August 2009, Vol 2, No 5 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

ASCO 2009: PAYER’S PERSPECTIVES Personalizing Cancer Care Is Oncologists Grapple with CostEffectiveness of Cancer Therapies Everyone’s Mission AUGUST 2009 I VOL 2, NO 5 I SPECIAL ISSUE

By Wayne Kuznar

By Caroline Helwick Richard Schilsky, ASCO President

ncologists desire cost-effectiveness information about treatments, but lack the confidence to interpret it, said Peter J. Neumann, ScD, Director, Center for the Evaluation of Value and Risk in Health at the Institute for Clinical Research and Health Policy Studies, Tufts–New England Medical Center in Boston, in reporting the results of a survey of oncologists during a session on the cost-effectiveness of new cancer technologies. Oncologists Conflicted on Cancer Care Cost A 2006 survey of 90 oncologists by Dr Neumann and colleagues showed that oncologists were conflicted about the role of costs in their practices. Most of the oncologists believed that all

he era of personalized medicine in oncology has begun. In fact, ASCO chose Personalizing Cancer Care as the theme of its 2009 annual meeting, “in light of our increased understanding of cancer biology and genetics, the availability of new diagnostic tools and assessments, and growing concerns about the cost and effectiveness of cancer

treatment,” said ASCO President Richard Schilsky, MD, Professor of Medicine and Associate Dean of Clinical Research, University of Chicago, in his presidential address at the meeting. Personalizing cancer care—delivering the right care to the right patient at the right time—is becoming a universal and realizable goal, he said. Continued on page 3

Maintenance Pemetrexed Therapy Extends Survival in NSCLC By Audrey Andrews

emetrexed (Alimta) as maintenance therapy for patients with advanced non–small-cell lung cancer (NSCLC) led to an improvement in overall survival and progression-free survival (PFS) in patients

enrolled in an international phase 3 trial. Lead investigator Chandra P. Belani, MD, Deputy Director of the Penn State Hershey Cancer Institute, said, “This is the first randomized, double-blind, placebo-controlled study Continued on page 13

patients should have access to cancer drugs, regardless of cost, “yet they also told us that they were increasingly considering cost in their prescribing decisions,” Dr Neumann said. They also predicted that costs would play a larger role in the next 5 years. Their implicit cost-effectiveness threshold for new cancer therapies was high— about $300,000 per life-year saved. A more recent and larger survey of 1379 US-based oncologists randomly selected from the ASCO membership list generated 790 responses. Key findings were: • Only 7% of oncologists always discuss the costs of new cancer treatments with patients, 36% frequently do, 37% occasionally do, 17% rarely do, and 3% never discuss treatment costs with patients Continued on page 6

PARP Inhibitors Promising New Class for Several Advanced Breast Cancers

nhibitors of the enzyme poly (ADPribose) polymerase (PARP) show significant activity in triple-negative and BRCA-deficient advanced breast cancer. PARP-1 Inhibitor, BSI-201 In the treatment of triple-negative breast cancer—a very aggressive cancer (30% of patients develop metastatic disease) for which no targeted therapies exist—the PARP-1 inhibitor BSI-201, when added to standard chemotherapy, significantly improved progression-free survival (PSF) and overall survival compared with chemotherapy alone,

reported Joyce O’Shaughnessy, MD, Co-Director Joyce O’Shaughnessy, MD of the Breast Cancer Research Program at the Baylor Sammons Cancer Center, Dallas. The nuclear enzyme PARP is involved in a tumor’s DNA repair mechanism and is upregulated in most triple-negative breast cancers, said Dr O’Shaughnessy. Similar to BRCA1associated cancers, triple-negative breast cancers “block the ability to repair double-stranded DNA breaks. When they block that ability, they’re reliant now on single-strand DNA repair, and that’s where PARP comes Continued on page 25

CHRONIC MYELOGENOUS LEUKEMIA BREAST CANCER OTHER ASCO NEWS PATIENT’S PERSPECTIVE PAYER’S PERSPECTIVES

22 24 28 30 31

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their ﬁrst cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic speciﬁcally approved for prevention of both acute and delayed CINV associated with MEC6* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

ALOXI® (palonosetron HCl) injection 0.25 mg is indicated 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 include headache (9%) and constipation (5%). Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapyinduced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497503. Epub November 14, 2006. 4. 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. 5. 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. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

www.ALOXI.com

Personalized Medicine Personalizing Cancer Care... Continued from page 1 The past year has seen many challenges, “but it has also been a year of great hope, as we have a new administration that is committed to curing cancer,” he said. Personalized medicine is “the new buzz word in healthcare and health policy. But what does it mean to patients and oncologists?” 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=633) (N=194) 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.

VOL. 2

NO. 5

SPECIAL ISSUE

Every Patient and Tumor Are Unique Personalized medicine is based on the concept that cancer specialists have long recognized: each patient is unique in clinical terms, treatment response, and supportive care needs. In addition, there is a growing recognition that tumors are unique. 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.

For example, KRAS mutations have become established as biomarkers for the lack of efficacy of epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, and ASCO has issued a provisional opinion calling for KRAS testing (see page 15). “Personalizing cancer care is all 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. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL350 10/08

about bringing our insights and skills from biology, medicine, engineering, informatics, social sciences, and other disciplines to solving the enormous problem of cancer,” he said. “We will increasingly be able to design optimal treatment strategies that offer the best hope of controlling cancer with the least toxicity. And with sophisticated imaging techniques…we can more quickly assess treatment efficacy. This all has the potential to substantially reduce the cost of care.”

“As oncologists, our focus has been and must remain treating the person, not the disease.”—Richard Schilsky, MD Personalized cancer care extends to end-of-life care and survival, Dr Schilsky said, encouraging oncologists to communicate with their patients “as an individual and not a statistic.” “As oncologists, our focus has been and must remain treating the person, not the disease,” Dr Schilsky said. “We must acquire the skills and devote the time and receive compensation for doing so in an optimal way.” Growing Burdens By 2030, the global cancer burden will triple and cancer will be the leading cause of death, and this will be coupled with a 30% shortfall in oncologists. As for rising costs of care, “oncologists need to be part of the conversation and the solution,” he maintains. Finally, the US clinical research infrastructure is “the best in the world,” but it is underfunded and “mired in a regulatory matrix that slows our progress and saps our energy,” said Dr Schilsky. More than 700 cancer drugs are in development, but fewer than 10% will likely be approved. “There are not enough patients, dollars, and time” to test all these “within our conventional clinical trial paradigm.” ASCO has convened an expert group to tackle some aspects of clinical trials and to produce a white paper for the FDA. Meanwhile, he advocates the use of biomarkers to streamline patient selection and preliminary marketing approval based on randomized phase 2 (rather than phase 3) trials. Currently, a phase 3 cooperative group trial requires about 400 steps and 2 years to launch. “We must fix this problem now,” he demands, “because our patients cannot wait.” ■ SEE ALSO page 15.

www.AHDBonline.com

CONTENTS PERSONALIZED MEDICINE Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman 732-992-1892 Senior Production Manager Lynn Hamilton

The Economics of Personalized Medicine in Oncology Targeted Trastuzumab Improves Survival in Gastric Cancer

HEALTH ECONOMICS

6 Oncologists Underestimate Cost of Cancer Care 8 The Complex Economics of Cancer Treatments 9 Cost, Noncompliance Bitter Pills to Swallow in the Age of Oral Chemotherapy

10 Rising Cost of Cancer Care Requires Action Now 12 VTE Hospitalizations in Cancer Patients Costly, with

AUGUST 2009 I SPECIAL ISSUE I VOL 2, NO 5 CHRONIC MYELOGENOUS LEUKEMIA 22 New and Emerging Drugs for Treatment-Resistant CML 23 7-Year Survival Confirms Imatinib as Standard Care for Chronic-Phase CML BREAST CANCER

24 The Emerging Importance of Bone Health in EarlyStage Breast Cancer

25 Novel Investigational HER2-Targeted Therapy Making News

26 Cost Comparisons of Adjuvant Hormonal Therapy for Breast Cancer

High Mortality

LUNG CANCER

OTHER NEWS FROM ASCO

Business Manager Blanche Marchitto

Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

COLORECTAL CANCER

28 Gaining Access to Investigational Drugs 29 Fast-Track Follicular Lymphoma Vaccine

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions. This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1880 F: 732-992-1881 American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline. com, Telephone: 732-992-1889. Fax: 732-992-1881. Permission requests to reprint all or part of any article published in this journal should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

Targeted Agents Delay Disease Progression in NSCLC

15 Pretreatment Biomarker Testing Indisputable in Colorectal Cancer

PATIENT’S PERSPECTIVE

30 Coping with the Cost of Cancer Care

Colorectal Cancer Screening Cost-Effective

PAYER’S PERSPECTIVES

31 ASCO 2009: Payers’ Reaction to the Latest

MULTIPLE MYELOMA

17 Carfilzomib Shows Promise in Multiple Myeloma When Bortezomib Fails

Clinical Trials

32 The Cost of Oncology Care

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EDITORIAL BOARD Wayne M. Lednar, MD, PhD Thomas G. McCarter, MD, FACP Global Chief Medical Officer Chief Clinical Officer Director, Integrated Health Services Executive Health Resources, PA DuPont, Wilmington, DE CLINICAL EDITOR

MANAGED MARKETS

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

GOVERNMENT EDITOR

Jeffrey A. Bourret, MS, RPh Executive Director, CustomerCentric Strategy and Innovation, Healthcare Systems Marketing Wyeth Pharmaceuticals

Kevin B. “Kip” Piper, MA President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC ACTUARY

David Williams Health Consultant Milliman, Windsor, CT CANCER RESEARCH

Al B. Benson, III, MD Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern U. Chair, Board of Directors, NCCN Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research U. of Michigan Health Systems CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine State University of New York

Arthur F. Shinn, PharmD President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Senior Scholar, Dept. of Health Policy, Thomas Jefferson University

PATIENT ADVOCACY EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

William E. Fassett, MBA, PhD Professor of Pharmacy Law & Ethics J. Warren Salmon, PhD College of Pharmacy, Washington Professor of Health Policy State University, Spokane, WA School of Public Health REIMBURSEMENT POLICY

Grant D. Lawless, BSPharm, MD Executive Director for Payor Relations, Corporate Account, Amgen

HEALTH INFORMATION TECHNOLOGY

J. B. Jones, PhD, MBA Research Associate, Geisinger

PHARMACOECONOMICS

HEALTH OUTCOMES RESEARCH

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy, U. of Colorado Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

EMPLOYERS

MANAGED CARE & GOVERNMENT AFFAIRS

August 2009

Alex Hathaway, MD, MPH Senior Medical Policy Advisor GlaxoSmithKline, Philadelphia, PA

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

AMERICAN HEALTH & DRUG BENEFITS

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri

PERSONALIZED MEDICINE

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger

ENDOCRINOLOGY RESEARCH

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, BoehringerIngelheim

Sharad Mansukani, MD Chief Strategic Officer Nations Health

Jeff Jianfei Guo, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, U. of Cincinnati Medical Center PHARMACY BENEFIT DESIGN

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology SPECIALTY PHARMACY

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy

Paul Anthony Polansky, BSPharm James T. Kenney, RPh, MBA Executive VP and Chief Pharmacy Pharmacy Operations Manager Officer, Sanovia Corp., Philadelphia Harvard Pilgrim Health Care Scott R. Taylor, RPh, MBA Associate Director, Industry Relations, Geisinger VOL. 2

NO. 5

SPECIAL ISSUE

Personalized Medicine

The Economics of Personalized Medicine in Oncology Huge Cost-Savings Projected with Biomarkers By Caroline Helwick

udging from the number of sessions and abstracts on the topic at ASCO, the era of “personalized medicine” has dawned in the field of oncology. Beyond improving outcomes for individual patients, personalization of care will no doubt greatly reduce the cost of treating cancer. “Personalized cancer care is likely to be cost-effective cancer care,” predicted Richard Schilsky, MD, current President of ASCO. Because each patient with cancer is different—biologically, clinically, and economically—and because each tumor, even within the same type of cancer, is unique, response to and tolerance of treatment are different in each patient, as is disease prognosis, and even preventive interventions. Scientists are on the path to discovering just what makes histologically similar tumors behave differently. The development of assays to identify these biomarkers is helping to match a patient to the targeted therapy. The most obvious example is overexpression of the HER2/neu protein in breast cancer, which identifies the subgroup of patients who will benefit from trastuzumab (Herceptin) based on a simple test. In colorectal cancer (CRC), KRAS

testing to eliminate patients who will not respond to inhibitors of the epidermal growth factor receptor (EGFR) has recently become established. This is only the beginning. Al B. Benson, III, MD, Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer, Northwestern University, and Chair of the Board of Directors of the NCCN, and colleagues, recently documented the savings when KRAS testing is used in metastatic CRC.

“To develop effective drugs, we must better define the patient population.” —Al B. Benson, III, MD Many studies have established that patients with CRC only respond to the EGFR inhibitors cetuximab (Erbitux) and panitumumab (Vectibix) if they have normal KRAS gene status. More than one third of patients have tumors with KRAS mutations (wild-

Table Annual Drug Cost-Savings with KRAS Testing Variable

Number/Cost

Estimated annual patients with CRC

N = 28,724

Cost of KRAS testing in all patients

$13 million

Patients with KRAS mutations

N = 10,065

Cost of treating all patients with mutated KRAS

$617 million

Net savings: cost of treating mutated KRAS patients less cost of KRAS testing

$617 million – $13 million = $604 million

type), however, and they do not respond to these agents. Testing for KRAS status before firstline treatment with EGFR inhibitors would save the US healthcare system $604 million annually, Dr Benson says, when cetuximab is limited to patients with normal KRAS (Table). They used the American Cancer Society estimate of 28,724 annual cases of metastatic CRC, a cost of $452 per KRAS test (totaling $13 million), and a cost of $3986 per loading dose and $2491 per weekly dose of cetuximab (wholesale price), multiplied by 24 infusions per patient (in combination with the FOLFIRI regimen). Drug cost per patient was determined to be $61,279. Excluding the estimated 35.6% of patients with KRAS mutations, and treating only patients with

normal KRAS, the projected savings is $604 million. This is the first analysis to demonstrate cost-savings by customizing drug therapy in a gastrointestinal malignancy using a molecular test. These findings show that KRAS testing is not only good medicine, it is good economics. “The intent is to enable much more specific patient selection, because if we can do this overall, we can save money,” Dr Benson said. “The theme of this meeting is personalized medicine, and to develop effective drugs we must better define the patient population. That’s difficult work, but we have to do it.” ■ SEE ALSO Pretreatment Biomarker Testing Indisputable in Colorectal Cancer, page 15.

Targeted Trastuzumab Improves Survival in Gastric Cancer “Poster Child” of Personalized Medicine

hen added to chemotherapy for gastric cancer, trastuzumab (Herceptin)— better known as a breast cancer treatment—outperformed the standard treatment in patients overexpressing HER2, reported Eric Van Cutsem, MD, PhD, of the University Hospital Gasthuisberg, Leuven, Belgium. In this first large phase 3 study of trastuzumab in patients with gastric cancer, patients receiving trastuzumab had a 26% reduction in the risk of death compared with chemotherapy with cisplatin and capecitabine or 5-fluorouracil (5-FU). “This is the first phase 3 study to report improved overall survival with a personalized, target treatment for gastric cancer,” Dr Van Cutsem said; it is the first time trastuzumab has been shown to improve survival in a tumor other than breast cancer. David Cunningham, MD, Consultant, Royal Marsden Hospital, United

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Kingdom, commented, “This is an absolutely excellent study. It was a major undertaking to screen nearly 4000 patients for the presence of HER2 expression….All the end points were positive.” High levels of HER2 were found in this patient population. The study included 3807 patients with advanced gastric cancer; 810 patients (22%) had overexpression of HER2. Investigators randomized 594 HER2-positive patients to standard chemotherapy or to chemotherapy plus trastuzumab, given every 3 weeks for 6 cycles, with trastuzumab continued until disease progression. Median overall survival was significantly greater with the addition of trastuzumab—13.8 months versus 11.1 months (P = .048) with standard chemotherapy. After a median of 17 months of follow-up, mortality was reduced by 26% with the combination, and overall response rates were 47.3%

“This is the first phase 3 study to report improved overall survival with a personalized, target treatment for gastric cancer.” —Eric Van Cutsem, MD, PhD versus 34.5% with chemotherapy alone, a significant difference (P = .017). In a preplanned subgroup analysis, patients with the highest degree of HER2 overexpression (FISH+/IHC3+) had even greater benefit from trastuzumab, with overall survival of 17.8 months versus 12.3 months for chemotherapy alone, a 42% reduction in mortality risk. The combination was well-tolerated, with no significant increase in symptomatic congestive heart failure; however, as expected, asymptomatic left ventricular ejection fraction decreases occurred more frequently with the combination (4.6%-5.9%,

depending on the criteria) versus chemotherapy alone (1.1%). Dr Cunningham said, “Trastuzumab produced a modest but clinically meaningful improvement in outcome for patients who have a relatively poor prognosis with conventional therapies.” ASCO President Richard Schilsky, MD, called the study “a great example of the concept of personalized medicine,” pointing out that for the first time there is an indication that “we need to think about 2 different molecular subtypes of stomach cancer—HER2-positive and HER2negative.”—CH ■

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Health Economics Oncologists Grapple with Cost... Continued from page 1 • 67% of the respondents agreed that every American patient should have access to effective cancer treatments, regardless of cost • 84% strongly or somewhat agreed that their treatment recommendations were influenced by patient out-of-pocket costs • 43% responded that they frequently or occasionally discuss the cost of new cancer treatments with many of their patients • 35% agreed that >$100,000 per lifeyear represented “good value for the money,” 49% said $50,000 to $100,000, and 21% said <$50,000 • 56% said cost of new drugs influences their treatment recommendations • 80% expressed a desire for more use of cost-effectiveness data in coverage and payment decisions for cancer drugs

effectiveness of cancer drugs is needed, but 60% said that physicians should determine whether a drug provides good value. Only 42% of oncologists agreed that they were well-prepared to interpret and use cost-effectiveness information in their treatment decisions. “Interestingly, most oncologists tell us that they believe that more costeffective analysis should be used, but most are saying that they don’t feel prepared themselves to use it,” said Dr Neumann. Cancer-Related Cost-Effective Analysis Although the number of published medical cost-effective analyses (CEAs) has grown markedly over the past 30 years, only 12% to 15% of such analyses have pertained to cancer thera-

“The survey indicated that oncologists favor government research on the comparative value of treatments, but want to remain in charge of decisions.”—Peter J. Neumann, ScD

• 42% said they feel prepared to interpret and use cost-effectiveness information in their treatment decisions. “The survey indicated that oncologists favor government research on the comparative value of treatments, but want to remain in charge of decisions,” Dr Neumann said. Indeed, 79% agreed that more government research on the comparative

pies, said Dr Neumann. Health-related CEAs assess the value of resources used (costs) and the health benefits achieved (effects) for an intervention compared with an alternative treatment strategy. A CEAs registry at Tufts University includes 200 cancer-related cost-utility analyses (that consider both quality of life and added life-years) on

screening, prevention, and treatment, from which 531 incremental costeffectiveness ratios (ICERs) have been developed. The goals of this CEAs registry are to identify society’s best opportunities for targeting resources to improve health, assist policymakers in healthcare resource allocation decisions, and advance the field toward the use of standardized methodology, Dr Neumann said. About 25% of the studies were funded by pharmaceutical/medical device companies and 46% by government agencies; 32% did not disclose a funding source. In examining the ICERs in 2008 US dollars, only 8% to 9% of the studies investigated interventions that provided cost-saving. “Most of the reported studies were in the range of $0 to $20,000 per quality-adjusted life-year [about 34%] and $20,000 to $50,000 per quality-adjusted life-year [about 23%],” he said. About 11% of the studies were of interventions with worse health outcomes and increased costs. “There does seem to be a publication bias in the sense that most reported cancer interventions are reported to be good value for the money,” Dr Neumann noted. Value in Healthcare Good value depends on society’s willingness to pay for a health gain, said Elena B. Elkin, PhD, Health Outcomes Research Group, Memorial Sloan-Kettering Cancer Center, New York, who chaired the session. There are no strict criteria to define value in healthcare in the United States, she

said, but the common perception is that an ICER of less than $50,000 represents good value; $50,000 to $100,000 is a “judgment call”; and more than $100,000 is a high ICER for which an intervention can be justified mainly on clinical grounds. Dr Elkin noted that the qualityadjusted life-year (QALY) threshold of $50,000 of good value was established in 1982 and has not been changed since then, and if the healthcare inflation rate of 5.5% annually is considered, the threshold should have jumped to $197,000 by 2007. Even using the much lower overall inflation rate increases the QALY threshold to $126,000. “Cost-effective does not mean costsaving,” said Dr Elkin. Most medical interventions do not save money but result in a net monetary expenditure. ■

Oncologists Underestimate Cost of Cancer Treatment By Caroline Helwick

ncologists have a poor understanding of the monetary costs of the newer treatments they are prescribing. Although oncologists are educated to deal with the medical complexities of their treatments, a new “side effect,” that of “financial toxicity,” has arisen in recent years, said Kenneth R. Hoffman, MD, MPH, of Teaneck, NJ, who surveyed 39 oncologists regarding their understanding of out-of-pocket costs to patients. “One of the major challenges in private practice is explaining the monetary cost of treatment to the patient,” Dr Hoffman explained. The survey assessed their knowledge of the cost of treatments used for common tumors treated in the office—breast cancer, non–small-cell

lung cancer, colorectal cancer, nonHodgkin’s lymphoma, chronic myelogenous leukemia, multiple myeloma, and ovarian cancer. His survey focused on treatments used in the adjuvant and the first-line settings for metastatic cancer. “Physicians were asked to calculate the cost of treatments to the patient and not the acquisition price of the drugs, which included completion of treatment and, if desired, maintenance therapy,” Dr Hoffman said. “For example, if they decide to prescribe modified FOLFOX 6 for stage III colorectal cancer and treat for 6 months with bevacizumab, what will this cost the patient?” In almost all cases in which intravenous (IV) or oral targeted therapies were used, the physician underesti-

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mated the cost to the patient by 25% to 40%. Solo practitioners, who are more directly involved in the financial aspects of their practices, tended to be more aware of cost than those in group practices, Dr Hoffman reported.

