TAP Vol 3 Issue 5 by Harborside Press LLC

Frederick Appelbaum on Autologous Transplant 15

Triple-negative Breast Cancer 22

BRAF-mutated Melanoma 24

Re-analysis of RADIANT-2 Finds Benefit for Everolimus in Patients with Carcinoid Tumors

Moving the Field of Geriatric Oncology Forward

Controlling for imbalances at baseline yielded a 38% reduction in risk of progression.

By Stuart M. Lichtman, MD

By Caroline Helwick

re-analysis of the RADIANT-2 trial, which evaluated everolimus (Afinitor) in patients with advanced nonpancreatic neuroendocrine tumors, has yielded prognostic factors that identify a group of patients who are not only at high risk for James C. Yao, MD recurrence but who may derive benefit from treatment with everolimus plus octreotide.1 The results were presented at the 2012 Gastrointestinal Cancers Symposium by James C. Yao, MD, of The University of Texas MD Anderson Cancer Center, Houston. Everolimus is approved for the treatment of advanced pancreatic neuroendocrine tumors based on

a 65% reduction in the risk of progression or death (P < .001),2,3 but is not indicated for neuroendocrine tumors originating outside of the pancreas—ie, carcinoid—where its benefit has been less certain.

SEE PAGE 72

Original Trial In the original phase III RADIANT-2 trial, which included 429 patients with carcinoid syndrome, median progression-free survival improved by 5.1 months with everolimus/octreotide compared with ocreotide alone, but the P value just missed the prespecified boundary for statistical significance (.0246). There were randomization imbalances in the study, largely because appropriate prognostic factors continued on page 8

Searching for Quality in an Increasingly Complex Health-care Environment

Expert’s Corner

A Conversation with Sean R. Tunis, MD, MSc By Ronald Piana

ith the Presidential election just around the corner, the health-care debate will undoubtedly heat up. The ASCO Post spoke with Sean R. Tunis, MD, MSc, Founder and Director, Center for Medical Technology Policy, and former Chief Medical Officer for the Centers for Medicare & Medicaid Services, about how regulatory agencies make coverage deci-

MARCH 15, 2012

ASCOPost.com

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

2012 Gastrointestinal Cancers Symposium

VOLUME 3, ISSUE 5

sions, and how we might take steps to bring more value to our clinical decisions.

The Bevacizumab Issue

Despite FDA’s decision to revoke its approval of bevacizumab (Avastin) for breast cancer, Medicare—the nation’s largest payer—continues to provide coverage for this very expensive drug. Why? The issue about how Payers are naturally going to look at Medicare decides which cancer treatments to pay value [in health care] on a population for is complicated by the extensive legal and regulalevel, patients judge value on a very tory history of this issue. personal level, and clinicians are Some of the rules guiding Medicare’s reimbursement increasingly caught in the middle. policy in the oncology sec— Sean R. Tunis, MD, MSc tor leave the agency with

ith the aging of the population, virtually all of the subspecialties of oncology will soon be concerned primarily with the care of older patients. While there is not one precise definition of the age of “geriatric” patients, it is clear that the aging of our society has necessitated a focus on the older segment of the population. It has long been recognized that the most significant risk factor for the development of cancer is aging. Together with the epidemiologic shift, this has resulted in a striking increase in the number of older patients with cancer, which, in turn, has markedly increased the burden of cancer on our nation.1 Cancer compromises the life expectancy as well as the active life expectancy of older individuals. Moreover, the disease and its treatment are among the prime causes of disability in older individuals. continued on page 75

Dr. Lichtman is a Medical Oncologist at Memorial Sloan-Kettering Cancer Center in Commack, New York, and participates in the 65+ Clinical Geriatric Program at the Center. He is Professor of Medicine, Weill Cornell Medical College.

MORE IN THIS ISSUE Oncology Meetings Coverage 2012 Gastrointestinal Cancers Symposium �� 8, 11 2012 Genitourinary Cancers Symposium �� 3, 7, 13 Rising Costs in Radiation Oncology �� 29 Direct from ASCO �� 34 FDA Update �� 38–42 Letter to the Editor �� 72

continued on page 12

March Is Colorectal Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | MARCH 15, 2012

PAGE 2

Letter to the Editor

Erratum

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

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

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

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

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

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University

Robert W. Carlson, MD Stanford University Medical Center

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

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

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

“The activity of MLN 9708 is very encouraging,” said Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston. “Upfront we have seen 100% response rates in combination with lenalidomide and dexamethasone, including some very good partial and complete responses. In the relapsed setting we are also seeing single-agent activity, which is promising, as this setting is where we might expect to see much less [activity].1 This signal, in fact, is most promising with the twice-a-week dos-

ing in the advanced disease setting. Also, the main side effect is not neuropathy, but some mild to SEE PAGE 72 moderate skin rash, which has proven generally to be manageable. For example, my relapsed patients who participated in the study and who were veterans of neuropathy from exposure to prior bortezomib did not find the skin issue to be a significant problem.”

A later quote should have read:

“MLN 9708, carfilzomib, and marizomib should provide a tremendous platform going forward,” Dr. Richardson said. Reference 1. Richardson PG, Baz R, Wang L, et al: Investigational agent MLN9708, an oral proteasome inhibitor, in patients with relapsed and/or refractory multiple myeloma: Results from the expansion cohorts of a phase I dose-escalation study. 53rd American Society of Hematology Annual Meeting. Abstract 301. Presented December 12, 2011.

INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com.

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

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

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

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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n a recent supplement to The ASCO Post (February 15, 2012, page 21), a quote attributed to Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, was inaccurate. The ASCO Post regrets this error. A revised version of the article may be viewed online at ASCOPost.com or by scanning the QR code shown here. In the Expert Point of View for the article, “Next-generation Proteasome Inhibitors Will Improve Outcomes in Bortezomib-refractory Myeloma Patients,” Dr. Richardson’s remarks should have read as follows:

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

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2012 Genitourinary Cancers Symposium Prostate Cancer Studies Compare Outcomes, Toxicities, and Costs By Alice Goodman

atients with prostate cancer are treated with various forms of radiotherapy and/or radical prostatectomy with little comparative data to inform treatment selection. Two studies presented at the 2012 Genitourinary Cancers Symposium attempt to address that gap. In one study of men with localized prostate cancer, intensity-modulated radiation therapy (IMRT) proved superior to conformal radiation therapy for prevention of recurrence, with a more favorable sideeffect profile. Proton-beam therapy, the most expensive form of radiotherapy, was no better than IMRT. A second study found that externalbeam radiation therapy was more toxic and two to three times more expensive than either radical prostatectomy or brachytherapy, yet brachytherapy was used much less often. IMRT has largely supplanted use of the older conformal radiation therapy

Prostate Cancer Treatment Approaches Compared ■■ A large study found that IMRT was less toxic and superior to conformal

radiotherapy in reducing recurrence, whereas proton-beam therapy was no better than IMRT in controlling cancer and more toxic to the bowel.

■■ A second study showed that external-beam radiotherapy was more toxic and more expensive than either prostatectomy or brachytherapy.

technique in men with prostate cancer. In 2000, almost 100% of patients with prostate cancer treated with radiation were treated with conformal radiation therapy, but by 2008, almost no patients with prostate cancer who required radiation received conformal radiation therapy, while nearly 100% received IMRT. “IMRT has largely replaced conventional conformal radiation therapy as the main radiation technique for prostate cancer without much data to support it. This study validates the change in practice, showing better cancer con-

trol and fewer side effects with IMRT vs conformal radiation therapy,” explained senior author Ronald Chen, MD, University of North Carolina, Chapel Hill.1 The Surveillance, Epidemiology, and End Results (SEER)-Medicare– based study, which included more than 12,000 patients with localized cancer treated with radiation between 2002 and 2007, showed that IMRT was superior to conformal radiation therapy in improving cancer control, as measured by the need for additional cancer treatments: 3.1 per 100 personyears of follow-up for conformal radia-

Ronald Chen, MD

tion therapy vs 2.5 in the IMRT group (P < .001). IMRT significantly reduced the frequency of bowel side effects from 14.7 to 13.7 per 100 person-years of follow-up (P < .01), although the effects on erectile dysfunction were increased from 5.3 to 5.9 per 100 personyears of follow-up in the IMRT group. When IMRT was compared with proton-beam therapy, proton-beam therapy was associated with a significant increase in bowel side effects continued on page 6

EXPERT POINT OF VIEW

Nicholas B. Vogelzang, MD

icholas B. Vogelzang, MD, moderator of the press briefing where these findings were presented, agreed that the first study supports intensity-modulated radiotherapy (IMRT) as the current standard of care. With costs of health care increasing exponentially, it is important to establish the comparative benefits of newer, more costly therapies, he said. “There is no clear evidence that proton-beam therapy is better than IMRT, and given its cost and bowel effects, we must continue to study these modalities,” Dr. Vogelzang stated. Regarding the second study, Dr.

Vogelzang said, “This begs the question as to why brachytherapy—the least toxic and most cost-effective of the three techniques—is less used. At its inception, the target population consisted of low-risk patients, which is a limited population. With experience, doctors are becoming more comfortable expanding its use to more patients. The lower cost is impressive.” Dr. Vogelzang is Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology, Las Vegas.

Cautionary Flag Leonard Gomella, MD, Urology Chair and Associate Director of Clinical Affairs at the Kimmel Cancer Center at Jefferson, Philadelphia, said that people often think that the newer and more expensive therapy will be better. “This large dataset shows us that what we consider a safer, better way to deliver radiation to the prostate [ie, proton-beam therapy] is not actually

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

the case,” he commented. “Improvements in targeting techniques have improved the side-effect profile of IMRT dramatically over the past 10 years,” he stated. “Proton-beam therapy is the most

Leonard Gomella, MD

expensive treatment available for localized prostate cancer. We have to step back and realize that although protons are of benefit in certain areas of medicine—for example, children with CNS tumors—when we expand it to the most common tumor in men, the presumed toxicity benefits are not there based on this study. The study

will put up a cautionary flag in the field of radiotherapy, as some rush out to open these very expensive technology centers.” Regarding the second study, Dr. Gomella pointed out that many people who choose certain treatments for prostate cancer make their choice based on perceived side-effect profile. This study shows that minimally invasive procedures such as prostatectomy and brachytherapy may have a better side-effect profile than external-beam radiation therapy. “External-beam radiation therapy may not be as good as presumed in avoiding side effects of so-called more invasive treatments,” he commented. Dr. Gomella maintained that treatment selection has to be individualized. He did think that cost should be included in the discussion, as well as comorbidities, symptoms, and patient preferences.

■

Disclosure: Dr. Gomella is Urology Chair for RTOG. Dr. Vogelzang reported no potential conflicts of interest.

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

The ASCO Post | MARCH 15, 2012

PAGE 6

2012 Genitourinary Cancers Symposium Prostate Cancer Studies continued from page 3

(17.8 per 100 person-years of followup vs 12.2 for IMRT; P < .001). No significant difference in cancer control was observed. “We have seen a rapid growth in the number of proton facilities in the Unit-

ed States over the past 5 years, despite the high cost of this technique. Currently, there is no clear evidence that proton therapy is better than IMRT,” Dr. Chen stated. ”This technology needs to be closely examined through comparative effectiveness research before we adopt it as the ‘next’ treatment

for prostate cancer.”

SEER-Medicare Study A second study, based on the SEERMedicare database from 1991 to 2007, found that external-beam radiation therapy was the most toxic and most expensive therapy compared with radi-

cal prostatectomy and brachytherapy.2 The study included 137,427 patients diagnosed with prostate cancer at age 65 or older. “Our analysis is one of the first to examine the quality of life and financial cost of these three very common prostate cancer treatment strategies for more than 5 years after treatment,” stated lead author Jay P. Ciezki, MD, of the Cleveland Clinic.

Jay P. Ciezki, MD

After 15 years of follow-up, the cumulative incidence of genitourinary toxicity was significantly higher for external-beam radiation therapy (approaching 20% of patients) than for prostatectomy (about 7%) or SEE PAGE 72 brachytherapy (about 5%; P < .001). The cumulative incidence of gastrointestinal toxicity was also significantly higher with external-beam radiation therapy than for prostatectomy or brachytherapy (P < .0001 for both comparisons), although the overall incidence was under 3% for all groups at 15 years. The cost per patient-year was $6,412.29 for external-beam radiation therapy, $3,205.71 for prostatectomy, and $2,557.36 for brachytherapy (P < .0001 for all comparisons). Despite the positive picture for brachytherapy, only about 12% of patients were treated with brachytherapy, while 44% had radical prostatectomy and 44% had external-beam radiation therapy.

■

Disclosure: Dr. Chen reported that his study was funded by the Agency for Healthcare Research and Quality (AHRQ). Dr. Ciezki reported no conflicts of interest.

References 1. Sheets C, Goldin G, Meyer A-M, et al: Comparative effectiveness of intensity modulated radiation therapy, proton therapy, and conformal radiation therapy in the treatment of localized prostate cancer. 2012 Genitourinary Cancers Symposium. Abstract 3. Presented February 2, 2012. 2. Ciezki J, Reddy CA, Angermeier K, et al: A SEER/Medicare database study. 2012 Genitourinary Cancers Symposium. Abstract 4. Presented February 2, 2012.

ASCOPost.com | MARCH 15, 2012

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2012 Genitourinary Cancers Symposium Important News Briefs: New Data Reported in Prostate, Bladder, and Kidney Cancers By Alice Goodman

he recent 2012 Genitourinary Cancers Symposium featured a wealth of presentations on prostate, bladder, kidney, and other genitourinary cancers. Brief summaries of some of the oral and poster sessions are presented.

Exercise and Recurrence Vigorous exercise has been shown to reduce cancer recurrence and cancerrelated mortality in men with prostate cancer in several studies. A new study found that vigorous exercise for 1 hour three times per week exerts favorable changes on genetic expression in normal prostate tissue of men with early prostate cancer opting for active surveillance.1

June M. Chan, ScD

“Our prior studies indicated that increased intensity and duration of exercise were linked to lower risk of prostate cancer recurrence or death. In the current study, longer duration of vigorous exercise was related to greater expression of genes involved in DNA repair and cell-cycle in the normal prostate tissue, which may act to protect against cancer progression,” said senior author June M. Chan, ScD, University of California, San Francisco. The study included 70 men diagnosed with low-risk prostate cancer who were managed with active surveillance. These men were previously enrolled in a trial of nutritional supplements and provided biopsy tissue at baseline. In

the men who reported vigorous exercise at least three times per week (n = 23), 184 genes were differently expressed in normal prostate tissue vs those who did not (n = 47). Dr. Chan said that vigorous exercise included jogging, walking briskly, swimming, singles tennis, and other exercise that increases the heart rate consistently. Upregulated genes included known tumor-suppressor genes, BRCA1, and BRCA2. Further, gene-set analysis demonstrated that cell cycle and DNA repair pathways were positively modulated in men who reported vigorous exercise at least three times a week vs those who exercised less. A separate analysis found no effect on genes and pathways in men who reported engaging in any type of physical activity (but not vigorous exercise three times per week) vs no exercise. According to Dr. Chan, these findings suggest that a certain threshold of intensity or duration of exercise may be important in reducing the risk of prostate recurrence. Nevertheless, this was a small study, and further investigation is needed.

ported in 2,461 patients in the VEGF tyrosine kinase inhibitor arms vs 10 in 2,218 patients assigned to the control arm. The majority of fatal adverse events were due to hemorrhage; other causes included myocardial infarction, cardiac ischemia, sudden death, congestive heart failure, hypotension, pulmonary embolism, and ischemic stroke. The risk was independent of tumor type and drug, but the meta-analysis included only one trial of pazopanib with a total of about 400 patients. Six trials of sorafenib and three trials of sunitinib were included. “As these drugs become more commonly used for clinical purposes, oncologists should be aware of the risks associated with their use and must conduct rigorous monitoring to continue to improve patient outcomes,” stated lead author Christopher J. Richards, MD, Beth Israel Deaconess Hospital, Harvard Medical School, Boston. The study was published recently in Journal of Clinical Oncology3 (see related news item on page 73).

