suggests that DA-EPOCH-R is very effective in aggressive cMYC–positive B-cell lymphomas—Burkitt lymphoma and diffuse large B-cell lymphoma,” Dr. Dunleavy told The ASCO Post. “The outcome for patients with c-MYC–positive diffuse large B-cell lymphoma is poor with standard therapy, but DA-EPOCH-R appears to be effective in this group of patients. Based on these results, a confirmatory multicenter study of DA-EPOCH-R in Burkitt lymphoma and c-MYC–positive diffuse large B-cell lymphoma was designed and currently is ongoing,” said Dr. Dunleavy.

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

Dunleavy K, et al: MYC + aggressive-B-cell lymphomas: Novel therapy of untreated Burkitt lymphoma (BL) and MYC + diffuse large B-cell lymphoma (DLBCL) with DA-EPOCH-R (Abstract 071).

Autologous vs Reduced-intensity Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma

T

Timothy S. Fenske, MD

imothy S. Fenske, MD, and colleagues from the Center for International Blood and Marrow Transplant Research at the Medical College of Wisconsin analyzed outcomes of 640 patients with mantle cell lymphoma undergoing a first autologous (n = 433) or reduced-intensity allogeneic (n = 207) stem cell transplantation. Their findings indicate that allogeneic transplantation is associated with higher treatment-related mortality but similar 5-year overall survival compared with autologous transplantation and that patients undergoing transplantation early in

disease course have better survival outcomes than do more heavily pretreated patients. Among 50 patients undergoing allogeneic transplant and 251 with autologous transplant for early mantle cell lymphoma—ie, patients who were in first complete or partial remission after one or two prior chemotherapy treatments—1-year treatment-related mortality was significantly higher in the allogeneic group (25% vs 4%, P = .001), 5-year progression/relapse rate was significantly lower in the allogeneic group (16% vs 32%, P = .012), and 5-year overall survival rates were similar (62% vs 61%, P = NS). Chronic graft-vs-host disease occurred in 56% of allogeneic transplant patients. Among 99 allogeneic transplant patients and 159 autologous transplant patients with late mantle cell lymphoma (patients not meeting the criteria for early disease) who had chemosensitive disease, 1-year treatment-related mortality was significantly higher in SEE PAGE 39 the allogeneic group (18% vs 9%, P  = .036), whereas 5-year progression/relapse rate (38% vs 49%, P = NS) and 5-year overall survival (32% vs 44%, P = NS) were numerically but not significantly lower in the allogeneic group. Chronic graft-vs-host disease occurred in 45% of allogeneic transplant patients with late mantle cell lymphoma. “Our findings indicate that for patients with mantle cell lymphoma early in the disease course, outcomes overall do not appear to be superior with allogeneic transplantation, even with the use of nonablative allotransplant techniques. Thus, the increased risk of toxicity with allotransplantation does not appear justified for such patients,” Dr. Fenske told The ASCO Post. “For patients later in the disease course, the outcomes are less favorable overall, and comparable for autologous and allogeneic transplants. One of the more unexpected results is that autologous transplantation may still offer benefit for patients later in the disease course.”

Financial Disclosure: Dr. Fenske has received honoraria as a consultant for Seattle Genetics and Spectrum Pharmaceuticals, and has received research/grant support from Millennium (Takeda) Pharmaceuticals.

Fenske TS, et al: Outcome of patients with mantle cell lymphoma undergoing autologous versus reduced-intensity allogeneic transplantation (Abstract 018).

Early Dose Intensification in T-cell Non-Hodgkin Lymphoma

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tandard therapies for T-cell non-Hodgkin lymphoma remain undefined, as does the impact of dose intensification and first-line high-dose therapy with autologous stem cell transplantation in this setting. Reinhard Marks, MD, and colleagues from the University Medical Center in Freiburg, Germany, analyzed outcomes in 113 patients with newly diagnosed T-cell NHL at a single center according to specific diagnoses and types of treatment. Specific diagnoses included peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in 46 patients (most with stage III/IV disease), angioimmunoblastic lymphoma in 25, and ALK-negative anaplastic large cell lymphoma in 26. Initial chemotherapy primarily consisted of CHOP-like regimens. If complete remission was not achieved, early intensification with primarily VIPE/ VCPE (epirubicin, etoposide, cisplatin, ifosfamide or cyclophosphamide) or DHAP (cytarabine, cisplatin, dexamethasone) regimens and primary autologous stem cell transplantation after BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy (67% of transplant cases) was initiated. At a median follow up of 59.7 months, 5-year overall survival was 53.1% for the entire cohort, 62.8% in patients with PTCL-NOS, 45.1% in those with continued on page 15


To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

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

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

Indications

Pregnancy warning

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Based on animal data, Avastin may cause fetal harm and may impair fertility Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for GI perforation

In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastin-related adverse events (grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

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 in patients with wound dehiscence. 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 Hemorrhage — Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/ pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

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%)

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

Additional serious adverse events with increased incidence in the Avastintreated arm vs control included: — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Most common adverse events 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

Avastin is not approved for use in combination with irinotecan.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Reference: 1. Avastin Prescribing Information. Genentech, Inc. February 2011.

©2011 Genentech USA, Inc.

All rights reserved.

AVA0000383301

Printed in USA.

(05/11)

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

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone. The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. 1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3−4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).] NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).] Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy. 14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24-hour urine collection.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. NCI-CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued. System Organ Class/ IFN-α + Placebo IFN-α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5-FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin. Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under-estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8  patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose-related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma). 1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus South San Francisco, CA 94080-4990 ©2011 Genentech, Inc. Avastin compared to the IFN-α plus placebo arm are presented in Table 4.


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11th International Conference on Malignant Lymphoma Important Briefs continued from page 12

angioimmunoblastic lymphoma, and 48.6% in those with ALK-negative anaplastic large cell lymphoma. A first complete remission was achieved in 68.9% of PTCL-NOS patients with induction therapy. Primary high-dose therapy with autologous stem cell transplantation did not significantly improve 5-year overall survival (64.6% vs 60.1%) in PTCL-NOS. However, the cumulative 5-year relapse rate among patients with first complete remission was significantly higher in patients not undergoing autologous transplantation (68.0% vs 15.6%, P = .0046). Five-year overall survival in ALK-negative anaplastic large cell lymphoma patients was 60.8% with autologous transplant vs 38.5% without (P = NS) and the relapse rates among those with first complete remission were 11.1% vs 40.0%, respectively (P = NS). In contrast, primary therapy with autologous transplant was associated with significantly improved 5-year overall survival among patients with angioimmunoblastic lymphoma (87.5% vs 21.8%, P = .01).

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

Marks R, et al: Long term disease control and overall survival after early dose intensification in T-NHL depend on specific entities (Abstract 101).

Follicular Lymphoma Marker in Healthy Individuals

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he t(14;18) (IgH/BCL2) translocation is the characteristic abnormality in follicular lymphoma, and disappearance of cells containing this abnormality from blood or marrow is often termed a molecular remission. However the translocation can be found in healthy persons. As reported by Carsten Hirt, MD, and colleagues from Greifswald University Medical Center and the University of Greifswald in Germany, real-time polymerase chain reaction analysis of DNA samples from 3,966 subjects (aged 20–81 years) without lymphoma in a population-based health study showed that 1,526 (38.5%) were positive for t(14;18). Positive subjects had a median number of t(14;18)–positive cells of 3.9 per million nucleated cells (range: 0.6–9,299/million). Prevalence of t(14;18) was lowest in the 20- to 29-year-old age group (24.1%), highest in the 50 to 59 year age group (47.2%), and higher in men than in women (43.3% vs 33.7%, P < .0001). On multivariate analysis, t(14;18) prevalence was significantly associated with age and gender (both P ≤ .001) but not with smoking status or with smoking pack-years by numeric category or as a continuous variable. Age was the only variable showing a significant association with t(14;18)–positive cell frequency on multivariate analysis, with no significant correlations with gender or smoking exposure variables being observed.

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

Hirt C, et al: Prevalence and frequency of circulating t(14;18)-positive cells in healthy individuals of a population-based cross sectional study—association with age and gender but not with smoking status (Abstract 009).

Lenalidomide plus Rituximab in Indolent B-cell Non-Hodgkin Lymphoma

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n a phase II study conducted by Nathan H. Fowler, MD, and colleagues from the University of Texas MD Anderson Cancer Center, 75 patients with untreated indolent non-Hodgkin lymphoma received lenalidomide (20 mg/d on days 1–21) and rituximab (375 mg/m2 on day 1 every 28 days), with response being assessed every three cycles. No prophylactic growth factor was used. Histologies consisted of follicular lymphoma in 41 patients, marginal zone lymphoma in 19, and Nathan H. Fowler, MD chronic lymphocytic leukemia/small lymphocytic lymphoma in 15. The overall response rate among 70 evaluable patients was 90%, with com-

plete response in 66%, partial response in 25%, and stable disease in 9%. A complete response was observed in 87% of patients with follicular lymphoma, and response rates were high in this group despite 80% having a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥ 2 and 54% having high tumor burden on Groupe d’Etudes des Lymphomes Folliculaires (GELF) criteria. After six cycles, nearly all patients with follicular lymphoma had a molecular response, with no detectable BCL-2 on polymerase chain reaction analysis. Overall, four patients had disease progression at a median follow-up of 14.4 months. The most common grade 3 or higher nonhematologic adverse events included rash (9%), muscle pain (9%), thrombosis (4%), and infection (4%). Grade 3 or higher neutropenia and thrombocytopenia occurred in 27% and 5%, respectively. Five patients (7%) stopped treatment due to adverse events (2 infusion reactions and 1 case each of rash, arterial thrombosis, and transient episode of respiratory failure), with all discontinuations occurring during the first two cycles. Randomized trials are planned to evaluate this regimen in follicular lymphoma.

Financial Disclosure: Dr. Fowler has received research funding from Celgene and Genentech. He has served on the scientific advisory board for Celgene and Genentech.

Fowler N, et al: Lenalidomide plus rituximab is a highly effective and well-tolerated biologic therapy in untreated indolent B cell non-Hodgkins lymphoma (Abstract 137).