“One of the major challenges in private practice is explaining the monetary cost of treatment to the patient.” —Kenneth R. Hoffman, MD, MPH When conventional IV chemotherapy was used, the oncologists were either correct or they overestimated the cost of treatment by 25% to 33%, especially when generic substitution was available.

Not all physicians were aware, for example, that some pharmacies (eg, Walmart) are offering 3-month medications for $10, including tamoxifen. So patients with breast cancer can be prescribed tamoxifen for 3 months at a cost of just $10, instead of its usual cost of approximately $100 a month, or an aromatase inhibitor for about $250 a month. “Can the physician say that the benefit of taking the aromatase inhibitor is that much greater?” he asked. “Physicians do know the efficacy data, and they decide whether a drug is beneficial based on phase 2 trials, but they have a poor understanding of the cost-benefit analysis,” Dr Hoffman concluded. He added, “These discussions should begin in medical school.” ■

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Health Economics Oral Oncologic Drugs: Out-of-Pocket Costs Vary by Agent, Payer Type By Wayne Kuznar

ccording to a study of pharmaceutical claims from 98 managed care plans in the United States, most out-of-pocket (OOP) payments for oral drugs for cancer are less than $50 per claim, although about 1 of 5 patients have OOP expenses of more than $500. The current pharmacy benefit design trend toward higher-tiered copayments for specialty drugs, such as oral oncologic agents, has the potential to increase the OOP cost burden to patients, said the study’s lead investigator, Elise M. Pelletier, MS, Director, Health Economics and Outcomes Research, IMS Consulting, Watertown, Mass. As the costs of these therapies increasingly become part of treatment decisions, a better understanding of a patient’s OOP costs is important to inform providers’ treatment decisions.

The median OOP cost ranged from $14 to $39 per claim: • 69% of patients paid <$50/claim • 22% of patients paid ≥$250/claim • 17% of OOP payments were >$500 per claim.

PPO and indemnity plans had the largest OOP payments for almost all oral therapies. When analyzed by payer type, OOP payments were significantly higher with Medicaid and Medicare Advantage plans compared

with commercial HMO, PPO, or other payers ($586 vs $309; P <.001). ■ SEE ALSO Oncologists Underestimate Cost of Cancer Treatment, page 6.

We focus on the human in human health care

The current benefit design trend toward higher-tiered copayments for specialty drugs has the potential to increase the OOP cost burden to patients.

Ms Pelletier and colleagues identified 10,400 patients from 98 health plans. Two thirds of the patients were in a health maintenance organization (HMO) or preferred provider organization (PPO) plan; 83% were insured by a commercial payer. The most common cancer was lung cancer (ie, 25% of the patients). All patients had claims evidence of receiving at least 1 of the following oral oncologic agents in 2007: • Bexarotene • Capecitabine • Dasatinib • Erlotinib • Gefitinib • Imatinib • Lapatinib • Lenalidomide • Sorafenib • Sunitinib • Temozolomide • Thalidomide • Vorinostat. Among these 13 agents, capecitabine had the lowest OOP payment, averaging $117 per claim, and lenalidomide had the highest, with an average of $1014. Patient OOP expenses ranged from 4.9% of the cost of vorinostat to 16.4% of the cost of lenalidomide.

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At Eisai (a•zi), caring for people is our work Satisfying unmet medical needs and increasing benefits to patients, their families, and caregivers is Eisai’s human health care (hhc) mission. This includes the development of innovative medicines– notably the discovery of the world’s most widely used treatment for Alzheimer’s disease. Eisai is recognized for our business and patient advocacy partnerships, as well as our commitment to working with healthcare professionals to achieve improved patient care worldwide. That is our quest. That is our promise. That is what makes us Eisai.

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Health Economics

The Complex Economics of Cancer Treatments By Caroline Helwick

pending on healthcare is clearly out of control in the United States, but mechanisms are emerging to address the ever-worsening problem, according to Brent K. Hollenbeck, MD, MS, Assistant Professor, Urologic Oncology, at the University of Michigan, who chaired a session on healthcare economics and quality at ASCO.

“We are exceeding where we should be, and the spending is irrational.” —Brent K. Hollenbeck, MD The United States spent $2.2 trillion on healthcare in 2007, which was 16% of the gross domestic product and amounted to $7421 per capita. General Motors spent $4.6 billion (more than they spent on steel), which increased each vehicle’s sticker price by $1525. The average cost of an employer-based insurance plan, now at $12,680 per person, is equivalent to the annual earnings of a minimum-wage job. “We are exceeding where we should be, and the spending is irrational,” Dr Hollenbeck said. It’s no surprise that the United States is an outlier in per capita healthcare

Table National Variations in Cancer Outcomes, 2005 Indicator Healthcare expenditure per capita, US$ Cancer mortality per 1000 births, N Pharmaceutical spending per capita, US$

United States

Norway

Switzerland

France

Japan

6401

4364

4177

3374

2249

6.8

3.1

4.2

3.6

2.8

752

375

424

559

425

Source: Emanuel EJ, et al. JAMA. 2008;299:2789-2791.

spending. For example, US medical centers boast 4 times the number of magnetic resonance imaging units per million residents compared with other industrialized countries. “There is a growing recognition that throwing money at the problem won’t fix it,” he said. Hospitals that spend more have similar risk-adjusted mortality rates as those that spend less. “Are we at the tipping point for healthcare reform?” More Healthcare Is Not Always Better Care Some degree of growth and increase in healthcare utilization is inevitable, but “more” healthcare is not always better care, although this has been a long held assumption, said Sandra L. Wong, MD, Assistant Professor of Surgery, University of Michigan, Ann Arbor.

Unwarranted variations in the use of healthcare are significant, as measured by resources and spending. And studies have found no relationship between the availability of care and the quality of care. But “more specialists plus newer treatments equals increased availability of services,” fueled by fee-for-service (FFS) incentives for physicians and hospitals. “A hospital bed built is a hospital bed filled,” Dr Wong said. “Too much” care can actually be harmful, suggested Dr Wong. Studies have documented higher mortality in hospitals with more beds per capita. According to Dr Hollenbeck, under the current FFS system, providers have incentives to offer lucrative services. Rates of surgery rise dramatically on the opening of a physicianowned ambulatory surgery center.

Is There Too Much Cancer Care? Variations in cancer treatments have not been well studied. Dr Wong questioned whether the availability (supply) of cancer treatment influences their use (demand). In cancer treatment especially, there is a feeling that “if a little is good, then a lot must be better,” said Dr Wong, but the experience with high-dose chemotherapy with stem-cell rescue for breast cancer proved the fallacy of that concept. The treatment “exploded” in the late 1980s (and cost up to $500,000 per patient), but randomized controlled trials eventually found no survival advantage over conventional treatment. Some 42,000 women had undergone the grueling treatment, at a cost of billions of dollars. Chest computed tomography (CT) for lung cancer screening is another example of an expensive resource that increases surgical resection rates but does not lead to improved survival. “Despite the initial enthusiasm for chest CT to screen high-risk patients, there have been no recommendations for widespread adoption of CT screening,” Dr Wong said. Despite the dramatic increase in dollars spent on cancer care, the cancer-specific mortality of patients with cancer in the United States is not better than in other countries (Table). ■

ASCO Task Force Takes on Costs of Cancer Care By Wayne Kuznar

SCO has formed the Cost of Cancer Care Task Force, chaired by Lowell E. Schnipper, MD, Professor of Medicine, Harvard Medical School, who described the goals of the task force at the ASCO annual meeting. The task force was formed in August 2007 and has been charged with defining the challenges related to the cost of cancer care and to develop strategies to address these challenges. “We’re reaching a critical point, if we’ve not already passed it, with respect to healthcare costs in this country,” said Dr Schnipper. “The price of pharmaceuticals that we use is rising enormously, and at times, the enormous cost of the drugs for our healthcare system and patients don’t necessarily match with the type of long-term therapeutic value we would hope for.” In the United States, 1 of 5 patients with cancer have delayed or missed treatments because of cost. This impact is far greater in uninsured

patients, with nearly 70% of uninsured patients missing or delaying care, and 43% going without vital prescriptions because of costs. “Patients are extremely confused by the aspects of the insurance coverage that they have or don’t have, and find it impossible to negotiate their way through the system,” he noted. Working in Phases The efforts of the task force are divided into several phases. The first phase addresses how physicians discuss cost of care with patients and provides practical resources for physicians and patients. “Talking about cost of care with our patients is one of the key elements in being an exemplary physician. We feel this is not something that can be easily discarded, blown off, or even left to someone else except at particular junctures,” Dr Schnipper explained. The task force has just begun implementing phase 2, which involves a subsequent, longer-term

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“Patients are extremely confused by the aspects of the insurance coverage that they have or don’t have, and find it impossible to negotiate their way through the system.”—Lowell E. Schnipper, MD

effort to develop an ASCO policy to address the fundamental question of how to control costs. An ASCO guidance statement for physicians appears in the July 2009 issue of the Journal of Clinical Oncology. It describes the importance of oncologists in addressing these issues in the context of quality care. Task Force Subcommittees To better address the myriad aspects involved in costs of cancer care, the task force consists of several subcommittees, including a patient resources subcommittee, which has developed a decision-making guide to help patients:

•Ask questions about cost •Understand the realities of the cost involved in their care •Interpret cost-benefits for themselves. This booklet has been developed for print and online distribution, and can be accessed at www.cancer.net. In addition, a research subcommittee will examine how oncologists view their role in considering cost as part of the physician–patient interaction, as well as analyze how community- or hospital-based clinical units are addressing costs to determine best practices. The results of this research will be incorporated into ASCO’s best practices statement. ■

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Health Economics Cost, Noncompliance Bitter Pills to Swallow in the Age of Oral Chemotherapy By Wayne Kuznar

s more oral cancer therapies are introduced into practice, adherence is likely to play a larger role in outcomes, said Angela DeMichele, MD, Associate Professor of Medicine and Epidemiology, University of Pennsylvania’s Abramson Cancer Center. Drug cost is a major barrier to adherence, potentially leading to drug-taking behaviors that can compromise outcome.

we have glimpses that patients are nonadhering a fair percentage of the time,” said Dr DiMichele. This lack of adherence “can lead us to some mistakes or to not being able to optimize

therapy for our patients, or to not optimize the development of drugs for our diseases” (Table). Nonadherence in clinical trials can lead to an underestimation of a drug’s

efficacy. “Particularly in randomized trials where an oral agent is being compared to an IV agent, there can be a perceived inferiority of the oral drug when it’s compared to an IV Continued on page 10

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“Even in oncology, we have glimpses that patients are nonadhering a fair percentage of the time.” —Angela DeMichele, MD About 10% of oncology therapies are oral medications, and this percentage is expected to increase to about 30% in the next 5 years. Oral therapies include cytotoxic agents, targeted therapies, and supportive (ie, antiemetics, antidiarrheals) therapies. The monthly cost of oral regimens ranges from $2200 to almost $8000, representing a chief reason for patient nonadherence. “We can have the best drugs in the world, but they’re not going to work if patients don’t, or can’t, take them,” said Dr DeMichele. The magnitude of the effect of nonadherence is startling. Up to two thirds of hospital admissions are due to poor medication adherence overall, with an estimated annual cost of about $110 billion, she said. Oncologyspecific data are lacking, and oncology is clearly an understudied area. In a disease as potentially lethal as cancer, one might assume that nonadherence to a treatment regimen would be minimal, but “even in oncology,

Table Consequences of Nonadherence in Oncology In practice May lead to false conclusions about the effectiveness of therapy May lead to a change to a less efficacious or more toxic regimen due to perceived lack of effectiveness In clinical trials May lead to underestimation of drug efficacy May lead to perceived inferiority of drug when compared with intravenous formulation In policy Increases healthcare costs Wastes resources

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Rising Cost of Cancer Care Requires Action Now By Wayne Kuznar

he increasing economic burden to the US healthcare system posed by cancer care has created many challenges to stakeholders— patients, payers, employers, providers, and health plans—said Neal J. Meropol, MD, Director, Gastrointestinal Cancer and Gastrointestinal Tumor Risk Assessment Programs, Fox Chase Cancer Center, Philadelphia. The growth in healthcare spending has exceeded the growth in gross domestic product, a trend that is not sustainable. Spending on cancer care consumes about 5% of total healthcare spending. “Oncology is not going to bankrupt the economy, at least not today,” said Dr Meropol, but “that’s not to say it’s not a problem.” Cancer drugs are first among hospital and clinic drug expenditures. The rate of growth in spending on antineoplastics is 16% annually, far outpacing the 9.9% growth rate on spending for all drug expenditures. And $200,000 is the annual cost spent in the United States on drugs alone to extend the life of a patient with metastatic colorectal cancer (CRC) by 1 year. For drug developers, the financial incentive for moving forward with

only marginally better treatments is substantial. “The likelihood of moving from phase 1 to phase 2, and from phase 2 to phase 3, is higher in oncology than in other fields in medicine, partly because of the payoff that might exist at the end of the day,” Dr Meropol said.

“The likelihood of moving from phase 1 to phase 2, and from phase 2 to phase 3, is higher in oncology than in other fields in medicine, partly because of the payoff that might exist at the end of the day.”—Neal J. Meropol, MD Patients with cancer, however, place a high value on treatments with a modest benefit, he said. Targeted drug development—personalized medicine—narrows the markets for developers but offers a competitive advantage. A great deal of uncertainty exists with targeted drug development. For example, will drug development be faster, cheaper, or more successful with a targeted approach? Will patients stay on treatment longer, knowing that the likelihood

Cost, Noncompliance... Continued from page 9 drug if the oral drug is one that people are poorly adherent to,” she said. Cancer Drug Coverage An important contributor to nonadherence in oncology is the uncertainty in coverage by health plans and insurance companies, which is quite variable. Oral therapies for cancer are not covered by a medical benefit but rather fall under a patient’s prescription drug benefit. “The patient responsibility is tremendous,” Dr DiMichele said. “There are copays and deductibles. When set up by copayers, they were not designed to take into account the extreme expense of these medications that patients would be using for oncology indications,” she said. “Only Oregon so far has passed some legislation that would adjust patient copays and deductibles for oncology medications, and make those rules different from what they are for patients taking medications for other indications.” Drug Rationing Anecdotal evidence indicates that

of benefit of treatment is greater? And will there be a pricing premium for targeted drugs that will offset the narrowed market? Individual patients increasingly feel the burden of the increased cost of cancer care through higher premiums, larger copays, increased coin-

rationing of medications is occurring in oncology, she said. Rationing has the potential for poorer outcomes at a higher cost. The impact of cost on adherence is: • Patients rationing medication • Patients/families losing assets, financial security • Potential for poorer outcomes, including disease resistance. Furthermore, taking medications not according to the intended schedule (ie, less frequently, missing doses) may increase the likelihood of changing the biology of the disease. “Are cancers going to mutate or become more aggressive if they’re only going to be partially treated in the same way we are seeing the emergence of resistance with antibiotics and in the HIV world?” she asked. In one study, in which 5 years of tamoxifen treatment was found to be equally effective as 10 years in preventing breast cancer recurrence, only 81% of patients adhered to the medication for more than 5 years. The investigators concluded that such nonadherence might have underestimated by approximately 33% the true effect of continuing this drug.—WK ■

surance, tiered formularies, and the Medicare Part D doughnut hole. As a result, patients may limit or alter their therapies. “We need to realize that cost is a component of decision-making for patients,” he emphasized. Insurance premiums have outstripped earnings and inflation, and the problem is accelerating: 29% of families spend more than 10% of their income on cancer care; in 20032004, 10% spent more than $18,000 on out-of-pocket expenses. The contribution of oncologists to

the overall cost of cancer care has received enormous scrutiny, but singling them out is unfair. Historically, oncologists’ income has been tied to chemotherapy administration. “Why focus on oncologists when all others in the treatment chain also prescribe expensive therapies,” he asked, pointing to diagnostic radiology and surgical oncology as 2 examples. In addition, drug/device makers and insurers also seek to maximize their profits. Oncologists often feel ill-equipped to discuss costs with patients, but increasingly cost considerations have an appropriate role in the assessment of treatment options, according to Dr Meropol. The high cost of cancer has not only affected treatment options but has promoted disparities in cancer outcomes. For example, patients with CRC who are uninsured or are in Medicaid are diagnosed at a later stage, regardless of race or sex, and uninsured patients with CRC have worse survival than insured patients. In the end, the search for answers to address the cost of cancer care must begin now. “The time may be quite right for meaningful healthcare reform,” said Dr Meropol. ■

Improving Cancer Care by Guidelines Implementation ASCO’s Guidelines Among the Most Utilized By Caroline Helwick

espite good intentions, healthcare providers have not universally embraced clinical practice guidelines. Strategies to improve guideline use were discussed in a session at ASCO.

Providers often ignore guidelines that they view as too rigid or as not cost-effective. Providers often ignore guidelines that they view as too rigid or as not cost-effective. Logistic problems, especially reimbursement issues, can also interfere with guideline implementation. Negative influences may also come from within the clinical setting or from other organizational factors, said Edward Paul Balaban, DO, of the University of Pittsburgh Medical Center Cancer Center. Once barriers are recognized, there must be a strategy for effectively disseminating and implementing the

guidelines, Dr Balaban said. The following strategies can enhance acceptance and utilization: • Clinicians/institutions should develop or critique a guideline at a local level • Guidelines should be widely disseminated, for example, through mailings or conference presentations • Make guidelines readily accessible and available for reference • Accountability is part of the process, for example, via peer pressure, financial incentives, or administrative reward. The ASCO Guideline Process ASCO practice guidelines are among the most widely used, perhaps because ASCO makes a concerted effort to make them widely available and applicable, said Gary H. Lyman, MD, MPH, of Duke University Medical Center. This includes publication in the Journal of Clinical Oncology and Journal Continued on page 11

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Health Economics

The “Perfect Storm”: Should We Stop the Unconditional Adoption of New Technology in Healthcare? By Caroline Helwick

he near-universal adoption of new technology in oncology represents a “perfect storm” that brings together rare or life-threatening conditions, strong patient demand, expensive products and implementation, along with uncertain evidence of benefit, said David C. Miller, MD, MPH, Assistant Professor of Urology and Epidemiology and research scientist at the VA Center for Clinical Management Research, University of Michigan, Ann Arbor. Dr Miller discussed the challenge of new technologies that include biologics and other drugs, devices, and diagnostic and procedural tools. New technology is an area of great “tension,” he noted, marked by a tug of war between forces—patients, physicians, and manufacturers—that favor rapid adoption and coverage of technology and other forces—including payers, evidence-based medicine advocates, and policymakers—who are calling for “prudent” adoption and coverage. There are individual motivations to adopt new technologies, including “reputational” and financial incentives, as well as the earnest desire to provide all available diagnostic and treatment options for patients with serious conditions. The “perfect storm,” where all these things converge, has created a scenario in which technology is adopted in spite of limited advantages.

The Cost of Innovation in Oncology All sections of oncology care are experiencing the temptation of new technology. In surgical oncology, robotics and cryosurgery have made inroads. In radiation oncology, it is proton beam radiotherapy. In clinical oncology, novel biologics and targeted agents are entering clinical use for virtually all tumor types. The cost of these innovations is tremendous. The average monthly cost of treating cancer clustered around $1000 in the early 1990s; it is now close to $5000/month, and, for example, exceeding $10,000 when cetuximab is prescribed, or $23,000 with alemtuzumab. “We are using very expensive therapies that do not have a large therapeutic margin,” Dr Miller observed.

these national coverage decisions: • No change in coverage • Noncoverage • Coverage without special conditions • Coverage with special conditions— patients with specific characteristics, providers or facilities meeting certain criteria, coverage only when additional data provided.