Risk of Fatal Adverse Events with Tyrosine Kinase Inhibitors

In the phase III AXIS trial of axitinib (Inlyta) vs sorafenib for second-line metastatic renal cell carcinoma, axitinib significantly prolonged median progression-free survival. In a secondary analysis presented by Brian Rini, MD, of the Cleveland Clinic Foundation,4 investigators evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy. As Dr. Rini reported, the new analysis demonstrated similar outcomes and similar safety in titrated patients (those who failed to achieve therapeutic levels on standard-dose axitinib) and nontitrated patients. Both groups treated with axitinib had superior outcomes compared with standard sorafenib in the secondline setting. These outcomes were similar to the main results of AXIS reported last year, with a median progression-free survival of 6.7 months for axitinib vs 4.7 months for sorafenib (HR = 0.665, P < .0001).5 AXIS enrolled 723 patients with clearcell metastatic renal cell carcinoma that progressed after one of four prior regimens (sunitinib, bevacizumab [Avastin] plus interferon alfa, temsirolimus [Torisel], or cytokines). They were randomly

Use of tyrosine kinase inhibitors of vascular endothelial growth factor (VEGF), such as sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient), is associated with a greater than twofold increased risk of fatal adverse events vs controls, according to a metaanalysis of 10 randomized trials including about 4,600 patients (more than 2,000 with renal cell carcinoma, the main indication for these drugs).2 The absolute risk of fatal adverse events was small, but the difference between the treatment arm and control arm was statistically significant (P = .02): 30 fatal adverse events were re-

Trends in Genitourinary Cancer Research ■■ A small study suggests a threshold of intensity or duration of exercise may be important in reducing the risk of prostate cancer recurrence.

■■ A meta-analysis of 10 randomized trials showed that use of tyrosine

kinase inhibitors of VEGF is associated with significantly increased risk of fatal adverse events compared to controls.

■■ A secondary analysis of the phase III AXIS trial evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy. Both groups treated with axitinib had superior outcomes compared with standard sorafenib in the second-line setting.

Secondary Analysis of AXIS Trial

Brian Rini, MD

assigned to axitinib starting at 5 mg twice daily, with the option for dose titration or standard dose and schedule of sorafenib at 400 mg twice daily. Dr. Rini said that the findings in titrated vs nontitrated patients were what he expected, given phase II pharmacokinetic trials that showed intrapatient variability in the ability to achieve therapeutic levels on standard-dose axitinib (5 mg twice daily). This led to a strategy of dose titration to normalize plasma levels of axitinib exposure. In the study, criteria for dose titration included no toxicity greater than grade 2 for 2 weeks or more, blood pressure < 150/90 mm Hg, and no antihypertensive medication. At their discretion, investigators could titrate axitinib to 7 mg twice daily and then to 10 mg twice daily. All patients randomly assigned to axitinib started at 5 mg twice daily; 25% experienced dose reductions for progression; one-third had no dose change; and doses were escalated in 37%. Of these, 17% were escalated to 7 mg twice daily, and 20% to 10 mg twice daily. Patients with prior exposure to sunitinib of more than 9 months had a greater progression-free survival for both axitinib and sorafenib.

■

Disclosure: Dr. Rini has been a consultant for and has received research funding from Pfizer. Drs. Chan and Richards reported no potential conflicts of interest.

References 1. Magbanua MJM, Richman EL, Sosa EV, et al: 2012 Genitourinary Cancers Symposium. Abstract 189. Presented February 3, 2012. 2. Richards CJ, Je Y, Schutz FAB, et al: 2012 Genitourinary Cancers Symposium. Abstract 349. Presented February 4, 2012. 3. Schultz DAB, et al: J Clin Oncol. February 6, 2012 (early release online). 4. Rini BI, Escudier BJ, Michaelson MD, et al: Genitourinary Cancers Symposium. Abstract 354. Presented February 4, 2012. 5. Rini B, Escudier B, Tomczak P, et al: Lancet 378:1931-1939, 2011.

The ASCO Post | MARCH 15, 2012

PAGE 8

2012 Gastrointestinal Cancers Symposium RADIANT-2 Re-analysis continued from page 1

needed to stratify patients had not been well defined at the start of the study, Dr. Yao explained. These included performance status, primary tumor site, and percentage of patients with biomarkers deemed important in neuroendocrine tumors, which are chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA).

Results Reexamined In the current study, Dr. Yao and colleagues reexamined the original phase III results to both identify prognostic factors and adjust for randomization imbalances. “We performed this analysis to identify prognostic factors that showed which patients with neuroendocrine tumors are at risk for disease progression and to adjust for these imbalances,” Dr. Yao said. Patients with bone metastases had a 1.52 times greater risk for progression than those without bone metas-

tases, while those with lung as the primary site had a 1.55 times greater risk, compared with other sites of origin. Elevated CgA at baseline was another factor for poor prognosis, with a 53% lower risk observed in patients with normal CgA levels. Performance status of 0 was associated with a 31% reduced risk, and treatment with everolimus carried a 38% reduced risk. All these factors were statistically significant in the multivariate analysis. In an exploratory analysis that adjusted for these prognostic factors, a persistent significant benefit for everolimus and octreotide therapy was observed, compared with placebo and octreotide, with a hazard ratio of 0.62 (P = .003), Dr. Yao reported. “When we adjusted for the potential prognostic factors, the treatment effect led to a 38% reduction in the risk of progression with everolimus,” he said, noting the marked improvement over the 23% risk reduction seen in the first analysis. In other words, he emphasized, the original study data may have under-

EXPERT POINT OF VIEW

imothy J. Hobday, MD, of the Mayo Clinic in Rochester, Minnesota, discussed the findings of the RADIANT-2 re-analysis at the 2011 Gastrointestinal Cancers Symposium. Speaking from the perspective of a clinical researcher, he said, “the conclusions of the study are reasonable” and provide “valuable hypothesis-generating data to inform future trial design.” The heterogeneity of neuroendocrine tumors Timothy J. Hobday, MD continues to challenge researchers, he said, highlighting the importance of finding prognostic biomarkers and incorporating them into trial design. Quality-of-life measures should also be incorporated in trials that have a progression-free survival endpoint, especially for a disease that is “potentially indolent.” Speaking as a clinician, Dr. Hobday said that everolimus has “a known, reasonable safety profile,” noted that “progressive metastatic carcinoid remains without adequate systemic therapies,” and maintained that everolimus is “a reasonable option for therapy for those patients with progressive carcinoid tumor who are in need of systemic therapy.”

■

Disclosure: Dr. Hobday reported research funding from Novartis.

Visit

Everolimus in Carcinoid Tumors ■■ An exploratory re-analysis of the RADIANT-2 trial of everolimus in

advanced nonpancreatic neuroendocrine tumors was performed to look for treatment imbalances and prognostic factors that may have affected outcomes in the original analysis.

■■ Imbalances were found in performance status, primary tumor site,

and percentage of patients with biomarkers deemed important in neuroendocrine tumors (ie, chromogranin A and 5-hydroxyindoleacetic acid). These factors proved to be prognostic.

■■ A re-analysis of the data controlling for prognostic factors found that

everolimus plus octreotide resulted in a 38% reduction in risk of disease progression that was statistically significant (P = .003).

estimated the benefit of everolimus, which is likely “a little more active than previously thought,” said Dr. Yao at a press briefing.

Focus on CgA Levels Chromogranin A has been shown to be prognostic for both progressionfree and overall survival, but this was the first evaluation of CgA as a biomarker in a randomized placebo-controlled study. “We found a significant imbalance in the baseline distribution of CgA. The mean and median CgA levels were significantly higher in the group receiving everolimus, suggesting this is a worse prognosis group,” Dr. Yao reported. Median baseline CgA was 251 ng/mL in the arm receiving everolimus and 137 ng/mL in the placebo arm. In the re-analysis, median progression-free survival was significantly longer for patients with nonelevated CgA (27 vs 11 months; P < .001) and nonelevated 5-HIAA (17 vs 11 months; P < .001). “The hazard ratio for CgA was 0.47, suggesting this is a very significant predictor of the risk of progression,” Dr. Yao noted. In the placebo arm, median progression-free survival was approximately 20 months for patients with low CgA levels but 8 months for those with elevated CgA. In the everolimus arm, median progression-free sur-

vival was 31 and 14 months, respectively. The study, therefore, identified a group of patients likely to rapidly progress and who most warrant treatment, he said. “The data should be interpreted as exploratory,” Dr. Yao acknowledged. “Whether the magnitude of the treatment effect is greater than we initially estimated needs to be confirmed.” The phase III RADIANT-4 trial will seek to obtain that confirmation in advanced nonfunctional neuroendocrine tumors of gastrointestinal or lung origin.

■

Disclosure: Dr. Yao has received consulting or advisory fees from Endo Pharmaceuticals, Ipsen, Novartis, and Pfizer and research funding from Genentech and Novartis.

References 1. Yao JC, Hainsworth JD, Wolin EM, et al: Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus or placebo among patients with advanced neuroendocrine tumors. 2012 Gastrointestinal Cancers Symposium. Abstract 157. Presented January 20, 2012. 2. Pavel ME, Hainsworth JD, Baudin E, et al: Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): A randomised, placebo-controlled, phase 3 study. Lancet 378:2005-2012, 2011. 3. Yao JC, Shah MH, Ito T: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523, 2011.

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Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions]. INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology]. Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology]. General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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 [see Use in Specific Populations]. Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies]. Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

1 1

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. 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. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions]. Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions]. Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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. In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use There is no indication for use of FARESTON in pediatric patients. Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions]. Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved. 2E Rev. 03/2011

ASCOPost.com | MARCH 15, 2012

PAGE 11

2012 Gastrointestinal Cancers Symposium New Assays, Surveillance Techniques Reported for GI Malignancies By Caroline Helwick

wo studies highlighted in press conferences and one presented during an invited lecture at the 2012 Gastrointestinal Cancers Symposium, held recently in San Francisco, suggest that early detection of pancreatic, esophageal, and colorectal cancers could soon improve.

Enzyme Immunoassay Spots Pancreatic Cancer A serum-based enzyme immunoassay employing the PAM4 antibody combined with the serum marker CA19-9 proved highly sensitive and specific for the detection of pancreatic adenocarcinoma.1 The PAM4-based assay could be used for surveillance in patients at high risk for pancreatic adenocarcinoma, said David V. Gold, PhD, of the Garden State Cancer Center in Morris Plains, New Jersey. The combined PAM4 antibody and CA19-9 assay was evaluated in more than 600 blood specimens, detecting 84% of pancreatic adenocarcinoma cases. This was significantly more sensitive than the single tests alone (P < .0001). Out of 50 cases of chronic pancreatitis, 9 (18%) were labeled positive by the assay, but this 18% rate of positivity does not necessarily represent false-positives, Dr. Gold suggested. The investigaSEE PAGE 72 tors believe that such cases may represent patients harboring occult pancreatic adenocarcinoma or who have precursor lesions producing the PAM4 biomarker.

‘Optical Biomarkers’ Detect High-risk Barrett’s Esophagus In another study, investigators reported their use of an “optical biomarker” for surveillance of patients with

established Barrett’s esophagus, aimed at distinguishing patients who have no dysplasia from those with high-grade dysplasia or early adenocarcinoma.2 The approach uses spatial-domain low-coherence quantitative phase microscopy. Using this technique, Randall E. Brand, MD, and colleagues at the University of Pittsburgh, Pennsylvania, identified at least three new features that are based on light reflectance and which represent abnormalities in cells. Using these biomarkers, the researchers constructed a prediction model and applied it retrospectively to archived tissue from 60 patients with Barrett’s esophagus who underwent biopsies. The test had an overall accuracy rate of 87%. It

David Ahlquist, MD

Stool DNA Testing Becoming a Reality A third presentation, by David Ahlquist, MD, of the Mayo Clinic, Rochester, was an update on a next-generation stool DNA test (ColoGuard; Exact Science, Madison, Wisconsin) that might represent a promising ap-

GI Cancer Detection and Surveillance ■■ A serum-based enzyme immunoassay employing the PAM4 antibody

combined with the serum marker CA19-9 proved highly sensitive and specific for the detection of pancreatic adenocarcinoma.

■■ A quantitative phase microscopy–derived “optical biomarker” was used to distinguish patients with Barrett’s esophagus alone from those who also had high-grade dysplasia or early adenocarcinoma.

■■ A next-generation stool DNA test detected 85% of nonmetastatic

colorectal cancers and 64% of adenomas ≥ 1 cm among 678 individuals, including 253 with colorectal cancer and 130 with advanced adenomas.

was 89% sensitive and 76% specific in distinguishing Barrett’s esophagus patients with high-grade dysplasia or adenocarcinoma from patients without dysplasia. This approach could be used for monitoring Barrett’s esophagus patients to identify a subset at high risk who need more intensive surveillance or treatment. In addition, further studies are being performed to determine if this technology could identify a subset of patients in whom the surveillance interval can be lengthened.

proach for colorectal cancer.3 Stool DNA testing detects tumor-specific DNA alterations in cells that are continually shed into the stool from precancerous and cancerous lesions. In a large-scale, blinded case-control study of 678 individuals (pooled analysis of training and validation sets), including 253 persons with colorectal cancer and 130 with advanced adenomas, the investigators detected 87% of nonmetastatic colorectal cancers and 64% of adenomas > 1 cm, he reported. Neoplasms were detected in the

proximal and distal colons with equal accuracy, and cancer stage did not affect detection rates. Importantly, sensitivity increased with adenoma size; the test detected 77% if larger than 2 cm and 91% if larger than 3 cm. Dr. Ahlquist noted the test’s rational biologic basis, its “extraordinarily” high detection rates for curable cancers and precancers that are likely to progress, equal detection of lesions on both sides of the colon, and detection of flat polyps likely to be missed not only by fecal occult blood tests but also colonoscopy. It involves no diet or medication restrictions, no bowel preparation, and can be done at home using a stool sample. “It is user-friendly, affordable, and offers individuals unlimited access by mail,” he added.