R-CHOP Bests R-CVP for Induction in Follicular Lymphoma

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he Primary Rituximab and Maintenance (PRIMA) study showed that rituximab maintenance was associated with a significant increase in progression-free survival after first-line treatment in follicular lymphoma. Franck Morschhauser, MD, of Hospital Claude Huriez, CHU, Lille, France, and colleagues from the PRIMA study analyzed the effect on outcome of induction therapy (chosen by individual centers) with R-CHOP (n = 885), R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone; n = 272), or R-FCM (rituximab plus Franck Morschhauser, MD fludarabine, cyclophosphamide, and mitoxantrone; n = 45). Overall and complete response/unconfirmed complete response rates were 92.8% and 67.2%, respectively, with R-CHOP; 84.7% and 53.0%, respectively, with R-CVP; and 75.0% and 61.4%, respectively, with R-FCM. Serious adverse events occurred in 23%, 22%, and 17%, of patients, respectively, including infection in 6%, 7%, and 9%, and febrile neutropenia in 2%, 0%, and 11%. Among responding patients randomly assigned to rituximab maintenance vs no further treatment, 3-year progression-free survival rates were 78.6% vs 59.6% (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.39–0.65) in the R-CHOP induction group (n = 768), 61.6% vs 50.0% (HR = 0.68, 95% CI = 0.45-1.02) in the R-CVP group (n = 222), and 78.6% vs 64.3% (HR = 0.54, 95% CI = 0.13-2.24) in the R-FCM group (n = 28). Multivariate analysis showed that longer progression-free survival was significantly associated with random assignment to rituximab maintenance (HR = 0.55, P < .0001) and R-CHOP or R-FCM induction (HR = 0.39, P = .0029), as well as with age 60 years or greater (HR = 0.68, P = .0013), female gender (HR = 0.76, P = .013), and lower Follicular Lymphoma International Prognostic Index (FLIPI) score category (P < .0001). Overall survival did not differ among the three induction regimens; rates for rituximab maintenance vs no maintenance were 95.6% vs 95.2% with R-CHOP, 93.7% vs 89.9% with R-CVP, and 74.5% vs 100% with R-FCM.

Financial Disclosure: Dr. Morschhauser has received honoraria from and been a speaker for Roche.

Morschhauser F, et al: Impact of induction chemotherapy regimen on response, safety and outcome in the PRIMA study (Abstract 022).


The ASCO Post  |   JULY 1, 2011

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Direct from ASCO Donor Spotlight

Bequest from Dr. Nora Janjan and Jack Calvin Supports Conquer Cancer Foundation’s Work in Palliative Care

Jack Calvin and Nora Janjan, MD, MPSA, MBA

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or Nora Janjan, MD, MPSA, MBA, the practice of oncology is rooted in purpose, empathy, and trust. “You walk into the hospital and you know exactly why you’re there,” she says. “You are there to help patients and their loved ones through probably the most difficult experience that they will ever face. The greatest responsibility anyone can assume is to have a patient entrust his or her life to our care. “Each one of us will be a patient someday, and it is important to deliver the compassionate care that we hope to receive later in our own life. The impact of compassionate care is not only with the patient—it also has a lasting effect on the family.” Dr. Janjan learned the value of the physician-patient relationship early on, when her younger sister was born with Down syndrome and the family pediatrician supported her parents in their decision to keep her sister at home.

‘Where can I contribute the most?’ Dr. Janjan retired in 2008 as a Professor of Radiation Oncology and Symptom Research at the University of Texas MD Anderson Cancer

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Center in Houston. Her second act is dedicated to influencing the future of cancer care through health policy. Retirement from clinical practice was a hard decision—but the right one, she says. “I found myself telling my patients that I was going to D.C. on behalf of all patients. At some point, I started to ask myself where can I contribute the most?” Armed with a unique combination of credentials in medicine, business administration, and public policy, Janjan is working as a consultant to the National Center for Policy Analysis—a nonprofit think tank— focusing largely on the potential impact of health-care reform.

breast cancer. Together, they have made a bequest to the Conquer Cancer Foundation, with the gift earmarked for palliative care research. The Foundation’s vision— a world free from the fear of cancer—is one that resonates deeply with them. “A lot of the fear that people have about cancer is actually fear of the symptoms of the disease and its treatment,” says Dr. Janjan. She recalls a patient with cancer seated next to her on a plane; the patient had been treated 2 decades earlier but vividly recalled the side effects of therapy, while the cure of the disease seemed an afterthought.

Every choice we make in life is made on trust, and we trust the Foundation to be good stewards of our funds and improve the lives of patients with cancer. Creating a World Free from the Fear of Cancer Dr. Janjan is also working to shape the future of cancer care through philanthropy. In partnership with her husband, Jack Calvin, she is a strong supporter of the Conquer Cancer Foundation, an independent not-for-profit organization launched by ASCO and dedicated to conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. Both Dr. Janjan and Mr. Calvin have been touched by cancer—she through the experience of caring for her patients, and he through the experience of supporting his first wife through her struggle with

he generous bequest made to the Conquer Cancer Foundation by Nora Janjan and Jack Calvin will make a tangible difference for patients whose lives will be enhanced and extended by palliative care, an area in which the Foundation is already making an impact. To learn more about our work in the palliative care area, including two Foundation-funded landmark studies that have demonstrated the value of palliative care in supporting treatment and extending survivorship, visit the websites ConquerCancerFoundation.org or Cancer.Net.

A New Narrative for Cancer From childhood, Dr. Janjan remembers a great-aunt suffering unrelieved pain and the toxicities of treatment for metastatic colon cancer. Her mother’s best friend worked in a lingerie shop, specializing in fitting women who had had mastectomies, many of whom were suffering from lymphedema. “Cancer’s storyline has changed, as conservative treatment—combining radiation therapy with a limited surgical approach—has resulted in fewer disfiguring surgeries, less disability, and better quality of life,” says Dr. Janjan. “The symptoms of cancer and its treatment are now better controlled. We’re continuing to improve outcomes, and now deal with issues of survivorship that allow the patient to get past the cancer experience and reach important personal milestones.” Equally important, she says, is the cancer care community’s responsibility to be there in the most difficult moments. “Dealing with the diagnosis and treatment of cancer is among the most overwhelming challenges anyone can face. Relieving symp-

Many planned giving vehicles, including bequests, are available to help our community support the Conquer Cancer Foundation. For more information, please contact info@ conquercancerfoundation.org.

toms and providing comforting support and reassurance to the patient is a critical function of every member of the health-care team.”

Leaving a Legacy That mission—to provide supportive care all along the continuum of treatment—is what motivated Dr. Janjan and Mr. Calvin to make a bequest to the Conquer Cancer Foundation. “By applying our gift to palliative care research, we hope to continue to improve the lives of patients with cancer,” says Dr. Janjan. “ASCO is an outstanding organization. It’s multidisciplinary and creative. It’s the voice of oncology. And the Conquer Cancer Foundation is equally impressive and results-driven. Every choice we make in life is made on trust, and we trust the Foundation to be good stewards of our funds and improve the lives of patients with cancer.” “Cancer care is a team effort, involving everyone from the oncologist to the transport staff, who assume great responsibility in monitoring the patient’s status in often remote hospital corridors,” she adds. “Jack and I see philanthropy as a team effort as well. We all need to contribute to accomplish our shared goal of improving cancer care. It’s so important to leave a legacy, to appreciate what others have done to help you along the way, and to give something back—to help others with your skills, your time, and your resources.”

© 2011. American Society of Clinical Oncology. All Rights Reserved.


ASCOPost.com  |   JULY 1, 2011

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Direct from ASCO

Mark G. Kris, MD, Recipient of First ASCO Humanitarian Award

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he ASCO Humanitarian Award honors an oncologist who personifies ASCO’s mission and values by going above and beyond the call of duty in providing outstanding patient care through innovative means or exceptional service and leadership in voluntary, uncompensated endeavors in the United States or abroad. This award is unique in that nominations were accepted from visitors to Cancer.Net, ASCO’s patient information website, as well as from ASCO members.

limited to cancer care. He has spent much of his free time assisting with humanitarian efforts in poverty- and disaster-stricken areas in the United States and overseas. Since 2000, he

has assisted Habitat for Humanity in New York City, and when Walton, New York, flooded in 2006, Dr. Kris helped clean water-damaged basements and raised funds to supply fur-

naces to homeowners. Since 2005, Dr. Kris has traveled numerous times to Biloxi, Mississippi, and to Dulac, Louisiana, to recontinued on page 18

Mark G. Kris, MD Mark G. Kris, MD

Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, both professionally and personally, has exhibited a level of dedication and compassion that has touched the lives of countless individuals. Described by colleagues at Memorial Sloan-Kettering Cancer Center as a pioneer of lung cancer research and treatment, Dr. Kris also demonstrated exemplary patient care, even making house calls when a visit to the hospital would be too taxing.

Extracurricular Efforts Dr. Kris has participated in two full marathons and several halfmarathons to benefit patients with cancer through Fred’s Team (which raises funds for cancer research at Memorial Sloan-Kettering Cancer Center) as well as all seven “Run as One” races sponsored by The Thomas Labreque Foundation supporting lung cancer awareness and research. “It’s very gratifying to give patients with lung cancer and their families a place where they can celebrate their successes and meet other families dealing with the illness,” Dr. Kris said. “Seeing families rally around a member who is fighting the disease is even better than crossing the finish line in the marathon.” Dr. Kris’ work, however, is not

MER110068_ANZ_Cancer_Care.indd 1

09.02.11 17:17


The ASCO Post  |   JULY 1, 2011

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Direct from ASCO

Mark G. Kris, MD continued from page 17

build damaged homes that had been devastated by hurricanes. In 2004 and 2005, he traveled to Siquirres, Costa Rica, to help local youths build a basketball court and a church. After the earthquake in Haiti, he traveled to the small town of Furcy, where he led efforts to rebuild a school, assisted in the construction of new buildings, worked in a health clinic, formed a scholarship to build additional schools, and acquired seeds for local residents to plant new crops.

Service to Science Dr. Kris, a medical oncologist, currently serves as Chief of the Thoracic Oncology Service and the Wil-

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

liam and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center. He also is Professor of Medicine at Weill Cornell Medical College. He specializes in thoracic malignancies including lung cancer, thymoma, and cancer of unknown primary site. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management, with a focus on preventing emesis. An ASCO member since 1983, Dr. Kris has served on and led numerous committees. He received an ASCO Statesman Award in 2010 in recognition of his service to the Society.

© 2011. American Society of Clinical Oncology. All Rights Reserved.