Cost-Effectiveness and Coverage The utility of these technologies is assessed and approved by various parties, including the FDA, payers, private corporations, physician specialty societies, and health service researchers. Medicare, the country’s largest payer, makes coverage decisions based on whether a technology is “reasonable and necessary,” without explicit consideration of costs. Some local coverage decisions apply to limited geographic areas, and rarely, to national coverage. There are 4 potential outcomes from

“There is a recent movement within CMS,” Dr Miller said, “to move toward more prudent evaluation of new technology, in recognition that the ‘pie’ of money is not infinitely expanding.” Part of this greater scrutiny includes comparative effectiveness research (CER), which aims to compare technologies for their “bang for the buck,” he said. The Obama administration has allotted $700 million to accelerate the development and dissemination of CER, specifically research that compares clinical outcomes, effectiveness, and appropriateness of products and services used to prevent, diagnose,

“We are using very expensive therapies that do not have a large therapeutic margin.” —David C. Miller, MD, MPH

and treat diseases. The determination of cost-effectiveness often uses the incremental costeffectiveness ratio of cost per qualityadjusted life-year (QALY), with an arbitrary threshold set at $50,000 for US patients. The United Kingdom’s National Institute for Health and Clinical Excelence (NICE) makes coverage decisions based on both comparative and cost-effectiveness research and considers treatments cost-effective at $34,500 per QALY. In light of new targeted agents, this cap is being revisited. For the treatment of renal-cell carcinoma, for example, the cost per QALY (Steinbrook R. N Engl J Med. 2008;359:1977-1981) exceeds: • $122,000 for sunitinib • $162,000 for temsirolimus • $176,000 for sorafenib • $294,000 for bevacizumab. “The political uproar when NICE declined these agents demonstrates the challenge of considering costeffectiveness in approving treatments,” Dr Miller added. The current industry trend is to evaluate coverage for therapies or for technologies that are not costeffective based on a patient response to treatment. Under this scenario, the manufacturer of a drug would reimburse the payer when the drug is not effective in a particular patient—a revolutionary idea. ■

Improving Cancer Care by...Continued from page 10 of Oncology Practice (in print and online), and presentation by disease site (complimentary, www.asco.org/ guidelines). The guidelines are promoted and reviewed at the annual meeting and are disseminated at the local level in educational seminars. ASCO has also begun publishing provisional clinical opinions (PCOs) that are based on expedited review of potentially practice-changing evidence. Among these is the first PCO on using KRAS gene status testing to select patients who should/should not receive a targeted agent for colon cancer (see also page 16). A new component will be interactive disease-oriented continuing medical education programs based largely on selected ASCO guidelines, which will become available on the new ASCO University website. Guideline implementation and

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dissemination are also enhanced by ASCO’s Clinical Tools and Resource Program. This includes summaries, PowerPoint slides, aids for doctor– patient interactions, patient flow sheets, and decision-making discussion tools that can be used, for example, to help patients understand the various outcomes of possible cancer treatments.

based practice. The PEBC then develops specialized guidance documents designed for the provincial policy committee responsible for recommending which chemotherapy agents should be paid for in the publicly funded system.

Every organization involved in administering clinical Interface with Cancer Care of guidelines must adapt to that Ontario, Canada The Program in Evidence-Based change to achieve more Care (PEBC) is the guidelines pro- effective implementation. gram for Cancer Care of Ontario, the advisory body to the Ontario government. The PEBC develops practice guidelines targeting questions of interest at the clinician–patient interface, with the objective of guiding clinical decisions and facilitating evidence-

More recently, the PEBC has undertaken the development of guidelines designed to influence those responsible for the organization and delivery of cancer control, said Melissa C. Brouwers, PhD, of McMaster Uni-

versity, Hamilton, Ontario. ASCO and PEBC share a major goal of advancement of the quality of cancer care through the use of guidelines and supporting tools and resources to facilitate best practices, Dr Brouwers said. Both organizations are devoted to advancing evidence-based practice guidelines that are also clinically relevant and widely applicable. In this era of healthcare reform, there is little doubt that clinical practice guidelines will take on a more prominent role in the delivery of healthcare in both countries. Every organization involved in composing and administering clinical guidelines must remain wary of the constantly changing practice environment and be willing to adapt to that change to achieve more effective guideline implementation.—CH ■

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Health Economics Cost of Treating Cancer Projected to Reach Nearly $130 Billion in 10 Years By Caroline Helwick

ased only on population trends and fixed incidence and survival, the cost of cancer care is projected to increase by 40%, from $88.9 billion in 2005 to $128.3 billion in 2020, according to Robin Yabroff, PhD, MBA, an epidemiologist with the Health Services and Economics Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Washington, DC.

The cost of treating colorectal cancer will rise from about $10 billion in 2008 to about $14 billion in 2020. This growing economic burden is the result of US population trends (growing, aging, increasing life expectancy), the increasing incidence of cancer with age, and the addition of new and costly therapies. The

$88.9 billion is in fact an underestimate, as it is based on the 4 most common cancers only—breast, colorectal, lung, and prostate. In a study published last year, Dr Yabroff deciphered the cost of cancer care by using colorectal cancer (CRC) as a model (Yabroff KR, et al. J Natl Cancer Inst. 2008;100:1755-1762). The study evaluated patients with CRC identified in SEER (Surveillance, Epidemiology, and End Results) registries linked to Medicare claims, matched with control subjects without cancer. To estimate the direct cost of cancer care, the analysis combined tumor information with longitudinal service use and costs before, during, and after the cancer diagnosis. When cost was broken down by phase of care, the net costs per patient were approximately $2500/month during the “initial phase” (ie, consultations, diagnostic tests, treatment), less than $200/month during the “continuing phase,” and approxi-

Table Annual Mean Net Adjusted Costs of Cancer Care in Patients Age ≥65, 2005

Cancer site

Initial year, $

Phase of Care Continuing Last year year, $ cancer, $

Last year not cancer, $

Breast

18,079

1837

52,621

2748

Colorectal

42,616

2361

63,439

7979

Lung

51,187

5762

78,537

17,780

3708

300

4306

Prostate

Note: Estimates adjusted for deductibles and coinsurance.

mately $3000/month during the “last year of life phase.” When analysts applied monthly cost estimates by phase of care to crude monthly survival probabilities during 60 months, they calculated the annual cost per person during the first year to be approximately $25,000, and over a 5-year period, $36,000. The treatment for lung cancer costs more, and that for prostate cancer less. The main tumor sites also vary according to cost per disease phase (Table).

This burden will only grow, Dr Yabroff predicts. In a sensitivity analysis that included a model for increased survival, decreased incidence (as a result of screening), and increased costs, the cost of treating CRC will rise from $10 billion in 2008 to about $14 billion in 2020, she explained. These investigators plan to perform similar cost projects for other tumor sites, using current population projects and varying assumptions, as well as incidence and survival. ■

VTE Hospitalizations in Cancer Patients Costly, with High Mortality By Wayne Kuznar

he average cost of 1 hospitalization for a patient with cancer and venous thromboembolism (VTE) is in excess of $10,000. As such, aggressive practices to prevent deep-vein thrombosis (DVT)/ pulmonary embolism (PE) in this patient population can reduce the overall healthcare burden, by eliminating hospital admissions, according to Susan Weidner, MS, who presented her data during a poster session based on a study conducted while being Vice President of Health Outcomes and Pharmacoeconomics, Eisai Pharmaceuticals.

“If DVT/PE could be prevented in cancer patients, it would result in decreased utilization for pharmaceuticals, diagnostic testing, and other inpatient services.” —Susan Weidner, MS “If DVT/PE could be prevented in cancer patients, it would result in decreased utilization for pharmaceuticals, diagnostic testing, and other inpatient services,” said Ms Weidner. Using a US healthcare database of more than 342 inpatient facilities, representing about 11 million patients,

she identified patients with cancer who were hospitalized between January 2006 and May 2008. Patients with an ICD-9-CM code for malignant neoplasm in combination with DVT or PE were included in the study. Some 1136 patients with cancer at 74 inpatient facilities were admitted during that period with DVT/PE. The average length of stay was approximately 6 days, and the average overall hospitalization cost was $11,162, with 39% ($4376) of those costs attributed to routine hospitalization care (Table). The next 2 common cost drivers were pharmacy (average $1570) and diagnostic testing ($1059). The mortality rate among these patients was 6.1%, consistent with previously conducted studies. Routine prophylaxis of VTE in the general ambulatory cancer population cannot be recommended at this time, because of an uncertain risk-to-benefit ratio, said Nicole M. Kuderer, MD, Fellow in Hematology/Oncology at Duke University, Durham, NC. To better define the efficacy of lowmolecular-weight heparin (LMWH) in preventing VTE and the risk of major bleeding in patients with cancer in the outpatient setting, Dr Kuderer performed a meta-analysis of randomized controlled trials of VTE prevention in this setting. A total of 6 studies were identified

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August 2009

Table Hospitalizations for Cancer Patients with DVT/PE Variable (N = 1136) Average length of staya

Cost/Outcome 6.06 days

Average total costs

$11,162

Median total cost

$7694

Mortality rate

6.1%

Patients who died within 1 day of admission are excluded. DVT indicates deep-vein thrombosis; PE, pulmonary embolism.

in which dalteparin (3 studies), certoparin (2 studies) or nadroparin (1 study) were compared with placebo for prophylaxis in 2648 patients with cancer. The incidence of VTE was 2.95% among those randomized to LMWH and 5.25% among the controls. The relative risk of VTE was therefore reduced by 36% (P = .021) in the LMWH recipients. However, the relative risk of major bleeding was 85% higher in the LMWH group compared with the control group (1.57% vs 0.98%), although this difference did not reach significance. The VTE rate in the control groups did not influence the relative risk of VTE in the prophylaxis groups, which suggests that all VTE risk groups ben-

efited similarly from LMWH prophylaxis. A higher baseline VTE risk predicted a greater absolute VTE risk reduction in the groups receiving LMWH prophylaxis. “This meta-analysis shows that LMWH is effective in reducing the risk of VTE, but the absolute risk reduction was only 1.8% compared with a 0.9% absolute increase in major bleeding,” said Dr Kuderer. “So while they work, the risk-to-benefit ratio right now is not good enough in the general outpatient setting. We need to find out who is at high risk.” Models to predict who is at higher bleeding risk will also need to be developed. For now, the only group of patients with cancer for whom routine VTE prophylaxis is generally recommended (although not considered a necessity) is those with multiple myeloma. “We’re still waiting for the randomized trials to give us the answer. We encourage putting patients in a randomized trial,” she said. “If you don’t have access to the trial, if the patient is on lenalidomide and thalidomide in conjunction with chemotherapy or steroids, because the VTE risk is so high in this setting, it is acceptable to institute prophylaxis.” A new trial is planned to determine the risk-to-benefit ratio of LMWH prophylaxis in the high-risk cancer population, Dr Kuderer added. ■

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Lung Cancer Maintenance Pemetrexed... Continued from page 1 to show the benefit of pemetrexed in the maintenance setting after initial therapy.” Dr Belani said that the findings could “change the standard of care” and lead to a new treatment paradigm. The phase 3 study included patients with advanced or metastatic (stage IIIB or IV) NSCLC that had progressed after 4 cycles of platinum-based chemotherapy. Investigators randomized a total of 663 patients to 1 of 2 arms: (1) 441 patients to treatment with pemetrexed 500 mg/m2 every 3 weeks until further disease progression, and (2) 222 patients to placebo.

“This is the first randomized, double-blind, placebocontrolled study to show the benefit of pemetrexed in the maintenance setting after initial therapy.” —Chandra P. Belani, MD Overall survival was 13.4 months for the pemetrexed maintenance group compared with 10.6 months for the placebo group, representing a 21% mortality risk reduction (P = .012). Median PFS was 4.0 months with pemetrexed maintenance and 2.0 months with placebo, for a 40% risk reduction with pemetrexed (P <.001); clinical benefit was attained by 51.7% and 33.3%, respectively (P <.001). Benefit from pemetrexed maintenance was limited to patients with nonsquamous histology, as has been shown in previous trials with this agent. These results reinforce the concept of individualized medicine in cancer therapy, Dr Belani said. For the nonsquamous histology group, PFS was 15.5 months with pemetrexed, compared with 10.3 months with placebo, for a 30% reduction in risk (P = .002). In those with squamous histology, PFS was similar at 9.9 months and 10.8 months, respectively. Maintenance pemetrexed was relaFDA Approves Pemetrexed Injection for NSCLC In July 2009, the FDA approved pemetrexed injection for maintenance treatment of patients with locally advanced or metastatic nonsquamous non–small-cell lung cancer (NSCLC) whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy. The approval was based on the findings in the study reported by Dr Belani, which was in part requested by the FDA.

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tively well tolerated, with 5% of patients requiring dose reductions. Patients receiving pemetrexed had more grade 3 and 4 neutropenia (3% vs 0%) and fatigue (5% vs 1%). After discontinuing the study, 67% of the placebo group received additional treatment, although only 19%

received pemetrexed. Some NSCLC specialists believe that had more of these patients received pemetrexed at some point, the benefit for maintenance therapy may have been reduced. Nasser Hanna, MD, of Indiana University, Indianapolis, acknowledged that maintenance therapy with pemetrexed did increase the PFS, but noted he would like to see more data on over-

all survival to support these findings. Although maintenance therapy in metastatic NSCLC may be preferable in some patients, he said, it is not a good idea for all patients. “I will individualize my care,” Dr Hanna said. “Patients with more indolent disease or those with a strong response to treatment may be able to take treatment holidays.” ■

2009 ASCO Special Report

Payer Reactions That Matter How will payers perceive progression-free and overall survival endpoints? How will reported findings impact treatment patterns in key tumor types? What do payers believe will be the trend in future price points and contracting? For key products in- and post-development, how will payers react to reported data in terms of formulary management, restrictions, pricing sensitivity and gene selection testing requirements? This report focuses on ASCO presentations on trial data in breast cancer, NSCLC, prostate cancer, colon cancer, multiple myeloma and RCC. For more information or to order the report, please contact Reimbursement Intelligence at 973.805.2300 or e-mail asco@reimbursementintelligence.com Reimbursement Intelligence is a nationally recognized consulting firm specializing in Managed Markets and Reimbursement.

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Lung Cancer

Targeted Agents Delay Disease Progression in NSCLC

everal oral presentations at ASCO added to a growing body of data supporting the use of targeted therapies in non–small-cell lung cancer (NSCLC). Erlotinib with Bevacizumab An international study showed that adding erlotinib (Tarceva) to bevacizumab (Avastin) maintenance therapy after initial treatment with chemotherapy and bevacizumab delayed disease progression, compared with bevacizumab alone. “Bevacizumab is a core component of the treatment of advanced NSCLC, and we have shown here that we can delay progression with the addition of a targeted agent, erlotinib,” said Vincent A. Miller, MD, of Memorial Sloan-Kettering Cancer Center and lead investigator of the study. “Future work will try to determine which patients will get the greatest benefit from this combination, based in large part on the identification of genetic biomarkers,”Dr miller said.

The randomized, double-blind phase 3 ATLAS trial enrolled 768 patients with advanced NSCLC to receive bevacizumab plus erlotinib or bevacizumab plus placebo as maintenance therapy. All patients had completed 4 cycles of chemotherapy plus bevacizumab as first-line treatment. Interim analysis showed significant benefits with the addition of erlotinib, which reduced recurrence risk by 29%. Median progression-free survival (PFS) was 4.8 months in the erlotinib/bevacizumab arm compared with 3.7 months in the placebo/bevacizumab arm (P = .012). No unexpected side effects occurred. The benefit of adding erlotinib to bevacizumab was most impressive among persons who never smoked (66% risk reduction) and Asians (84% risk reduction).

to target both the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) prolonged the time to disease recurrence and prevented a worsening of disease-related symptoms. Vandetanib is also being evaluated for the treatment of thyroid cancer. In this study, 1391 patients previously treated with chemotherapy were randomized to receive docetaxel 75 mg/m2 every 21 days plus either vandetanib 100 mg/day or placebo. After a median follow-up of 12.8

Vandetanib Targets EGFR and VEGF In another study, the experimental oral agent vandetanib, the first agent

months, patients in the vandetanib group had a 21% reduction in the risk of disease progression, compared with patients in the placebo group. The median PFS time was 17.3 weeks with vandetanib versus 14 weeks with placebo (P <.001). Patients treated with vandetanib also had a 22% reduction in time to the deterioration of symptoms related to their disease (P <.001), reported Roy S. Herbst, MD, PhD, Chief of Thoracic Medical Oncology, University of

“Bevacizumab is a core component of the treatment of advanced NSCLC…we can delay progression with the addition of a targeted agent, erlotinib.” —Vincent A. Miller, MD

©Copyright iStockphoto.com/DoctorKan.

By Caroline Helwick

Lung cancer seen on an x-ray.

“Clearly, in a disease as heterogeneous as lung cancer, the need to target multiple pathways has become clear.”—Roy S. Herbst, MD, PhD

Texas M.D. Anderson Cancer Center. “Clearly, in a disease as heterogeneous as lung cancer, the need to target multiple pathways has become clear. Hence, this agent targeting 2 key pathways critical for NSCLC growth and metastasis is novel and could play a key role,” Dr Herbst said. “That more patients had an improvement in symptoms from lung cancer suggests that the drug could be important for the future management of this disease.” ■

MSH2 Expression Predicts Chemotherapy Benefit in Early-Stage NSCLC

n patients with non–small-cell lung cancer (NSCLC), long-term response to cisplatin-based chemotherapy after surgical resection can be predicted on the basis of tumor levels of the human MutS homolog 2 (MSH2) protein expression, according to findings from the International Adjuvant Lung Trial (IALT). Damage to cancer cells inflicted by cisplatin can be repaired with the help of the MSH2 protein. In patients with low levels of MSH2 or no protein expression, chemotherapy extends survival compared with no chemotherapy. Low levels of another DNA repair protein, ERCC1, are also predictive of treatment benefit, according to a previous analysis from the IALT trial. This study included 257 (38%) patients whose tumors expressed MSH2 and 416 (68%) patients whose tumors contained no MSH2 or only low levels of this protein. Adjuvant cisplatin-based chemotherapy was associated with improved survival among

MSH2-negative patients but did not affect MSH2-positive patients, reported Pierre Fouret, MD, PhD, Professor, Institut Gustave Roussy, Villejuif, France, and the Université Pierre et Marie Curie, Paris.

Patients with low tumor levels of MSH2 and ERCC1 who were treated with chemotherapy lived 21 months longer than those not receiving chemotherapy. “There was an overall survival gain of 16 months from chemotherapy in patients with low MSH2,” Dr Fouret announced. Patients with high levels had similar outcomes whether they received chemotherapy or not. Median survival for MSH2-negative patients who received cisplatinbased chemotherapy was 58 months, compared with 42 months with no

AMERICAN HEALTH & DRUG BENEFITS

August 2009

chemotherapy. For MSH2-positive patients, median overall survival was 49 months with chemotherapy and 58 months without. When MSH2 and ERCC1 levels were used together, their predictive power was greater than either alone. Patients with low tumor levels of both biomarkers who were treated with chemotherapy lived 21 months longer than those not receiving chemotherapy, and their risk of death was reduced by 35% (P = .01). “The long-term survival benefit from cisplatin-based chemotherapy may be different according to MSH2 expression,” Dr Fouret concluded, “and there is better prediction of chemotherapy benefit when both biomarkers are used together.” Biomarkers Can Guide Chemotherapy Commenting on the study, Heather Wakelee, MD, Assistant Professor of Medicine, Stanford University, Palo Alto, Calif, said that MSH2 should be

added to a growing list of potential biomarkers in early-stage NSCLC that will help identify patients with early disease who may benefit from adjuvant chemotherapy. What this and other studies have shown is that low levels of several biomarkers can predict sensitivity to chemotherapy, including: • ERCC1 and platinum agents • Thymidylate synthase and pemetrexed • RRM1 and gemcitabine • BRCA1 and platinum agents • Epidermal growth factor receptor (EGFR) mutation and EGFR tyrosine kinase inhibitors. High levels of BRCA1, in contrast, predict for benefit of therapy with taxanes, and KRAS mutation predicts for a lack of benefit of theraphy with EGFR tyrosine kinase inhibitors. When biomarkers are used prospectively in adjuvant trials, which is now being done, the findings should be more clinically useful, Dr Wakelee said.—CH ■

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Colorectal Cancer

Pretreatment Biomarker Testing Indisputable in Colorectal Cancer By Caroline Helwick

he treatment of metastatic colorectal cancer (CRC) is being rapidly refined with the use of biomarkers to determine which patients will benefit from which treatments. “We are very excited about having a pretreatment selection strategy based on biomarkers,” said Axel Grothey, MD, Professor of Oncology, Mayo Clinic, Rochester, Minn.