■

Disclosure: Mayo Clinic has licensed intellectual property to and is a minor equity investor in Exact Sciences. Dr. Ahlquist is one of the inventors of the licensed technology and also serves as a scientific advisor to Exact Sciences. Dr. Gold and Dr. Brand reported no potential conflicts of interest.

References 1. Gold DV, Gaekcke J, Ghadimi BM, et al: Detection of early-stage pancreatic ductal adenocarcinoma (PDAC): Sensitivity, specificity, and discriminatory properties of the serum-based PAM4-immunoassay. 2012 Gastrointestinal Cancers Symposium. Abstract 151. Presented January 20, 2012. 2. Brand R, Rizvi S, Davison JM, et al: Use of optical biomarkers from nondysplastic metaplastic cells on the detection of high-grade dysplasia and adenocarcinoma from Barrett’s esophagus. 2012 Gastrointestinal Cancers Symposium. Abstract 14. Presented January 19, 2012. 3. Ahlquist DA: Stool DNA testing: A step closer to eradicating colorectal cancer. Invited presentation at the 2012 Gastrointestinal Cancers Symposium. Presented January 21, 2012.

March Is

Colorectal Cancer Awareness Month.

The ASCO Post | MARCH 15, 2012

PAGE 12

Expert’s Corner

Sean R. Tunis, MD, MSc continued from page 1

relatively limited choices in their policy regarding off-label use, which accounts for approximately 50% or more of cancer care treatments. In the case of bevacizumab, many would think that because the agent had its breast cancer indication revoked in quite dramatic fashion, it would be a cut-and-dry coverage decision for Medicare. But because bevacizumab continues to be an FDA-approved product for some cancer indications, the breast cancer indication essentially falls into the off-label use area.

Coverage Decisions What factors does Medicare consider for coverage decisions? Medicare coverage decisions rely largely on the core belief that physicians will use drugs or technologies in a clinically responsible way, guided by training and current evidence, all within the regulatory realities of the day. On the surface there might seem to be conflicts among particular coverage policies, as in the case of bevacizumab. The expectation is that whether or not Medicare pays for a drug or service, if it’s not appropriate for patient care, physicians would not use it. That’s an oversimplification, but that’s pretty much how Medicare has historically looked at coverage issues— depending heavily on providers to apply evidence-based clinical decision-making. Moreover, Medicare looks for guidance from the recognized drug compendia, and has formal policies stating that the agency will pay for off-label uses of agents that are listed in one or more of the authorized compendia. The National Comprehensive Cancer Network’s NCCN Drugs & Biologics Compendium is a mandated reference for establishment of coverage policy and coverage decisions regarding the use of drugs and biologics in cancer care. Since metastatic breast cancer remains listed by NCCN as an appropriate indication for bevacizumab, Medicare covers its off-label use, regardless of the recent FDA revocation.

Clinical Trials Is there a better way to weed out agents that seem to make it through the clinical trial system, then underperform in the general population? One thing that would help bring better drugs to the patient population is simply having more adult participation in cancer clinical trials. That’s the only way to get the data we need to make

qualitative decisions. To my mind, we need to have some form of public relations campaign and educational effort that would help debunk myths about trials and reinforce the benefits of receiving new therapies in the context of trials. By trying strategies to match the high rate of pediatric clinical trial participation, it might be possible to move to a place in which adult participation is the rule, not the exception. Substantially increasing the volume of patients with cancer participating in trials would probably ensure that the failure rate of early trials wouldn’t be as great, plus it would give us more information about what compounds truly offer benefits that exceed the risks, and for which specific patient subgroups.

Health Information Technology Quality and value of care are at the heart of the current political health-care vernacular. An interoperable health information technology system to help foster those goals is part of the larger plan. Are we moving in the right direction? We’re making headway in that initiative in terms of focusing on interoperability and performance standards of

that truly change the way our health system operates.

Comparative Effectiveness With the election season heating up, components of the Affordable Care Act will take center stage. One initiative that draws fire is comparative effectiveness research. Is this a viable mechanism to assess value on a large enough scale to make a difference? Yes, comparative effectiveness research will help to improve the value of health-care services, though only in conjunction with other major payment and delivery system reforms that are underway. I think of comparative effectiveness research as a way of approaching clinical research that is more conscientiously designed to inform clinical decision-making. For example, clinicians and patients often try to make comparative decisions when considering treatment choices. So it’s more helpful to have head-to-head comparative data with which to make those decisions. Comparative effectiveness research also looks at studies that emphasize more quality-of-life and patient-reported functional outcomes. In terms of patient experience, that kind of information is often more helpful than,

I think of comparative effectiveness research as a way of approaching clinical research that is more conscientiously designed to inform clinical decision-making. —Sean R. Tunis, MD, MSc

electronic medical records. However, that progress may not be highly visible yet within the overall structure of health care, in terms of making an impact on quality measurement, quality improvement, and clinical care. A big part of the reason we’re not seeing broader use of health information technology for quality measurement and performance improvement is because it takes time to reach a consensus on the standards and common data elements needed for interoperability. We also need the ability to integrate common data from electronic medical record systems made by different manufacturers. We are moving steadily forward to get information technologies in place, but we just won’t see a high level of practical impact for several years to come. After we make more progress on the technical issues of interoperability, we’ll see much more rapid advances

for instance, clinical endpoints focusing solely on the rate and extent of tumor growth. As drug and device companies, as well as the NIH, start thinking more clearly about designing studies that answer the practical questions that clinicians and their patients face daily, clinical research will better inform value-based decisions. No matter how you define comparative effectiveness research, we are seeing a concerted effort to make more of our research relevant to the needs of patients, clinicians, and payers. And that combined effort will inevitably lead to more and better judgments about risks, benefits, and value.

Clinical Value In order to achieve across-the-board value over volume, we need to harmonize the needs of clinicians, patients, and pay-

ers. Is that possible? There are ways to reduce the apparent disparity of viewpoints among these three major decision-makers about what constitutes important evidence of clinical value in specific clinical conditions. Through simple dialogue, we find that the dispersion of viewpoints doesn’t completely harmonize, but when people actually listen to each other, common understanding begins to materialize. So we need to provide more opportunities for stakeholders to have meaningful dialogue about issues of research priorities and study design. It can’t be done effectively if there continue to be separate conversations in separate forums. That said, payers are naturally going to look at value on a population level, patients judge value on a very personal level, and clinicians are increasingly caught in the middle. There are going to be persistent differences of opinion on what defines value in health care. But if we think in terms of specific clinical benefits such as quality of life, survival, or patient experience with side effects, there is likely to be more convergence about the meaning of clinical value. Building consensus across stakeholder groups about specific benefits through more sustained interaction is a good start.

Closing Thoughts Any closing thoughts on bringing muchneeded value to our health-care system? We have so much work to do that relates to discovering the relative benefits and risks of how we treat disease that when we integrate costs into the equation, it becomes very difficult to have a rational discussion about value. We tend to immediately jump to arguments about cost-effectiveness thresholds and how to interpret quality-adjusted life years, forgetting that all of these things are currently based on extremely uncertain estimates of just what the risks and benefits are. Decision-making would benefit from our spending more time and money on concrete ways to improve our knowledge of health risks and benefits, like improving our clinical trial system and advancing our health information technology capabilities. Once we have less uncertainty about these clinical effectiveness questions, we can at least have a more informed argument about the relative costs of achieving those benefits or avoiding those risks.

■

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

ASCOPost.com | MARCH 15, 2012

PAGE 13

2012 Genitourinary Cancers Symposium Immune Changes Reported with Early Use of Sipuleucel-T in Neoadjuvant Setting for Prostate Cancer By Alice Goodman

ipuleucel-T (Provenge) can generate a circulating immune response to treat men with metastatic castrateresistant prostate cancer, as per its FDA-approved indication.1 A neoadjuvant trial was performed to investigate whether earlier use of sipuleucel-T can generate an immune response in the prostate gland. This study suggests that sipuleucel-T treatment increases the number of immune cells in the prostate tumors, noted lead author Lawrence Fong, MD, UCSF Comprehensive Cancer Center, San Francisco. Dr. Fong presented the results at the recent 2012 Genitourinary Cancers Symposium in San Francisco. Several clinical trials are ongoing to evaluate the effect of the vaccine in earlier stages of disease, he noted.

interface of the benign and malignant glands, suggesting that treatment promotes the infiltration of T cells at the prostate tumor site.

■

Disclosure: Dr. Fong reported receiving research report from Dendreon.

Reference 1. Fong L, Weinberg VK, Corman JM, et

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

CMYK

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved:

Phase II Study Details The phase�� II�� trial included 42 patients with localized prostate cancer slated for radical prostatectomy. Patients received three planned infusions of sipuleucel-T at 2-week intervals prior to radical prostatectomy. Prostate specimens were obtained pretreatment and following sipuleucel-T treatment. Radical prostatectomy subjects were further randomly assigned to receive a booster treatment with the vaccine or no further treatment and were followed for 72 weeks. Treatment with the vaccine was safe, and use of the vaccine did not appear to affect surgery and postoperative course. Neoadjuvant sipuleucelT increased the numbers of CD3+, CD3+/CD4+, and CD3+/CD8+ cells in prostate cancer tissue at the

al: Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer. 2012 Genitourinary Cancers Symposium. Abstract 181. Presented February 3, 2012.

�

94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2

�

93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2

�

80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta ®-treated patients as compared with placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2011 Amgen. All rights reserved.

60070-R1-V1

08-11

www.neulastaHCP.com

The ASCO Post | MARCH 15, 2012

PAGE 14

Journal Spotlight

Adjuvant Therapy for Stage III Colon Cancer: Survival Advantage of Oxaliplatin Reported in Clinical Trials Extends to Diverse Group of Patients By Charlotte Bath

he survival advantage conferred by adding oxaliplatin to adjuvant chemotherapy with fluorouracil (5FU) in stage III colon cancer, as previ-

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

ously shown in patients in randomized controlled trials, extends to patients in the general population, including older and minority group patients and those

(n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of 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 Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder: Sickle cell crisis and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders: Sweet’s syndrome, are bone pain and pain in extremity. Cutaneous vasculitis Clinical Trials Experience DRUG INTERACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice. Neulasta clinical trials safety data are based upon 932 patients these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The USE IN SPECIFIC POPULATIONS population was 21 to 88 years of age and 92% female. The Pregnancy ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy Category C 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant tumors (n = 53) and lymphoma (n = 56) received Neulasta women. Pegfilgrastim was embryotoxic and increased after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative received a single 100 mcg/kg (n = 259) or a single 6 mg doses approximately 4 times the recommended human dose (n = 546) dose per chemotherapy cycle over 4 cycles. (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta

with higher comorbidity. These results, reported in the Journal of the National Cancer Institute, were obtained by comparing data for 4,060 patients from five

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegﬁlgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

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observational sources to pooled data for 8,292 patients from five randomized controlled trials.1 “To mirror the trial cohorts, we restricted our analyses to patients diagnosed before age 75 years,” the researchers noted. “The survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings,” the researchers stated. The 3-year overall survival for patients receiving oxaliplatin was 86% for the randomized controlled trials and ranged from 79% to 88% for the observational sources. “The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity,” the authors remarked. .

Qualifying Remarks The authors pointed out that while the “addition of oxaliplatin to 5-FU unequivocally improves outcomes of patients enrolled in [randomized controlled trials], those patients are substantially younger, healthier, and less racially and/or ethnically diverse” than the general population of patients with cancer. In addition, the oxaliplatin/5-FU combination “has a greater risk of severe cytopenias, nausea and vomiting, diarrhea, and peripheral neuropathy than 5-FU alone,” which could limit its use among more diverse patients in community settings. Results showed, however, that adjuvant chemotherapy with oxaliplatin improved survival in “patients cared for across the spectrum of treatment venues in the United States: at specialty cancer centers, academic oncology groups, community oncology practices, and Veterans Administration hospitals,” the researchers reported. “In summary, our analyses suggest that the benefit of oxaliplatin evident in clinical trials appears to manifest in dayto-day practice,” they concluded. “Physicians and patients should be reassured from our findings that oxaliplatin is associated with marginally but consistently superior survival for patients [with stage III colon cancer] diagnosed before age 75 years in community settings.”

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Reference 1. Sanoff HK, Carpenter WR, Martin CF, et al: Comparative effectiveness of oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer. J Natl Cancer Inst 104:211-227, 2012.

ASCOPost.com | MARCH 15, 2012

PAGE 15

Clinical Perspective Hematology

Autologous Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia: A Question That Doesn’t Go Away By Frederick R. Appelbaum, MD

ore than 3 decades ago, the first trials of autologous hematopoietic cell transplantation as consolidation therapy for acute myeloid leukemia (AML) in first remission were conducted. The initial results were inconclusive; most patients survived the procedure, but post-transplant relapse was common and overall survival did not appear to be markedly different from that which could be achieved with chemotherapy alone. Unable to make a more definitive statement, we reached the not particularly insightful but obviously true conclusion that “to improve results, both transplant-related deaths and posttransplant relapse must be decreased.”1

Progress and Challenges Over the ensuing 30 years, multiple studies have been conducted attempting to achieve these goals. Those aimed at reducing transplant-related deaths have had some success. The combination of busulfan (Busulfex, Myleran) Dr. Appelbaum is Director of the Clinical Research Division, Fred �� Hutchinson Cancer Research Center, and Professor, Medical Oncology Division, University of Washington School of Medicine, Seattle.

and cyclophosphamide has largely replaced high-dose total body irradiation–based regimens with a decrease in regimen-related toxicity. Modern antimicrobials provide better protection against opportunistic infections. And the use of peripheral blood stem cells as opposed to marrow results in faster, more reliable engraftment. With these changes, the nonrelapse mortality associated with autologous hematopoietic cell transplantation for AML is now less than 5% in most series.2 In contrast, there has not been any obvious success in efforts to reduce post-transplant relapse rates. More aggressive chemotherapy prior to stem cell harvest, purging of the stem cell product using antibodies or chemotherapies, tandem rather than single transplants, and post-transplant immunotherapies have all been explored, but there is as yet no conclusive evidence that any of these approaches has been successful in reducing relapse rates. Unfortunately, some of the approaches that make the procedure safer may, in fact, increase relapse rates. In particular, Gorin et al, after analyzing 2,165 patients who received autografts for AML in first remission, concluded

that the relapse rates were significantly higher with peripheral blood as opposed to marrow, resulting in inferior leukemia-free survival.3 They further found that those patients infused with the highest CD34-positive cell doses, although engrafting faster, had the highest relapse rates of all.4

Role in Survival Since the initial trials demonstrating the feasibility of the approach, multiple prospective studies have been performed attempting to evaluate the actual role of autologous hematopoietic cell transplantation as therapy for AML in first complete remission. In the decade between 1989 and 1998, six prospective randomized trials were performed in which patients with AML in first remission were randomized to receive either autologous hematopoietic cell transplantation with bone marrow as the source of stem cells or further chemotherapy. A meta-analysis of these trials showed that autologous transplant was associated with better disease-free survival but similar overall survival.5 In the decade since the completion of these trials, at least three similar studies have been conducted

Frederick R. Appelbaum, MD

using peripheral blood rather than marrow as the stem cell source. The general conclusions of these more recent studies were similar to those using marrow, and a meta-analysis of all trials comparing autologous hematopoietic cell transplantation to chemotherapy published through 2010 concluded that autologous transplant is associated with improved diseasefree survival but no benefit in overall survival.6 Based on these outcomes, an evidence-based review of the field conducted by the American Society for Blood and Marrow Transplantation concluded that “there is no significant advantage for autologous hematopoietic cell transplantation over chemotherapy.”7 continued on page 16

Journal Spotlight

Autologous Transplant vs Consolidation Chemotherapy in Acute Myeloid Leukemia: A Recent European Trial

By Matthew Stenger nvestigators in the Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group recently reported in the journal Blood that autologous peripheral blood stem cell transplantation significantly reduced relapse rate compared with intensive consolidation chemotherapy in acute myeloid leukemia (AML) patients in first complete remission.1 Five-year relapse-free survival was nonsignificantly improved with autologous stem cell transplant. Nonrelapse mortality was significantly greater in autologous transplant patients. There was no differSEE PAGE 72 ence between treat-

ments with regard to overall survival, reflecting the fact that more relapsing chemotherapy patients had salvage treatment with late stem cell transplant and achieved second complete remissions.