What’s Hot in

JCO

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

JCO.org 1. Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results Alberto F. Sobrero, et al 29(15): 1938

6. Future of Treatment for LowRisk Prostate Cancer: For All, for Some, or for None? Anthony V. D’Amico 29(15): 1940

2. How Long Is Long Enough? Andrew D. Seidman 29(16): 2129

7. Hope and Realism: The Perfect Balance? Shirish M. Gadgeel 29(16): 2291

3. Lymphocyte Infiltration in Breast Cancer: A Key Prognostic Factor That Should Not Be Ignored Roger Mouawad, et al 29(15): 1935 4. Mesorectal Fascia Instead of Circumferential Resection Margin in Preoperative Staging of Rectal Cancer Bengt Glimelius, et al 29(16): 2142 5. Genetic Testing for Lung Cancer: Reflex Versus Clinical Selection Paul A. Bunn Jr., et al 29(15): 1943

8. Advanced Insights Into the Biology of Malignant Lymphomas Richard I. Fisher 29(14): 1799 9. Myelodysplastic Syndromes: Dissecting the Heterogeneity Peter L. Greenberg 29(15): 1937 10. Contralateral Prophylactic Mastectomy: What Do We Know and What Do Our Patients Know? Seema A. Khan 29(16): 2132

Accelerating Progress vs Cancer

A

t the opening press briefing and throughout ASCO’s 47th Annual Meeting, presenters marked the 40th anniversary of the National Cancer Act by highlighting the significant progress made in cancer treatment over the past 4 decades, the major challenges ahead, and new research models to find better treatments faster. NCI Director Harold Varmus, MD, said the National Cancer Act was a clarion call to make bigger investments into federal agencies devoted to health. The Act led to greater investments in clinical trials and cancer research and set the stage for many advances in understanding retroviruses, genomics, and cell biology. “The notion 40 years ago was that cancer is a disease we could win or lose against. Now what we are doing is not waging a simple war against a single enemy, but trying to make progress against a vast array of diseases that dictate changes in cell behavior,” Dr. Varmus said. “Since 1971, the average 5-year survival rate for all cancers has increased by 18%, and since its peak in 1991, the overall cancer death rate is down 17%. Today, two out of three patients with cancer live at least 5 years after a cancer diagnosis, said George W. Sledge, Jr, MD, Immediate Past President of ASCO (2010–2011) and the BallveLantero Professor of Oncology and Professor of Pathology and Labora-

tory Medicine at Indiana University School of Medicine. “This progress has occurred not by chance, but through many decades of public and private funding of cancer research. Sustained investment in cancer research will continue to offer hope for patients worldwide,” he said. To demonstrate the progress, ASCO launched a dynamic website featuring an oncologist-curated, interactive timeline of major milestones in cancer research in several common cancer types. The new site, CancerProgress.Net, is designed to be a “living” site where new advances and information will be added in real time.

Forging Ahead “We are continuing to find the best ways to use the therapies we have based on greater knowledge of how they work, while at the same time, we’re forging ahead to test new treatments that match the specific molecular profiles of each patient,” said opening briefing moderator Richard L. Schilsky, MD, Past President of ASCO (2008–2009), Professor of Medicine and Chief, Section of Hematology-Oncology, University of Chicago Pritzker School of Medicine, and Deputy Director, Comprehensive Cancer Center, University of Chicago. Attended by nearly 100 reporters, the opening press briefing highlighted two abstracts that tell the story of the progress that is being made: continued on page 19

Help Your Patients Understand the Latest Research

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irect your patients to www. cancer.net/podcasts to hear ASCO experts discuss the research that was presented at the 2011 ASCO Annual Meeting. This series of “Research Round-up” podcasts provides the latest information on treatment and care for

people with cancer, and will help your patients understand how it affects them. These podcasts cover new research in breast cancer, brain tumors, gastrointestinal cancers, gynecologic cancers, and leukemia, as well as other topics of interest to patients.

© 2011. American Society of Clinical Oncology. All Rights Reserved.


ASCOPost.com  |   JULY 1, 2011

PAGE 19

Direct from ASCO

Newly Elected Society Officials for 2011

ASCO in Action continued from page 18

■■ New Chemotherapy Regimen Boosts Event-Free Survival for Children and Young Adults With ALL: A randomized phase III Children’s Oncology Group study shows that a high-dose methotrexate regimen is superior to the standard regimen of escalating methotrexate for children and young adults with high-risk B-precursor acute lymphoblastic leukemia. This regimen improved 5-year, event-free survival and had no greater significant side effects compared to the standard regimen. The trial establishes a new standard treatment for these patients. ■■ Innovative Model That Matches Targeted Drugs to Tumor Aberrations in Patients with Advanced Cancer in Phase I Clinical Trials Proves Feasible and Often Improves Outcomes: A major personalized medicine initiative at The University of Texas MD Anderson Cancer Center found that matching patients in phase I trials with targeted drugs on the basis of the molecular profiles of the patients’ tumors resulted in longer survival and time to treatment failure and better response rates compared to treating patients without molecular matching.

© 2011. American Society of Clinical Oncology. All Rights Reserved.

I

n December 2010, ASCO announced the results of its 2011 Election for President-Elect and for members of the Board of Directors and the Nominating Committee. Sandra M. Swain, MD (Washington Hospital Center’s Washington Cancer Institute, Georgetown University, and Uniformed Services University of the Health Sciences), took office as President-Elect during ASCO’s 47th Annual Meeting and will serve a 1-year term as President beginning in June 2012. As President-Elect and as President, Swain will reach out to the NCI to improve translational medicine by increasing the connection between clinical and basic scientists. She will also promote the training of extended practice nurses, physician assistants, and other health-care providers and ensure that ASCO’s Quality Oncology Practice Initiative (QOPI) moves forward and develops metrics for successful outcomes. Finally, she will champion ASCO’s work in tandem with NCI and other leaders to implement a successful national clinical research plan in oncology.

Board of Directors Gary I. Cohen, MD (Berman Cancer Institute at Greater Baltimore Medical Center, Sidney Kimmel Foundation for Cancer Research, and Johns Hopkins University), Carolyn D. Runowicz, MD (Carole and Ray

Neag Comprehensive Cancer Center and University of Connecticut Health Center), Eric P. Winer, MD (Dana-Farber Cancer Institute), and Daniel F. Hayes, MD (University of Michigan Comprehensive Cancer Center) have been elected to the Board of Directors. During this term, Dr. Cohen will work to involve community physicians in clinical trials through education, encouragement, and funding; urge community oncologists to encourage patients to enroll in clinical trials; and promote a rational approach to cancer care driven by appropriate clinical care guidelines. Dr. Runowicz will confront workforce issues, develop ASCO’s strategic plan, address access to quality care in oncology, and focus on physician reimbursement. Dr. Winer will work to eliminate wasted expenses in health-care costs, lobby for additional funding for clinical research, and minimize the delays and administrative obstacles in health-care systems. Dr. Hayes envisions ASCO partnering with complementary societies to bring standardized, high-quality care to patients, and he advocates partnerships with constituencies that have considerable political weight and leadership to enhance, streamline, and facilitate properly conducted clinical and translational research.

Nominating Committee Finally, Kathy D. Miller, MD (Indiana University School of Medicine), and Harold J. Burnstein, MD (Harvard Medical School and DanaFarber Cancer Institute and Brigham & Women’s Hospital), have been elected as members of ASCO’s Nominating Committee. Dr. Miller seeks to provide members with a clear choice of candidates as well as with opportunities to pose questions directly to candidates and to share their opinions about important matters facing ASCO. Dr. Burstein will put forward slates of candidates with broad and resonant appeal to ASCO membership and promote the idea of “paying” members to vote by offering vouchers good toward annual membership dues, educational materials, or other ASCO products. He will also support the scheduling of elections at the Annual Meeting, when thousands of members are available to cast ballots. The newly elected officials will take office at the 2011 Annual Business Meeting.

Adapted from ASCO Connection. © American Society of Clinical Oncology. (“2011 ASCO Election Results Now Available.” ASCO Connection: From the Society, December 9, 2010.) All rights reserved.

Save the Date Breast Cancer Symposium 2011

EORTC-NCI-ASCO Annual Meeting on Molecular Markers in Cancer

September 8-10, 2011

October 27-29, 2011

San Francisco Marriott Marquis San Francisco, California

Brussels Meeting Center Brussels, Belgium


In the treatment of advanced RCC

When prognostic risk is high —let evidence chart the course

Important Safety Information • TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1 - 1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN.

• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.

• Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.

• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.

• Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.

• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.

• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL. • Live vaccinations and close contact with those who received live vaccines should be avoided. • Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.


Powerful 1st-line evidence— TORISEL significantly extended overall survival in poor-risk patients

Powerful evidence

Overall survival (OS)* results—TORISEL vs IFN1

Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

• Studied 1st-line in patients with ≥3 of 6 preselected prognostic risk factors1II • Median duration of treatment was 17 weeks (range 1 - 126 weeks) for the TORISEL arm and 8 weeks (range 1 - 124 weeks) for the IFN arm1

TORISEL has a Category 1 NCCN recommendation specific to poor-risk patients as 1st-line treatment in advanced renal cell carcinoma (RCC)2 TORISEL is indicated for the treatment of advanced renal cell carcinoma.1

• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%). • Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%). • Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended. • St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization). Please see the brief summary of the full Prescribing Information on the next page. RCC=renal cell carcinoma. IFN=interferon alpha. CI=confidence interval. NCCN=National Comprehensive Cancer Network. * Time from randomization to death. † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths). ‡ Based on log-rank test stratified by prior nephrectomy and region. § Based on Cox proportional hazard model stratified by prior nephrectomy and region. II Prognostic risk factors included: <1 year from time of initial RCC diagnosis to randomization, Karnofsky Performance Status of 60 or 70, hemoglobin <lower limit of normal, corrected calcium >10 mg/dL, lactate dehydrogenase >1.5 x upper limit of normal, >1 metastatic organ site. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Kidney Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2011. TRS00216/282520 All rights reserved.

© 2011 Pfizer Inc. Printed in USA/April 2011


TORISEL® Kit

[tor-a<sel] (temsirolimus) injection

% only FOR INTRAVENOUS ADMINISTRATION Brief Summary of Prescribing Information This product’s label may have been revised after this insert was used in production. See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our Medical Communications Department toll-free at 1-800-934-5556. INDICATIONS AND USAGE TORISEL is indicated for the treatment of advanced renal cell carcinoma. CONTRAINDICATIONS TORISEL is contraindicated in patients with bilirubin >1.5 x ULN. WARNINGS AND PRECAUTIONS Hepatic Impairment The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5 x ULN when treated with TORISEL. The overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5 x ULN. TORISEL is contraindicated in patients with bilirubin >1.5 x ULN due to increased risk of death. Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week (see USE IN SPECIFIC POPULATIONS, Hepatic Impairment). Hypersensitivity Reactions Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TORISEL. An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). Hyperglycemia/Glucose Intolerance The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. Infections The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections (see ADVERSE REACTIONS). Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms. Hyperlipemia The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL. Bowel Perforation Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain,

metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools. Renal Failure Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis. Wound Healing Complications Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TORISEL in the perioperative period. Intracerebral Hemorrhage Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL. Co-administration with Inducers or Inhibitors of CYP3A Metabolism Agents Inducing CYP3A Metabolism: Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John’s Wort may decrease TORISEL plasma concentrations unpredictably. Patients receiving TORISEL should not take St. John’s Wort concomitantly.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the Phase 3 randomized, open-label study of interferon alfa (IFN-) alone, TORISEL alone, and TORISEL and IFN-, a total of 616 patients were treated. Two hundred patients received IFN- weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN- weekly. Treatment with the combination of TORISEL 15 mg and IFN- was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN- alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN- alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN- alone arm are shown for comparison. Table 1—Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Adverse Reaction

Agents Inhibiting CYP3A Metabolism: Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

139 (67)

199 (100)

155 (78)

Asthenia

106 (51)

23 (11)

127 (64)

52 (26)

Edemaa

73 (35)

7 (3)

21 (11)

1 (1)

Pain

59 (28)

10 (5)

31 (16)

4 (2)

Pyrexia

50 (24)

1 (1)

99 (50)

7 (4)

Weight Loss

39 (19)

3 (1)

50 (25)

4 (2)

Headache

31 (15)

1 (1)

30 (15)

0 (0)

Chest Pain

34 (16)

2 (1)

18 (9)

2 (1)

17 (8)

1 (1)

59 (30)

3 (2)

General disorders

Chills

Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Gastrointestinal disorders

Pregnancy Pregnancy Category D Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.