“We are very excited about having a pretreatment selection strategy based on biomarkers.”—Axel Grothey, MD It is well established that KRAS gene status is a very predictive marker of response to the epidermal growth factor receptor (EGFR) inhibitors cetuximab (Erbitux) and panitumumab (Vectibix). Patients with the wild-type (normal) KRAS respond to EGFR inhibitor therapy, but those with KRAS mutations do not. “KRAS is one of the best biomarkers we could ever think of,” Dr Grothey said.

EGFR-Targeted Therapy Many studies have shown significantly improved response rates and time to progression for patients with normal KRAS who receive cetuximab or panitumumab in combination with chemotherapy. However, a surprising finding has recently emerged, suggesting that patients with CRC and KRAS mutations may actually have worse outcomes when treated with EGFR inhibitors, Dr Grothey emphasized. “If we want to use cetuximab firstline, we really need to know what is going on with KRAS [ie, the patient’s KRAS status]. Otherwise, we might actually harm our patients,” he said. “This has dampened our enthusiasm for anti-EGFR antibody treatment, and we still do not understand it.” The concept of combining an antiEGFR antibody with an antibody against VEGF (vascular endothelial growth factor) is also being evaluated, with some advantages seen in patients with normal KRAS, and again, some detriment shown in patients with the mutation. The effect of bevacizumab (Avastin), however, is independent of KRAS status. Emerging Biomarkers Other biomarkers are emerging for

targeted CRC therapy. The BRAF gene is another emerging biomarker that can benefit patient selection for EGFR inhibitor therapy. BRAF gene mutation occurs in 10% of patients with cancer—independent of the KRAS status—and is associated with poor response to EGFR-targeted treatment as well. “In other words, using KRAS and BRAF assays, it will be possible to eliminate 50% of patients who have no chance of benefiting from this treatment,” Dr Grothey said. Response to these agents is also associated with normal expression of the phosphatase and tensin homologue, PTEN, a key tumor suppressor, and high EGFR ligand expression, which includes amphiregulin and epiregulin. With these emerging markers— KRAS wild-type gene, BRAF wildtype gene, normal PTEN expression, and high EGFR ligand expression—it should now be possible to identify the “ideal” patient who would benefit from treatment with one of the EGFR inhibitors. ■ SEE ALSO The Economics of Personalized Medicine in Oncology, page 5.

KRAS According to Dr Grothey 1. Colorectal cancer (CRC) has morphed into 2 distinct tumor types: • Wild-type (normal) KRAS gene tumor, and KRAS mutation tumor • No EGFR inhibitor therapy should be used in patients with KRAS mutated tumors 2. Using KRAS genetic testing: • 40% of patients with metastatic CRC can be spared from ineffective therapy with EGFR antibodies • Avoids unnecessary toxicity • Improves cost-effectiveness of therapy 3. KRAS is a model for the development of biomarkers in oncology, not only in CRC 4. KRAS mutation cohort can be the target for new drug development

FDA Recognizes KRAS Status in CRC On July 20, 2009, the FDA requested a label change for the EGFR inhibitors cetuximab (Erbitux) and panitumumab (Vectibix), limiting their indication for use in patients with colorectal cancer to those without the KRAS gene mutations. All patients with colorectal cancer (CRC) will now have to be tested for KRAS gene status before beginning therapy.

Bevacizumab Prolongs Survival Only Gene Signature Shows Prognostic Value atients with stage III colorectal in QUASAR, who were followed for During Treatment, No Cure in Early CRC cancer (CRC) always receive about 7 years. The 7-gene prognostic By Audrey Andrews

esults of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which evaluated maintenance therapy with bevacizumab (Avastin) in the adjuvant colorectal cancer (CRC) setting, did not show increased cure rate in early-stage CRC, the study primary end point. However, investigators emphasized that the drug was effective as long as patients were receiving it. NSABP Chairman Norman Wolmark, MD, Chairman of Oncology at Allegheny General Hospital, Pittsburgh, said at the plenary session, “The prespecified and hoped-for end point—increase in the cure rate of early-stage colon cancer—was simply not met. But it wasn’t bevacizumab that failed. If anything, we failed to provide our patients with a novel intervention that would increase cures.” NSABP randomized 2710 stage II and III patients with CRC to modified FOLFOX6 (mFOLFOX6) regimen (5fluorouracil, leucovorin, and oxaliplatin) for 6 months or to the same regimen plus bevacizumab 5 mg/kg

every 2 weeks for an additional 6 months (1 year total). At a median follow-up of 36 months, disease-free survival was 75.5% in the control arm and 77.4% in the bevacizumab arm (hazard ratio 0.89; P = .05), said Dr Wolmark. However, a recent post-hoc analysis showed a significant benefit for bevacizumab for the 1 year that patients were receiving the drug. Disease-free survival at 1 year was 94.3% with bevacizumab and 90.7% with mFOLFOX6 alone, for a 3.6% absolute improvement—a 40% reduction in events (P = .004). Dr Wolmark reiterated that bevacizumab was effective, but the effect diminished once the drug was stopped. The challenge is to learn how to use bevacizumab to its maximum potential in the adjuvant setting, he said. The ongoing international phase 3 AVANT study is also evaluating the use of bevacizumab in the adjuvant setting, and these results should help determine the role of this agent in patients with early-stage CRC. ■

chemotherapy; however, whether to give chemotherapy in stage II CRC remains controversial. Investigators from the Quick and Simple and Reliable (QUASAR) study have developed a 7-gene signature that could help guide decision-making in CRC, but its benefit remains debatable. According to David Kerr, MD, Oxford University, England, “This signature represents a new molecular tool that can determine which patients with stage 2 disease have a recurrence risk profile that may encourage the use of adjuvant treatment with chemotherapy following surgery.” A gene signature was developed based on tumor samples from >3500 patients from several clinical trials who underwent surgery for stage II CRC, regardless of adjuvant 5-fluorouracil–based chemotherapy. The study identified a set of genes that could be prognostic of recurrence, and another set expected to be predictive of benefit from chemotherapy. The gene signature was narrowed down to 7 genes and was validated using samples from 1436 participants

signature showed a continuous relationship between prognosis for recurrence and outcome. Based on low, intermediate, and high expression levels, the signature could separate patients into low-, intermediate-, and high-risk groups, respectively.

“This signature represents a new molecular tool.” —David Kerr, MD The group deemed to be at high risk for recurrence proved to have a 47% greater recurrence risk rate than the low-risk group. “Now we can identify patients with a low risk for cancer recurrence— approximately 10%—who are likely to be candidates for surgery alone, and can separate them from patients at higher risk—nearly 25%—who are candidates for adjuvant chemotherapy as well,” Dr Kerr said. Charles S. Fuchs, MD, MPH, of Harvard Medical School and DanaFarber Cancer Institute, Boston, said there is a growing interest in bioContinued on page 16

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Colorectal Cancer

Colorectal Cancer Screening Cost-Effective: Fecal DNA Promising By Caroline Helwick

olorectal cancer (CRC) is the second most common solid tumor in the United States, accounting for nearly 150,000 new cases annually and 50,000 deaths. Robert Mayer, MD, the Stephen B. Kay Family Professor of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute, Boston, chaired the update on CRC screening, emphasizing the importance of screening in the average-risk population. In its “war on cancer” in the era of budget deficits, the National Cancer Institute highlights its recommendation to increase the rates of CRC screening, as part of advances in cancer care in 2009. CRC almost always arises from adenomatous polyps, found in nearly 33% of persons aged ≥50 years and in almost 50% of those >65 years. Removal of polyps prevents cancer. The National Comprehensive Cancer Network and the American Cancer Society (ACS) screening guidelines recommendations are outlined in the Table. Fecal occult blood test (FOBT) was the first screening method developed, but its high false-positive rate is problematic. Colonoscopy is the bestestablished and most reliable screening method, but questions about screening frequency, operator variability, and diagnostic accuracy remain, Dr Mayer said. Computed tomography (CT) or virtual colonography has gained interest, but the Centers for Medicare & Medicaid Services (CMS) has been reluctant to endorse its coverage for Medicare patients. CT colonography is “seemingly equivalent” to endoscopy, but “it is not clear that the expertise is there” outside of specialty centers, he said. Few if any head-to-head comparisons of the screening methods have

mary data to answer whether CT colonography or optical colonoscopy is clearly superior.” Organizations differ on their conclusions, but the ACS says “there are sufficient data to include CT colonography as an acceptable option for screening.” CMS recently decided against coverage, citing insufficient evidence in the Medicare age-group. Dr Pignone believes that CMS is mostly concerned about cost. CT colonography is covered by some insurers, and in some states coverage is mandated.

mutant tumor DNA fragments in a pool of 10,000 total DNA fragments.” The next generation of markers will be “epigenetic markers,” such as the methylation marker vimentin, which can be enriched in tumor cells compared with normal tissue and have been found in stool samples of 46% to 87% of persons with CRC. The sensitivity of a 2-panel assay that searches for epigenetic markers and mutant DNA is 86%, with a specificity of 73%. “At this point, we have gone from a single DNA analysis, with a sensitivity of about 40%, to multiple gene analysis, with a sensitivity of 50%, to an analysis of methylation markers plus multiple gene assay, with a sensitivity of up to 80%,” Dr Diaz said. These are all analog approaches. Next to come is digital PCR, which should increase the sensitivity to nearly 90%, he added. Compared with analog assays, digital PCR can detect more mutant molecules, more accurately quantify, and more easily genotype, but it is more labor intensive and expensive.

New Molecular Approaches A noninvasive approach to screening would greatly increase screening rates, but FOBT is not very effective. An exciting new possibility is a molecular approach that identifies mutations and genes associated with cancer in stool. The key mutations occur in 50% to virtually 100% of cancerous polyps and can be identified by polymerase chain reaction (PCR) analysis of DNA fragments. According to Luis Diaz, MD, of Johns Hopkins University, Baltimore, while the technology is advancing, “it’s still like finding a needle in a haystack, with the tumor DNA being the needle and the nontumor DNA being the haystack. There are about 5

Fecal DNA Screening Despite its high sensitivity, the adoption of the fecal DNA test has been controversial. The ACS deems fecal DNA acceptable as a test that “primarily detects cancer,” and the US Preventive Services Task Force maintains the evidence is insufficient “for or against” it. Modeling studies show that screening with fecal DNA every 5 years is clinically effective and cost-effective compared with no screening, but not compared with FOBT and colonoscopy. “Significant technical improvements in sensitivity have been achieved in small studies, but large prospective trials are needed,” Dr Diaz concluded. ■

Table 2009 NCCN/ACS Screening Recommendations for Average-Risk Personsa Screening test Colonoscopy

Frequency (begin age 50) Every 10 years

Fecal occult blood test

Annually

If positive: colonoscopy If negative: sigmoidoscopy every 5 years Virtual colonography

Every 5 years

Double-contrast barium enema (soon to be eliminated) Every 5 years Fecal DNA test: role still uncertain

N/A

No family history before age 50, no hereditary syndromes. ACS indicates American Cancer Society; NCCN, National Comprehensive Cancer Network.

been conducted; therefore, the optimal method has not been declared. Meanwhile, “Surveillance colonoscopy represents the gold standard, but whether it can achieve wider and more cost-effective use remains to be determined,” noted Dr Mayer.

CT colonography is very cost-effective compared with no screening but is less cost-effective compared with colonoscopy. CT Colonography Coverage Advances in software have yielded better image interpretation, said Michael Pignone, MD, MPH, University of North Carolina, Chapel Hill, “but CT colonography is still a bit of a moving target.” In addition to accuracy, the potential for slight radiation exposure, and the additional work-up cost and anxiety related to extracolonic findings are concerns. “CT colonography is very costeffective compared with no screening, and it buys additional life-years at a reasonable cost” compared with FOBT. But it is less cost-effective compared with colonoscopy, Dr Pignone said. “We need more pri-

Standard of Care for Rectal Cancer Unaltered

esults from ACT II, the largest trial to date of rectal cancer, suggest that the standard chemoradiotherapy regimen should not be altered, and that maintenance chemotherapy offers no additional benefit. Most rectal cancer (which is relatively rare) is squamous-cell carcinoma that is very sensitive to radiotherapy and chemotherapy. Chemoradiotherapy with 5-fluorouracil (5-FU) and mitomycin-C became the standard treatment in the 1990s, said Roger James, MD, a radiation oncologist from Maidstone Hospital, Kent, England.

The goal of ACT II, conducted by the UK National Cancer Research Institute, was to evaluate whether replacing mitomycin-C with cisplatin would increase response rates, and whether adding 2 cycles of maintenance chemotherapy with 5-FU and cisplatin after chemoradiation would reduce disease recurrence. In this study, 940 patients received 5-FU and radiotherapy and were then randomized to receive mitomycin-C or cisplatin, as well as maintenance chemotherapy with 2 cycles of cisplatin and 5-FU in weeks 11 and 14,

AMERICAN HEALTH & DRUG BENEFITS

August 2009

beginning 4 weeks after chemoradiation, or no maintenance therapy. At median follow-up of 2.5 years, there was no significant difference in outcomes between the 2 groups. Maintenance therapy also offered no additional benefit. At 3 years, recurrence-free survival was 75% in both groups. “ACT II did not show any significant differences between cisplatin and mitomycin-C,” Dr James said, adding that very high response rates and excellent tolerability can be achieved with either chemoradiotherapy schedule.—CH ■

Gene Signature... Continued from page 15 markers to identify patients who can avoid chemotherapy. He applauded the study design, but said the findings were inadequate for guiding clinical decision-making. Comparing this signature to the 21gene signature now used in breast cancer, which indisputably established chemotherapy benefits in patients with high recurrence scores, Dr Fuchs said that the difference of 10% between low- and high-risk groups in CRC is not sufficiently discriminative for patient selection.—CH ■

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Multiple Myeloma

Add-on Thalidomide Shows Mixed Results in Multiple Myeloma By Wayne Kuznar

dding thalidomide to standard chemotherapy has not resulted in improved progression-free survival (PFS) or overall survival (OS) in the treatment of newly diagnosed elderly patients with multiple myeloma, according to an interim analysis of a phase 3 multicenter study. The study investigated the use of the standard chemotherapy regimen—which consists of bortezomib, melphalan, and prednisone (VMP)— plus thalidomide (VMPT). However, “the complete response rate was significantly superior for the 4-drug combination in comparison with the 3-drug combination: 21% complete response for VMP versus 35% for bortezomib, melphalan, and prednisone plus thalidomide, and the difference is highly significant [P <.001],” said lead investigator Antonio P. Palumbo, MD, of Azienda Ospedaliera Universitaria San Giovanni Battista, Italy. In the study, 511 patients 65 years or older (median age, 71 years) with symptomatic disease and organ damage were randomized to VMPT—nine 5-week cycles of bortezomib, 1.3 mg/m2 on days 1, 8, 15, and 22; melphalan, 9 mg/m2 on days 1 to 4; prednisone, 60 mg/m2 on days 1 to 4; and thalidomide, 50 mg/day continuously through day 35—or to VMP at the same doses and schedules. At a median follow-up of 16.1 months, the PFS and OS were not sig-

nificantly different between the treatment arms. “More follow-up is needed to make a final assessment,” said Dr Palumbo. In the group assigned to VMPT, those 75 years or younger had a significantly superior PFS compared with patients older than 75 years (P = .006); no such difference was evident in the VMP group. The frequency of grade 3 and 4 hematologic adverse events was similar between treatment groups. “Thalidomide is not adding additional hematologic toxicity to the standard bortezomib, melphalan, and prednisone,” said Dr Palumbo. But nonhematologic toxicity was different, with a higher incidence of infection from adding thalidomide to bortezomib, and as expected, “a higher incidence of cardiologic side effects,

“The complete response rate was significantly superior for the 4-drug combination in comparison with the 3-drug combination: 21% complete response for VMP versus 35% for bortezomib, melphalan, and prednisone plus thalidomide.” —Antonio P. Palumbo, MD

Table Toxicity Level, by Bortezomib Infusion Schedule VMPT arm VMP arm Twice weekly, % Weekly, % Twice weekly, % Weekly, % (N = 71) (N = 150) (N = 64) (N = 165) Grade 3-4 peripheral neuropathy

Dose reductiona

Discontinuationa

Due to peripheral neuropathy. Note: 25 VMPT and 19 VMP patients receive both once- and twice-weekly bortezomib. VMP indicates bortezomib, melphalan, and prednisone; VMPT, bortezomib, melphalan, prednisone, and thalidomide.

again probably due to thalidomide.” There was also an increase in fatigue and thrombosis in the VMPT group, but deep-vein thrombosis rates were still <5% in each group. Of note, in addition to the 2 regimens, 64 patients in the VMP arm and 71 patients in the VMPT arm were treated with twice-weekly infusions of bortezomib. Perhaps the most noteworthy finding was that weekly bortezomib was just as effective as twice-weekly bortezomib, but the weekly infusions reduced the incidence of grade 3 and 4 peripheral neuropathy in each regimen (Table). In each arm, patient discontinuations were lower with once-weekly compared with twice-weekly bortezomib (4% vs 15% with VMP; 3% vs 10% with VMPT). The study “will impact clinical

practice today,” noted S. Vincent Rajkumar, MD, Professor of Medicine, Mayo Clinic, Rochester, Minn, although “VMPT is not ready for prime time.” He added, “We cannot make any strong conclusions about one regimen versus the other, so VMPT still remains an experimental regimen.” The practice-changing information is the reduction in neuropathy with weekly versus twice-weekly bortezomib, said Dr Rajkumar. “If you just go weekly, instead of twice weekly, you reduce grade 3 neuropathy to virtually nothing,” he pointed out. “To me, the main message of this trial is that you will probably be able to deliver the full planned schedule of bortezomib and get the maximum benefit.” He added, “In my practice, I will be moving elderly patients to the weekly regimen.” ■

Carfilzomib Shows Promise in Multiple Myeloma When Bortezomib Fails By Caroline Helwick

n relapsed and refractory multiple myeloma, treatment is generally not effective, and only a minority of patients have prolonged survival. Encouraging activity was shown at ASCO with a novel proteasome inhibitor, carfilzomib, in patients who had become resistant to bortezomib and either thalidomide or lenalidomide, the standard treatment for multiple myeloma. Based on its high level of proteasome selectivity and antitumor activity, carfilzomib was studied in a multicenter, phase 2, open-label study of 46 patients who had progressed after treatment with all available therapies, averaging 5 therapies per patient. In addition to bortezomib and immunomodulating agents, more than 80% of patients had also received stem-cell

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transplantation, anthracyclines, and/ or alkylating agents. With carfilzomib (20 mg/m2 intravenous on days 1, 2, 8, 9, 15, and 16 mg/m2 every 28 days), 10 of 39 evaluable patients (26%) showed clin-

“Single-agent carfilzomib is active in heavily pretreated refractory multiple myeloma in patients who have failed all proven agents.” —Sundar Jagannath, MD ical benefit, including a molecular response in 5 patients and partial response in 5 patients. The median progression-free survival was 5.1 months, and median

response duration was 7.4 months, reported Sundar Jagannath, MD, Chief, Multiple Myeloma Service, St. Vincent’s Comprehensive Cancer Center, NY. “Single-agent carfilzomib is active in heavily pretreated refractory multiple myeloma in patients who have failed all proven agents,” Dr Jagannath said. “The drug is well tolerated, producing low rates of peripheral neuropathy.” About 25% of patients were able to complete 12 cycles of treatment, suggesting the drug was well tolerated. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine, and diarrhea. Peripheral neuropathy occurred in <10% of patients. ■

www.AHDBonline.com

Demonstrating the value of innovation

Herceptin is a standard of care for one of the most aggressive forms Herceptin is developed by Genentech

1990

Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer: • As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • With docetaxel and carboplatin • As a single agent following multi-modality anthracycline-based therapy Metastatic indications Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

*High-risk features for patients with ER/PR+ breast cancer include: tumor size >2 cm, age <35 years, and histologic and/or nuclear grade 2/3.