Study Design In this multicenter trial, 517 AML patients aged 16 to 60 years in first complete remission after two cycles of intensive induction chemotherapy who were not eligible for allogeneic stem cell transplant were randomly assigned to receive autologous transplant (n = 258) or intensive consolidation chemotherapy with etoposide (100 mg/m2 on days 1–5) and mitoxantrone (10 mg/m2 on days 1–5) (n=259). Remission induction thera-

py consisted of one cycle of cytarabine plus idarubicin and one cycle of cytarabine plus amsacrine, with patients being randomly assigned between intermediate- and high-dose cytarabine. Patients at some sites were also randomized between granulocyte colonystimulating factor (G-CSF [Neupogen]) and no G-CSF priming during induction. Conditioning for autologous transplant consisted of treatment with busulfan (Busulfex, Myleran) and cyclophosphamide. Patients in the chemotherapy and autologous transplant groups were well matched with regard to gender (49% vs 51% male), age (median, 47 vs 49 years), cytogenetic risk (favorable, 9% vs 7%; intermediate, 70% vs 72%; unfavorable, 6% vs 6%; very un-

favorable, 7% vs 4%), induction cytarabine dose level (intermediate, 58% vs 54%), induction with G-CSF priming (25% vs 26%), and cycle of induction during which complete remission was reached (cycle 1, 81% vs 79%). Median follow-up of patients alive was 106 months. A total of 93% of chemotherapy patients received the planned consolidation chemotherapy, and 91% of those randomized to autologous transplant actually underwent transplantation.

Patient Outcomes Five-year relapse rates were 58% in the transplant group vs 70% in the chemotherapy group (P = .02). A nonsignificant improvement in 5-year recontinued on page 16

The ASCO Post | MARCH 15, 2012

PAGE 16

Clinical Perspective

Autologous Transplant continued from page 15

New Findings

Two recent publications yet again raise the question of a possible role of autologous hematopoietic cell transplantation as consolidation therapy for AML in first remission. Vellenga et al for the Dutch, Belgian, and Swiss groups has published the results of their AML-29 and AML-42 trials, in which patients without donors were randomly assigned to either autologous hematopoietic cell transplantation or chemotherapy.2 They show a relatively low transplant-related mortality with autologous transplantation (4%) and better relapse-free survival at 5 years (38% vs 29%). However, like other studies of autologous hematopoietic cell transplantation, overall survival at 5 years was not superior to that seen with chemotherapy (44% vs 41%) because of more opportunities for salvage therapy among patients relapsing on the chemotherapy arm (see sidebar). More recently, Pfirrmann et al for the German Study Alliance Leukaemia, using data from their AML96 and AML 2003 trials, developed a postremission treatment score capable of predicting the risk of relapse after attainment of complete remission.8 Using age, percent of CD34-positive blasts, FLT3-ITD allelic ratio, cytogenetic risk, and de novo vs secondary AML, they were able to segregate patients into favorable-, intermediate-, and unfavorable-risk groups. They then analyzed the overall survival in each group according to treatment.

Acute Myeloid Leukemia continued from page 15

lapse-free survival was observed with augologous stem cell transplantation (38% vs 29%, P = .065). Nonrelapse mortality, a measure of treatment procedure–related death, was significantly greater in the transplant group (4% vs 1%, relapse-free survival = .02). Median overall survival was similar in the two groups (44% vs 41%, P = .86). Second-line treatment was received by 74% of the 156 relapsing patients in the transplant arm, and consisted of autologous transplantation in 1%, allogeneic transplantation in 17%, and chemotherapy in 55%. By comparison, second-line treatment was received by 80% of the 187 relapsing patients in the chemotherapy arm, consisting of autologous transplant in 14%, allogeneic transplant in 25%, and chemotherapy

In all three risk groups, those receiving chemotherapy did the worst. Somewhat surprisingly, allogeneic transplantation led to the best outcome in those in the favorable and unfavorable risk groups, but for those in the intermediate-risk group, autologous transplant was associated with the best overall outcome.

getting closer to defining a population who might benefit from it. But we have accomplished almost nothing to attack the major problem of post-transplant relapse. Perhaps that is not surprising given that we really don’t know why the procedure works in the first place. Do we really

We have convincingly made the transplant procedure safer, and we may be getting closer to defining a population who might benefit from it. But we have accomplished almost nothing to attack the major problem of post-transplant relapse. —Frederick R. Appelbaum, MD

Confirmation of these results by other groups should be encouraged. It should be possible to further improve on the approach to patient selection taken by Pfirrmann. Their analysis did not include recently identified mutational markers of disease-risk, such as IDH1 and 2, DNMT3A, and ASXL1. Nor did they incorporate advances in detection of minimal residual disease, such as modern multiparametric flow cytometry, which we have found to be a very sensitive predictor of post-transplant relapse in the allogeneic setting.9

Questions Remain So after 3 decades, what do we as a community have to show for our work? We have convincingly made the transplant procedure safer, and we may be in 40%. Thus, a greater proportion of patients in the chemotherapy arm had the potential for salvage with autologous or allogeneic transplant (39% vs 18%). Second complete remissions were achieved in 27% of the relapsed transplant patients vs 47% of the relapsed chemotherapy patients, resulting in long-term survival in 7% vs 15%.

Predictive Factors In the total study population, a number of factors were predictive of outcome. Increasing age was associated with reduced relapse-free survival (P = .01) and overall survival (P < .001). Extramedullary disease at diagnosis was associated with reduced relapse-free survival (P = .016). Cytogenetics was strongly associated with both relapse-free and overall survival (P < .001 for both), as was achieve-

think that if there are leukemic stem cells in the patient, they aren’t in the stem cell inoculum? Are they less able than normal stem cells to survive cryopreservation or to re-engraft? Is there a transient autologous graft-vs-tumor reaction during the early engraftment period? Until we understand more about why the procedure works, we’ll have to be pretty lucky to make it much better.

■

Disclosure: Dr. Applebaum reported no conflicts of interest.

References 1. Stewart P, Buckner CD, Bensinger W, et al: Autologous marrow transplantation in patients with acute nonlymphocytic leukemia in first remission. Exp Hematol 13:267-272, 1985. 2. Vellenga E, van Putten W, Ossenkop-

ment of first complete remission in the first vs second cycle of induction chemotherapy (P < .001 for both). There was no significant treatment group effect for any of these factors. However, it was noted that when patients with the monosomal karyotype (very unfavorable cytogenetics) with very poor relapse-free survival in both groups were excluded from analysis, the overall increase in relapse-free survival with autologous transplant treatment became statistically significant (P = .014). Neutrophil counts of greater than 0.5 × 109/L were achieved by 32% of autologous transplant patients by day 14 and by 88% by day 28 after transplantation, compared with 1% and 42% of patients in the chemotherapy group, respectively, after the end of consolidation therapy. Plate-

pele GJ, et al: Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 118:6037-6042, 2011. 3. Gorin NC, Labopin M, Blaise D, et al: Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission. J Clin Oncol 27:39873993, 2009. 4. Gorin NC, Labopin M, Reiffers J, et al: Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission. Blood 116:3157-3162, 2010. 5. Nathan PC, Sung L, Crump M, et al: Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia. J Natl Cancer Inst 96:38-45, 2004. 6. Wang J, Ouyang J, Zhou R, et al: Autologous hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission. Acta Haematol 124:61-71, 2010. 7. Oliansky DM, Appelbaum F, Cassileth PA, et al: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults. Biol Blood Marrow Transplant 14:137-180, 2008. 8. Pfirrmann M, Ehninger G, Thiede C, et al: Prediction of post-remission survival in acute myeloid leukaemia. Lancet Oncol 13:207-214, 2012. 9. Walter RB, Gooley TA, Wood BL, et al: Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 29:1190-1197, 2011.

let counts recovered somewhat more rapidly in transplant patients than in chemotherapy patients over the first month, but significantly more slowly thereafter in patients with counts that had not recovered by this time. A similar pattern was observed for platelet transfusion independence. There were no differences between groups with regard to grade 3 or 4 bleeding events or infections. However, a number of grade 2 to 4 adverse events were more common in the autologous transplant group, including fever of unknown origin and gastrointestinal, hepatic, and neurologic adverse events.

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Reference 1. Vellenga E, van Putten W, Ossenkoppele GJ, et al: Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 118:6037-6042, 2011.

new indication

for the First-Line Treatment of Recurrent Locoregional or Metastatic SCCHN in Combination With Platinum-Based Therapy With 5-FU

erbitux: now approved

In 5 IndIcatIons across 2 tumor types ERBITUX Indications Head and Neck Cancer

new

n ERBITUX速 (cetuximab) is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck n ERBITUX, in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck n ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer n ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens n ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma n Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS n Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions n Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated Scan QR code for in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with more information. By squamous cell carcinoma of the head and neck treated in a clinical trial with European scanning the QR code, Union (EU)-approved cetuximab in combination with platinum-based therapy you are confirming you with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum are a US Healthcare Professional. magnesium, potassium, and calcium, during and after ERBITUX administration SCCHN=squamous cell carcinoma of the head and neck.

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Important Safety Information Including Boxed WARNINGS Infusion Reactions n Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical

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

Cardiopulmonary Arrest n Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of

the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity n Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD

Dermatologic Toxicities n In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial

inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 4 and 5. Severe acneiform rash occurred in 1-17% of patients — Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin n The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established

— Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

Electrolyte Depletion n Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 4 and two other clinical trials in colorectal

cancer and head and neck cancer, respectively and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3-4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidence of hypomagnesemia was similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3-4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy. — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities n The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX (cetuximab) in combination

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

Pregnancy and Nursing n In women of childbearing potential, appropriate contraceptive measures must be used during treatment with

ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

n It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in

human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events n The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

n The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

n The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX

in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

n The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with

5-FU (CT) (n=219) vs CT alone (n=215) (incidence ≥40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) vs CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

n The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%)

n The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US12AB01813

11/11

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4), in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer: Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Pharmacology (12.1), Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 4, and 5 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 4, and 5. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 4 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

Erbitux1111PBSwip3.indd 1

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

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse events in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

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Table 2:

Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU Alone 5-FU (n=215) (n=219) Table 2: Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease or System Organ Class Grades Grades Grades Metastatic SCCHN Grades Preferred Term 1–4 3 and 4 Cetuximab1–4 3 and 4 EU-Approved % of Patients Platinum-based plus Platinum-based Therapy with Therapy with Eye Disorders 5-FU Alone 5-FU Conjunctivitis 10 0(n=219) 0 0 (n=215) Gastrointestinal Disorders System Organ Class Grades Grades Grades Grades Nausea 54 4 Preferred Term 1–4 4 3 and 4 47 1–4 3 and 4 Diarrhea 26 5 16 1 % of Patients General Disorders and AdministrationEye SiteDisorders Conditions Conjunctivitis 10 0 0 13 0 0 Pyrexia 22 1 Disorders a 10 2 <1 0 Infusion ReactionGastrointestinal Nausea 54 4 47 4 Infections and Infestations Diarrhea 26 5 16 1 44 11 27 8 Infectionb General Disorders and Metabolism and Nutrition Disorders Administration Site Conditions Anorexia 25 1 Pyrexia 22 5 0 14 13 1 Hypocalcemia Infusion Reactiona 12 5 1 10 4 2 <1 0 Hypokalemia Infections and Infestations 12 7 7 5 b 44 5 11 5 27 8 HypomagnesemiaInfection 11 1 Metabolism and Nutrition Skin and Subcutaneous Tissue DisordersDisorders c Anorexia 25 9 5 14 1 70 2 0 Acneiform Rash Hypocalcemia 12 5 4 5 1 Rash 28 2 0 Hypokalemia 12 2 7 7 5 Acne 22 0 0 Hypomagnesemia 11 2 5 5 1 Dermatitis Acneiform 15 0 0 Skin and Subcutaneous Tissue Disorders Dry Skin 14 0 <1 0 70 9 2 0 Acneiform Rashc Alopecia 12 7 0 Rash 28 0 5 2 0 a Infusion reactionAcne defined as any event of “anaphylactic reaction”, “hypersensitivity”, “dyspnea”,0 22 2“fever and/or chills”, 0 b sepsis-related or “pyrexia” on Dermatitis the first day of dosing. Infection – this term excludes Acneiform 15 2 events which 0 are presented0 separately. c Acneiform as “acne”, “dermatitis acneiform”, Dry Skin rash defined as any event described 14 0 <1 “dry skin”,0 “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash =0 Alopecia 12 papular”, or “rash 0 pustular”. Chemotherapy 7 cisplatin + 5-fluorouracil or carboplatin a Infusion reaction defined +as5-fluorouracil any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first dosing. inInfection this term excludes sepsis-related events which are For cardiac disorders, approximately 9%dayof ofsubjects both the– EU-approved cetuximab plus chemotherapy andpresented c Acneiform rash defined as any event event. described “acne”,of“dermatitis acneiform”, chemotherapy-onlyseparately. treatment arms in Study 2 experienced a cardiac Theasmajority these events occurred “dry in skin”, “exfoliative rash”, “rash”, erythematous”, “rash “rashand papular”, pustular”. Chemotherapy = patients who received cisplatin/5-FU, with“rash or without cetuximab as macular”, follows: 11% 12% or in “rash patients who received + 5-fluorouracil or carboplatin + 5-fluorouracil cisplatin/5-FU withcisplatin or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with For cardiac disorders, of subjects in both the EU-approved cetuximab and or without cetuximab, respectively. In approximately both arms, the9%incidence of cardiovascular events was higher inplus thechemotherapy cisplatin chemotherapy-only treatment armstoincardiovascular Study 2 experienced event. Thewas majority of these events occurred in with 5-FU containing subgroup. Death attributed eventaorcardiac sudden death reported in 3% of the patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with with 5-FU alone arm. or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin Colorectal Cancer: Monotherapy —Death Tableattributed 3 contains selected adverse in 562 patients receiving with Erbitux 5-FU containing subgroup. to cardiovascular eventevents or sudden death was reported in 3% of the best supportive patients care (BSC) or with (cetuximab) monotherapy forand metastatic cancer in in thealone cetuximab plusErbitux platinum-based therapy with 5-FU arm 2% in thecolorectal platinum-based chemotherapy alone arm. at the recommended dose and schedule (400 mg/m2 initial dose, followed by Study 4. Erbitux with was5-FU administered 250 mg/m2 weekly). Colorectal Cancer: Erbitux Monotherapy — Table 3 contains selected adverse events in 562 patients receiving b