Mucositisb

86 (41)

6 (3)

19 (10)

0 (0)

Anorexia

66 (32)

6 (3)

87 (44)

8 (4)

Nausea

77 (37)

5 (2)

82 (41)

9 (5)

Diarrhea

56 (27)

3 (1)

40 (20)

4 (2)

Abdominal Pain

44 (21) 42 (20)

34 (17) 36 (18)

3 (2)

Constipation

9 (4) 0 (0)

Vomiting

40 (19)

4 (2)

57 (29)

5 (3)

Infectionsc

42 (20)

6 (3)

19 (10)

4 (2)

Urinary tract infection d

31 (15)

3 (1)

24 (12)

3 (2)

Pharyngitis

25 (12)

0 (0)

3 (2)

0 (0)

Rhinitis

20 (10)

0 (0)

4 (2)

0 (0)

28 (14)

7 (4)

1 (1)

Infections

In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer patients at the recommended human dose). Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Musculoskeletal and connective tissue disorders Back Pain

41 (20)

Arthralgia

37 (18)

2 (1)

29 (15)

2 (1)

16 (8)

1 (1)

29 (15)

2 (1)

Myalgia

6 (3)

Respiratory, thoracic and mediastinal disorders

Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TORISEL.

Dyspnea

58 (28)

18 (9)

48 (24)

11 (6)

Cough

53 (26)

2 (1)

29 (15)

0 (0)

Epistaxis

25 (12)

0 (0)

7 (4)

0 (0)

Skin and subcutaneous tissue disorders

Monitoring Laboratory Tests In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion. ADVERSE REACTIONS The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label (see WARNINGS AND PRECAUTIONS).

The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

All Grades* n (%)

Any

Concomitant use of TORISEL with sunitinib The combination of TORISEL and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest).

Hypersensitivity Reactions Hyperglycemia/Glucose Intolerance Interstitial Lung Disease Hyperlipemia Bowel Perforation Renal Failure

IFN- n=200

Rash e

97 (47)

10 (5)

14 (7)

0 (0)

Pruritus

40 (19)

1 (1)

16 (8)

0 (0)

Nail Disorder

28 (14)

0 (0)

1 (1)

0 (0)

Dry Skin

22 (11)

1 (1)

14 (7)

0 (0)

Acne

21 (10)

0 (0)

2 (1)

0 (0) 0 (0)

Nervous system disorders Dysgeusiaf

41 (20)

0 (0)

17 (9)

Insomnia

24 (12)

1 (1)

30 (15)

0 (0)

9 (4)

0 (0)

27 (14)

4 (2)

Depression

* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a

Includes edema, facial edema, and peripheral edema

b Includes

aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis

c

Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster


d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary

tract infection

e

Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash

f

Includes taste loss and taste perversion

The following selected adverse reactions were reported less frequently (<10%). Gastrointestinal Disorders – Fatal bowel perforation occurred in 1 patient (1%). Eye Disorders – Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%). Immune System – Allergic/Hypersensitivity reactions occurred in 18 patients (9%). Angioneurotic edema-type reactions have been observed in some patients who received TORISEL and ACE inhibitors concomitantly. Infections – Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%). General Disorders and Administration Site Conditions – Impaired wound healing occurred in 3 patients (1%). Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 patients (2%), including rare fatalities. Vascular – Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%). Table 2—Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Laboratory Abnormality

IFN- n=200

All Grades* n (%)

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

162 (78)

195 (98)

144 (72)

Hemoglobin Decreased

195 (94)

41 (20)

180 (90)

43 (22)

Lymphocytes Decreased**

110 (53)

33 (16)

106 (53)

48 (24)

Neutrophils Decreased**

39 (19)

10 (5)

58 (29)

19 (10)

Platelets Decreased

84 (40)

3 (1)

51 (26)

0 (0)

Leukocytes Decreased

67 (32)

1 (1)

93 (47)

11 (6)

Alkaline Phosphatase Increased

141 (68)

7 (3)

111 (56)

13 (7)

AST Increased

79 (38)

5 (2)

103 (52)

14 (7)

Creatinine Increased

119 (57)

7 (3)

97 (49)

Glucose Increased

186 (89)

33 (16)

Phosphorus Decreased

102 (49)

Any Hematology

Agents Inhibiting CYP3A Metabolism Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2fold compared to TORISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered. (see Dosage and Administration in full Prescribing Information). Interactions with Drugs Metabolized by CYP2D6 The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of TORISEL was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D (see WARNINGS AND PRECAUTIONS, Pregnancy). Nursing Mothers It is not known whether TORISEL is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of TORISEL) in animal studies, a decision should be made whether to discontinue nursing or discontinue TORISEL, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of TORISEL in pediatric patients have not been established. Geriatric Use Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Renal Impairment No clinical studies were conducted with TORISEL in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of TORISEL is recommended in patients with renal impairment. TORISEL has not been studied in patients undergoing hemodialysis. Hepatic Impairment TORISEL was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Table 3—Adverse Reactions in Patients With Advanced Malignancies Plus Normal or Impaired Hepatic Function Hepatic Function*

TORISEL Dose Range

Adverse Reactions Grade ≥ 3** n (%)

Death*** n (%)

Normal (n=25)

25 – 175

20 (80.0)

2 (8.0)

Mild (n=39)

10 – 25

32 (82.1)

5 (12.8)

2 (1)

Moderate (n=20)

10 – 25

19 (95.0)

8 (40.0)

128 (64)

6 (3)

Severe (n=24)

7.5 – 15

23 (95.8)

13 (54.2)

38 (18)

61 (31)

17 (9)

10

1 (50.0)

0 (0)

16 (8)

2 (1)

25 (13)

4 (2)

Total Cholesterol Increased

181 (87)

5 (2)

95 (48)

2 (1)

Triglycerides Increased

173 (83)

92 (44)

144 (72)

69 (35)

43 (21)

11 (5)

15 (8)

0 (0)

Chemistry

Total Bilirubin Increased

Potassium Decreased

* NCI CTC version 3.0 ** Grade 1 toxicity may be under-reported for lymphocytes and neutrophils. DRUG INTERACTIONS Agents Inducing CYP3A Metabolism Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to TORISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered (see Dosage and Administration in full Prescribing Information).

TRS00216/282520

Liver Transplant (n=2)

* Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3 x ULN; severe = bilirubin >3 x ULN; liver transplant = any bilirubin and AST. ** Common Terminology Criteria for Adverse Events, version 3.0, including all causality. *** Includes deaths due to progressive disease and adverse reactions. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic Impairment). OVERDOSAGE There is no specific treatment for TORISEL intravenous overdose. TORISEL has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of TORISEL greater than 25 mg. This brief summary is based on TORISEL Prescribing Information W10524C011 ET01, revised 09/10. © 2010, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101

© 2011 Pfizer Inc.

All rights reserved.

Printed in USA/April 2011


The ASCO Post  |   JULY 1, 2011

PAGE 24

2011 ASCO Annual Meeting Hematology

Plenary Report: High-dose Methotrexate Improves Outcome for High-risk Acute Lymphoblastic Leukemia in Younger Patients By Alice Goodman

H

igh-dose methotrexate achieved superior event-free survival rates compared with standard Capizzi (escalating) methotrexate treatment in children and young adults with high-risk acute lymphoblastic leukemia (ALL), according to a practice-changing study reported during the Plenary Session of the 2011 ASCO Annual Meeting.1

Eric Larsen, MD

“Methotrexate has been around for a long time. The Children’s Oncology Group (COG) planned this study almost 10 years ago in an effort to optimize the use of an older agent in childhood ALL. The trial was halted early [in January 2011] when a planned interim analysis showed clear superior-

ity of the high-dose arm,” stated lead author Eric Larsen, MD, Barbara Bush Children’s Hospital, SEE PAGE 39 Maine Medical Center, Portland. Although methotrexate is a key component in treating childhood ALL, before this trial the best way to use this agent was not established, Dr. Larsen explained. Additionally, a trend had been seen toward increased central nervous system failure relative to marrow failure in this setting. COG AALL0232 was designed to evaluate two different established methods of administering methotrexate in children with high-risk ALL, with the goal of reducing central nervous system failure. In 2004, 3,154 patients aged 1 to 30 years with newly diagnosed high-risk Bcell precursor ALL were randomized to receive standard Capizzi methotrexate followed by asparaginase (Elspar) or high-dose methotrexate with leucovorin rescue. continued on page 26

Expert Point of View

T

he acute lymphoblastic leukemia study presented by Eric Larsen, MD, during the 2011 ASCO Plenary Session “was designed to test intensified CNS-directed therapy during the interim maintenance phase of treatment. CNS control is an important issue. Although CNS involvement occurs in less than 10% of cases, CNS relapse has increased while bone marrow relapse has decreased,” said Martin Tallman, MD, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center in New York and formal discussant of the trial. Martin Tallman, MD “The study found fewer marrow relapses and fewer isolated CNS relapses with high-dose methotrexate.” Childhood ALL represents one of the great triumphs in oncology, with very high cure rates, Dr. Tallman continued. The present study showed a 7% difference in 5-year event-free survival favoring high-dose methotrexate, “demonstrating that we can improve survival in this disease even further,” he commented. “High-dose methotrexate should be a new standard of care for childhood ALL.” Issues for future study include elucidating the mechanism of methotrexate resistance, study of “pediatric-inspired” therapies for adult ALL (which has much lower cure rates), and de-escalation of methotrexate doses. Dr. Tallman cited lessons from this trial that could be applied to adults with ALL. These include the importance of sequential trials in improving outcomes and the importance of accrual of all patients with an uncommon disease to clinical trials. The study also showed that improvement in outcomes can occur without new agents, but with different uses of older ones. Financial Disclosure: Dr. Tallman reported no potential conflicts of interest.

Plenary Report: Busulfan/Melphalan Improves Survival in High-risk Neuroblastoma Patients, Phase III Study Results Show

Pediatric Oncology

By Alice Goodman

M

yeloablative therapy with a busulfan (Busulfex, Myleran)/ melphalan combination (BuMel) was superior to a regimen of carboplatin/etoposide/melphalan (CEM) in pediatric patients with high-risk neuroblastoma, according to results of the large, phase  III HR-NBL1/ SIOPEN trial presented at the 2011 ASCO Annual Meeting.1 Three-year

event-free and overall survival rates were both significantly higher in BuMel-treated patients, with the strongest effect in patients with residual disease.