1998 Herceptin approved for treatment of HER2+ metastatic breast cancer

Herceptin approved for weekly use in the adjuvant treatment of HER2+, node-positive breast cancer

2006

Boxed WARNINGS and Additional Important Safety Information Cardiotoxicity and cardiac monitoring • Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF) – The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens – Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function •Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment – More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction •In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens

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

the treatment of HER2+ breast cancer — of breast cancer 10-year anniversary of Herceptin approval Adjuvant indication expanded to include high-risk node-negative disease and additional dosing options, including the first non-anthracycline Herceptin-containing regimen

2008

Infusion reactions, pulmonary toxicity, and neutropenia •Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported – In most cases, symptoms occurred during or within 24 hours of administration of Herceptin – Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension – Patients should be monitored until signs and symptoms completely resolve – Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome •Exacerbation of chemotherapy-induced neutropenia has also occurred Pregnancy category D •Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman Most common adverse events •The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia

So. San Francisco, CA

9665200

4/09

HERCEPTIN® (trastuzumab) Brief Summary For full Prescribing Information, see package insert. WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and PULMONARY TOXICITY Cardiomyopathy Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration] Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions] INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies]) breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • with docetaxel and carboplatin • as a single agent following multimodality anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline. Withhold Herceptin for 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and 10% absolute decrease in LVEF from pretreatment values. [see Dosage and Administration] The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of Herceptin • LVEF measurements every 3 months during and upon completion of Herceptin • Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration] • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as 50%) on continuing medical management at the time of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Study 1 & 2a 3 4 4 a

Regimen ACb Paclitaxel+ Herceptin Chemo Herceptin ACb Docetaxel+ Herceptin Docetaxel+Carbo+ Herceptin

Incidence of CHF Herceptin Control 2% (32/1677) 2% (30/1678)

0.4% (7/1600) 0.3% (5/1708)

2% (20/1068)

0.3% (3/1050)

0.4% (4/1056)

0.3% (3/1050)

Includes 1 patient with fatal cardiomyopathy. b Anthracycline (doxorubicin) and cyclophosphamide

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies

Study 5 (AC)b 5 (paclitaxel)

Incidence NYHA I-IV NYHA III-IV Herceptin Control Herceptin Control

Event Cardiac 28% 7% 19% 3% Dysfunction Cardiac 11% 1% 4% 1% Dysfunction Cardiac 6 7% N/A 5% N/A Dysfunctionc a Congestive heart failure or significant asymptomatic decrease in LVEF. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide c Includes 1 patient with fatal cardiomyopathy. Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions]. In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications. Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials in women with metastatic breast cancer, the perpatient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was not significantly increased. [see Adverse Reactions]. Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Assessment for HER2 overexpression and of HER2 gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several FDA-approved commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTestTM and Pathway® HER-2/neu (IHC assays) and PathVysion® and HER2 FISH pharmDxTM (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay. Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single method to rule out potential Herceptin benefit. A negative FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Table 9. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) as a function of IHC and FISH testing are provided in Table 7. HER2 Protein Overexpression Detection Methods HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest®, one test approved for this use, was assessed for concordance with the Clinical Trial Assay (CTA), using tumor specimens collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest®. HER2 Gene Amplification Detection Method The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysion®, one test approved for this use, was evaluated in an exploratory, retrospective assessment of available CTA 2+ or 3+ tumor specimens collected as part of patient screening for clinical studies in metastatic breast cancer (Studies 5 and 6). Data are provided in the package insert for PathVysion®. Embryo-Fetal Toxicity (Pregnancy Category D) Herceptin can cause fetal harm when administered to a pregnant woman. Postmarketing case reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a

fetus. [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions] • Pulmonary toxicity [see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to Herceptin across three randomized, open-label studies, Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. Table 3 Adverse Reactions for Study 3, All Gradesa: MedDRA (v. 7.1) 1 Year Herceptin Adverse Event Preferred Term (n= 1678) Cardiac Hypertension 64 (4%) Dizziness 60 (4%) Ejection Fraction Decreased 58 (3.5%) Palpitations 48 (3%) b Cardiac Arrhythmias 40 (3%) Cardiac Failure Congestive 30 (2%) Cardiac Failure 9 (0.5%) Cardiac Disorder 5 (0.3%) Ventricular Dysfunction 4 (0.2%) Respiratory Thoracic Mediastinal Disorders Nasopharyngitis 135 (8%) Cough 81 (5%) Influenza 70 (4%) Dyspnea 57 (3%) URI 46 (3%) Rhinitis 36 (2%) Pharyngolaryngeal Pain 32 (2%) Sinusitis 26 (2%) Epistaxis 25 (2%) Pulmonary Hypertension 4 (0.2%) Interstitial Pneumonitis 4 (0.2%) Gastrointestinal Disorders Diarrhea 123 (7%) Nausea 108 (6%) Vomiting 58 (3.5%) Constipation 33 (2%) Dyspepsia 30 (2%) Upper Abdominal Pain 29 (2%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) Back Pain 91 (5%) Myalgia 63 (4%) Bone Pain 49 (3%) Muscle Spasm 46 (3%) Nervous System Disorders Headache 162 (10%) Paraesthesia 29 (2%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) Nail Disorders 43 (2%) Pruritis 40 (2%) General Disorders Pyrexia 100 (6%) Edema Peripheral 79 (5%) Chills 85 (5%) Aesthenia 75 (4.5%) Influenza-like Illness 40 (2%) Sudden Death 1 (.06%) Infections Nasopharyngitis 135 (8%) UTI 39 (3%) Immune System Disorders Hypersensitivity 10 (0.6%) Autoimmune Thyroiditis 4 (0.3%)

Observation (n= 1708) 35 (2%) 29 (2%) 11 (0.6%) 12 (0.7%) 17 (1%) 5 (0.3%) 4 (0.2%) 0 (0%) 0 (0%) 43 (3%) 34 (2%) 9 (0.5%) 26 (2%) 20 (1%) 6 (0.4%) 8 (0.5%) 5 (0.3%) 1 (0.06%) 0 (0%) 0 (0%) 16 (1%) 19 (1%) 10 (0.6%) 17 (1%) 9 (0.5%) 15 (1%) 98 (6%) 58 (3%) 17 (1%) 26 (2%) 3 (0.2%) 49 (3%) 11 (0.6%) 10 (.6%) 0 (0%) 10 (0.6%) 6 (0.4%) 37 (2%) 0 (0%) 30 (2%) 3 (0.2%) 0 (0%) 43 (3%) 13 (0.8%) 1 (0.06%) 0 (0%)

a The incidence of Grade 3/4 adverse reactions was <1% in both arms for each listed term. b Higher level grouping term.

The data from Studies 1 and 2 were obtained from 3206 patients enrolled, of which 1635 patients received Herceptin; the median treatment duration was 50 weeks. The median age was 49.0 years (range: 24-80); 84% of patients were White, and 7% were Black, 4% were Hispanic, and 4% were Asian. In Study 1, only Grade 3-5 adverse events, treatment-related Grade 2 events, and Grade 2-5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following noncardiac adverse reactions of Grade 2-5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions NCICTC Grade 4 and 5 hematologic toxicities, Grade 3–5 nonhematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of

Grade 2–5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, openlabel study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 5 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 100% had breast cancer, 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and 12 months were 31% and 16%, respectively. Table 4 Per-Patient Incidence of Adverse Reactions Occurring in 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6) (Percent of Patients) Herceptin Single + Paclitaxel Herceptin ACb a Agent Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135 Body as a Whole Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Cardiovascular Tachycardia 5 12 4 10 5 Congestive 7 11 1 28 7 heart failure Digestive Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Nausea and 8 14 11 18 9 vomiting Anorexia 14 24 16 31 26 Heme & Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 <1 Urogenital Urinary tract 5 18 14 13 7 infection a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6. b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in

the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF <50% or 15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2). Table 5a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4 LVEF <50% and Absolute Decrease from Baseline

Studies 1 & 2b AC TH (n=1606) AC T (n=1488) Study 3 Herceptin (n=1678) Observation (n=1708) Study 4c TCH (n=1056) AC TH (n=1068) AC T (n=1050)

LVEF ≥10% ≥16% <50% decrease decrease

Absolute LVEF Decrease <20% and ≥10% ≥20%

22.8% 18.3% (366) (294) 9.1% 5.4% (136) (81)

11.7% (188) 2.2% (33)

33.4% (536) 18.3% (272)

9.2% (148) 2.4% (36)

8.6% (144) 2.7% (46)

7.0% (118) 2.0% (35)

3.8% (64) 1.2% (20)

22.4% (376) 11.9% (204)

3.5% (59) 1.2% (21)

8.5% (90) 17% (182) 9.5% (100)

5.9% (62) 13.3% (142) 6.6% (69)

3.3% (35) 9.8% (105) 3.3% (35)

34.5% (364) 44.3% (473) 34% (357)

6.3% (67) 13.2% (141) 5.5% (58)

a For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization. b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC T) or paclitaxel plus Herceptin (AC TH) c Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC T) or docetaxel plus Herceptin (AC TH); docetaxel and carboplatin plus Herceptin (TCH)

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy. Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization. Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization. The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or

subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2–5 neutropenia (7.1% vs. 4.5 % [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCICTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4 % vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2–5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of grade 1-4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category D [see Warnings and Precautions] Herceptin can cause fetal harm when administered to a pregnant woman. Postmarketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. In the postmarketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred. Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents, however the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys. [See Nonclinical Toxicology] Because animal reproduction studies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Registry Pregnant women with breast cancer who are using Herceptin are encouraged to enroll in MotHER- the Herceptin Pregnancy Registry: phone 1-800-690-6720. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy]. • Advise women with reproductive potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy]. • Encourage pregnant women who are using Herceptin to enroll in MotHER- the Herceptin Pregnancy Registry [see Pregnancy].

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HERCEPTIN® [trastuzumab] Manufactured by: 4839803 Genentech, Inc. Initial US Approval: Sept. 1998 1 DNA Way Revision Date: March 2009 South San Francisco, CA LK0726 7172911 94080-4990 7172713 ©2009 Genentech, Inc.

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Chronic Myelogenous Leukemia New and Emerging Drugs for TreatmentResistant CML By Wayne Kuznar

he tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) is associated with very good event-free survival as first-line therapy for chronic myelogenous leukemia (CML), and has shown declining rates of adverse events with time, but what options are available for patients who fail to respond to this agent? Jorge Cortes, MD, Professor of Medicine, M.D. Anderson Cancer Center at University of Texas, outlined new and emerging treatments. Roughly, 33% of patients treated with imatinib will either have a lack of response, lose hematologic or major cytogenetic response after 5 to 7 years, or be removed from treatment because of intolerance to the drug. Most patients are successful with one of the second-generation TKIs, and for nonresponders, other drugs under development appear promising. Second-Generation TKIs Nilotinib, derived from imatinib, has increased binding affinity and selectivity in its inhibition of the BCRABL fusion gene. Dasatinib also has increased potency

and, in addition, covers the Src family of tyrosine kinases. Both of these second-generation TKIs are currently approved for the treatment of CML.

Nilotinib and dasatinib are about 30 to 300 times more potent than the other agents, except for the T315I mutation. Nilotinib and dasatinib are approximately 30 to 300 times more potent than other agents against mutations that are resistant to imatinib, with the exception of the T315I mutation. “It is important to keep in mind that there is a gradient of potency against the different mutations. Not all mutations are equally sensitive,” Dr Cortes said. Less sensitive mutations are relatively uncommon, representing only 7% of patients who failed imatinib therapy in one study, and 15% of patients in another study, he said. Investigational Agents Omacetaxine acts by a different mechanism from the TKIs, independ-

Acute Myeloid Leukemia: Challenging Disease, Few Good Options

lack of effective therapy and high rates of relapse are 2 major problems that must be addressed in the treatment of acute myeloid leukemia (AML), said Jeffrey E. Lancet, MD, Section Chief, Leukemia Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa. Traditionally, AML has been treated with a combination of cytarabine and daunorubicin, but front-line therapy fails to induce a response in a significant number of patients, particularly older patients. “We have a failure of front-line therapy to induce durable responses….The typical patient with AML will have a relapse. We clearly need to do better,” said Dr Lancet. He reviewed some of the available options for AML. Daunorubicin and idarubicin are each a widely used anthracycline for AML. When used alone, daunorubicin produces complete remission in 30% to 50% of patients; when used in combination with cytarabine, the rate increases to up to 75%. Composite results from 5 randomized trials comparing the efficacy of standard-dose daunorubicin (45-50 mg/m2) with that of idarubicin (12

mg/m2) in conjunction with cytarabine suggest a modest but significant improvement in complete remission rates and 4-year survival with idarubicin in patients under age 60 years. Other data also suggest that idarubicin is superior to conventional-dose daunorubicin, but its benefit over higher-dose daunorubicin remains unclear. Double-induction therapy (backto-back induction courses of chemotherapy) is the norm in many European countries but has failed to show any clear benefit. In the Acute Leukemia French Association 9000 multi-institutional study, the rates of complete remission, cumulative incidence of relapse, and 5-year overall survival were similar among patients treated with single induction with high-dose daunorubicin and cytarabine and in those treated with induction followed by early or late reinduction. The German AML study group found high-dose cytarabine plus mitoxantrone superior to double induction with thioguanine, daunorubicin, and standard-dose cytarabine on the outcome of complete remission and event-free survival in patients

AMERICAN HEALTH & DRUG BENEFITS

August 2009

ent of the BCR-ABL gene, so the presence or absence of the T315I mutation does not affect its efficacy in vitro. An ongoing open-label study of 66 patients with CML who have the T315I mutation and have failed TKI therapy has produced encouraging results with omacetaxine. The drug has led to a complete hematologic response in 85% of the 40 patients with the chronic phase and in 50% of the 16 patients with the accelerated phase and 40% of the 10 patients with the blast phase of CML. “Responses have been durable in many instances,” Dr Cortes said. “Twenty-two of the 34 patients who achieved or had complete hematologic response…have maintained this response, with a median duration of 9 months.” After 1 year of therapy, 90% of patients in the chronic phase remain alive. Bosutinib, still under development, is an inhibitor of the Src family of kinases, but unlike nilotinib and dasatinib, it does not inhibit the c-Kit receptor or the platelet-derived growth factor (PDGF) receptor. There are “hypotheses that some toxicities, such as fluid retention and myelosuppression, may have to do with inhibition of the PDGF receptor and c-Kit, but this is very controversial,” Dr Cortes stated.

After only a 7-month trial with bosutinib, a 30% rate of complete cytogenetic response was seen in patients with resistant CML, and no evidence of toxicity, he said. Although the T315I mutation is not sensitive to any available drugs, several compounds have early promising data behind them—AP24534, DCC2036, XL228, and PHA-739358. XL228 is a multikinase inhibitor, inhibiting the BCR-ABL gene and the insulin growth factor receptor. Although still in phase 1 trials, it has already been reported to induce complete cytogenetic responses and some major molecular responses in patients who have failed multiple trial therapies. In some cases, the patients “have failed 6, 7, or 8 trial therapies,” Dr Cortes noted, “including some patients who have the mutation T315I,” he added. Another multi-TKI, AP24534, also still in phase 1 clinical trials, is potent against the T315I mutation and covers the other mutations also very well, according to Dr Cortes. DCC2036 binds in a different way from the other TKIs, in what is called the “switch pocket,” which determines whether BCR-ABL is in the active or inactive configuration. In vitro, this drug has good potency against all mutations, including T315I. ■

with poor prognosis but no difference in overall survival or relapse-free survival at 5 years. Overall, patients with AML do very poorly, noted Dr Lancet, with a longterm survival rate >20%. Several new agents have recently been introduced, but more data are needed. These include gemtuzumab,

cladribine, voreloxin, CPX-351 or liposomal cytarabine-daunorubicin, capecitabine, midostaurin (PKC412A), herbimycin A, and inhibitors of histone deacetylase. “These promising new agents may offer improved drug delivery and overcome traditional mechanisms of resistance,” Dr Lancet said.—WK ■

Dasatinib an Effective Second-Line Treatment for Chronic-Phase CML

he second-generation oral tyrosine kinase inhibitor dasatinib (Sprycel) represents an effective option for patients with chronic myelogenous leukemia (CML), in whom first-line therapy with imatinib mesylate (Gleevec) fails. Richard Stone, MD, Clinical Director of the leukemia program at the DanaFarber Cancer Institute, Boston, presented the results of a dose-optimization study of dasatinib in patients with the chronic phase of CML who failed treatment with imatinib. As a result of this study, dasatinib received full approval from the FDA as a second-line treatment for CML. It is approved for use in adults in any of the 3 phases of CML—chronic, accelerated, or the blast phase—who have resistance or have developed tolerance to previous drug treatments,

including imatinib. In the study, 670 patients were randomized to 1 of 4 dosage arms: 100 mg once daily; 50 mg twice daily; 140 mg once daily; or 70 mg twice daily. Median treatment duration was 28 months; minimum follow-up was 36 months. Hematologic and cytogenetic response rates among dosage arms were roughly equivalent at 24 months. The major molecular response was 40% across dose arms at 30 months. The 100-mg daily dose offered the best efficacy compared with other dosages. Progression-free survival (PFS) and overall survival were numerically superior for the 100-mg once-daily dose. At 36 months, PFS was 73% and overall survival was 87%. There was no difference in outcome based on a BCR-ABL mutation at outset.—WK ■

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Chronic Myelogenous Leukemia 7-Year Survival Confirms Imatinib as Standard Care for Chronic-Phase CML By Wayne Kuznar

ith a 7-year event-free survival rate of 81% and an overall survival rate of 86%, imatinib (Gleevec) has been confirmed as the standard of care for the initial therapy for the chronic phase of chronic myelogenous leukemia (CML). In reviewing these â&#x20AC;&#x153;remarkableâ&#x20AC;? survival figures from the International Randomized Study of Interferon and ST1571 (IRIS) study, Moshe Talpaz, MD, Associate Chief, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, noted that the 7-year survival leaps to 94% when only CML-related deaths are considered.

ing predetermined events that took place in the first 3 years. â&#x20AC;&#x153;We have a mix of patient biology, and have included patients with advanced disease as well as patients with early disease. Imatinib is not effective in controlling some of those events; but

later on, imatinib is highly effective in controlling prospective events. I use the term â&#x20AC;&#x2DC;freezingâ&#x20AC;&#x2122; of the disease. That term pertains here to the trickle of progressive events we see,â&#x20AC;? he said. Up to 60% of patients developed toxicities, including superficial ed-

ema (60%), nausea (50%), muscle cramps (49%), and musculoskeletal pain (47%). In years 6 and 7 of IRIS, 13 severe adverse events with a suspected relationship to imatinib were reported. â&#x20AC;&#x153;Not all of these events are truly drug related,â&#x20AC;? said Dr Talpaz. â&#x2013;

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â&#x20AC;&#x153;Those who do not achieve CCR are at increased risk for progression.â&#x20AC;? â&#x20AC;&#x201D;Moshe Talpaz, MD â&#x20AC;&#x153;Clearly, treatment has altered the scenario of the disease and interferes with the progressive events associated with chronic myelogenous leukemia,â&#x20AC;? Dr Talpaz told ASCO attendees, presenting the updated long-term outcomes and safety of patients randomized to imatinib in IRIS. The study originally included 1106 patients, 50% of whom remained in the study for the entire duration. A total of 456 of the 554 (82%) patients randomized to first-line imatinib achieved complete cytogenetic response (CCR), with 83% of these retaining CCR during the study duration. Of the 332 patients still receiving imatinib, 317 (57%) are in CCR, while 15 (3%) have not achieved CCR. â&#x20AC;&#x153;CCR is an excellent discriminator between patients who will do well and those that will not. Only 3% of patients had progressive events after achieving CCR, and only 2% died,â&#x20AC;? said Dr Talpaz. â&#x20AC;&#x153;Those who do not achieve CCR are at increased risk for progression.â&#x20AC;? The incidence rates of overall events, including progression and resistance, were 4.8% in year 1; 10.3% in year 2; 6.4% in year 3; 2.6% in year 4; 1.3% in year 5; 0.3% in year 6; and 2.4% in year 7. The spike in events in year 7 was due to the death of 1 patient from an unrelated cause. â&#x20AC;&#x153;The bulk of events happen in the first 3 years. Subsequently, you see a steady decline in the numbers of events beyond the third year. This is very much counterintuitive in oncology, where you expect either a steady state of events or an increased number of events with time,â&#x20AC;? he said. The most likely explanation is that imatinib was not effective in revers-

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Breast Cancer

The Emerging Importance of Bone Health in Early-Stage Breast Cancer Bisphosphonates, Denosumab Increase BMD in This Patient Population By Caroline Helwick

one health is increasingly recognized as an important factor in women with breast cancer, with adverse effects possible from both cancer and its treatment. Larry J. Suva, PhD, of the University of Arkansas for Medical Sciences, Little Rock, noted that 2 major bone-related processes are of concern in early-stage breast cancer: postmenopausal- and treatment-induced osteoporosis, and the development of bone metastases in any patient with breast cancer. Patients with breast cancer often have osteoporosis. Osteoporosis occurs when bone remodeling favors the resorption process mediated by osteoclasts, which are stimulated by the receptor activator of the nuclear factor kappa-beta ligand (RANKL). During bone resorption, activated osteoclasts produce molecules and enzymes that can degrade the bone matrix. Agents that inhibit osteoclast activity, therefore, can promote bone health, according to Dr Suva. In patients with breast cancer who have osteoporosis, recent data are

showing that bisphosphonates, as well as denosumab, which is currently under FDA review, can increase bone mineral density (BMD). Bisphosphonates inhibit an important enzyme in osteoclasts while denosumab inhibits RANKL, he explained.