best supportive care (BSC) aloneEvents or withOccurring Erbitux (cetuximab) for Advanced metastatic colorectal Incidence of Selected Adverse in ≥10% ofmonotherapy Patients with Colorectalcancer in Study 4. Erbitux waswith administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by a Carcinoma Treated Erbitux Monotherapy 250 mg/m2 weekly). Erbitux plus BSC BSC alone Table 3: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal (n=288) (n=274) Carcinomaa Treated with Erbitux Monotherapy Grades Any Grades Body System Any BSC alone 3Erbitux and 4plus BSC Grades 3 and 4 Preferred Term Gradesb (n=288) (n=274) % of Patients Grades Any Grades Body System Any Dermatology Preferred Term 3 and 4 Grades 3 and 4 Gradesb Rash/Desquamation 89 12 <1 % 16 of Patients Dry Skin 49 0 11 0 Dermatology Pruritus 40 8 0 Rash/Desquamation 89 2 12 16 <1 Other-Dermatology 27 6 1 Dry Skin 49 1 0 11 0 Nail Changes Pruritus 21 4 0 40 0 2 8 0 Body as a WholeOther-Dermatology 27 1 6 1 Nail Changes 21 33 0 4 0 Fatigue 89 76 26 Body as a Whole Fever 30 1 18 <1 c 89 5 33 76 26 20 Infusion ReactionsFatigue 30 <1 1 18 <1 Rigors, Chills Fever 13 4 0 c 20 5 Infusion Reactions Pain 13 14 <1 4 0 Abdominal Pain Rigors, Chills 59 52 16 Pain Pain-Other 51 16 34 7 Abdominal Pain 59 14 52 16 Headache 33 11 0 Pain-Other 51 4 16 34 7 Bone Pain 15 3 7 2 Headache 33 4 11 0 Pulmonary Bone Pain 15 3 7 2 Dyspnea 48 16 43 12 Pulmonary Cough 29 2 19 1 Dyspnea 48 16 43 12 GastrointestinalCough 29 2 19 1 Constipation Gastrointestinal 46 4 38 5 Constipation 46 4 38 5 Diarrhea 39 2 20 2 Diarrhea 39 6 2 20 2 Vomiting 37 29 6 Vomiting 37 1 6 29 6 Stomatitis 25 10 <1 Stomatitis 25 10 1 10 <1 Other-Gastrointestinal 23 18 8 23 0 10 18 8 Mouth Dryness Other-Gastrointestinal 11 4 0 Mouth Dryness 11 0 4 0 Infection Infection Infection without Infection neutropenia 35 13 17 6 without neutropenia 35 13 17 6 Neurology Neurology Insomnia 30 15 1 Insomnia 30 1 1 15 1 Confusion 15 9 2 Confusion 15 6 6 9 2 Anxiety 14 8 1 Anxiety 14 2 2 8 1 Depression 13 6 <1 Depression 13 1 1 6 <1 a a Adverse reactions frequently in Erbitux-treated patientswith compared with bcontrols. Adverse events Adverse reactions occurring moreoccurring frequentlymore in Erbitux-treated patients compared controls. Adverse bevents c CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, were using the NCI were graded using thegraded NCI CTC, V 2.0. Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, bronchospasm, chest tightness,chest swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, visual disturbances, or other)by recorded by the investigator as pain, pruritus, sweating, tremors, shaking, cough, visual cough, disturbances, or other) recorded the investigator as BSC = best infusion-related. infusion-related. BSC = best supportive caresupportive care

Table 3:

Erbitux in Combination with Irinotecan — The most frequently reported adverse events in 354 patients treated Erbitux in Combination with The most reported adverseasthenia/malaise events in 354 (73%), patients treated with Erbitux plusIrinotecan irinotecan in—clinical trials frequently were acneiform rash (88%), diarrhea (72%), and with Erbitux plus nausea irinotecan in clinical trials were Grades acneiform (88%), asthenia/malaise (73%), diarrhea (72%), andasthenia/ (55%). The most common 3–4rash adverse events included diarrhea (22%), leukopenia (17%), nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/ malaise (16%), and acneiform rash (14%). malaise (16%), and acneiform rash (14%).

Erbitux1111PBSwip3.indd 2

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux (cetuximab) has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody neutralizing positivityforin immunogenicity. an assay may be influenced responses by several Immunogenicity: As with (including all therapeutic proteins,antibody) there is potential Immunogenic factors toincluding assay timing radiometric of sample assay collection, medications, and cetuximab weremethodology, assessed usingsample either ahandling, double antigen or an concomitant ELISA assay. Due to limitations underlying disease. For theseandreasons, comparison the incidence of antibodies to Erbitux with receiving the incidence in assay performance sampling timing, theofincidence of antibody development in patients Erbituxof antibodies to other has products mayadequately be misleading. (cetuximab) not been determined. Non-neutralizing anti-cetuximab antibodies were detected in 5%

(49 of 1001) of evaluableThe patients without apparent effect has on the safety or antitumor activity of Erbitux. use of Erbitux. Postmarketing Experience: following adverse reaction been identified during post-approval BecauseThe thisincidence reactionofwas reported from is a population of uncertain size, it was always possible to reliably estimate antibody formation highly dependent on the sensitivity andnot specificity of the assay. Additionally, the observed incidence aofcausal antibody (including to neutralizing antibody) positivity in an assay may be influenced by several its frequency or establish relationship drug exposure. factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and

• Aseptic meningitis underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS

The following has been identified during post-approval use of Erbitux. A drug Postmarketing interaction studyExperience: was performed in whichadverse Erbituxreaction was administered in combination with irinotecan. There was Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. its frequency or establish a causal relationship to drug exposure.

USE IN • SPECIFIC POPULATIONS Aseptic meningitis Pregnancy: Category C — There are no adequate and well-controlled studies of Erbitux in pregnant DRUGPregnancy INTERACTIONS women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be A drug interaction study was performed in which was administered in combination withHuman irinotecan. wasto essential for normal organogenesis, proliferation, and Erbitux differentiation in the developing embryo. IgG isThere known no placental evidence ofbarrier; any pharmacokinetic interactions Erbitux cross the therefore, Erbitux may be between transmitted fromand theirinotecan. mother to the developing fetus, and has the potentialUSE to IN cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if SPECIFIC POPULATIONS the potential benefitPregnancy justifies theCategory potentialC risk to the are fetus. Pregnancy: — There no adequate and well-controlled studies of Erbitux in pregnant

women. Based on animal were models, EGFRweekly has been in the the control of prenatal human development andcetuximab may be Pregnant cynomolgus monkeys treated withimplicated 0.4 to 4 times recommended dose of for normal organogenesis, proliferation, and differentiation in theday developing embryo. Human IgGwas is known to (based essential on body surface area) during the period of organogenesis (gestation [GD] 20–48). Cetuximab detected cross the placental may from be transmitted from the thefetal developing fetus, and or hasother the in the amniotic fluid andbarrier; in the therefore, serum ofErbitux embryos treated dams at mother GD 49.toNo malformations potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred ifat potential benefit justifies the potential risk to the fetus. doses oftheapproximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab

Nursing(based Mothers: It issurface not known whether is organogenesis secreted in human milk.day IgG[GD] antibodies, such as Erbitux, can be on body area) during theErbitux period of (gestation 20–48). Cetuximab was detected excretedin inthehuman milk. many drugs excreted humandams milkatand of the potential fororserious amniotic fluidBecause and in the serum of are embryos fromintreated GDbecause 49. No fetal malformations other adverseteratogenic reactions effects in nursing infants from Erbitux, a decision should be made whether to discontinue occurred in offspring. However, significant increases in embryolethality and abortionsnursing occurredoratto discontinue drug, taking into account of the drugdose to the mother. If(based nursing interrupted, based on dosesthe of approximately 1.6 to 4 timesthe theimportance recommended human of cetuximab on istotal body surface area). the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be be resumed earlier than 60milk. days following thedrugs last dose of Erbitux. excreted in human Because many are excreted in human milk and because of the potential for serious adverse in nursing infants from Erbitux, a decision should bepatients made whether to discontinue nursing orThe to Pediatric Use:reactions The safety and effectiveness of Erbitux in pediatric have not been established. discontinue the drug, taking into account the importance of the drug evaluated to the mother. If nursing patients is interrupted, based on pharmacokinetics of cetuximab, in combination with irinotecan, were in pediatric with refractory the mean of cetuximab [see Clinical Pharmacology (12.3) inwas Full administered Prescribing Information], nursing shouldupnotto solid tumors in anhalf-life open-label, single-arm, dose-finding study. Erbitux once weekly, at doses 2 be resumed than 60 daysfrom following the years last dose Erbitux. 250 mg/m , to 27 earlier patients ranging 1 to 12 old;ofand in 19 patients ranging from 13 to 18 years old. No new safety signalsUse: were in pediatric patients. The pharmacokinetic profileshave of cetuximab theThe two Pediatric Theidentified safety and effectiveness of Erbitux in pediatric patients not been between established. pharmacokinetics combination with irinotecan, were patients appeared with refractory age groups were similarofatcetuximab, the 75 andin 150 mg/m2 single dose levels. Theevaluated volume inofpediatric the distribution to be 2 to solid tumors an open-label, single-arm, dose-finding administered once weekly, at doses independent of dosein and approximated the vascular spacestudy. of 2–3Erbitux L/m2.was Following a single dose of 250 mg/mup , the , to 0-inf 27 patients ranging from 1 tomg•h/mL 12 years old; andin inthe 19 younger patients ranging from(1–12 13 to 18 yearsn=9) old. and No 250 mean mg/m2AUC geometric (CV%) value was 17.7 (34%) age group years, new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours 2 single dose levels.55The volume of the appeared to be agetogroups were similar the 75 age and group, 150 mg/m (range 69 188 hours) for the at younger and 82 hours (range to 117 hours) fordistribution the adolescent age group. independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the Geriatric Use: Ofmean the 1062 who received with(34%) irinotecan Erbituxage monotherapy five n=9) studies geometric AUC0-infpatients (CV%) value was 17.7 Erbitux mg•h/mL in the or younger group (1–12 inyears, and of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 for the agepatients. group, and 82 hours (range 55 to 117 hours) for the adolescent age group. observed between thesehours) patients andyounger younger Use: Of theconducted 1062 patients who received withneck irinotecan or did Erbitux in five number studies ofof ClinicalGeriatric studies of Erbitux in patients with Erbitux head and cancer notmonotherapy include sufficient 363 patients werethey 65 years of age or older. No overall differences in safety or efficacy were subjectsadvanced aged 65colorectal and overcancer, to determine whether respond differently from younger subjects. observed between these patients and younger patients.

OVERDOSAGE

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of

2 subjects single aged 65dose and of over to determine whetheristhey respond from younger subjects.events were reported The maximum Erbitux administered 1000 mg/mdifferently in one patient. No adverse for this OVERDOSAGE patient.

NONCLINICAL TOXICOLOGY The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the NONCLINICAL TOXICOLOGY Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test in female cynomolgus monkeys weekly doses of 0.4 to 4 timespotential the human dose of cetuximab (based cetuximab for carcinogenic receiving potential, and no mutagenic or clastogenic of cetuximab was observed in theon total body surface area). Cetuximab-treated incidences of irregular or absent cycles, Salmonella-Escherichia coli (Ames) assayanimals or in theexhibited in vivo ratincreased micronucleus test. Menstrual cyclicity was impaired as compared to control animals. These effectsweekly were initially week 25 dose of cetuximab treatment in female cynomolgus monkeys receiving doses ofnoted 0.4 tobeginning 4 times the human of cetuximab (based and on continued the 6-week period. Inanimals this same study, increased there wereincidences no effectsof ofirregular cetuximab treatment on totalthrough body surface area). recovery Cetuximab-treated exhibited or absent cycles, measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and as compared to control monkeys. It is not known if cetuximab canthere impair fertility in humans. continued throughmale the 6-week recovery period. In this same study, were no effects of cetuximab treatment on male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) Animalmeasured Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic Pharmacology cynomolgus monkeys, cetuximab, when administered at dosesdose of findings,Animal including inflammationand/or at theToxicology: injection siteInand desquamation of the external integument. At the highest approximately 0.4 to 4 of times weekly humanesophagus, exposure (based on total body area), resulted in dermatologic level, the epithelial mucosa the the nasal passage, and tongue were surface similarly affected, and degenerative findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at level,dose the epithelial mucosaafter of theapproximately nasal passage,13esophagus, and tongue were similarly affected, and degenerative the highest level beginning weeks of treatment. changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at theCOUNSELING highest dose level beginning after approximately 13 weeks of treatment. PATIENT INFORMATION PATIENT COUNSELING INFORMATION Advise patients: Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both and females during and for 6 months following the last dose of Erbitux therapy. • Omales f the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC aLLC wholly-owned subsidiary of Eli LillyLilly andandCompany, USA Manufactured by ImClone a wholly-owned subsidiary of Eli Company,Branchburg, Branchburg, NJ NJ 08876 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJNJ08543 Distributed and marketed by Bristol-Myers Squibb Company, Princeton, 08543USA USA Co-marketed by Eli Lilly Indianapolis, IN 46285 USAUSA Co-marketed by Eliand LillyCompany, and Company, Indianapolis, IN 46285

Copyright © 2004–2011 ImClone a wholly-owned subsidiary Lillyand andCompany, Company,and and Copyright © 2004–2011 ImClone LLC aLLC wholly-owned subsidiary of of EliEli Lilly Bristol-Myers Company. All rights reserved. Bristol-Myers SquibbSquibb Company. All rights reserved. 1236886A9 1236886A9

Rev November 2011 Rev November 2011 693US11PBS17802

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The ASCO Post | MARCH 15, 2012

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News

Next-generation Sequencing in Metastatic Triple-negative Breast Cancer Yields Rewards

At least in the research arena, genotypes are beginning to guide treatment. By Caroline Helwick

he startling molecular heterogeneity of metastatic triple-negative breast cancer is now obvious and helps to explain the poor outcomes observed in this patient subset. Comprehensive genomic and transcriptomic interrogation of metastatic triple-negative breast cancer is elucidating the molecular biology SEE PAGE 72 of these tumors and resulting in treatment that takes “personalized medicine” to the next level.