‘Extraordinary’ Survival “Three-year event-free survival of 49% [in the BuMel arm] is extraordinary,” remarked lead author

Myeloablative Therapy for Neuroblastoma ■■ In pediatric patients with high-risk neuroblastoma who received rapid COJEC induction and achieved a good response to induction therapy, busulfan/melphalan achieved superior 3-year event-free and overall survival with less toxicity, compared with carboplatin/etoposide/ melphalan.

■■ Myeloablative therapy with busulfan/melphalan should be the new

standard of care for this discrete population of patients with high-risk neuroblastoma.

■■ Improved induction regimens are needed to boost survival.

Ruth Ladenstein, MD, of St. Anna Children’s Hospital and Research Institute, Austria. “This study shows that the choice of myeloablative therapy matters. BuMel should be the standard of care [in high-risk neuroblastoma].” Neuroblastoma is the most common extracranial solid tumor of childhood, and 50% of patients are high-risk at diagnosis. High-risk features include advanced disease (widespread dissemination to bone and other sites), age greater than 18 months, MYCN amplification, and diploid DNA content. Long-term survival is less than 40% at 5 years. High-risk neuroblastoma is currently treated by intensive multiagent induction chemotherapy SEE PAGE 39 and surgery, fol-

Ruth Ladenstein, MD

lowed by myeloablative therapy and stem-cell rescue, then radiation and maintenance therapy. “This is one of the few tumors where the role of myeloablative therapy is established over chemotherapy,” Dr. Ladenstein said.

Study Specifics Of 1,577 patients with high-risk neuroblastoma, 563 were randomly ascontinued on page 26


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

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

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

Cosponsored By

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

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

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

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The ASCO Post  |   JULY 1, 2011

PAGE 26

News

ALL in Younger Patients continued from page 24

Key Data

The 5-year event-free survival rate was 82% in the experimental arm vs 75% in the Capizzi methotrexate arm (P = .006). Event-free survival rates at

5 years were 86% vs 82% (P = not significant) among rapid early responders, and 79% vs 65% (P = .04) among slow early responders, in the highdose and Capizzi methotrexate arms, respectively. At the interim analysis, patients in the Capizzi methotrexate

Methotrexate in Acute Lymphoblastic Leukemia ■■ High-dose methotrexate improved event-free survival in children and young adults with high-risk acute lymphoblastic leukemia.

■■ High-dose methotrexate was superior to standard methotrexate

for 5-year event-free survival, with fewer treatment failures and less toxicity.

■■ High-dose methotrexate should be a new standard of care for high-risk acute lymphoblastic leukemia in children and young adults.

BuMel Improves Survival continued from page 24

signed in a 1:1 ratio to either BuMel or CEM following rapid induction therapy with cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (COJEC). At randomization, median age was 3 years, with 347 males and 216 females. Median follow-up was 3.5  years when the trial was stopped because a prespecified interim analysis showed a 49% event-free survival rate with BuMel vs 33% for CEM (P < .001). Three-year overall survival was 60% for BuMel vs 48% for CEM (P = .003), and the rate of relapse or progression

Drug Regimens Cited in This Report ■■ BuMel = busulfan and melphalan

■■ CEM = carboplatin, etoposide, and melphalan

■■ COJEC = cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide

was significantly lower in the BuMel group (47% vs 60%; P  <  .001). BuMel showed an impact by stage: 3-year event-free survival in stage IV patients was 43% for BuMel vs 29% for CEM (P = .001). For stage II and III patients, 3-year event-free survival was 84% for BuMel vs 65% for CEM, but this difference was not statistically significant. A multivariate analysis found that BuMel was significantly associated with improved event-free survival (P < .001). Moreover, the benefits of BuMel did not come at a cost of greater toxicity. The frequency of grade  3 or 4 infection, fever, and renal toxicity was higher in the CEM arm. BuMeltreated patients had no renal toxicity. The rate of acute toxic death was 3% for BuMel and 5% for CEM; severe toxicity in the first 100 days following treatment initiation (including death and admission to the ICU) was reported in 4% of BuMel patients vs 10% of CEM patients (P = .012). The rate of venous occlusive disease, which was reversible, was much higher in the BuMel arm.

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

arm were allowed to cross over to highdose methotrexate when feasible. Fewer treatment failures occurred in the high-dose methotrexate arm; 68 marrow failures were reported in the Capizzi methotrexate arm vs 42 in the high-dose methotrexate arm; a total of 68 and 32 central nervous system failures occurred in the two arms, respectively. Adverse events were closely monitored, and no increased toxicity was observed for high-dose methotrexate vs Capizzi methotrexate. Febrile neutropenia occurred in fewer patients treated with high-dose methotrexate vs Capizzi methotrexate (5.1% vs 8.2%, respectively; P = .006). No sta-

tistically significant differences were observed between the two arms in acute neurotoxicity, osteonecrosis, or other clinically relevant toxicities.

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

Reference 1. Larsen EC, Salzer WL, Devidas M, et al: Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate (C-MTX) plus asparaginase (C-MTX/ ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. 2011 ASCO Annual Meeting. Abstract 3. Presented June 5, 2011.

Expert Point of View

A

t the ASCO Plenary Session where the HRNBL1/SIOPEN trial was presented, formal discussant Julie R. Park, MD, of the University of Washington, Seattle, said, “Large randomized trials have previously shown that myeloablative therapy improves outcomes in high-risk neuroblastoma, and it is now considered standard of care.” Dr. Park explained that the COJEC regimen used in this study may have contributed to the Julie R. Park, MD lower-than-expected 3-year event-free survival in the CEM arm. Previous studies conducted by the Children’s Oncology Group achieved a 3-year event-free survival of 46% with CEM, but those studies used a different induction regimen with lower doses of cisplatin and etoposide and did not include carboplatin. “It is possible that rapid COJEC had a negative interaction with CEM, but not BuMel,” she said. “The SIOPEN trial is a great achievement and shows the unity of 20 European nations. This study confirms the importance of myeloablative therapy in a cohort of high-risk neuroblastoma with a good response,” Dr. Park stated. She said that improved induction regimens should be a focus of future research so that cure rates can be increased.

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

Reference 1. Ladenstein RL, Poetschger U, Luksch R, et al: Busulphan-melphalan as a myeloablative therapy (MAT) for high-

risk neuroblastoma: Results from the HRNBL1/SIOPEN trial. 2011 ASCO Annual Meeting. Abstract 2. Presented June 5, 2011.

Coming in the July 15, 2011 Issue of The ASCO Post Comprehensive coverage of the 2011 ASCO Annual Meeting, including reports on:

■■ Second Primary Malignancies in Multiple Myeloma

■■ Bevacizumab in High-Risk and Recurrent Ovarian Cancer

■■ Targeted and Maintenance Therapies for Non-Small Cell Lung Cancer

■■ Role of Exemestane in the Prevention of Breast Cancer

Plus much more from the Annual Meeting, along with important columns, features, and clinical departments.

Visit The ASCO Post online at ASCOPost.com.


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

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

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

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

STARTS STRONG. LASTS LONG.

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


The ASCO Post  |   JULY 1, 2011

PAGE 28

News Multidisciplinary Management

Vanderbilt Oncologists Partner with Cardiologists to Research Chemotherapy-related Cardiac Toxicity By Caroline Helwick

C

ardiac toxicity related to chemotherapy is not a new topic but it is an increasingly important

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

one, as concerns are no longer limited to the anthracyclines. Targeted agents unfortunately “target” the

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

cardiovascular system as well, especially bevacizumab (Avastin), trastuzumab (Herceptin) when given with

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

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

the anthracyclines, and the oral tyrosine kinase inhibitors. A number of studies suggest the problem of chemotherapy-related cardiotoxicity is underestimated and underappreciated. In the Dana-Farber Sunitinib Cardiac Study of 75 patients receiving sunitinib (Sutent) for gastrointestinal stromal SEE PAGE 39 tumors (with normal cardiovascular parameters at baseline), 11% experienced a cardiovascular event and 8% developed class III heart failure.1 Hypertension developed in 47% of the patients after only four cycles, including grade 3 hypertension in 17%. In a meta-analysis from Stony Brook University Medical Center, Stony Brook, New York, the use of bevacizumab in clinical trials increased the incidence of grade 3/4 hypertension fivefold over regimens that excluded this drug.2 And in a review from Moffitt Cancer Center & Research Institute, Tampa, Florida, investigators reported a 35% rate of trastuzumab-related cardiotoxicity, which was asymptomatic in most patients.3

Clinicians Are Proactive Oncologists must be concerned, therefore, about protecting the heart and blood vessels while treating the tumor. Clinicians and research scientists at Vanderbilt-Ingram Cancer Center, Nashville, not only appreciate this, but have developed a collaborative approach that partners oncologists with cardiologists. “The need for this became apparent to me 2  years ago when I began to see patients with cardiac complications from chemotherapy,” said David Slosky, MD, a cardiologist. Anthracyclines were initially to blame, but as the use of targeted agents grew, so did the volume of patients he saw. “As a result of newer agents, we began to see a number of issues besides reduction in leftventricular ejection fraction, such as hypertension and arrhythmias. In researching the problem, I found there was no systematic approach to managing these patients.” Dr. Slosky, along with Department Chair Douglas Sawyer, MD, PhD, set


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News

up a clinic in which oncologists could easily refer patients to cardiologists who were attuned to chemotherapyrelated problems. “We wanted to be able to co-manage patients with cardiovascular comorbidities that exist at the time of a cancer diagnosis or that develop during chemotherapy. The overall theme is the management of two different diseases. The implications are profound,” he said. “We have a lot of experience in taking care of these types of patients. Our goal now is to bring this knowledge to the oncology community,” Dr. Slosky added. “Vanderbilt is a university medical center with a spirit of collaboration. We hope we are creating a model that can be used in other places.” Ingrid Mayer, MD, a breast cancer specialist at Vanderbilt, said the collaboration has improved the care of her patients with underlying cardiac conditions, and has helped protect the hearts of her long-term survivors. “A partnership between oncologists and cardiologists can troubleshoot situations that we encounter with targeted therapies—for example, conduction problems like QT prolongation. It’s not just about ejection fraction anymore,” she agreed with Dr. Slosky. “We are learning how to spare our pa-

Cardio-oncology Programs Nationwidea ■■ Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston

■■ Duke University Medical Center, Durham, North Carolina

■■ Presbyterian Healthcare, Charlotte, North Carolina

■■ Stanford Hospital and Clinics, Palo Alto, California

■■ University of Kansas Hospital Cancer Center, Kansas City

■■ University of Minnesota Physicians Heart at Fairview, Twin Cities and Greater Minnesota locations

■■ University of Rochester Medical Center, Rochester, New York

■■ UW Health, Madison, Wisconsin ■■ Yale Cancer Center, New Haven, Connecticut

This list is not all-inclusive.

a

tients these long-term complications.” The result of collaborative management is early recognition of the potential for problems. Patients are more likely to remain on medications they need for their heart, more likely to be prescribed cardioprotective drugs, and less likely to discontinue chemotherapy for cardiac reasons.