Agents that inhibit osteoclast activity are now recognized for their protective role in breast cancer. Osteoclastic activity may also be important in the metastatic process. Interleukin 8 (IL-8) is an inflammatory marker common in postmenopausal women with osteoporosis and in women with breast cancer. IL-8 is implicated in bone resorption, and high levels of IL-8 have been correlated with decreased survival in patients with metastatic breast cancer. Agents that inhibit osteoclast activity are now recognized for their protective role in breast cancer, Dr Suva noted. A recent pivotal study (N Engl J Med. 2009;360:679-691) showed that

the addition of the bisphosphonate zoledronic acid to adjuvant endocrine therapy in patients with early-stage breast cancer reduced the risk of disease progression by 36%. “Patients with early-stage disease can have better clinical outcomes if treatment regimens also incorporate agents that inhibit osteoclast activity,” said Michael Gnant, MD, Medical University of Vienna, Austria, during this bone biology session at ASCO. Bone loss associated with aromatase inhibitors is a rising concern, said Catherine H. Van Poznak, MD, of the University of Michigan, Ann Arbor. In managing breast cancer, clinicians should address such comorbid factors and concerns as osteoporosis, and should balance the risk/benefit ratio of specific treatment options. Oral bisphosphonates, which are indicated for the prevention/treatment of osteoporosis, can substantially increase BMD in patients with bone loss associated with aromatase inhibitors in postmenopausal women, said Dr Van Poznak, and potentially also in premenopausal patients, and

in women with breast cancer and chemotherapy-induced ovarian failure, she said. Henry G. Bone, MD, of the Michigan Bone and Mineral Clinic, stressed the importance of calcium and vitamin D in patients with breast cancer, and emphasized the value of oral bisphosphonates as a means of preventing bone loss associated with aromatase inhibitors. “Strictly from the standpoint of preventing or treating osteoporosis, conventional dosages of bisphosphonates should be adequate in women receiving adjuvant therapy,” Dr Bone said, but he noted that studies evaluating bisphosphonates in conjunction with aromatase inhibitors used much higher doses than those used in postmenopausal women with osteoporosis. The “limiting dose” of these agents in the breast cancer setting is not yet clear. ■

Weekly Paclitaxel as Effective, Less Toxic than Docetaxel/ Capecitabine in Operable Breast Cancer By Wayne Kuznar

eekly paclitaxel is just as effective as docetaxel in combination with capecitabine on the outcomes of progression-free survival and disease-free survival (DFS) in women with earlystage breast cancer, but paclitaxel is better tolerated, especially with respect to myelotoxicity, said Aman U. Buzdar, MD, Professor of Medicine, University of Texas M.D. Anderson Cancer Center, Houston. The 2 therapies were compared as preoperative and adjuvant therapy in a study in which patients with operable T1 to T3 breast cancer and no evidence of metastatic disease were randomized to either paclitaxel (80 mg/m2) weekly for 12 weeks or to docetaxel 75 mg/m2 on day 1, and capecitabine 1500 mg/m2 daily for 14 days of each 3-week cycle, for a planned 4 cycles. After completing 12 weeks of randomized therapy, all patients received chemotherapy with 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2),

and cyclophosphamide (500 mg/m2). The primary end point was DFS, and the secondary end point in patients receiving preoperative therapy was pathologic complete response (pCR).

In the preoperative setting, 111 patients were treated with docetaxel/ capecitabine and 110 with weekly paclitaxel; after a median follow-up of 40 months, the pCR rates were 18.9%

“The study…was stopped after slightly more than [600] patients had been enrolled, because the predictive probability of concluding this study in favor of docetaxel and capecitabine…was extremely low.”—Aman U. Buzdar, MD “The study was initially designed to accrue 930 patients but was stopped after slightly more than [600] patients had been enrolled, because the predictive probability of concluding this study in favor of docetaxel and capecitabine on disease-free survival and complete pathologic response was extremely low,” noted Dr Buzdar. A total of 601 patients were randomized to weekly paclitaxel (n = 304) and to docetaxel/capecitabine (n = 297).

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and 16.4%, respectively. “Breast preservation rates were identical between the 2 groups,” Dr Buzdar pointed out, and clinical remission rates were also similar. Of the patients, 190 patients who received docetaxel/capecitabine and 192 patients who received weekly paclitaxel had local therapy before study entry and were evaluable. DFS was again nearly identical between the 2 treatment arms.

Docetaxel/capecitabine was associated with a higher incidence of handfoot syndrome and myelosuppression, Dr Buzdar pointed out. Nearly half (46.8%) of the patients in the docetaxel/capecitabine group had grade 2 myalgias, and 10.9% had grade 3 myalgias, compared with 36.7% (grade 2) and 6.1% (grade 3) in the weekly paclitaxel group. Grade 2 hand-foot syndrome occurred in 24.6%, and grade 3 hand-foot syndrome occurred in 18.4% of patients receiving docetaxel/capecitabine compared with 1.7% (grade 2) and 0.3% (grade 3) of patients receiving weekly paclitaxel. Neurotoxicity was slightly more common in the group assigned to weekly paclitaxel. The study was closed in June 2008 due to futility. If the trial had continued as planned, the predictive probability of concluding in favor of the docetaxel/capecitabine arm for DFS and pCR were .005 and .001, respectively, Dr Buzdar said. ■

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Breast Cancer PARP Inhibitors...Continued from page 1 in. Most triple-negative breast cancers have a lot of this PARP enzyme, because they block the ability to repair double-stranded breaks,” she said.

The addition of the PARP inhibitor to the regimen increased overall tumor response rate by 32%—from 16% to 48%. —Joyce O’Shaughnessy, MD BSI-201 is an intravenous PARP-1 inhibitor that potentiates the effects of platinum-based chemotherapy. “Different from what we’re used to seeing in the cancer world, BSI-201 does not add any toxicity to chemotherapy,” said Dr O’Shaughnessy. It was tested in a phase 2 trial of 120 women with metastatic triple-negative breast cancer, who were randomized to 21-day cycles of gemcitabine (Gemzar)/carboplatin (Paraplatin) alone (given on days 1 and 8) or gemcitabine/carboplatin plus BSI-201 (given on days 1, 4, 8, and 11). Patients were allowed to cross over to the BSI-201 arm at disease progression, and 40% did so. PFS more than doubled, from a median of 3.3 months to 6.9 months (P <.001), with the addition of BSI-201 to the chemotherapy regimen. Overall survival increased from a median of 5.7 months with gemcitabine/carboplatin to 9.2 months with the addition

of BSI-201 (P = .005). The addition of the PARP inhibitor to the regimen increased overall tumor response rate by 32%—from 16% to 48% (P = .002). No additional toxicities occurred by adding BSI-201 to gemcitabine/carboplatin. A large phase 3 trial will follow, with patient accrual starting in late June 2009. Oral PARP Inhibitor, Olaparib In another study, the oral PARP inhibitor olaparib also showed significant activity as a single agent in a phase 2 clinical trial of women with BRCA-deficient advanced breast cancer, reported Andrew Tutt, MD, PhD, Director of the Breakthrough Cancer Research Unit, Kings College, London. Olaparib targets a BRCA1/BRCA2 tumor’s DNA repair weakness, Dr Tutt said. In this open-label study, olaparib was given either at 100 mg twice daily or 400 mg twice daily to 54 women with advanced breast cancer that was refractory to chemotherapy. Women were exposed to a median of 3 previous lines of chemotherapy. The overall response rate was 22% in the 100-mg twice-daily arm and 41% in the 400-mg twice-daily arm; 1 patient in the latter arm had complete disappearance of tumor. The median PFS was 5.7 months. The most common side effects were low-grade nausea (26%), fatigue (33%), and vomiting (15%); grade 3 or 4 fatigue occurred in 5 patients, and grade 3 or 4 nausea in 2 patients. ■

Novel Investigational HER2Targeted Therapy Making News By Audrey Andrews

enefits from preliminary studies were reported for a novel HER2-targeted agent, trastuzumab-DM1 (T-DM1), an antibody-conjugate that is the only single-agent molecule in this investigational class. T-DM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of a potent antimicrotubule derivative, DM1. The result is that the drug directly enters the cancer cell, with minimal toxicity to surrounding tissues. The open-label, single-arm, multicenter study included 112 patients with advanced breast cancer who had disease progression after treatment with at least 2 HER2-targeted therapies. Patients received a 3.6-mg/kg intravenous dose every 3 weeks. The overall response rate to the single agent was 25% by independent review and 38% by investigator review, and the clinical benefit rate—

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response or stable disease at 6 months or longer—was 35% and 45%, respectively, at 6 or more months of follow-up.

“To see such efficacy with a monotherapy is highly unusual.”—Jose Baselga, MD Toxicity was minimal, mostly grade 3-4 thrombocytopenia in about 7% of patients, reported Charles Vogel, MD, of Lynn Regional Cancer Center, Boca Raton, FL. Ian E. Krop, MD, Dana-Farber Cancer Institute, Boston, presented results from a biomarker analysis of the study. HER2 positivity was confirmed by central laboratory review in 78% of the patients, and 22% were HER2 normal. Confirmed HER2 positivity corresponded with higher response rates and disease-free survival.

Biologic Agents Gain Traction as Adjuvant Therapy for Breast Cancer By Wayne Kuznar

iologic agents used for breast cancer are receiving a critical look in the adjuvant setting. Sandra M. Swain, MD, Medical Director, Washington Cancer Institute of the Washington Hospital Center, and Professor of Medicine, Georgetown University, reviewed some of the data collected to date on trastuzumab (Herceptin) and bevacizumab (Avastin). Trastuzumab Trastuzumab improves outcomes in HER2-positive breast cancer when used in the adjuvant setting, as demonstrated in several large randomized clinical trials, but questions about its optimal use remain, including the ideal chemotherapy combinations, duration, and scheduling of treatment, said Dr Swain. “The National Comprehensive Cancer Network [NCCN] guidelines for chemotherapy with trastuzumabcontaining regimens are pretty much [a reflection of] what we’ve seen from the clinical trials,” she said. The preferred adjuvant regimens include AC chemotherapy (doxorubicin [Adriamycin] and cyclophosphamide), followed by paclitaxel plus concurrent trastuzumab and TCH (docetaxel, carboplatin, trastuzumab). Other adjuvant regimens recommended in the NCCN guidelines (www. nccn.org) include docetaxel plus trastuzumab, followed by FEC (5-fluorouracil, epirubicin, and cyclophosphamide), followed by trastuzumab sequentially; and AC, followed by docetaxel plus trastuzumab. Completed clinical trials have studied treatment durations ranging from 9 weeks to 2 years. The standard treatment duration arbitrarily adopted is 1 year, she said. The optimal treatment schedule of HER2-positive patients had response rates of 32% by independent review and 48% by investigator review, compared with 5% and 9%, respectively, in the HER2-normal subset. Disease-free survival was 7.4 months for HER2-positive patients and 2.6 months for HER2-normal patients. “These differences show the need for high-quality HER2 testing in trials and in practice,” Dr Krop said. John Mackey, MD, Professor of Oncology, Cross Cancer Institute and the University of Alberta, Canada, commented that T-DM1 appears to specifically deliver a potent cytotoxic to HER2-positive cells, with minimal

trastuzumab has yet to be determined, said Dr Swain. “In Europe and other countries, most investigators have adopted the sequential regimen, whereas in the United States, we use the concurrent regimen.” Preclinical experiments suggest that trastuzumab given concomitantly with chemotherapy has a cytotoxic effect, whereas when used sequentially, it has a cytostatic effect. As reported by Perez and colleagues at the 2005 annual meeting of ASCO, trastuzumab given concurrently with paclitaxel improved disease-free survival and overall survival compared with chemotherapy alone. However, when trastuzumab was used sequentially after chemotherapy, there were no improvements. Bevacizumab Other biologic agents currently investigated in the adjuvant setting include bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor that has shown efficacy in patients with metastatic breast cancer. “We don’t have any results from clinical trials of adjuvant bevacizumab, but there are a lot of neoadjuvant data out there. The rationale for using angiogenesis inhibitors is that VEGF and different markers of angiogenesis are independent prognostic factors in breast cancer. VEGF expression is increased in HER2-positive tumors, and several trials show the benefit of bevacizumab in the first-line setting,” Dr Swain said. Most recently, data from the RIBBON-1 study showed that bevacizumab added to capecitabine (Xeloda) results in significant improvements in progression-free survival (P = .002) compared with capecitabine alone as first-line treatment for metastatic breast cancer. ■ cardiotoxicity and only transient thrombocytopenia. “It appears less toxic than combinations of trastuzumab and taxanes, and it has impressive activity in a pretreated population, especially with central confirmation of HER2 positivity, without loss of activity after prior lapatinib treatment,” Dr Mackey commented. Jose Baselga, MD, Professor of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, and President of ESMO, observed, “To see such efficacy with a monotherapy is highly unusual. It’s important that we continue to explore this promising agent in phase 3 studies.” ■

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Breast Cancer Cost Comparisons of Adjuvant Hormonal Therapies for Breast Cancer By Wayne Kuznar

tailored approach to adjuvant hormonal treatment in women with breast cancer, predicated on the risk of cancer recurrence, could improve the cost-effectiveness of adjuvant therapy, suggest researchers from Dalhousie University in Halifax, Nova Scotia. In a separate economic analysis, these researchers discovered that sequential letrozole–tamoxifen (Femara–Nolvadex) is the economically preferred adjuvant hormonal treatment strategy in postmenopausal women with breast cancer. Significant improvements in breast cancer outcomes have been demonstrated conclusively with adjuvant hormonal treatment, but such treatment is associated with upfront drug costs. These costs depend on the hormonal treatments used, their duration, and the schedule of therapy. The reduction in the risk of cancer recurrence, the researchers argue, depends on the relative risk reduction achieved with hormonal strategies, as well as the baseline risk of breast cancer recurrences without hormonal treatment. They compared the cost-effectiveness of 3 adjuvant regimens: (1) adjuvant tamoxifen, (2) sequential tamoxifen plus an aromatase inhibitor, and (3) upfront aromatase inhibitor in postmenopausal women with breast can-

cer to determine the optimal strategies. Using the Markov model, they calculated cumulative costs and qualityadjusted life-years (QALYs) over a 25year horizon for hypothetical cohorts of 1000 postmenopausal women treated with 1 of these 3 regimens.

effectiveness ratio (ICER) of less than $50,000 per QALY gained in women with a 10-year recurrence risk of about 40% or more. The sequential tamoxifen–aromatase inhibitor regimen had an ICER of less than $50,000 per QALY

All the adjuvant therapy regimens were cost-effective, but in those with higher risks of recurrence, upfront aromatase inhibitor was the superior strategy. For women with lower recurrence risks, sequential tamoxifen-aromatase inhibitor was the optimal strategy. The efficacy of each regimen in the model was based on estimates from meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group. The model took a third-party direct payer perspective. Costs and outcomes were discounted at 3%. Results showed that any of the adjuvant treatment regimens was costeffective, but in the women with higher risks of cancer recurrence, upfront aromatase inhibitor was the superior cost-effective strategy. In contrast, for women with lower risks of recurrence, sequential tamoxifen–aromatase inhibitor was the optimal strategy. Compared with sequential tamoxifen–aromatase inhibitor, upfront aromatase inhibitor therapy was associated with an incremental cost-

gained compared with tamoxifen alone, as long as the 10-year risk of recurrence was more than about 7%. For the second analysis, data from the Breast International Group (BIG) 1-98 trial were used to compare the cost-effectiveness of letrozole and tamoxifen as monotherapies, and sequential therapies consisting of letrozole–tamoxifen, tamoxifen–letrozole, and upfront letrozole in postmenopausal women with breast cancer. The head-to-head comparison of letrozole and tamoxifen showed that letrozole was associated with a 19% risk reduction of an event ending a period of disease-free survival compared with tamoxifen. More skeletal and cardiac events occurred in patients treated with letrozole.

(BIG 1-98 started in 1998 and was initially a 2-arm trial comparing 5 years of tamoxifen with 5 years of letrozole, but was expanded 1 year later to include the 2 sequential arms.) In a direct comparison of monotherapies, letrozole had a cost-effectiveness of $6389 relative to tamoxifen, an ICER of $33,790. Because BIG 1-98 did not compare tamoxifen alone to sequential strategies, it was not possible to directly compare all strategies. In an indirect comparison, letrozole/tamoxifen had an indirect cost of $5063 relative to tamoxifen alone, and the former regimen was less costly and more effective than upfront letrozole or sequential tamoxifen–letrozole. “These results do not consider the economic or health outcome impacts of adverse events,” the investigators caution. They note that the economic superiority of sequential letrozole– tamoxifen appears to be driven by the relative cost-savings derived from a shorter duration of relatively expensive letrozole with the sequential letrozole–tamoxifen strategy compared with upfront letrozole. “This suggests letrozole–tamoxifen may be an economically preferred strategy, even though BIG 1-98 did not demonstrate a significant difference in clinical benefit between the upfront and sequential strategies.” ■

Predictive Testing of HER2 Status Cost-Effective in the Adjuvant Therapy Setting

redictive testing using immunohistochemistry and fluorescence in situ hybridization (FISH) offers an economically favorable approach to identify patients with breast cancer who will benefit the most from adjuvant treatment with trastuzumab (Herceptin), according to new data from Patricia R. Blank, MSc, medical economist at the Institute of Social and Preventive Medicine at the University of Zurich, Switzerland. Although trastuzumab has conferred significant benefit in the treatment of HER2-overexpressing breast cancer tumors, particularly in the adjuvant setting, it has also increased cancer-related healthcare costs. Ms Blank said that using FISH for the determination of HER2 status in patients with breast cancer reduces costs compared with a no-testing regimen. She and her colleagues assessed the cost-effectiveness of analyzing HER2 status with predictive tests to restrict trastuzumab treatment to

HER2-positive adjuvant breast cancer patients. Using outcomes data from randomized controlled trials, comparative studies, and retrospective reviews, they estimated costs associated with 5 strategies to deter-

“Economically as well as clinically, using HER2 testing is the preferred strategy in the direction to personalized cancer care.” —Patricia R. Blank, MSc mine HER2 status, the qualityadjusted life-years (QALYs) gained or lost with each strategy, and the incremental cost-effectiveness ratio (ICER) associated with each strategy. The findings were reported in euros. The model to assess cost-effectiveness (Markov model) used a hypothetical cohort of 10,000 women who were 50 years old. The model was run

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life-long (ie, for 50 years). “We found that only using the FISH test would be the most cost-effective strategy,” said Ms Blank. The costs for trastuzumab administration for 1 year of treatment was €42,588 ($60,084 US) per patient. The total lifetime costs per patient were €38,043 ($53,652 US) with the FISH strategy, €41,658 ($58,756 US) for combined immunohistochemistry/ FISH testing strategy, and €53,860 ($75,959 US) for the no-testing strategy. The FISH testing approach produced the lowest ICER, with a cost of €11,892 ($16,773 US) per QALY and an efficacy of 12.741 QALYs gained. The nontesting approach resulted in a cost of €53,860 ($75,959 US) to increase QALYs by 12.751. “It’s not very useful to use both tests, so the FISH test by itself would be enough even though the cost of the FISH test by itself is much higher compared to immunohistochemistry,” she said. The savings achieved by using the

FISH test (in Switzerland) versus the combined FISH/immunohistochemistry strategy was €18,403,965 ($25,958,078 US), and the savings by using FISH alone versus no testing was €80,524,347 ($113,591,847 US). “Over a life-long horizon, our model confirms that the use of HER2 tests is the dominant strategy,” said Ms Blank. “Economically as well as clinically, using HER2 testing is the preferred strategy in the direction to personalized cancer care.”—WK ■

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Breast Cancer New Small Molecule Added to Trastuzumab Improves Survival in Metastatic Disease By Wayne Kuznar

eratinib, an investigational small molecule inhibitor of the HER2 receptor (ErbB2), given with trastuzumab appears to improve progression-free survival (PFS) in women with HER2-positive metastatic breast cancer whose disease has progressed with previous trastuzumabbased therapies, according to results from an open-label study. Trastuzumab is standard therapy for women with HER2-positive metastatic breast cancer, but some women develop resistance to therapy. Neratinib, which blocks the intracellular portion of the HER2 receptor (trastuzumab blocks the extracellular portion), appears to be active in women who have disease progression despite treatment with trastuzumab.