Identifying Genomic Alterations Work performed at the Translational Genomics Research Institute, Phoenix, in collaboration with US Oncology/ Texas Oncology and Life Technologies, Carlsbad, California, was described at the 2011 San Antonio Breast Cancer Symposium by Joyce O’Shaughnessy, MD, of the Baylor Sammons Cancer Center, Dallas.1 “Our team of genome scientists and clinical oncologists is evaluating the sequencing findings and prioritizing investigational therapeutic options for each patient,” Dr. O’Shaughnessy said. The investigators are sequencing germline and tumor DNA to a depth that is sufficient for identifying somatic genomic alterations, including point

Genotype and Treatment Outcomes At the 2011 San Antonio Breast Cancer Symposium, Joyce O’Shaughnessy, MD, described how the genetic profiles of 12 patients with metastatic triplenegative breast were used to guide treatment for metastatic disease

Joyce O’Shaughnessy, MD

mutations, indels, and structural events such as translocations. Furthermore, RNA sequencing is performed on the tumors, along with tissue from age- and ethnicity-matched normal breast controls, to obtain deep differential expression analysis, isoform expression analysis, and fusion transcript detection.

Study Findings The study has revealed numerous known and novel mutations in metastatic triple-negative breast cancer. All patients’ cancers analyzed to date have alterations that would activate the MAPK and PI3K/AKT pathways, but through various mechanisms in different patients. This finding supports the concept that combination targeted therapy will be most effective in the treatment of this cancer, Dr. O’Shaughnessy said. “Every tumor is genomically unique,” she emphasized. “Some of the

EXPERT POINT OF VIEW

ope Rugo, MD, of the University of California, San Francisco, commented on Dr. O’Shaughnessy’s presentation on molecular pathways in triple-negative breast cancer at the 2011 San Antonio Breast Cancer Symposium. “The really exciting thing is that we have moved from intrinsic subtyping of breast cancer. While this may be important to do in the early setting, when we are looking at metastatic disease we really need to go several steps beyond this Hope Rugo, MD and figure out the targets,” she told The ASCO Post. “Dr. O’Shaughnessy’s experience is anecdotal, but it is a window into where we might be able to go from here,” she continued. “Still, we don’t understand enough yet. We cannot make conclusions based on anecdotes or data from single patients. We must be cautious moving forward. We don’t want to do expensive testing on every patient and then have them travel across the country for an experimental trial. But as a research area, this is very exciting.”

■

Disclosure: Dr. Rugo has received research funding from Genentech, Novartis, Merck, and Pfizer.

Patient #10 was a 59-year-old African-American woman with primary chemotherapy-refractory recurrent disease over the chest wall. She had not responded to doxorubicin/cyclophosphamide/docetaxel or to cisplatin. Sequencing revealed a KRAS amplicon with KRAS overexpression. Her diffuse disease responded well to pegylated SN-38, the active moiety of irinotecan, raising the hypothesis that irinotecan and SN-38 may be effective in the treatment of chemotherapy-refractory metastatic triple-negative breast cancer that demonstrates RAS pathway activation. Patient #2 was a 58-year-old Caucasian woman who had transient responses to preoperative doxorubicin/cyclophosphamide/docetaxel, platinum, and bevacizumab. Whole genome sequencing revealed a high-level BRAF amplicon, and she was enrolled on a phase I study of a novel MEK inhibitor plus a novel AKT inhibitor, to which she had a rapid response. Patient #9 was a 40-year-old Caucasian patient with cancer recurrence in the brain and cervical lymph nodes 18 months after a preoperative regimen of doxorubicin, cyclophosphamide, and paclitaxel, followed by adjuvant cisplatin. She had a strong family history but tested negative for a BRCA germline mutation. In this highly genomically unstable cancer, sequencing revealed multiple mutations and deletions in genes involved in homologous recombination. She underwent brain radiotherapy and had a complete response to iniparib/gemcitabine/carboplatin, “in keeping with numerous DNA repair mutations present in her cancer,” Dr. O’Shaughnessy noted. Patient #1 was a 53-year-old African-American woman with metastatic ipsilateral internal mammary and mediastinal nodal recurrence after a pathologic complete response to preoperative chemotherapy 18 months earlier. Sequencing revealed homologous deletion in NF1, plus PTEN deletion. She was treated with a combined PI3K /mTOR inhibitor on a phase I study, and achieved stable disease for 2 months in her very rapidly progressing disease. Progression on the PI3K pathway inhibitor may have been due to activation of the Ras/MAPK pathway in the settings of the NF1 deletion.

cancers have numerous translocations and a high degree of genomic instability. Others have simpler genomes.” An analysis of known cancer genes revealed p53 mutations in the majority of the patients. Other abnormalities were inactivating deletions in RB1, PTEN, CTNNA1, ERBB4, and NF1. Focal high-level amplifications were observed in BRAF, WT1, WHSC1L1, FGFR1, KRAS, ARAF, and MYB. RNA sequencing results also showed overexpression of the transcription factor FOXM1 in most patients, coupled with upregulation of G2M checkpoint and proliferation genes, especially in African-American patients. Downregulation of ERBB4 was also very common in metastatic triple-negative breast cancer.

At the San Antonio meeting, Dr. O’Shaughnessy described how the unique genetic profiles of 12 patients with metastatic triple-negative breast cancer might explain their disease recurrence, and how the clinicians used the information to guide treatment for metastatic disease (see sidebar, Genotype and Treatment Outcomes).

Putting It All Together “Whole genome and transcriptome sequencing of 12 patients with metastatic triple-negative breast cancer corroborated the heterogeneous biology of this cancer and identified a subset that may be driven by dominant mutations,” she summarized. “RAS/RAF/ MEK and PI3K/AKT/mTOR pathway continued on page 24

Standard CML therapies. Are we holding them to a high enough standard? We know that current chronic myeloid leukemia (CML) treatments are efficacious. But resistance still occurs. In fact, post-imatinib studies found approximately 65% of these patients eventually discontinue use of nilotinib and dasatinib as second-line therapy.1,2 Maybe itâ&#x20AC;&#x2122;s time to reconsider our definition of success.

Visit CMLResponseProject.com to learn more. References: 1. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. 2. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinibresistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL. ÂŠ2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5343712

The ASCO Post | MARCH 15, 2012

PAGE 24

JCO Spotlight Melanoma

Answer to Secondary Cancers with RAF Inhibitors May Be Concomitant MEK Inhibition By Matthew Stenger

eratoacanthomas and cutaneous squamous cell carcinomas are frequently observed in patients receiving the RAF inhibitor vemurafenib (Zelboraf) for treatment of BRAFmutated melanoma. As discussed by Lacouture and colleagues in a recent Journal of Clinical Oncology article, these effects appear to result from accelerated growth of lesions with HRAS mutations, and this SEE PAGE 72 accelerated growth appears to be inhibited by cotreatment with mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/ERK, or MEK) inhibitors.1

Approximately one-third of patients treated with vemurafenib develop a keratosis pilaris-like rash, and up to one-third develop keratoacanthomas or cutaneous squamous cell carcinomas. These adverse effects are not a major deterrent to use of vemurafenib in advanced melanoma; the keratoacanthomas and cutaneous squamous cell carcinomas are of low metastatic potential and are easily treated by such methods as surgical resection and cryotherapy. However, there is concern over the use of vemurafenib or other RAF inhibitors in earlier disease, as it remains unknown whether these agents might promote growth of tumors at other sites.

Recent Investigations

Paradoxical Problem Vemurafenib is approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. Highly selective RAF inhibitors, such as vemurafenib and sorafenib (Nexavar), inhibit RAF activation of ERK only in tumors expressing mutant BRAF; paradoxically, these inhibitors activate this pathway in tumors with wild-type BRAF and in normal cells (Fig. 1). This signaling appears to account for the skin toxicity and cutaneous squamous cell carcinomas associated with vemurafenib treatment.

Triple-negative Breast Cancer continued from page 22

mutations and their possible coactivation occur by multiple mechanisms and are common in metastatic triple-

Fig. 1: Model of extracellular signal–regulated kinase (ERK) activation by RAF inhibitors in RAS mutant tumors. (A) V600EBRAF, PLX4032-sensitive cells: In melanomas expressing V600EBRAF, RAS activity is low, and RAF dimerization is not required for ERK activation. In such cells, vemurafenib binds to and inhibits BRAF activation and thus ERK activity. (B) BRAF wild-type cancer cells/normal cells: RAS activation promotes formation of RAF dimers. In cells expressing high levels of RAF dimers, binding of vemurafenib to one member of RAF dimer transactivates non–drug-bound (adenosine triphosphate [ATP]–bound) RAF. In such cells, vemurafenib often induces ERK activity and cell proliferation. GTP = guanosine triphosphate; MEK = mitogen-activated protein kinase kinase. Reprinted with permission from Lacouture M, et al.1 Copyright © 2012 by the American Society of Clinical Oncology. All rights reserved.

negative breast cancer.” Based on the frequency of this genomic context, patients are being offered treatment with combined MEK (trametinib) plus AKT (GSK2110183)

Genomic Sequencing in Breast Cancer ■■ Numerous known and novel mutations have been revealed by compre-

hensive genome sequencing of metastatic triple-negative breast cancer.

■■ The tumors often have alterations that activate the MAPK and PI3K/AKT

pathways, but mechanisms of doing so are highly individualized among patients.

■■ Some tumors have suspected dominant molecular drivers for which

therapies might be selected; others have suspected drivers that are difficult to translate therapeutically; still others have nonobvious drivers for which targeted therapies cannot currently be identified.

■■ Genomic information is being used to design clinical trials in this difficult tumor type.

inhibitors on a phase I study, “Some metastatic triple-negative breast cancers have suspected dominant molecular drivers for which therapies might be selected,” she said. These include PTEN/NF1 deletions; BRAF, KRAS, and ARAF amplification; and FBXW7/FGFR1 alterations. “Other metastatic triple-negative breast cancers have suspected drivers that are difficult to translate therapeutically,” she continued. These include WT1 and WHSC1L1 amplifications. “Still others have nonobvious drivers for which targeted therapies cannot currently be identified,” she said, though efforts are now underway to distinguish driver mutations within this dataset. “We are beginning to use these insights to prioritize therapeutic targeting,” she said. They have observed, for

Two studies characterized mutations in the keratoacanthomas and cutaneous squamous cell carcinomas in patients receiving RAF inhibitors. As reported in the Journal of Clinical Oncology, Oberholzer and colleagues performed genomic analysis of 237 such lesions, including 19 from patients who had received RAF inhibitor therapy with either vemurafenib or sorafenib.2 They found that 21% of lesions from patients receiving RAF inhibitors had activating HRAS mutations compared with only 3% of lesions from patients not receiving these drugs. Su and colleagues reported in The continued on page 28

example, that one chemotherapy-refractory patient, with a high level BRAF amplification/overexpression along with downregulation of PTEN and INPP4B, had a major response to combined MEK plus AKT inhibitors on a phase I study at the START phase I program in San Antonio. Other sequenced patients are also being offered treatment on a phase I study of MEK plus AKT inhibitors.

■

Disclosure: Dr. O’Shaughnessy has served as a consultant for sanifi-aventis.

Reference 1. O’Shaughnessy J, Craig DW, Kiefer J, et al: Next generation sequencing reveals co-activating events in the MAPK and PI3K/AKT pathways in metastatic triple negative breast cancers. 2011 San Antonio Breast Cancer Symposium. Abstract S3-5. Presented December 7, 2011.

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

Introducing Jakafi™ (JAK-ah-fye) First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b ≥35% reduction in spleen volume1,2,a

≥50% improvement in Total Symptom Score1,2,a,b

41.9

P < 0.0001

30 20 10 0

45.9 P < 0.0001

Patients (%)

30 20 10

0.7 Jakafi (n = 155)

Placebo (n = 154)

5.3 Jakafi (n = 148) Placebo (n = 152) Baseline mean TSS = 18.0 Baseline mean TSS = 16.5

Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive and JAK2 V617F-negative patients, relative to placebo2 Most patients not treated with Jakafi experienced increased splenomegaly and worsening of symptoms1

Visit www.jakafi.com/JAKtarget for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

TSS = Total Symptom Score. a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

The ASCO Post | MARCH 15, 2012

PAGE 28

JCO Spotlight

Secondary Cancers continued from page 24

New England Journal of Medicine that 60% of 35 lesions from patients receiving vemurafenib harbored HRAS mutations, with the most prevalent being HRAS Q61L.3 Increased proliferation 07 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1 of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated

with MAPK-pathway signaling and activation of ERK-mediated transcription. These investigators then showed that a vemurafenib analog accelerated growth of lesions with HRAS mutations in a mouse model of HRAS Q61L–mediated skin carcinogenesis, but did not initiate or promote carcinogenesis. The growth promoted by the vemurafenib

analog was blocked by concomitant treatment with a MEK inhibitor. Thus, the emerging picture of vemurafenib-associated cutaneous squamous cell carcinoma is that induction of RAF signaling by the agent promotes the hyperproliferation of preexistent dormant RAS-mutant cancer cells—hence the concern that use

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

EXPERT POINT OF VIEW

Mario E. Lacouture, MD

“T

he development of nonmelanoma skin cancers secondary to RAF inhibitor treatment has been recognized since 2005, having been seen initially with sorafenib (Nexavar),” noted Mario E. Lacouture, MD, of Memorial Sloan-Kettering Cancer Center. Commenting on recently published studies in this setting, he told The ASCO Post, “Our understanding of these events has been improved by our experience with vemurafenib (Zelboraf). We hope that this improved understanding will minimize the impact these lesions have on dose intensity of RAF inhibitor therapies in advanced melanoma, since most of them are cutaneous squamous cell carcinomas or keratoacanthomas that lack an aggressive behavior. That being said, these observations may hamper the development of RAF inhibitors for use in earlier cancer until the full implications of the potential effects on tumor growth at other sites are understood.”