Quick Response to Problems The clinic operates more or less “as needed.” Vanderbilt oncologists, who are trained to be alert to cardiac signals and risk factors, simply phone Dr. Slosky, Dr. Sawyer, or Daniel Lenihan, MD, directly when they have concerns. Patients are seen almost immediately, so there is little delay in chemotherapy.

David Slosky, MD

Where Oncology and Cardiology Meet ■■ Numerous studies suggest chemotherapy-related cardiotoxicity is

underestimated, with the rising use of targeted agents accompanied by effects on the heart not typically seen with the anthracyclines.

■■ Vanderbilt-Ingram Cancer Center physicians have set up a clinic where oncologists can refer patients to cardiologists who are attuned to chemotherapy-related problems.

■■ A variety of trials are ongoing involving the intersection of these two fields,

and a number of cancer centers nationwide have implemented programs in cardio-oncology.

Opportunities for Research Vanderbilt faculty are not just helping today’s patients, but are also leading clinical trials and basic science experiments. Dr. Lenihan is heading up the

Ingrid Mayer, MD

If necessary, their cardiovascular care is optimized before chemotherapy is started. A dedicated echocardiographer performs all exams so that serial testing is consistent. Oncologists and cardiologists also meet monthly to review informative cases. Emily Chan, MD, PhD, a gastrointestinal cancer specialist, said the collaboration has raised awareness on both sides of the coin. “Both specialties now have greater awareness that oncology and cardiology are intertwined. Many of our drugs have shortor long-term implications for other organ systems.” She also said the university setting facilitates such collaboration. “In private practice, oncologists don’t always have easy and fast access to cardiologists. Here, if I am concerned about a patient and need cardiac clearance to start chemotherapy, I can set this up quickly. And if I have a question about an EKG, for example, I can talk directly to the cardiologists. They are willing to help us in every way.” “We have a tacit agreement,” added Dr. Mayer. “I can call these doctors any time, and they will see my patients as soon as possible.”

Emily Chan, MD, PhD

PREDICT trial, which is evaluating potential biomarkers of cardiac damage, including B-type natriuretic peptide and troponin I. “If we identify these markers, we can treat patients early to ameliorate cardiotoxicity,” Dr. Slosky said. Previous studies have suggested that early intervention of troponin-positive patients improves cardiac outcomes. “This is very exciting,” he added. “Typically, we do an echocardiogram or MUGA scan, and if we see significant cardiac dysfunction we initiate treatment. Measuring biomarkers moves this curve significantly.” Dr. Sawyer is interested in the mechanisms of action of chemotoxic agents, and his research aims to predict the cardiac effects of new agents. Other studies are evaluating the benefit of treating patients with underlying cardiac problems with ACE inhibitors or angiotensin blockers. The effect of exercise on cardiac function during chemotherapy is another research area, based on animal models showing adverse effects of exercise during treatment with anthracyclines. “Dr. Sawyer obtained data in animals. We are now designing a study in pa-

tients,” Dr. Slosky noted. Another Vanderbilt-led study is exploring the effect of statins on reducing the risk for thromboembolism in patients with cancer. Dr. Slosky is also developing a registry of Vanderbilt cancer patients to facilitate enrollment in trials of chemotherapy-related cardiotoxicity. The Vanderbilt cardiologists’ work is not confined to their own institution. Dr. Lenihan, together with Carlo Cipolla, MD, of Milan, Italy, wanted a more formal appreciation of the problem and thus started the International CardiOncology Society 4 years ago, which attracted 150 clinicians and scientists to its last annual meeting (www.cardioncology.it). The society’s goal is the education of clinicians and the development of research protocols and clinical guidelines.

Financial Disclosures: Dr. Slosky and Dr. Mayer reported no potential conflicts of interest. Dr. Chan has reported a compensated consultant or advisory relationship with Amgen, Genentech, Pfizer, sanofi-aventis, ImClone, Bristol-Myers Squibb, and Celgene. She has reported receiving research funding from Astellas, Pfizer, Genentech, Amgen, Idera, Merck, Bristol-Myers Squibb, Lilly, ImClone, and MethylGene.

References 1. Chu TF, Rupnick MA, Kerkela R, et al: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011-2019, 2007. 2. Pulipati BC, Chu D, Wu S: The incidence and risk of high-grade hypertension in cancer patients treated with bevacizumab: A meta-analysis of randomized controlled studies. American College of Cardiology 58th Annual Scientific Session. Abstract 1001-303. Presented March 29, 2009. 3. Reynolds CC, Hartlage G, Patel V, et al: Trastuzumab cardiotoxicity: Not as benign as it looks? American College of Cardiology 58th Annual Scientific Session. Abstract 1033-191. Presented March 30, 2009.


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Investigational Agents Lung Cancer

Understanding Crizotinib, 1 Year after High-profile Presentation

T

he findings from a phase I study of crizotinib in non–small cell lung cancer (NSCLC) were presented in a Plenary Session at the 2010 ASCO Annual Meeting—an unusual event, since such early-phase data are not generally the topic of plenary sessions. The study showed that a majority of mostly pretreated patients bearing rearrangements of the anaplastic lymphoma kinase (ALK) gene had response or stable disease SEE PAGE 39 with crizotinib treatment. ALK rearrangements appear to be present in approximately 5% of patients with NSCLC, suggesting that some 10,000 new cases of NSCLC with ALK rearrangements may occur each year in the United States. Since the announcement of results of the phase I study at the 2010 ASCO Annual Meeting, FDA has fast-tracked the new drug application (NDA) for crizotinib; the rolling submission of the NDA was recently completed. A phase III trial has been initiated to assess crizotinib vs standard-of-care therapy in ALK-positive patients for whom one prior platinum-based treatment has failed. There is considerable excitement over the potential for ALK rearrangements to define a subgroup of tumors in NSCLC and other cancers.

Mutations and Mechanisms Activating mutations or translocations of the ALK gene have been identified in several types of cancer in addition to NSCLC, including anaplastic large-cell lymphoma, neuroblastoma, and inflammatory myofibroblastic tumor. These alterations lead to activation of ALK, a tumor-specific protein

involved in tumor cell growth and survival signaling pathways; inhibition of ALK can block these pathways, leading to stabilization or regression of tumors. The genetic rearrangements are evident in oncogenic fusion genes, including EML4-ALK, which is found in NSCLC. This aberrant fusion gene encodes a cytoplasmic chimeric protein with constitutive kinase activity. Multiple EML4-ALK chimeric variants have been identified (representing different breakpoints in various EML4 exons), with all being transforming in vitro. In the phase I study of crizotinib, although all patients had ALK rearrangements, not all patients could be identified as harboring EML4-ALK. Other, rarer fusion partners for ALK have been found in NSCLC, including KIF5B and TFG. Numerous potential downstream targets of EML4-ALK and TGF-ALK fusion proteins involved in cell-cycle progression, proliferation, and survival have been identified (Fig.1). In NSCLC, EML4-ALK rearrangements are more common in never-smokers or those with a history of light smoking and in those with adenocarcinomas. ALK gene rearrangements are rarely coincident with EGFR, HER2, or KRAS mutations, indicating that these rearrangements define a distinct disease subtype that is not likely to respond to inhibitors of the other targets. Crizotinib is a first-in-class selective, ATP-competitive, oral small-molecule inhibitor of ALK and c-Met/ hepatocyte growth factor receptor (HGFR) tyrosine kinases and their oncogenic variants (eg, ALK or c-Met/HGFR mutant variants). Crizotinib shows dose-dependent inhibition of phosphorylation of ALK and c-Met/HGFR and selected variants as well as inhibition of their kinase target-

Crizotinib at a Glance ■■ Phase I trial in ALK-positive NSCLC shows response rate of 57% and disease control rate of 87% in largely pretreated patients.

■■ Crizotinib NDA for NSCLC fast-tracked; rolling submission was recently completed.

■■ Phase III trial underway comparing crizotinib vs standard of care (pemetrexed or docetaxel) in ALK-positive NSCLC patients with disease progression after one prior line of chemotherapy including a platinum drug.

■■ Crizotinib-resistant EML4-ALK mutants identified in NSCLC patient losing response to crizotinib (L1196M, C1156Y).

■■ Response to crizotinib observed in patient with ALK-positive inflammatory myofibroblastic tumor.

■■ Studies of crizotinib in ALK-positive cancers other than NSCLC are underway.

Artwork by Alexandra and David Baker © 2011 DNA Illustrations, Inc.

By Matthew Stenger

Fig. 1: Signaling pathways activated by ALK fusion proteins. Reprinted with permission from Hallberg and Palmer.3 © 2010 Massachusetts Medical Society.

dependent functions in tumor cells both in vitro and in vivo. Crizotinib exhibits potent and selective growth inhibitory activity against tumor cells exhibiting amplification of the c-Met/HGFR gene locus or translocation/inversion of the ALK gene locus—eg, EML4-ALK or NPM-ALK fusion variants.

Phase I Data Complete data from the phase I study were reported by Kwak and colleagues in a 2010 New England Journal of Medicine article.1 In this study, 82 patients with advanced NSCLC who were fluorescence in situ hybridization (FISH)-positive for ALK rearrangements received crizotinib in escalating doses of 50 mg once daily to 300 mg twice daily (primarily 250 mg twice daily). Patients (52% male) had a mean age of 51 years, 94% had received at least one prior therapy for NSCLC, 96% had adenocarcinoma, and 76% had never smoked.

Of 82 patients, 46 had a confirmed partial response and 1 had a complete response, for an overall response rate of 57%. An additional 27 (33%) had stable disease (including 5 with an unconfirmed partial response). The 8-week disease control rate was 87% (71 of 82 patients). All patient samples tested for MET amplification were negative, indicating that the MET inhibitory activity of crizotinib was not a determinant of response in these patients. Grade 1 nausea and diarrhea were the most common side effects, and visual disturbance occurred in 41% of patients. Grade 3 or 4 adverse events consisted of ALT elevation and AST elevation in 6% of patients each, lymphopenia in 2%, and hypophosphatemia, neutropenia, hypoxia, pneumonitis, and pulmonary embolism in 1% each. After a median follow-up of 6.4 months, the estimated 6-month progression-free survival was 72%. continued on page 34


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Investigational Agents

Understanding Crizotinib continued from page 33

Other Trials

A number of other trials of crizotinib in ALK-positive NSCLC are underway. A large single-arm, open-label phase II study (PROFILE 1005) of crizotinib 250 mg twice daily in patients with

advanced NSCLC who have received previous treatment is underway (clinicaltrials.gov identifier NCT00932451). The target enrollment is 400 patients. The primary outcome measures are objective response rate and safety. A pivotal phase III randomized, open-label trial (PROFILE 1007) is

comparing crizotinib (250 mg twice daily continuously) vs standard-of-care therapy consisting of pemetrexed (500 mg/m2 IV on day 1 of 21-day cycle) or docetaxel (75 mg/m2 IV on day 1 of 21-day cycle) as second-line treatment in patients with disease progression after chemotherapy that included a plati-

num drug (clinicaltrials.gov identifier NCT00932893). Target enrollment is 318 patients. The primary outcome measure is progression-free survival. Patients in whom disease progresses on standard-of-care treatment are eligible to cross over to crizotinib treatment in the phase II trial described above. Other studies of crizotinib in NSCLC that are currently recruiting patients include a phase I/II study of the addition of crizotinib to erlotinib (clinicaltrials.gov identifier NCT00965731). In a phase III trial, crizotinib is also being compared with pemetrexed plus carboplatin or cisplatin in previously untreated patients with ALK-positive non-squamous cell carcinoma of the lung (clinicaltrials.gov identifier NCT01154140).