â&#x20AC;&#x153;This is very promising. Neratinib induces clinically meaningful responses.â&#x20AC;? â&#x20AC;&#x201D;Ramona Swaby, MD More than 25% of the women in the phase 1/2 trial had a reduction in tumor size after combination therapy with neratinib plus trastuzumab, said Ramona Swaby, MD, medical oncologist and attending physician at Fox Chase Cancer Center, Philadelphia. â&#x20AC;&#x153;This is very promising. Neratinib induces clinically meaningful responses,â&#x20AC;? noted Dr Swaby. Phase 3 studies are under way, she added. For the phase 1 portion of the trial, 45 women received either neratinib (160 mg/day or 240 mg/day) plus trastuzumab (4 mg/kg intravenous loading dose, followed by 2 mg/kg weekly). No dose-limiting toxicities occurred in any patients. The most common grade 3/4 adverse events included diarrhea (13%), nausea (4%), and vomiting (4%). There was no evidence of cardiac toxicity. â&#x20AC;&#x153;Including stable disease and wider response, most patients benefited from treatment with the combination of neratinib/trastuzumab,â&#x20AC;? she said. â&#x20AC;&#x153;The combination of neratinib (240 mg/day) and weekly trastuzumab was well tolerated. Neratinib in combination with trastuzumab did not cause clinically significant cardiac disease.â&#x20AC;? In the phase 2 portion of the trial, of the 28 patients who were evaluated for response, 27% had an objective response to the combination therapy, and 45% met the primary end point of the trialâ&#x20AC;&#x201D;PFS at 16 weeks, which was the median PFS. In addition, 7 women have remained on active therapy for more than 1 year.

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Objective response was seen in 28.6% of the patients, complete response in approximately 7%, and partial response in 21% of patients. Only 2 patients at the maximum dose required dose reductions, because of

diarrhea and angioedema. The predominant reason for treatment discontinuation was disease progression. In this heavily pretreated population, the 16-week PFS rate of 45% with the combination exceeded the

protocol-specified 35% target, Dr Swaby noted. â&#x2013; SEE ALSO Targeted Trastuzumab Improves Survival in Gastric Cancer: â&#x20AC;&#x153;Poster Childâ&#x20AC;? of Personalized Medicine, page 5.

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CINV: Defining the Preferred Dose of Palonosetron By Caroline Helwick

hemotherapy-induced nausea and vomiting (CINV) is a common side effect in patients receiving cancer therapy. Controversy continues as to whether there should be a guideline-preferred 5-hydroxytryptamine-3 (5-HT3) receptor antagonist for the prevention of CINV. In large trials, 0.25 mg of the secondgeneration 5-HT3 antagonist palonosetron (Aloxi) demonstrated advantages over earlier 5-HT3 antagonists, but because these trials omitted the recommended addition of dexamethasone, guideline groups have not consistently adopted palonosetron as the

preferred preventive agent. A multicenter research team recently conducted a meta-analysis of all 8 randomized double-blind clinical trials of palonosetron to determine if there are differences in the drug’s efficacy according to the dose regimen. Harry Raftopoulos, MD, North Shore-Long Island Jewish Health System, Lake Success, NY, presented the results at ASCO. “A recent 1100-patient randomized double-blind trial by Yoshizawa and colleagues [ESMO 2008] found superiority for palonosetron 0.75 mg plus dexamethasone versus granisetron 3

Table Comparing Emesis Control with 2 Doses of Palonosetron

Number of studies (patients)

All studies 8 (1926)

0.25 mg vs 0.75 mg HEC studies MEC studies 4 (720) 4 (1206)

Relative risk: 5-day complete response

0.998 (P = .97) 1.102 (P = .27) 0.958 (P = .45)

Relative risk: acute emesis

1.002 (P = .96) 1.075 (P = .49) 0.985 (P = .77)

Relative risk: delayed emesis

1.003 (P = .95) 1.065 (P = .44) 0.978 (P = .67)

Note: Relative risk >1 indicates better control with 0.75 mg. HEC indicates highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy.

mg plus dexamethasone,” Dr Raftopoulos said. “Both palonosetron and granisetron are approved at varying doses in different countries. This abstracted data meta-analysis was conducted to see if this palonosetron dosing yields differences. If not, results from randomized trials at either dose can aid practice and guideline committees in 5-HT3 agent selection.” A literature search and surveys of colleagues identified randomized double-blind trials that included treatment arms with 0.25 mg and 0.75 mg of palonosetron. The primary end point was complete response (no vomiting, no rescue) over days 1 through 5 after chemotherapy. Secondary end points were acute complete response (day 1), delayed complete response (days 2-5), and rate of grade 3-4 toxicities. The 8 trials involved 1926 patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy. The analysis demonstrated no differences in efficacy and safety between palonosetron 0.25 mg and 0.75 mg (Table), Dr Raftopoulos

reported. For all types of emesis, the relative risks hovered around 1.0, indicating that both doses were very effective in preventing acute and delayed emesis, and in achieving complete responses over 5 days. “Results with either dose can aid in practice and guideline considerations for all chemotherapy groups studied,” he concluded. ■

• Imatinib (Gleevec) for chronic myelogenous leukemia (N = 7000). Beyond this widespread access, patients can apply for compassionate use through the single-patient Investigational New Drug or, less often, a special protocol exception program (which is used, for example, in cases of ambiguity over eligibility). These requests are addressed by the pharmaceutical company on a caseby-case basis.

detailed information about the patient, especially the relevant history, and will want to hear strong rationale for treatment with the drug. The proposal should also include a treatment plan, including dosing regimen and measures of safety and efficacy. The sponsor will make a decision based on this information, as well as the availability of the drug. “Supply is usually the biggest limitation,” Dr Krivoshik said. If the sponsor agrees, the physician and sponsor collaborate on a proposal to the FDA. If access is approved, the physician is required to follow “normal study conduct,” that is, to perform good clinical practices and obtain approval from his or her Institutional Review Board (IRB) and informed consent from the patient. The IRB committee typically recognizes the request as a priority and moves the process. Similarly, despite the necessary involvement of many parties on the sponsor’s side—the drug development team, contracts group, regulatory liaison, drug supply department, safety tracking team— and the regulatory requirements to be satisfied, the process from patient request to FDA approval is generally less than 1 month, he said. The key is to start the dialogue early, Dr Krivoshik emphasized.—CH ■

NCCN Adds Palonosetron In April 2009, the National Comprehensive Cancer Network (NCCN)’s Clinical Practice Guidelines in Oncology on Antiemesis added the second-generation palonosetron as the preferred HT3 antagonist for the prevention of chemotherapy-induced emesis. Palonosetron is recommended for use in a combination regimen with aprepitant and dexamethasone. The NCCN’s recommendation was based on this multicenter Japanese study, which was published earlier this year (Saito M, et al. Lancet Oncol. 2009;10:115-124. Epub 2009 Jan 8).

Gaining Access to Investigational Drugs Partnering with Pharma to Help Patients

lthough a clinical trial is best for a desperate patient with cancer, access to the same investigational agent can often be gained when physicians have some understanding of the process. Andrew P. Krivoshik, MD, PhD, Medical Director of the Oncology Group at Abbott Laboratories, Abbott Park, IL, described the steps involved in obtaining access to investigational drugs to treat cancer outside of clinical trials. The main reason for doing so is to offer a promising investigational agent to a patient who is not eligible for a clinical trial of the compound and who has exhausted all treatment options. “This is the mechanism for the rare patient who may not otherwise have access to the drug,” he said. The main reasons to access investigational drugs are: • Patient has undergone standard treatment that has not been successful • Patient is ineligible for any ongoing clinical trials of this drug • Patient has no acceptable treatment alternatives • Patient has a cancer for which the investigational drug has activity • Patient is likely to experience benefits that outweigh potential risks.

Many physicians do not take advantage of this process, which can be wieldy but may pay off for the patient. “When I first started in academic medicine, I didn’t realize at first how unusual these requests are,” Dr Krivoshik commented. For one compound his team is developing, approximately only 40 requests have been granted over 4 or 5 years. But now he understands some of the limitations from the industry’s perspective. “It’s about the soundness of the data that support the request, and it’s about the availability of the drug. There can be a limited supply, validation issues, and other obstacles. For a drug early in development, there’s no guarantee,” he said. Types of Access Expanded access protocols for a drug in late-stage development may be the simplest way to obtain it. Examples of adult oncology expanded-access programs and the number of participants include: • Gefitinib (Iressa) for non–small-cell lung cancer (N = 24,000) • Oxaliplatin (Eloxatin) for colorectal cancer (N = 8500) • Gemcitabine (Gemzar) for pancreatic cancer (N = 2500)

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“At the end of the day, a lot of people need to talk to each other to obtain access.” —Andrew P. Krivoshik, MD, PhD The process becomes a dialogue between the physician and the patient. The physician’s first step is to determine which drug and clinical trials might benefit the patient. If the patient cannot meet the eligibility requirements, the physician can then proceed with a request for compassionate use. When the physician is not a trial investigator, the process gets more complex. Begin the Dialogue Early “At the end of the day, a lot of people need to talk to each other to obtain access,” he said. The sponsor will want

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Other News from ASCO

Gemcitabine/Cisplatin New Standard for Advanced Biliary Cancers By Wayne Kuznar

emcitabine (Gemzar) with cisplatin represents a new standard of care for patients with advanced biliary tract cancer, because it is the first regimen to demonstrate improved survival in this disease, said Juan W. Valle, MD, Medical Oncologist, University of Manchester, United Kingdom. “For these patients, surgery is the only chance of longterm cure, but despite this, the 5-year survival is very poor; in the region of 5% to 10%,” he said. There has been no standard of care for patients with advanced biliary tract cancer, because of the small number of patients involved and the small published series. “The most prominent reason, however, has been the lack of multicenter collaboration,” said Dr Valle. “When reviewing the literature, we can see that studies

include heterogenous populations, including patients with pancreatic cancer, as well as hepatocellular carcinoma, and because of the proximity to gastrointestinal tumors and cancer of the pancreas, most of the treatments in the literature have been 5fluorourcil or gemcitabine-based.” The tumor type is difficult to confirm histologically, and measureable disease is often difficult to delineate on routine radiology. In a prospective, national, multicenter phase 3 study, 410 patients with metastatic or locally advanced disease were randomized 1:1 to receive (1) single-agent gemcitabine chemotherapy or (2) gemcitabine in combination with cisplatin. Treatment duration was an initial 3 months and, in the absence of progression, an additional 3 months. Treatment was at the clinician’s discretion

at the start of disease progression. After a median follow-up of 6.1 months, there was an increase in median survival from 8.3 months with gemcitabine alone to 11.7 months with the combination of cisplatin and gemcitabine (P = .002). “The combination chemotherapy reduces the risk of death by 30%,” Dr Valle noted. “We found a similar reduction in our secondary end point, progression-free survival.” Progression-free risk was reduced by 30% from 8.4 months to 6.5 months (P = .003). “This benefit has been gained with no clinically significant added toxicity,” he said. Toxicity was similar between the arms, though there was a slight excess of neutropenia using gemcitabine with cisplatin versus gemcitabine alone (15.1% vs 11.0%). “We consider cisplatin and gemc-

itabine to now be the worldwide standard of care and the backbone for further studies for patients with advanced biliary tract cancers,” Dr Valle noted.

“We consider cisplatin and gemcitabine to now be the worldwide standard of care.” —Juan W. Valle, MD “We’re unlikely to gain any further benefit by adding any further chemotherapy…because of probably increasing toxicities,” he said. “The exciting future directions are probably going to be trying to add in some of the more targeted therapies, with the theme of personalizing care, trying to be able to identify patients who may benefit most from those individual treatments.” ■

Gemcitabine/Chemoradiation Potential New Standard for Cervical Cancer By Caroline Helwick

nother phase 3 multicenter international study showed the benefit of adding gemcitabine to cisplatin chemoradiation to treat locally advanced cervical cancer. The findings have particular value for women in developing countries. “In most developing countries, where cervical cancer screening programs are deficient or not available, about 70% of women with cervical cancer are diagnosed with locally advanced disease and require chemotherapy and radiation,” said Alfonso Duenas-Gonzales, MD, PhD, of the National Cancer Institute of Mexico. “Our findings are the first to show that adding gemcitabine to cisplatin chemotherapy slows cancer growth and improves survival. It suggests that this regimen may become a

standard of care for these patients.” Conducted in 8 countries, the study included 256 women assigned to standard therapy (cisplatin plus radiation therapy) and 259 women who received the same treatment plus gemcitabine. Gemcitabine was given along with cisplatin and radiation for 6 cycles, with an additional 2 cycles of gemcitabine plus cisplatin after the completion of radiotherapy. After a median follow-up of 3 years, progression-free survival was almost 75% with gemcitabine versus 65% with standard treatment, a 32% reduction in progression risk. Overall survival was 78% versus 69%, respectively, also a 32% risk reduction. The greatest benefit was seen in the reduction in the distant recurrence, although there was a trend for better

local disease control as well. As expected, toxicity increased with the new regimen, primarily neutropenia and diarrhea, which led to a higher discontinuation rate in the experi-

These findings are “potentially the most significant advance in chemoradiation of cervical cancer that we have seen in the past decade.” —Amit M. Oza, MD mental arm (18% vs 1%). “But rates of grade 3-4 toxicity were low overall and considered clinically acceptable in the context of a survival benefit,”

he said. “This is the first study showing that a combination of drugs with radiation improves survival versus single-agent cisplatin.” Amit M. Oza, MD, of the University of Toronto, Canada, called the findings, “potentially the most significant advance in chemoradiation of cervical cancer that we have seen in the past decade,” and offers “lessons that will be important to share with the international community.” “I can accept that the evidence supports concurrent chemoradiation and adjuvant chemotherapy as the new standard of care,” Dr Oza continued, “although confirmatory trials are needed to determine if gemcitabine is the optimal second agent, and to identify the optimal sequence and duration of therapy.” ■

Fast-Track Follicular Lymphoma Vaccine: Promising Results Reported at ASCO

he long-awaited phase 3 clinical trial of an investigational vaccine for follicular lymphoma was reported at ASCO, suggesting that despite consistent failures in the past, an effective vaccine may yet be realized. The vaccine, BiovaxID (BioVest International), is personalized for each patient to include a tumor-derived idiotype protein. It has been granted a fast-track status by the FDA and an orphan-drug status by the European Medicines Agency. The study, funded by the National Cancer Institute, included 177 patients

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with follicular lymphoma who received induction chemotherapy and maintained complete response for 6 months. This group was randomized to receive the vaccine (by subcutaneous injection) or placebo. The study achieved its primary end point of prolonging disease-free survival (DFS). After a median followup of 4.7 years, median DFS was 44.2 months with BiovaxID vaccination and 30.6 months in the control arm, reported Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia. “With this vaccine,

we’ve now moved into an era where we can safely use a patient’s immune system to effectively fight follicular lymphoma and enhance the response to conventional chemotherapy,” Dr Schuster said. Ron Levy, MD, Chief of Oncology, Stanford University, Calif, and a pioneer in the field of idiopathic vaccine development, raised some limitations about these findings. “The data were positive in patients in whom it was tested,” he said, and “there may be a role for this vaccine, but further evidence will be needed.”

Also, the chemotherapy regimen used is out of date, and patient selection was a problem. Although 234 patients were originally enrolled, only 177 were randomized—those that responded to induction and maintained complete remission for ≥6 months. The patients included were, therefore, “the best of the best.” Despite these reservations, Dr Levy reiterated that the trial was positive, and future studies will evaluate the vaccine with rituximab—the current standard of care—during induction chemotherapy.—CH ■

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Patient’s Perspective

Coping with the Cost of Cancer Care: The Patient’s Perspective Kim Thiboldeaux President and CEO, The Wellness Community, Washington, DC, www.thewellnesscommunity.org

n a June 2009 Washington Post– ABC News national poll of 1001 adults, 83% of respondents were either “somewhat” or “very” satisfied with the healthcare they receive and 81% had similar feelings about their insurance.1 However, the poll did not clarify to what extent respondents have had to depend on the current healthcare delivery system. I would venture to guess that this poll and others like it do not accurately reflect the concerns of the growing number of cancer survivors and other patients dealing with serious diseases. Managing the cost of healthcare today can be extremely challenging for the 12 million cancer survivors and the 1.5 million of people diagnosed with cancer each year in the United States. According to a study released in July 2009 by Harvard Law School, Harvard Medical School, and Ohio University, medical bills are involved in more than 60% of US bankruptcies, up from 50% just 6 years ago.2 And more than 75% of these families reported having health insurance, but they were overwhelmed by the outof-pocket (OOP) expenses.2 In addition, a February 2009 study by the Kaiser Family Foundation and the American Cancer Society suggest that high healthcare cost-sharing, caps on benefits, and lifetime insurance coverage maximums leave cancer patients vulnerable to high OOP costs.3 As the healthcare debate heats up this summer on Capitol Hill, patients are becoming increasingly restless. And the recent economic downturn, which has led to loss of jobs, homes, and healthcare coverage, has certainly exacerbated these financial concerns for patients with cancer and their families. In the wake of the current recession, and in light of the political momentum around healthcare and associated costs, The Wellness Community—an international nonprofit that provides free support and educa-

“Managing the cost of healthcare today can be extremely challenging for the 12 million cancer survivors and the 1.5 million of people diagnosed with cancer each year in the United States.” —Kim Thiboldeaux

tion to people affected by cancer— recently launched a national education program aimed directly at addressing the growing financial concerns of patients with cancer and their families. Shedding light on both the practical and psychological impact of incurring debt, sometimes for the first time, in combination with the psychological impact of coping with cancer, the program—Frankly Speaking About Cancer: Coping with the Cost of Care—streamlines crucial resources available to patients receiving treatment for cancer. The program addresses private health insurance, Medicare, Medicaid, Social Security Death Insurance, pharmaceutical assistance programs, and more. Patients and families acknowledge that this program is raising questions and issues that have never been addressed before by any member of their healthcare team. Having access to and an understanding of these resources are essential to empowering patients to activate a dialogue with their healthcare team that is open and honest. A 2007 Institute of Medicine report, Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs, states that today’s cancer care does not adequately address the emotional, social, spiritual, or financial challenges associated with the disease.4 The report emphasizes that quality psychosocial care is critical for patients to have optimal clinical outcomes. It goes on to say that community-based organizations are a crucial part of the healthcare delivery system

and need to be better incorporated into the continuum of cancer care. The Need for Open Dialogue Throughout The Wellness Community’s 27 years of empowering and educating patients with cancer, we’ve learned that open communication is a key ingredient to bridging the gap in care. Tina Seltzer, a participant at The Wellness Community in

available; when you are fighting for your life and struggling to be there for your family, these questions can make patients feel vulnerable. Ms Seltzer’s story is just one among thousands (or millions) of examples of how our healthcare system is failing those among us. Perhaps one of the positive side effects of the current debate on healthcare is the open dialogue about its potentially crippling costs. We are learning that the system is negatively affecting average American families who are working, and who are insured—those who we think are doing well. Even insured, employed families can be just one cancer diagnosis away from bankruptcy and a whole series of life-altering decisions no family should have to face. We need to take another look at what we think is working—and

“When I first got cancer, I had nowhere to turn, and I didn’t know what questions to ask, who to ask, or where to find financial resources available to help me manage the cost of my care.”—Tina Seltzer, with $500,000 medical debt San Francisco/East Bay and a stage IV colorectal cancer patient, recently told us of her $500,000 medical debt that she began incurring with her 2007 diagnosis. Before her diagnosis she was insured through her employer, but faced with a rigorous treatment plan and raising 2 teenage daughters alone, she left her job and decided to simply focus on her oncologist’s orders and not ask questions. “When I first got cancer I had nowhere to turn, and I didn’t know what questions to ask, who to ask, or where to find financial resources available to help me manage the cost of my care,” she says. She was too embarrassed to ask her doctors about generic treatments or sliding scales because she feared they wouldn’t give her the best treatment

ensure it also works in the face of a cancer diagnosis. Many of the people we serve, like Ms Seltzer, would encourage you to remember that for our commitment to healthcare reform to succeed, it should be there in sickness and in health. ■ References 1. Current satisfaction vs future worry defines the battle on health reform. http://abcnews.go.com/ images/pollingunit/1091a2Healthcarereform.pdf. Accessed July 28, 2009. 2. Himmelstein DU, Thorne D, Warren E, Woolhandler S. Medical bankruptcy in the United States, 2007: results of a national study. Am J Med. 2009;122:741-746. 3. Schwartz K, Claxton G, Martin K, Schmidt C. Spending to survive: cancer patients confront holes in the health insurance system. www.kff.org/ insurance/upload/7851.pdf. Accessed July 28, 2009. 4. Institute of Medicine. Cancer care for the whole patient: meeting psychosocial health needs. Washington, DC: The National Academies Press; 2008. www.iom.edu/CMS/3809/34252/47228. Accessed July 28, 2009.