Other Mutations Two other reports on crizotinib during the past year are of interest. Choi and colleagues2 identified two mutations in EML4-ALK—C1156Y and L1196M—that confer resistance to crizotinib, both being identified in a patient with NSCLC who had an initial strong response to crizotinib. The L1196M mutation represents a mutation of the gatekeeper residue of the ALK kinase domain (similar to T790M EGFR and T315I ABL drug-resistance mutations) that could prevent crizotinib binding to ALK. Although it would not appear to have a direct effect on crizotinib binding, the effect of the C1156Y mutation is at present unclear.3 The mutants identified by Choi et al were less sensitive to crizotinib than wild-type EML4-ALK in cell culture, consistent with the loss of clinical response in the NSCLC patient. The loss of sensitivity of the C1156Y variant to crizotinib was greater in vivo than in vitro, indicating that resistance associated with this mutation may involve interaction with additional cell factors. The absence of response to crizotinib in patients in the phase I trial may be related to development of or selection for resistance mutants, raising the likelihood that additional ALK inhibitors will be needed to target crizotinib-resistant disease. Another report describes a sustained partial response to crizotinib in a patient with an abdominopelvic inflammatory myofibroblastic tumor with an ALK rearrangement (RANBP2-ALK fusion) and no response in another patient with inflammatory myofibroblastic tumor and no ALK rearrangement.4 In the responding patient, who continued on page 35


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PAGE 35

2011 ASCO Annual Meeting Genitourinary Cancer

Sunitinib/Prednisone Improves Progression-free Survival but not Overall Survival in Metastatic Castrate-resistant Prostate Cancer By Larry J. Rosenberg, PhD

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ccording to M. Dror Michaelson, MD, PhD, second-line therapy with sunitinib (Sutent) and prednisone improves progression-free survival but not overall survival in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel-based chemotherapy. Dr. Michaelson, of the Massachusetts General Hospital in Boston, recently presented these findings at the 2011 ASCO Annual Meeting.1

trial compared the combination of sunitinib and prednisone to prednisone alone in men with metastatic castrateresistant prostate cancer.

Expert Point of View

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hilip W. Kantoff, MD, of the Dana-Farber Cancer Institute, emphasized that this was essentially a negative study. “There is no evidence that VEGFRtargeted agents provide a survival benefit for men with advanced prostate cancer,” he indicated. “With shrinking resources and a rapidly improving understanding of the genetic and biologic basis of disease, we need to be more selective about what agents to bring forward to be tested in the phase III setting” said Dr. Kantoff.

Study Design and Results Eligible patients were required to have metastatic castrate-resistant prostate cancer and progressive disease, with resistance or intolerance to docetaxel. Patients were stratified by Eastern Cooperative Oncology Group performance status, type of disease progression (prostate-specific antigen–based only or radiographic), docetaxel-resistant or docetaxel-intolerant status, and prior therapy with a vascular endothelial growth factor (VEGF) inhibitor. Enrolled patients were randomly assigned in a 2:1 ratio to treatment with prednisone at 5 mg twice daily combined with either placebo or sunitinib at 37.5 mg on a continuous once-daily dosing schedule. The primary endpoint of the study was overall survival, with secondary endpoints of radiographic progression-free survival and decrease in pain. A total of 873 men were randomized to receive sunitinib (n = 584) or placebo (n = 289). Median age was 68 years, and 49% of patients had a Gleason score ≥ 8. The trial was stopped after a second futility analysis in September 2010. In data collected through February 2011, the median treatment duration was 3.7 months (range, 0−23.2) on the sunitinib

Financial Disclosure: Dr. Kantoff has been a consultant for Progenics Pharmaceuticals, Inc, Amgen USA, Tokai, BN ImmunoTherapeutics, Ortho Biotech, Bellicum, Genentech, and Johnson & Johnson. He has served on the science advisory board for BIND Biosciences, Inc, and the data safety monitoring boards for Celgene, Millennium, and OncoGeneX. Philip W. Kantoff, MD

■■ The toxicity profile of sunitinib was consistent with that previously

arm and 3.4 months (range, 0−22.1) on the placebo arm. Progression-free survival was significantly greater on the sunitinib arm than the placebo arm (5.6 vs 3.7 months; HR = 0.74; P = .0022), although overall survival was not significantly different (13.1 vs 11.7 months; HR = 0.91; P = .1630, stratified log-rank test for both). The overall response rate with sunitinib was also significantly higher compared with placebo (6.1% vs 1.8%; P = .04). The safety profile for sunitinib was consistent with that previously reported in castrate-resistant prostate cancer and other tumor types, Dr. Michaelson noted. Leading treatment-related grade 3/4 adverse events with sunitinib and placebo were fatigue (16.5% vs 3.5%) and anemia (5.5% vs 2.5%). Substantially more patients in the placebo group discontinued treatment due to disease progression (50% vs 31%), while more patients in the sunitinib arm discontinued due to adverse events (26% vs 6%).

■■ Further analysis may determine whether select subpopulations of men

Would Subgroups Benefit More?

M. Dror Michaelson, MD, PhD

First-line therapy for men with metastatic castrate-resistant prostate cancer generally consists of docetaxel-based therapy. However, there are few effective therapeutic options for patients in whom disease subsequently progresses. “A number of phase II clinical trials in advanced prostate cancer have suggested that sunitinib may have important efficacy and an acceptable safety profile,” said Dr. Michaelson. This randomized, placebo-controlled phase  III

Treating Castrate-resistant Prostate Cancer ■■ In patients with castrate-resistant prostate cancer, treatment with sunitinib

plus prednisone significantly improved progression-free survival and overall response rate compared with placebo plus prednisone, although overall survival did not significantly differ between treatment arms. reported in castrate-resistant prostate cancer and other tumor types. with castrate-resistant prostate cancer may benefit from treatment with sunitinib or other antiangiogenic therapy.

Understanding Crizotinib continued from page 34

had received prior treatment, response was substantial and rapid and persisted for at least 6  months despite a heavy tumor burden.

Other Cancers Crizotinib is being evaluated in a

number of settings outside of lung cancer. A phase I study is assessing crizotinib in patients with ALK-positive tumors other than NSCLC (clinicaltrials.gov identifier NCT01121588). A phase I/II study is examining crizotinib in children with ALK-positive relapsed/refractory solid tumors, primary CNS tumors, and anaplastic

Dr. Michaelson concluded that “progression-free survival was significantly large cell lymphoma (clinicaltrials.gov identifier NCT00939770).

References 1. Kwak EL, Bang Y-J, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010. 2. Choi YL, Soda M, Yamashita Y, et

improved in men treated with sunitinib plus prednisone compared with placebo plus prednisone, although overall survival did not significantly differ between treatment arms.” Results of this trial demonstrate that while addition of sunitinib to prednisone improved progression-free survival in patients with metastatic castrate-resistant prostate cancer, it did not increase overall survival when used in the second-line setting. It is possible that selected patient subpopulations that do exhibit a survival advantage with sunitinib may be identified with further study.

Financial Disclosure: Dr. Michaelson has been a consultant for Abbott Laboratories, AVEO, Genentech, Novartis, Pfizer, and Wyeth, and has received research funding from Abbott Laboratories, Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Wyeth.

Reference 1. Ou Y, Michaelson MD, Sengeløv L, et al: Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC). 2011 ASCO Annual Meeting. Abstract 4515. Presented June 6, 2011. al: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734-1739, 2010. 3. Hallberg B, Palmer RH: Crizotinib—Latest champion in the cancer wars? N Engl J Med 363:1760-1762, 2010. 4. Butrynski JE, D’Adamo DR, Hornick JL, et al: Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 363:1727-1733, 2010.


The ASCO Post  |   JULY 1, 2011

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FDA Update

Test Approved to Help Determine Candidacy for Trastuzumab

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he FDA has approved a new genetic test that will help healthcare professionals determine whether women with breast cancer are HER2positive and, therefore, candidates for trastuzumab (Herceptin). The test,

called Inform Dual ISH, allows for measurement of the number of copies of the HER2 gene in tumor tissue. The FDA based its approval of the Inform Dual ISH on a U.S. study involving tumor samples from 510 pa-

tients with breast cancer. This study showed that the test was effective in confirming that a patient’s tumor sample contained more than the normal number of copies of the HER2 gene in 96% of the HER2-positive

Measure and Improve the Quality of Cancer Care Participate in QOPI and discover what more than 700 registered practices already know ®

QOPI : THE QUALITY ONCOLOGY PRACTICE INITIATIVE ®

QOPI® is a practice-based quality measurement program, developed to promote excellence in cancer care. QOPI guides participating medical oncology practices through a data collection and review process that includes using a set of critical quality measures to assess practice performance, comparison of individual practice performance to national cancer care standards, a HIPAA-compliant and secure system for automated and confidential data analysis and reporting, and feedback for continuous practice improvement. Additional benefits of data collection include: • Reports which are the only ABIM-approved oncology-specific data source for use towards MOC Part IV-Practice Improvement requirements • CME credit • Fellowship program quality assessment experience • Initial step towards earning QOPI® Certification, a designation that recognizes practices that consistently achieve the highest standards of care

The fall 2011 data collection round is scheduled to start on September 22. Practices new to QOPI should register by mid-August. For more information, visit qopi.asco.org, or call 571-483-1660 to speak with a QOPI staff member.

tumor samples. Patients with more than the normal number of copies of the HER2 gene are considered candidates for trastuzumab therapy.

The study also showed that the test was effective at excluding the possibility that more than the normal number of copies of the HER2 gene were present in 92.3% of the HER2-negative tumor samples. Patients who do not have more than the normal number of copies of the HER2 gene are typically not candidates for trastuzumab therapy.

Changes Introduced to Better Inform Consumers about Sunscreen

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he FDA announced that sunscreen products meeting modern standards for effectiveness may be labeled with new information to help consumers find products that, when used with other sun protection measures, reduce the risk of skin cancer and early skin aging, as well as help prevent sunburn. The final regulation allows sunscreen products that pass the FDA’s test for protection against both ultraviolet A and ultraviolet B rays to be labeled as “Broad Spectrum.” Products with SPF values between 2 and 14 may be labeled as Broad Spectrum if they pass the required test, but only products that are labeled as Broad Spectrum and have SPF values of 15 or higher may state that they reduce the risk of skin cancer and early skin aging, when used as directed. Any product that is not Broad Spectrm, or that is Broad Spectrum but has an SPF between 2 and 14, will be required to have a warning stating that the product has not been shown to help prevent skin cancer or early skin aging. The new regulations will become effective for most manufacturers in 1  year. Manufacturers with annual sales less than $25,000 have 2 years to comply.


ASCOPost.com  |   JULY 1, 2011

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2011 ASCO Annual Meeting Colorectal Cancer

Capecitabine Noninferior to 5-FU with Improved Toxicity Profile in Rectal Cancer, Two Studies Demonstrate By Alice Goodman

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differences between the two arms were found for node positivity or for surgical complications. At the Annual Meeting, Dr. Roh reported secondary outcomes in this trial, which was a collaboration among the NSABP, North Central Cancer Treatment Group (NCCTG), Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and Southwest Oncology Group (SWOG) with an NCI-designed protocol. The trial was designed as a noninferiority trial for capecitabine vs 5-FU for local-regional disease control and sphincter preservation, and to determine whether the addition of oxaliplatin to either drug addMark S. Roh, MD Ralf Hofheinz, MD ed benefit. The study randomly asR-04 Trial signed 1,608 patients to one of four treatIn the National Surgical Adjuvant ment groups: continuous venous infuBreast and Bowel Project (NSABP) sion of 5-FU with or without oxaliplatin, R-04 trial, capecitabine plus preoperaor capecitabine with or without oxaliplative radiotherapy achieved similar outtin. The study was designed to determine comes compared with continuous vewhether the addition of chemotherapy nous infusion of 5-FU in patients with during radiation therapy will improve stage II or III rectal cancer.1 The study local-regional relapse rate, disease-free design incorporated a comparison of survival, and overall survival, and these both drugs given concomitantly with results are expected in 2013. oxaliplatin after the drug was approved MARGIT Trial in the United States. Adding oxaliplatin Long-term results of the phase III to either strategy did not improve outMARGIT trial also showed noninfericomes but did increase toxicity, espeority for capecitabine vs 5-FU as part cially grade 3 or 4 diarrhea (41% with of adjuvant or neoadjuvant chemorano oxaliplatin, 67% with oxaliplatin). diotherapy for locally advanced rectal “Administration of capecitabine with cancer.2 The study randomly assigned preoperative radiotherapy achieved 392 patients to either arm as adjuvant similar rates to continuous infusion therapy (n = 231) or neoadjuvant ther5-FU for surgical downstaging, sphincapy (n = 161) in addition to total mesoter-saving surgery, and complete pathorectal excision surgery. The side-effect logic response,” said Mark S. Roh, MD, profiles of the two drugs differed, with of MD Anderson Cancer Center Orlana greater incidence of hand-foot syndo in Orlando, Florida. No significant wo separate trials presented during an oral session at the 2011 ASCO Annual Meeting suggest that capecitabine (Xeloda) can replace fluorouracil (5-FU) as part of chemoradiotherapy for rectal cancer. Patients randomly assigned to either treatment had comparable outcomes but with less toxicity from capecitabine in both phase III trials.

Capecitabine vs Fluorouracil in Rectal Cancer R-04 Trial:

■■ Capecitabine is noninferior and has an improved side-effect profile compared to 5-FU as part of chemoradiotherapy in patients with rectal cancer.

■■ Oxaliplatin, at doses given in the trial, did not improve outcomes when added to capecitabine or 5-FU.

MARGIT Trial:

■■ Overall survival was noninferior with capecitabine vs 5-FU–based

chemoradiotherapy, and 3-year disease-free survival was superior with capecitabine.

Expert Point of View

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ormal discussant of the trial, Robert Glynne-Jones, MD, Mount Vernon Centre for Cancer Treatment, London, said: “It is arduous to perform rectal cancer trials. That is one of reason we are interested in short endpoints.” Regarding the first study, he said that historically, compliance has been poor with adjuvant therapy in this setting, but that the German R04 investigators achieved a high compliance. “This is an excellent rate of compliance and it should impact outcomes.” He also said that pathologic complete response is not an appropriate outcome to measure in a phase III trial. “The message from this trial is that we need to review our assumptions regarding oxaliplatin as a radiosensitizer when it is used in only four doses. Oxaliplatin should be given with optimized fluoropyrimidine,” he said. Dr. Glynne-Jones also said that current imaging methods overstage stage III rectal cancer. “If most patients are really stage II, we have to question a benefit for oxaliplatin. We need more accurate clinical staging in clinical trials to have more meaningful results.” Regarding the study reported by Dr. Hofheinz, Dr. Glynne-Jones said that he was uncomfortable with the control arm, with infusional 5-FU given for 2 weeks followed by bolus 5-FU. “This control arm is a problem,” he said. Infusional 5-FU should be the standard. He found the MARGIT investigators’ finding of an association between the development of hand-foot syndrome and improved disease-free and overall survival “intriguing.”

Financial Disclosure: Dr. Glynne-Jones has received research funding from Roche.

drome, proctitis, diarrhea, and fatigue in the capecitabine arm, and more alopecia and leukopenia in the 5-FU arm. “Capecitabine may replace 5-FU as perioperative treatment of locally advanced rectal cancer,” stated Ralf Hofheinz, MD, Interdisciplinary Tumour Center, Mannheim, Germany. Neoadjuvant capecitabine improved downstaging and achieved a numerically higher rate of pathologic complete response compared with 5-FU. It appears that radiotherapy given concurrently with capecitabine significantly increased the rate of diarrhea compared with concurrent radiotherapy plus 5-FU (P = .07). At 52 months of follow-up, both arms had similar rates of local recurrence: 6.1% with capecitabine vs 7.2% with 5-FU, but capecitabine was superior regarding distant metastases, with 18.8% of patients vs 27.7% in the 5-FU group. For the study’s primary endpoint of overall survival, capecitabine was noninferior to 5-FU: the 5-year overall survival rate was 75.7% for capecitabine vs 66.6% for 5-FU (P = .0004). The 3-year disease-free survival rate was superior for capecitabine: 75.2% vs 66.6% with 5-FU (P = .034). The development of hand-foot syndrome was associated with superior

3-year disease-free and 5-year overall survival, Dr. Hofheinz said. Threeyear disease-free survival was 83.2% for capecitabine-treated patients with hand-foot syndrome vs 71.4% for those patients treated with capecitabine who did not have hand-foot syndrome vs 66% for 5-FU paSEE PAGE 39 tients (P = .031); 5-year overall survival rates were 91.4%, 68%, and 66.6%, respectively (P = .001).

Financial Disclosure: Dr. Roh reported no potential conflicts of interest. Dr. Hoffheinz has been a consultant for and has received honoraria from Amgen, Merck, KGaA, and Roche, and has conducted research for Roche.

References 1. Roh MS, Yothers GA, O’Connell MJ, et al: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. 2011 ASCO Annual Meeting. Abstract 3503. Presented June 4, 2011. 2. Hofheinz R, Wenz F, Post S, et al: Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Long-term results of a randomized, phase III trial. 2011 ASCO Annual Meeting. Abstract 3504. Presented June 4, 2011.


ASCOPost.com  |   JULY 1, 2011

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Patient’s Corner

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

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

1 2

3

Simply text the word “scan” to 43588.

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

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

Scanning 2D codes When you see a code that you would like to scan, start the ScanLife application. The screen will look similar to camera mode. Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically. A short audio chime will indicate a successful scan and the phone will contact the server for further instructions. This may take up to a minute depending on data speeds and phone type.

Cancer Diagnosis Can Spark Worry over Numerous Health Concerns By Cate Dolan, as told to Jo Cavallo

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he early discovery of my endomeache and pain I experience makes me trial cancer is a prime example of nervous. A month following my radiathe health rewards you can reap if you tion treatment, I had severe lower back are lucky enough to have good medispasms and, even more alarming, my cal care and a dogged physician. Long hair started falling out. It wasn’t the kind past menopause, I wasn’t experiencing of hair loss that patients going through any of the typical warning signs of the chemotherapy describe, but it was disease—vaginal enough to send me bleeding or pelvic back to my doctors. pain—when I made Because my I had been so an appointment with symptoms seemed single-minded my gynecologist for to be unrelated to my yearly checkup. my cancer or subseabout making the It was fortunate for quent treatment, no best decisions to me that my doctor one really took them believes that pelvic seriously. But losing cure my cancer, sonograms should my hair was really I didn’t consider be part of the routine scary to me, and no the emotional gynecologic exam one had warned me for postmenopausal that it’s common to ramifications of women, and she rechave this kind of hair having this disease. ommended that I shedding following have one. major surgery. I know The test revealed that losing your hair several polyps, which turned out to be is practically irrelevant compared to havmalignant. Although getting the diagnoing cancer, but that’s where the emotional sis was initially alarming, I was quickly part of having this disease came up for me. reassured by my doctor that my cancer Preoccupation with Symptoms was in its earliest, most curable stage— I had been so single-minded about stage I—and that it was “absolutely the making the best decisions to cure my canbest of bad news.” She recommended a cer, I didn’t consider the emotional ramiradical hysterectomy and suggested that I fications of having this disease. I think get a second opinion. the emotional form my disease takes at Looking for Alternatives this time is my preoccupation with any Hoping to find an alternative to a radnew symptom I experience. Although ical hysterectomy, I got into active mode, my hair loss has subsided, I’m still having searching the Internet for information lower back problems and I have numbabout endometrial cancer and treatment ness in my lower left leg. My doctor says options and asking everyone I knew who I may have spinal stenosis and that it may had had some experience with cancer be age, injury, or treatment related. But in for advice. After a second opinion conthe back of my mind, I’m thinking, “This firmed the diagnosis and treatment plan, isn’t stenosis, it’s cancer.” I decided that I couldn’t take absolute But it’s not just cancer I’m worried charge of my cancer. I had to put my trust about these days. My family history is in my doctors. Less than 3  weeks after riddled with other serious illnesses that my diagnosis, I had the surgery. concern me. And then there’s the specter A week later, I was sitting in my onof myriad health problems that can decologist’s office for my follow-up visit. velop as part of the normal aging process. Although the surgery had gone well, exHaving cancer has taught me that it’s plained my doctor, a second pathology not enough for doctors to focus solely on report showed that cancer cells had penthe physical part of the disease. Although etrated the endometrial wall more deepI don’t expect them to be psychotheraly than first thought. She recommended pists, they also need to be sensitive and a regimen of three high-dose radiation responsive to the toll cancer takes on a treatments to kill any errant cells. patient’s emotional well-being. Although my doctors now consider Cate Dolan is a New York–based attorney me cured of my cancer (I’ll feel more specializing in project management for nonconfident of that prognosis after I pass profit organizations. the 2- and then 5-year mark), every new

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


Now Enrolling

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TAP Vol 2 Issue 10