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August 2009

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Payer’s Perspective

ASCO 2009: Payers’ Reaction to the Latest Clinical Trials Rhonda Greenapple, MSPH President, RADical Group, LLC, Madison, NJ

Oncology Formulary Trends Payers recognize that new agents

Figure 1 Interventions Plans Use/Will Use in 2 Years to Control Costs

Responses, %

Not utilized

Current intervention

100 80 60 40 20 0

10% 10%

will be entering into the marketplace but want to see substantial improvement over current treatment regimens or standards of care. Regardless of the tumor type, 25% of the survey respondents expect to see 5 to 7 months of incremental survival benefit for a new drug to demonstrate a clinical advantage. In terms of efficacy, progressionfree and overall survival rates represent the most important end points in determining coverage. In addition to efficacy and safety issues, respondents rated the importance of other factors in evaluating a new cancer therapy (Table). The National Comprehensive Cancer Network (NCCN) guidelines are important to coverage decisions according to this survey; it is critical for manufacturers to develop clinical and

Factor Retrospective data of real-world effectiveness Comparison of drug acquisition cost NCCN guidelines Incidence of down dosing Cost of down dosing Quality-of-life data Tolerability Side effects Impact on long-term disability Cost of adverse event management Off-label use Toxicity data Frequency of administration Route of administration Total cost when used in combination with another agent Likelihood of off-label use 1 indicates very important; 5, not very important.

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53% 27%

ASP indicates average sales price.

Table Factors Affecting Payers’ Attitudes toward New Cancer Therapies

Figure 2 Payers’ View of NSCLC Treatments’ Efficacy

Next 2 years

AS Pba se dp ay me nts Ca pit ate dp Lim ay it u me se nts of co mp en Pa dia ylis for tin -p g er for ma nc Ph ep ar ro ma gr cy am b en On efi co tc log las yf sif or ica mu tio lar n y Re w/ du p re ce fer do re ffdb lab ra el nd us er eim bu rse me Sp nt ec ific dia gn os tic tes t

esearch has brought great promise to cancer treatment and new options for oncologists and patients. However, commercial and government payers are facing medication costs that range from $30,000 to $90,000 for a complete treatment regimen. The monthly and median costs of cancer drugs at the time of approval by the FDA in 2008 were $5000 and are rising (Bach PB. N Engl J Med. 2009;360:626-633). To understand how oncology management will change in light of the many new products in development, Reimbursement Intelligence surveyed 60 formulary decision makers who represent the top health plans in the United States. The survey results suggest that the latest trends in utilization management, use of guidelines, and benefit design all play a critical part in reducing oncology drug costs and cost-shifting to members. The study was designed to capture medical and pharmacy directors’ reactions to data from the latest clinical trials in the following key tumor types—breast cancer, colon cancer, non–small-cell lung cancer (NSCLC), multiple myeloma, and melanoma. Information was obtained immediately after this year’s ASCO meeting, giving a “gut check” to the clinical findings before the information was put into formal communications. The highlights of the survey results are provided below.

Average ratinga 2.03 2.23 1.87 3.07 2.98 2.97 2.23 2.02 2.46 2.41 2.30 1.98 2.77 2.79 1.92 2.13

health outcomes programs that are credible to the experts in a tumor type. Although prior authorization is often used to ensure appropriate drug use according to FDA indications, the survey showed that 50% of payers do not track off-label drug use. Other methods used are diagnosis requirements and claims analysis. Commercial and government health plans must look for new methods to control rising costs. Our survey indicated that more than 60% of health plans would implement an oncology formulary, with preferred brands, in the next 2 years (Figure 1). For example, in reviewing data from clinical trials involving pemetrexed (Alimta), erlotinib (Tarceva), and bevacizumab (Avastin) for NSCLC therapy, more than 50% of the payers indicated they saw no difference among these oncolytic therapies (Figure 2). As new therapies become available for different tumor types, plans can start asking, “Do the data outweigh the cost of these therapies?” and, “Is it worth it?” The Obama administration is discussing the lowest-cost alternative as well as comparative effectiveness analysis as a way of measuring cost-effectiveness. Although these methods are currently being designed and implemented, these 60 payers indicated that in the future health plans would be looking at comparative effectiveness analysis of different regimens, studies with active comparators, gene selectivity, and survival rates. Over the next 5 years, payers will increase the threshold of data needed for optimal access and reimbursement. Manufacturers will need to plan early in the product develop-

Tarceva Alimta

Avastin All equally effective

ment process to create end points that demonstrate cost-effectiveness and improved health outcomes. Moving oncology therapies from the medical to the pharmacy benefit may be another method to manage cost, utilization, health outcomes, and patient adherence. Payers expect to see use of specialty pharmacy grow substantially over the next 2 years. Payers would like to see tracking data from specialty pharmacies that measure oncology therapy in more detail. These measurements include: • Reductions in gaps in therapy • Compliance with regimen • Use of NCCN guidelines • Episode-of-care analysis • Medical cost-savings • Use of secondary therapy. Reimbursement and management of oncology agents will only increase over the next 2 years. Currently, cancer therapies have been “sacred”; they have not been managed but rather oncologists have been allowed to make treatment decisions. However, the costs of new agents, off-label use, and multiple treatment options will drive more management and cost-shifting to the plan members. Because Medicare will be carrying a significant burden for oncology care, it is expected that more restrictions will be placed on expensive oncology agents and benefit design will increase coinsurance and copayments for members. These trends create an opportunity to show how advancements in care can be cost-effective and should be carefully monitored by oncology drug manufacturers. ■

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Payerâ&#x20AC;&#x2122;s Perspective

The Cost of Oncology Care Gary M. Owens, MD P & T Committee Chairman, Towers Perrin RxCollaborative

he rising cost of healthcare is a major national concern. Lawmakers in our nationâ&#x20AC;&#x2122;s capital are struggling with how to provide healthcare benefits to millions of uninsured Americans at a cost in the trillions of dollars. Cancer care costs are a representative example of this issue. In 2008, there were almost 1.5 million new cases of cancer, and that number will only grow as the population ages. Over the past decade, there have been many revolutionary advances in the treatment of cancer, but these advances have come at a cost. Peter B. Bach, MD, Associate Attending Physician, Memorial SloanKettering Cancer Center, New York, recently wrote, â&#x20AC;&#x153;In part because of rising prices, and in part because of increased rates of use, spending on cancer drugs has risen faster than spending in many other areas of healthcare. For Medicare, spending on Part B drugsâ&#x20AC;&#x201D;a category dominated by drugs used to treat cancerâ&#x20AC;&#x201D; rose from $3 billion in 1997 to $11 billion in 2004 (an increase of 267%), as compared with a rise in overall Medicare spending from $210 billion to $309 billion (an increase of 47%) during the same periodâ&#x20AC;? (Limits on Medicareâ&#x20AC;&#x2122;s ability to control rising spending on cancer drugs. N Engl J Med. 2009;360:626-633; erratum in N Engl J Med. 2009;360:944). This is precisely the issue for pay-

-R EV TH E PE ER JUNE/JULY

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CE R EV ID EN FO RU M FO

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ersâ&#x20AC;&#x201D;rising costs for cancer treatments are of major importance as payers struggle to maintain access to and affordability of care for patients. No longer can payers simply take a â&#x20AC;&#x153;hands-offâ&#x20AC;? approach to cancer care.

tions, â&#x20AC;&#x153;What can you do to manage the cost of oncology care,â&#x20AC;? and, â&#x20AC;&#x153;Am I getting value for the money I am spending on this care?â&#x20AC;? Until recently, payers were likely to respond by saying that they generally had a â&#x20AC;&#x153;hands-

Gone is the era of hands-off approach to oncology care. The ultimate goal is to provide access, at an affordable level, for interventions that work best, and not pay for treatments that offer little or no incremental value. This change will not be easy or rapid. According to Medcoâ&#x20AC;&#x2122;s Drug Trend Report, there are more than 630 cancer drugs in development, making this category of drugs one of the largest drivers of pharmaceutical cost increase (The great healthcare debates: prescriptions for meaningful reform. Drug Trend Report. 2009;11:1-108). Therefore, it is no surprise to payers that the 2009 ASCO meeting focused many of its sessions on the cost of oncology care. Payers have also begun to increase their focus on the cost of new technology for the treatment of cancer. Not all of this cost is related to drug treatment. Advances in diagnostic imaging, radiation therapy, and robotic surgical techniques are also important drivers of cancer care costs. Therefore, employers have begun to ask payers the difficult ques-

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offâ&#x20AC;? approach to the management of cancer care. But that is no longer an option, as medical costs continue to escalate in a struggling economy. Many payers are now actively engaged in oncology management, including advanced imaging management programs and prior authorization of select oncology treatments. In addition, benefits have begun to change; it is common these days to see coinsurance rates for oncology drugs in the range of 20% to 25%. Gone is the era of hands-off approach to oncology care. However, these changes are only a short-term remedy. In fact, some of these activities may have the unintended consequence of creating barriers to needed care. For payers to more effectively manage oncology care and not create barri-

ers for patients, more information is needed. Simply put, we must begin to better understand what works, for whom, and at what cost. As is evident from the articles in this special issue, it is encouraging to see that oncologists are beginning to ask these questions. According to data presented at ASCO by Dr Peter Neumann (see page 1), more than 43% of oncologists now frequently or occasionally discuss the cost of care with their patients, and 80% expressed a desire for more costeffective data in coverage and payment decisions for cancer drugs. It is therefore time for all stakeholders in the cancer care arenaâ&#x20AC;&#x201D;payers, employers, physicians, manufacturers, and, most important, patientsâ&#x20AC;&#x201D;to join together in the quest for these answers. Having this information will enable patients and clinicians to make evidence-based treatment decisions, and payers will be able to develop health and drug benefits consistent with the evidence. The ultimate goal is to provide access, at an affordable level, for interventions that work best, and not pay for treatments that offer little or no incremental value. This change will not be easy or rapid, so all stakeholders must begin to develop the clinical and financial comparative effectiveness tools that will be central to maintaining access to high-quality and affordable cancer care. â&#x2013;

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IXEMPRA速 Kit (ixabepilone) for Injection, for intravenous infusion only Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: TOXICITY IN HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications and Warnings and Precautions ]. INDICATIONS AND USAGE IXEMPRA (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting. IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. CONTRAINDICATIONS IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor速 EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions]. IXEMPRA is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3 [see Warnings and Precautions]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions]. WARNINGS AND PRECAUTIONS Peripheral Neuropathy Peripheral neuropathy was common (see Table 1). Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2) in Full Prescribing Information]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. Table 1:

Cardiac Adverse Reactions The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function. Potential for Cognitive Impairment from Excipients Since IXEMPRA contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol [see Description (11) in Full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections. N '6C:A96C2= ?6FC@A2E9J 0D66 Warnings and Precautions] N $J6=@DFAAC6DD:@? 0D66 Warnings and Precautions] N JA6CD6?D:E:G:EJ C624E:@?D 0D66 Warnings and Precautions] Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions (*20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in *20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 2 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 3. Table 2:

Treatment-related Peripheral Neuropathy

Peripheral neuropathy (all grades)a,b Peripheral neuropathy (grades 3/4)a,b Discontinuation due to neuropathy Median number of cycles to onset of grade 3/4 neuropathy Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 a

0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation.

IXEMPRA with capecitabine Study 046 67% 23% 21%

IXEMPRA as monotherapy Study 081 63% 14% 6%

6.0 weeks

4.6 weeks

Sensory and motor neuropathy combined. 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1).

A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy. Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropeniarelated death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN. [See Boxed Warning, Contraindications, and Warnings and Precautions.] Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced [see Dosage and Administration (2.2) in Full Prescribing Information]. Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT )2.5 x ULN or bilirubin )1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater [see Warnings and Precautions]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use in Specific Populations]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning, Contraindications, and Warnings and Precautions]. Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see Dosage and Administration (2.2) in Full Prescribing Information]. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients [see Dosage and Administration (2.2) in Full Prescribing Information]. Hypersensitivity Reactions Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor速 EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration (2.3) in Full Prescribing Information and Contraindications ]. Pregnancy Pregnancy Category D. IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. 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. Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA (ixabepilone)

System Organ Classa/ Preferred Term Infections and Infestations Upper respiratory tract infectionb Blood and Lymphatic System Disorders Febrile neutropenia Immune System Disorders Hypersensitivityb Metabolism and Nutrition Disorders Anorexiab Dehydrationb Psychiatric Insomniab Nervous System Disorders Peripheral neuropathy Sensory neuropathy b,e Motor neuropathyb Headache Taste disorderb Dizziness Eye Disorders Lacrimation increased Vascular Disorders Hot flushb Respiratory, Thoracic, and Mediastinal Disorders Dyspneab Coughb Gastrointestinal Disorders Nausea Vomitingb Stomatitis/mucositisb Diarrheab Constipation Abdominal painb Gastroesophageal reflux diseaseb Skin and Subcutaneous Tissue Disorders Alopeciab Skin rashb Nail disorderb Palmar-plantar erythrodysesthesia syndromeb,f Pruritus Skin exfoliationb Skin hyperpigmentationb a

Study 046 IXEMPRA with Capecitabine capecitabine n=369 n=368 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

34 5

3d 2

15 2

1d <1d

19 2

2d 1d

<1d

65 16 8 12 8

21 5d <1d 0 1d

16 <1 3 4 5

0 0 0 0 1d

62 10 11 6 7

14 1d 0 0 0

<1d

7 6

1 0

4 2

1 0

9 2

1d 0

53 39 31 44 22 24 7

3d 4d 4 6d 0 2d 1d

40 24 20 39 6 14 8

2d 2 3d 9 <1d 1d 0

42 29 29 22 16 13 6

2d 1d 6 1d 2d 2d 0

31 17 24 64

0 1d 2d 18d

3 7 10 63

0 0 <1d 17d

48 9 9 8

0 2d 0 2d

5 5 11

0 <1d 0

2 3 14

0 0 0

6 2 2

1d 0 0 (Continued)

System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS). b A composite of multiple MedDRA Preferred Terms. c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions ]. d No grade 4 reports. e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 046.

Table 2: (Continued)

Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA (ixabepilone) Study 046 IXEMPRA with Capecitabine capecitabine n=368 n=369 Total Grade 3/4 Total Grade 3/4 (%) (%) (%) (%)

System Organ Classa/ Preferred Term Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgiab Musculoskeletal painb General Disorders and Administrative Site Conditions Fatigue/astheniab Edemab Pyrexia Painb Chest painb Investigations Weight decreased

Study 081 IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%)

39 23

8d 2d

5 5

<1d 0

49 20

8d 3d

60 8 10 9 4

16 0 1d 1d 1d

29 5 4 2 <1

4 <1d 0 0 0

56 9 8 8 5

13 1d 1d 3d 1d

Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA Study 046 Study 081 IXEMPRA with IXEMPRA Capecitabine capecitabine monotherapy n=368 n=369 n=126 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) Hematology Parameter Neutropeniaa #6F<@A6?:2 - Anemia (Hgb) Thrombocytopenia

32 41 8 5

36 16 2 3

9 5 4 2

2 1 1 2

31 36 6 5

23 13 2 2

G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively.

The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as monotherapy or in combination with other therapies in Phase 2 and 3 studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue Disorders, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase. DRUG INTERACTIONS Effect of Other Drugs on Ixabepilone

Drugs That May Increase Ixabepilone Plasma Concentrations CYP3A4 Inhibitors: Co-administration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA). [See Dosage and Administration (2.2) in Full Prescribing Information.] Drugs That May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: IXEMPRA is a CYP3A4 substrate. Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, and phenobarbital) may decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. Johnâ&#x20AC;&#x2122;s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Capecitabine In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [See Warnings and Precautions.] Nursing Mothers It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA (ixabepilone) taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of IXEMPRA in pediatric patients have not been established. Geriatric Use Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects. Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were *65 years of age and 3 patients were *75. Overall, the incidence of grade 3/4 adverse reactions were higher in patients *65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients *65 years with normal baseline hepatic function or mild impairment. Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were *65 years of age and 6 patients were *75. No overall differences in safety were observed in these patients compared to those <65 years of age. Hepatic Impairment IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by: N

:? A2E:6?ED H:E9 2 3:=:CF3:? M I +#% or 3 )* +#% 3FE 3:=:CF3:? I +#% N :? A2E:6?ED H:E9 3:=:CF3:? M I +#% 2?5 2?J )* =6G6= 2?5 N :? A2E:6?ED H:E9 3:=:CF3:? I +#% 2?5 2?J )* =6G6= Doses of 10 and 20 mg/m2 2D >@?@E96C2AJ H6C6 E@=6C2E65 :? A2E:6?ED H:E9 D6G6C6 96A2E:4 :>A2:C>6?E 3:=:CF3:? I +#% !. $'( :? 4@>3:?2E:@? H:E9 42A64:E23:?6 >FDE ?@E 36 8:G6? E@ A2E:6?ED H:E9 )* @C #* I +#% @C 3:=:CF3:? I +#% 0D66 Boxed Warning, Contraindications, and Warnings and Precautions]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3) in Full Prescribing Information]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter. Renal Impairment Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance @7 ># >:? !. $'( 2D >@?@E96C2AJ 92D ?@E 366? 6G2=F2E65 :? A2E:6?ED H:E9 4C62E:?:?6 E:>6D +#% !? 2 A@AF=2E:@? pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency C # ># >:? @? E96 A92C>24@<:?6E:4D @7 :I236A:=@?6 OVERDOSAGE One case of overdose of IXEMPRA has been reported. The patient mistakenly received 100 mg/m2 (total dose 185 mg) and was admitted to the hospital for observation. The patient experienced myalgia (grade 1) and fatigue (grade 1) one day after infusion and was treated with a centrally acting analgesic. The patient recovered and was discharged without incident. There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses *0.625 mg/kg/day. There were no effects on male or female rat mating or fertility at doses up to 0.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at 0.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (40 mg/m2) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and 0.5 and 0.75 mg/kg (10 and 15 mg/m2) in dogs (approximately 0.2 and 0.4 times the expected clinical exposure based on AUC). Animal Toxicology Overdose In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m2 (mean AUC values * ?8N9 ># H6C6 2DD@4:2E65 H:E9 mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m2 >62? + G2=F6 @7 ?8N9 ># H2D >2C<65=J E@I:4 :?5F4:?8 D6G6C6 82DEC@:?E6DE:?2= E@I:4:EJ 2?5 562E9 52JD 27E6C 5@D:?8 PATIENT COUNSELING INFORMATION )66 AAC@G65 '2E:6?E #236=:?8 in Full Prescribing Information Peripheral Neuropathy Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see Warnings and Precautions]. Fever/Neutropenia Patients should be instructed to call their physician if a fever of 100.5Â° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see Warnings and Precautions]. Hypersensitivity Reactions Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions]. Pregnancy Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see Warnings and Precautions and Use in Specific Populations ]. Cardiac Adverse Reactions Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain [see Warnings and Precautions]. IXEMPRAÂŽ (ixabepilone) for injection Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany !#+ %* 7@C !. $'( $2?F724EFC65 3J 2IE6C &?4@=@8J >3 2==6 -6DE72=6? 6C>2?J Distributed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

1236925A3

5645-002

XG-B0001A-05-09

Rev May 2009

Important Safety Information Toxicity in hepatic impairment

IXEMPRA® (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment

Contraindications

IXEMPRA is contraindicated in patients: s with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives such as polyoxyethylated castor oil s who have a baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3

Hypersensitivity reaction

Pregnancy

Peripheral neuropathy was common. Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening peripheral neuropathy may require changes in the dose or discontinuation of IXEMPRA Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy

Myelosuppression

Myelosuppression is dose-dependent and primarily manifested as neutropenia Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. Neutropenia-related death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy

Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetus

Cardiac adverse reactions

Peripheral neuropathy

Premedicate with an H1 and an H2 antagonist approximately 1 hour before IXEMPRA (ixabepilone) infusion and observe for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm) In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered

Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function due to reports of cardiovascular adverse reactions (eg, myocardial ischemia, supraventricular arrhythmia, and ventricular dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group

Potential for cognitive impairment from excipients

IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the possibility of central nervous system and other effects of alcohol

Adverse reactions

The most common adverse reactions ( 20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/ asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/ mucositis, diarrhea, and musculoskeletal pain. The following additional events occurred in 20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug-associated hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia

Cremophor is a registered trademark of BASF AG. AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; CTC = common terminology criteria.

For additional information, please call 1-888-IXEMPRA (493-6772) or visit www.IXEMPRA.com. Please see brief summary of full Prescribing Information, including boxed WARNING regarding hepatic impairment, on the previous pages.

Permanent J-code J9207 – Effective 1/1/2009

The first and only epothilone approved for metastatic or locally advanced breast cancer For patients progressing on an anthracycline, a taxane, and/or capecitabine For additional information, please call 1-888-IXEMPRA (493-6772) or visit www.IXEMPRA.com. Indications IXEMPRA® (ixabepilone) is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. IXEMPRA is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting. Important Safety Information Toxicity in hepatic impairment IXEMPRA (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment Contraindications IXEMPRA is contraindicated in patients: s with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives such as polyoxyethylated castor oil s who have a baseline neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3

Please see complete Important Safety Information, including boxed WARNING regarding hepatic impairment, on the previous page.