■

Disclosure: Dr. Lacouture has served as a consultant to Roche, Genentech, GlaxoSmithKline, Bayer, and Onyx Pharmaceuticals.

of selective RAF inhibitors in patients with early cancer could be associated with risk of promoting growth of such dormant tumors in other sites. It also appears that combining RAF inhibitors and MEK inhibitors may be a strategy for avoiding these effects of RAF inhibitors in the setting of mutated BRAF codon 600. RAF and MEK inhibitors both inhibit ERK pathway activation in tumors with mutations in BRAF codon 600. However, in contrast to RAF inhibitors, MEK inhibitors also inhibit this pathway when wild-type BRAF is present. Thus, use of such agents in combination may result in synergistic effects continued on page 30

ASCOPost.com | MARCH 15, 2012

PAGE 29

Issues in Oncology

Rising Costs in Radiation Oncology Linked to Medicare Coverage Billing technicalities and overtreatment drive costs in radiation therapies. By Ronald Piana

n the ongoing debate over how to control rising cancer care costs, it is vital to identify usage patterns of expensive new technologies. A recent study examined the relationship between Medicare reimbursement and the increasing use of intensity-modulated radiation therapy (IMRT).1 The ASCO Post spoke with the study’s lead author, Benjamin D. Smith, MD, Assistant Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center.

with localized breast cancer who had undergone surgery and radiation from 2001 to 2005. They found that Medicare billing for IMRT increased from 0.9% of patients diagnosed in 2001 to 11.2% of women whose breast cancer was diagnosed in 2005. The average cost for radiation treatment during the first year was $7,179 for non-IMRT and $15,230 with IMRT. Moreover, billing for IMRT was more than five times higher in regions across the nation where the local Medicare

With respect to breast radiation therapy, the study data suggest that much of the variation in cost can be directly attributed to inconsistent treatment definitions and their associated reimbursement rates. —Benjamin D. Smith, MD

Over the past decade, the use of advanced radiation technologies has risen rapidly in the management of many solid cancers. For breast cancer, radiation practice patterns have shifted from conventional two-dimensional therapy to a more refined three-dimensional approach using computed tomography planning. The ultimate goal in the development of new radiation therapies is to eradicate tumor cells and do as little harm as possible to healthy tissue. “Two randomized trials have compared intensity-modulated radiation therapy with conventional radiation therapy in women with breast cancer who had lumpectomy,” said Dr. Smith. “Both trials showed a significant improvement in sideeffect profile in the IMRT arms, especially in long-term cosmesis of the breast.” The important question, however, is whether the benefits from IMRT are justified by the cost of this technology, particularly when less expensive alternatives that yield similar target dose coverage and normal organ-sparing are readily available.

Medicare Billing Incentives Using Surveillance, Epidemiology and End Results (SEER)-Medicare data, the researchers looked at 26,163 women

coverage determinations were favorable to IMRT compared to regions where coverage was unfavorable.

Inverse Planning Dr. Smith explained that although IMRT has been shown to lower toxic effects for patients receiving whole-breast irradiation, less expensive, relatively simple techniques might suffice. “Inverse planning—optimizing treatment configurations by calculating backwards from the prescribed dose, rather than through trial and error—is a prerequisite to IMRT billing; however, it is more expensive because of the increased physician and treatment planning time involved. Moreover, the less expensive field-in-field planning is likely to have similar outcomes,” said Dr. Smith. Dr. Smith concluded, “With respect to breast radiation therapy, the study data suggest that much of the variation in cost can be directly attributed to inconsistent treatment definitions and their associated reimbursement rates authorized by the Medicare program and its intermediaries.”

Unnecessary Treatment Past President of the American Society for Radiation Oncology (ASTRO)

and Director of the Radiation Oncology Residency Program at Massachusetts General Hospital, Anthony L. Zietman, MBBS, MD, weighed in on radiation therapy practices in prostate cancer that also drive up costs. According to Dr. Zietman, prostate cancer is unlike most other malignancies in that a significant amount of the cancers detected on screening do not need treatment simply because they will not prove fatal during the course of the man’s lifetime. “As clinicians, we need to learn to use restraint and understand that not all men presenting with prostate cancer need treatment, especially older men. Most of the major cancer organizations are getting that message out; however, many of us are not practicing what we preach,” said Dr. Zietman. He cited several reasons for the overtreatment phenomenon in prostate cancer. “It is much easier to treat a patient and be a hero than it is to make the decision not to treat. It pays much better to treat than to follow a patient and do periodic biopsies. And of course we have the legal aspect: In the United States we are afraid of giving fewer medical services for fear of a malpractice suit, so in turn we end up, in many instances, giving too many services,” said Dr. Zietman. “Of course, our diagnostic systems are not perfect. Just because I think a prostate cancer is small and mild, sometimes I’m

do not have proven value over standard treatments,” stressed Dr. Zietman.

The Coding Conundrum In 1992, Medicare significantly changed the way it pays for physicians’ services. Instead of basing payments on charges, the federal government established a standardized physician payment schedule based on a resource-based relative value scale; payments for services are determined by the resource costs needed to provide them. To ensure that physician services across all specialties are well represented, the American Medical Association (AMA) established the AMA/ Specialty Society Relative Value Scale Update Committee. Dr. Zietman explained that the committee makes annual recommendations regarding new and revised physician services to the Centers for Medicare & Medicaid Services (CMS) and performs broad reviews of the relative value scale every 5 years. “However, as far as IMRT, the valuation code in 1999 was particularly generous, especially since at that time we really did not have data to prove its clinical value—certainly not whether it was cost-effective,” said Dr. Zietman. On a broader scale, Dr. Zietman stressed that our current payment system is a larger part of the problem. “In the United States we currently have what I call ‘code-driven’ clinical practice. In other words, the practice follows the

In radiation oncology, our first question should be, not how should I treat this patient, but whether I should be treating this patient at all. —Anthony L. Zietman, MBBS, MD

wrong and there is more cancer lurking around than I thought. It is a complicated issue,” he added. “That said, in radiation oncology, our first question should be, not how should I treat this patient, but whether I should be treating this patient at all. Just as medical oncologists are drawn to new biologics, we in radiation are seductively drawn to the most sophisticated new technologies out there, many of which

most lucrative reimbursement codes. It’s simply human nature. So our coding structure is certainly one area in which we could save money and, in some instances, deliver more appropriate care. ”

The Bigger Picture Dr. Zietman pointed out that a shift in government policy—empowering CMS to use cost-effectiveness metcontinued on page 30

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Issues in Oncology

Radiation Oncology continued from page 29

rics—could substantially reduce rising health-care costs. “The British have the National Institute of Clinical Effectiveness (NICE), which rigorously evaluates cost-effectiveness of new drugs and technologies. In the United States, we have our own quasi ‘national health service,’ CMS, and if the agency would flex its very large muscles and begin reexamining its reimbursement policies, all the insurance companies would follow suit,” said Dr. Zietman. Dr. Zietman offered NICE’s methodology as a model of how cost-effectiveness research works in the real world. “After NICE does a rigorous independent evaluation of a drug or technology, the agency says, ‘This is valuable, but it only has X amount of value. So we’ll pay a certain amount but you go out and negotiate with the drugs or technology companies for a better price to make up the difference.’ With NICE, it is not an all-or-nothing reimbursement schema.” Dr. Zietman used sorafenib (Nexavar) in kidney cancer as an example. “NICE evaluated sorafenib as it was indicated for kidney cancer and determined

Secondary Cancers continued from page 28

in BRAF-mutant tumors and reduce the toxicity associated with each. In a phase I trial of such a combination, the toxicity of the combination appeared to be less than that with either agent alone, and a randomized phase II trial of the combination is underway in patients with BRAF-mutant melanoma.4

■

References 1. Lacouture ME, O’Reilly K, Rosen N, et al: Induction of cutaneous squamous cell carcinomas by RAF inhibitors: Cause for concern? J Clin Oncol 30:329-330, 2012. 2. Oberholzer PA, Kee D, Dziunycz P, et al: RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 30:316-321, 2012. 3. Su F, Viros A, Milagre C, et al: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207-215, 2012. 4. Infante JR, Falchook GS, Lawrence DP, et al: Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol 29(suppl):526s, Abstract CRA8503, 2011.

that it indeed had value, but not $80,000 per year’s worth. The agency said that it would reimburse one-third of the total cost, and if the drug company wants to market their product to 60 million British citizens, they will need to be price flexible,” said Dr. Zietman. Dr. Zietman stressed that although in the United States we have been loath

to bring costs of cancer care into the clinical discussion, we have reached a critical time that behooves providers and policymakers to make solid changes in our system. “It will entail a sea change, but we need to institute better evidence review and evidence-based payments,” concluded Dr. Zietman.

■

Disclosure: Dr. Smith currently receives

research funding from Varian Medical Systems. Dr. Zietman reported no potential conflicts of interest.

Reference 1. Smith BD, Pan IW, Shih YC, et al: Adoption of intensity-modulated radiation therapy for breast cancer in the United States. J Natl Cancer Inst 103:798-809, 2011.

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Journal Spotlight

Eating Problems and Pain Prevalent in Survivors of Head/Neck Cancer By Charlotte Bath

“E

ating problems due to poor oropharyngeal functioning and persistent pain are the most prevalent problems” faced by patients 5 years after being treated for head and neck cancer, according to a study pub-

lished online by the Archives of Otolaryngology–Head & Neck Surgery.1 More than 50% of 5-year survivors reported problems eating and 17.3% reported substantial pain. The study included 337 patients

diagnosed with head and neck cancer and who completed surveys measuring health-related quality of life (HRQOL) as part of the Outcomes Assessment Project at the University of Iowa College of Medicine Depart-

ment of Otolaryngology–Head and Neck Surgery. The mean age of patients at time of diagnosis was 57 years, and more than 50% were initially diagnosed as having advanced disease. The long-term general health of the study participants was similar to that of agematched norms from the general population. The authors pointed out that the oral deficits among 5-year survivors “may be due to neuromuscular changes, anatomic deficits following surgery, soft-tissue fibrosis, xerostomia, pain, and dental deficits.” Poor swallowing function may affect more than HRQOL, they added. “Unrecognized aspiration following chemoradiation to treat [head and neck cancer] may also contribute to mortality. Aspiration pneumonia may add substantially to the SEE PAGE 72 morbidity and mortality associated with … treatment, although this long-term adverse effect may not be easily identified as a result of cancer therapy.” The best predictors of 5-year HRQOL outcomes were reports by patients at 1 year of pain and type of diet—full, soft/liquid, or nil per os/ minimum oral intake. These were stronger predictors than pretreatment variables such as stage, site, and age. “Previous studies have noted that HRQOL scores tend to increase after treatment, then level off at 1 year with little subsequent improvement. But the findings in the present study speak to the need for very early intervention done concurrently with treatment to maximize the early swallowing function and to address pain,” the researchers stated. Findings that 13.6% of the survivors continued to smoke and 38.9% drank alcohol “suggest that aggressive smoking and alcohol use education and interventions are warranted,” the authors added. “This is important not only from an oncologic standpoint but also from a comorbid illness and general health maintenance perspective.”

■

Reference 1. Funk GF, Karnell LH, Christensen AJ: Long-term health-related quality of life in survivors of head and neck cancer. Arch Otolaryngol Head Neck Surg 138:123133, 2012.

The ASCO Post | MARCH 15, 2012

PAGE 32

In the Clinic

What You Need to Know About Axitinib, New Agent for Treating Advanced Renal Cell Carcinoma By Matthew Stenger

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

Indication

n January 2012, the second-generation vascular endothelial growth factor receptor (VEGFR) kinase inhibitor axitinib (Inlyta) was approved for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.1 Approval was based on an inter-

Of Note

Axitinib is a selective second-generation inhibitor of VEGFR, effective at lower concentrations and with reduced inhibition of other kinases compared with older VEGFR kinase inhibitors.

national, open-label trial2,3 in which 723 patients with advanced renal cell carcinoma after failure of one prior systemic regimen were randomly assigned to receive oral axitinib at 5 mg twice daily (n = 361) or oral sorafenib (Nexavar) at 400 mg twice daily until disease progression or unacceptable toxicity; sorafenib is a VEGFR kinase inhibitor already approved in this setting. Patients with uncontrolled hypertension were excluded from the trial. Patients had a median age of 61 years, 72% were male, all had ECOG performance status of 0 or 1, and 99% had clear cell histology. Prior systemic treatment had to consist of sunitinib (Sutent; 54% of total population), cytokines (35%), bevacizumab (Avastin; 8%), or temsirolimus (Torisel; 3%). Median durations of treatment were 6.4 months in the axitinib group and 5 months in the sorafenib group.

Median progression-free survival, the primary endpoint of the trial, was significantly increased to 6.7 months with axitinib from 4.7 months with sorafenib, representing a 33% reduction in risk of progression (HR = 0.67, P < .0001). There was no significant difference between axitinib and sorafenib in median overall survival (20.1 vs 19.2 months).

How It Works Axitinib is a selective second-generation inhibitor of VEGFR-1, -2, and -3.3,4 Compared with older VEGFR kinase inhibitors (eg, sorafenib), which inhibit a wide range of kinases in addition to VEGFR kinases, axitinib inhibits VEGFR at lower concentrations and exhibits reduced inhibition of other kinases. The wider range of activity of older inhibitors may underlie some of the toxicities associated with these agents.

How It Is Given The recommended dose of axitinib is 5 mg twice daily. It should be taken with a glass of water and may be taken with or without food. The dose may be increased to 7 mg and then to 10 mg twice daily in normotensive patients not receiving antihypertensive medication if no adverse events higher than grade 2 occur during 2 weeks of treatment at the lower dose. Concomitant treatment with strong CYP3A4/5 inhibitors should be avoided; if such an agent is necessary, the dose of axitinib should be reduced by approximately half. The starting dose should also be

Of Note

The most common adverse reactions to axitinib are diarrhea, hypertension, and fatigue; warnings/precautions in the drug’s label include hypertension, thrombotic events, and hemorrhagic events.

Axitinib in Renal Cell Carcinoma ■■ The second-generation VEGFR kinase inhibitor axitinib (Inlyta) was

approved for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

■■ The recommended dose of axitinib is 5 mg twice daily; after 2 weeks, if

no serious adverse events have occured, the dose may be increased to 7 mg and then to 10 mg twice daily in normotensive patients not receiving antihypertensive medication.

decreased by half in patients with mild hepatic impairment.

Safety Profile The most common (≥ 20%) adverse reactions in patients treated with axitinib in the comparative trial with sorafenib were diarrhea (55%), hypertension (40%), fatigue (39%), decreased appetite (34%), nausea (32%), dysphonia (31%), palmar-plantar erythrodysesthesia (hand-foot) syndrome (27%), weight decreased (25%), vomiting (24%), asthenia (21%), and constipation (20%).2,3 The most common adverse events in the sorafenib arm were diarrhea (53%), palmar-plantar erythrodysesthesia (51%), alopecia (32%), and rash (32%). The most common grade 3 or 4 adverse events in the axitinib group were hypertension (16%), diarrhea (11%), and fatigue (11%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (5%), hyponatremia (4%), hypokalemia (3%), and decreased lymphocytes (3%). Severe adverse reactions reported in axitinib patients included hypertensive crisis, arterial and venous thrombotic events, hemorrhage, gastrointestinal perforation and fistula formation, and reversible posterior leukoencephalopathy syndrome. Discontinuation of treatment due to adverse events occurred in 9% of axitinib patients and 13% of sorafenib patients. Axitinib carries warnings/precautions for hypertension, thrombotic events, hemorrhagic events, gastro-

intestinal perforation and fistula, hypothyroidism, reversible posterior leukoencephalopathy syndrome, proteinuria, liver enzyme elevation, and fetal harm.

■

References 1. US Food and Drug Administration: Approved drugs. Axitinib. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202324lbl.pdf. Accessed February 21, 2012. 2. INLYTA® (axitinib) tablets prescribing information. Pfizer Labs, January 2012. Available at http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm289439.htm. Accessed February 21, 2012. 3. Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 378:1931-1939, 2011. 4. Escudier B, Gore M: Axitinib for the management of metastatic renal cell carcinoma. Drugs RD 11:113-126, 2011.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1800-FDA-1088).

Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®. Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

The ASCO Post | MARCH 15, 2012

PAGE 34

Direct from ASCO

ASCO Launches Community Research Forum to Tackle Top Research Conundrums

ust how many research-focused staff members is it optimal to have when conducting clinical trials in a community-practice setting? To properly gauge that, should the practice look closely at how many studies it’s working on? The complexity of those studies? The number of patients enrolled? Some combination of all three? Community physicians just aren’t sure. That’s one of the key challenges soon to be tackled by the Community Research Forum, a new initiative born out of ASCO’s

Volume 29, Issue 15

May 20, 2011

Board of Directors’ Clinical Trial Strategic Plan of 2010, a document that has helped define the society’s role in supporting clinical investigators and increasing their participation in cancer clinical trials. Since a large percentage of cancer care takes place in community practices, ASCO decided to get started there. “ASCO realized that we, the community physicians, have significant challenges to performing research, but that with 85% of the patients being seen in community

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

JOURNAL OF CLINICAL ONCOLOGY

What’s Hot in

Official Journal of the American Society of Clinical Oncology

JCO

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

www.jco.org

JCO.org 1. “Doctor, Will the Treatment You Are Recommending Cause Chemobrain?” Patricia A. Ganz 30(3): 229 2. Moving Beyond Anti–Vascular Endothelial Growth Factor Therapy in Ovarian Cancer Anil K. Sood, et al 30(4): 345 3. Not Only Response but Early Response to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Jorge E. Cortes 30(3): 223 4. Induction of Cutaneous Squamous Cell Carcinomas by RAF Inhibitors: Cause for Concern? Mario E. Lacouture, et al 30(3): 329 5. Breast Cancer Radiotherapy and Coronary Artery Stenosis: Location, Location, Location Timothy M. Zagar, et al 30(4): 350

6. Comparing Poly (ADP–Ribose) Polymerase Inhibitors With Standard Chemotherapy in BRCA-Mutated, Recurrent Ovarian Cancer: Lessons Learned From a Negative Trial Panagiotis A. Konstantinopoulos, et al 30(4): 347 7. Targeting the Angiopoietin/Tie2 Pathway: Cutting Tumor Vessels With a Double-Edged Sword? Tina Cascone, et al 30(4): 441 8. It Takes a Village Craig C. Earle 30(4): 353 9. Factors Dictating Outcomes in Patients With Colorectal Cancer and Peritoneal Carcinomatosis: Selection, Resection, or Convection? Andrea Cercek, et al 30(3): 226 10. Induction Chemotherapy and Surgery for Early-Stage Non–SmallCell Lung Cancer: What Have We Learned From Randomized Trials? Gary M. Strauss 30(2): 128

settings, in order for research to advance more quickly, those issues need to be addressed,” said Community Research Forum chair, Rogerio Lilenbaum, MD, who is Chair of the Hematology and Medical Oncology Department at Cleveland Clinic Florida in Weston, Florida.

Rogerio Lilenbaum, MD

Two Tough Issues per Year Each year, the forum plans to identify two key issues to be tackled on behalf of community physicians involved in research, and to spend much of the year in small groups coming up with ideas, solutions, and then, ideally, benchmarking metrics and solutions to address the problem. The group will meet each fall to discuss its findings. This year’s meeting will be held September 14 at ASCO headquarters in Alexandria, Virginia. The two issues that the forum is digging in on this year are (1) workload assessment and (2) quality assessment. Those topics were chosen after a survey of community physicians showed that these were two major areas of concern. Dr. Lilenbaum noted that many community physicians working on trials must appeal to the hospital with which they have a relationship in order to get research assistants and study coordinators, and there is much confusion about what’s appropriate. The forum hopes to end that uncertainty.

Calculations about Staff Numbers Are Underway “As community physicians, we deal with this every day,” said Dr. Lilenbaum. “Depending on the size and the scope of the research program, how do you come up with a number for a community physician to take to a hospital and say, ‘Look, I need six people, and here’s the ASCO paperwork to support that’?” The forum is working on calculations for that now. Quality assessment—which translates to making sure your practice’s research enterprise has all i’s dotted and all t’s crossed in the data, and thus is in full com-

pliance with all regulations at all times—represents another area of confusion. “Compliance audits are done by the NCI, the sponsors, and the FDA,” said Dr. Lilenbaum. “The level of scrutiny is increasing, as is the level of complexity in study protocols. But many doctors don’t even have time to think about how to get ready for that, and then someone shows up at their door, finds major deviations, and puts them on probation.” This is alarming—and occurs all too frequently, he said.

Coming Soon: Quality Assessment Software To remedy that, the forum seeks to equip community physicians with a software program that will help them continually assess the quality of their program and identify areas that need improvement. The forum is working on that now. Community oncologists’ contributions have enormous potential for accelerating the clinical trial process, which is necessary for improving treatment options for patients, Dr. Lilenbaum commented. Just over half of clinical trial accrual is from the community. Yet among practice settings, only 2% to 7% of all patients with cancer participate in clinical trials, and oncologists’ participation is also low, with estimates of less than 20%. By tackling the concerns highest on the list of oncologists in community settings, where 85% of the patients are, the forum hopes to dramatically change all that.

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ASCOPost.com | MARCH 15, 2012

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Direct from ASCO

Research of Former Foundation Grantee James Yao Highlighted at the GI Cancers Symposium angiogenesis and antiangiogenic therapy in carcinoid tumors, which are of neuroendocrine origin.

Greatly Needed Support

James C. Yao, MD

study led by James C. Yao, MD, Assistant Professor and Deputy Chair of Gastrointestinal Oncology at The University of Texas MD Anderson Cancer Center, Houston, was presented at the 2012 Gastrointestinal (GI) Cancers Symposium in San Francisco and highlighted in the meeting’s press program. In the study, Dr. Yao’s research team identified certain factors that predict whether an advanced neuroendocrine tumor will worsen, and based on these factors found that the drug everolimus (Afinitor) combined with octreotide may be a more effective treatment than previously thought. Dr. Yao received a 2003 Career Development Award from the Conquer Cancer Foundation. The award provides funding to faculty-appointed investigators to establish an independent clinical cancer research program with a patient-oriented focus. Dr. Yao’s earlier research also focused on neuroendocrine tumors, as he received the award to study

Dr. Yao notes that the Career Development Award helped lay the foundation for his work in this field. “My early work in carcinoid tumors is directly related to the neuroendocrine research I presented at the GI Cancers Symposium, as they focus on the same disease area,” said Dr. Yao. “We published several papers from that early study, and research is ongoing.” In addition, Dr. Yao credits the award for providing support during a time when it was greatly needed. “Early in my formative years, the Career Development Award really gave me the confidence to pursue science and work in what is considered an orphan disease,” he said. “There was not much other support to pursue research projects in neuroendocrine tumors. Awards like this really help retain people to work in areas where there is unmet need and otherwise not much funding available.” Learn more about the Career Development Award at m.conquercancerfoundation.org or visit Cancer.Net (www.cancer. net) for a summary of the study findings.

■

Pre–Annual Meeting Seminar Series Kicks Off Seminars in Chicago, May 31–June 1

his year, ASCO is cosponsoring a new series of intimate, discussion-based seminars to be held just before the start of the Annual Meeting in June. The three seminars, which start at 1:00 PM on Thursday, May 31, and continue through noon on Friday, June 1, the first day of the Annual Meeting, are: ■■ Clinical Care in Oncology for the Advanced Practice Provider ■■ Designs for Contemporary Earlyphase Clinical Trials ■■ New Drugs in Oncology ASCO’s goal in launching the new seminar series is twofold: (1) To meet the educational needs of health providers whose practices can’t afford to send them to the Annual Meeting or for whom the Annual Meeting’s topics aren’t closely targeted to their areas of focus, and

Todd Pickard, MMSc, PA-C

colon cancer. Todd Pickard, MMSc, PAC, Physician Assistant Program Director in the office of the Vice President of Medical Affairs at The University of Texas MD Anderson Cancer Center, Houston, is on the planning committee for the seminar. He said that an anticipated shortage of oncologists, coupled with the increasing population of people over 65 were the driving

Oncologists realize that very soon, they will have to work more closely with nurses and physicians assistants to handle the volume of patients. (2) To offer additional, expanded topics of interest to those who are attending the meeting, but who would like to drill down further into certain areas not typically covered at the meeting. The seminars will take place at the same location as the Annual Meeting, Chicago’s McCormick Place.

Difficult Conversations, Targeted Therapies The Clinical Care in Oncology for the Advanced Practice Provider seminar is being cosponsored with the Association of Physician Assistants in Oncology and the Oncology Nursing Society. The session will emphasize patient care and interactions and will include strategies for better handling of difficult conversations with patients and their families; new targeted therapies; advances in the treatment of hematologic malignancies; and updates on advances in breast cancer, prostate cancer, lung cancer, and

force behind choosing this focus for one of the seminars. “Oncologists realize that very soon, they will have to work more closely with nurses and physicians assistants to handle the volume of patients,” he said. “The question they face is: How do we reach out to that group so that they feel supported and bring them into the fold? This seminar was part of the answer.”

Early-phase Trial Design Explored A second seminar, Designs for Contemporary Early-phase Clinical Trials, is being cosponsored with the Society for Clinical Trials. It will bring together statisticians and clinicians to discuss the design, implementation, and analysis of earlyphase clinical trials. The format is designed to foster interaction with faculty: Lectures will be complemented by continued on page 36

The ASCO Post | MARCH 15, 2012

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Direct from ASCO

Pre–Annual Meeting Seminar continued from page 35

small breakout sessions in which a faculty member will assist as attendees work together to answer real case-study questions. Topics will include pathway-driven trials, adaptive features of trials, innova-

tive phase I trials, endpoints, and selection designs.

Knowledge about New Drugs Lacking The third seminar, New Drugs in Oncology, “is badly needed by general oncologists, who are faced with

absorbing information about the 8 to 10 new cancer drugs [introduced] per year before prescribing them to patients,” said George W. Sledge, Jr, MD, Immediate Past President of ASCO and Ballve-Lantero Professor in the Department of Medicine, Division of Hematology/Oncology at George W. Sledge, Jr, MD

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Indiana University School of Medicine, Indianapolis. “A huge number of drugs are being approved by the FDA and coming out or in the queue to come out,” said Dr. Sledge, who is on the planning committee for this seminar. “The general oncologist gets overwhelmed trying to learn all he or she needs to know about them all.” The primary ways in which phy-

During this seminar, oncologists who focus in specific disease areas will speak to generalists about the indications and side-effect profile of the market’s new drugs. sicians learn about new drugs are by word of mouth, the news, and pharmaceutical representatives. This is inadequate, Dr. Sledge commented. During this seminar, oncologists who focus in specific disease areas will speak to generalists about the indications and side-effect profile of the market’s new drugs. New pharmaceuticals the planning committee is considering for inclusion are ruxolitinib ( Jakafi), crizotinib (Xalkori), brentuximab vedotin (Adcetris), abiraterone acetate (Zytiga), vandetanib (Caprelsa), ipilimumab (Yervoy), rituximab (Rituxan), and axitinib (Inlyta). The New Drugs in Oncology seminar is sponsored only by ASCO. To learn more, and to register for one of the limited number of seats at the Pre–Annual Meeting seminars, visit chicago2012.asco.org today.

■

ASCOPost.com | MARCH 15, 2012

PAGE 37

Direct from ASCO

ASCO Submits Testimony for Congressional Hearing Examining Quality Programs that Reward High-quality Care

he House Ways and Means Health Subcommittee recently held a hearing on programs and initiatives that reward physicians who deliver high-quality, efficient care. ASCO submitted written testimony from CEO Allen S. Lichter, MD, on many aspects of quality care, including how the Quality Oncology Practice Initiative (QOPI®) helps oncologists effectively integrate quality measures into their practices.

only provide critical access points where patients can receive their cancer care, but are also extremely costeffective in the delivery of their care. He cited the fact that a significant number of oncologists have already demonstrated a remarkable willingness to devote time and resources to participate in a system designed to create meaningful improvements in the quality of cancer care. Dr. Lichter also noted that some

Over the past 4 decades, we have built an outpatient delivery system for cancer that is the envy of the world, and now as a nation, we need to act quickly to ensure that we do not lose this valuable resource. “To achieve the national goals of better health, enhanced quality of care, and lower costs within the uniquely complex context of patients with cancer, it is imperative that we implement a robust quality assessment system,” said Dr. Lichter. He cautioned, however, that it is critically important to provide safeguards that ensure efforts to lower healthcare costs do not jeopardize access to high-quality, high-value care for elderly Americans with cancer.

Power of QOPI Dr. Lichter cited ASCO’s endeavors to enhance quality improvement, most notably QOPI. “This effort, designed to facilitate quality measurement and continuous improvement, is the only comprehensive, national database for oncology care in the ambulatory setting, where the vast majority of cancer services are provided,” he said. He added that community-based oncology practices not

private health plans have already begun to recognize the power of QOPI. At least one health plan is subsidizing practice participation in the QOPI program, while others have included special recognition in provider directories or increased economic rewards and relief from certain administrative burdens. “Over the past 4 decades, we have built an outpatient delivery system for cancer that is the envy of the world, and now as a nation, we need to act quickly to ensure that we do not lose this valuable resource,” he said. He concluded by saying that ASCO stands ready to work with Congress “to test new ideas, to share what we have learned through QOPI, and to continue progress toward a system that supports delivery of high-quality care for every patient with cancer.”

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Help Your Patients Organize Their Cancer Care

irect your patients to Cancer. Net/podcasts, where they can listen to a podcast about staying organized during cancer treat-

ment, getting financial information in order, preparing questions ahead of appointments, and setting up a filing system for important documents.

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Save the Date ASCO’12 Annual Meeting June 1-5, 2012 McCormick Place Chicago, Illinois

Best of ASCO® Chicago July 12-13, 2012 Hyatt Regency Chicago Chicago, Illinois

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

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

The ASCO Post | MARCH 15, 2012

PAGE 38

FDA Update

FDA Acts to Bolster Supply of Critically Needed Cancer Drugs

he FDA has announced a series of steps to increase the supply of critically needed cancer drugs and build on President Obama’s Executive Order to help prevent future drug shortages. The President’s order, issued last October 31, directed the FDA to take action to help further prevent and reduce prescription drug shortages, protect consumers, and prevent price gouging.

Margaret A. Hamburg, MD

“A drug shortage can be a frightening prospect for patients, and President Obama made it clear that preventing these shortages from happening is a top priority of his administration,” said FDA Commissioner Margaret A. Hamburg, MD. “Through the collaborative work of FDA, industry, and other stakeholders, patients and families waiting for these products or anxious about their availability should now be able to get the medication they need.”

Proactive Steps In response to the critical shortage of the cancer drug liposomal doxorubicin (Doxil) and rapidly declining supplies of methotrexate, the FDA took proactive steps needed to increase available supply for patients in the United States. For Doxil, there will be temporary importation of a replacement drug, Lipodox (another liposomal doxorubicin product manufactured in India), which is expected to end the shortage and fully meet patient needs. For methotrexate, in addition to already announced actions, the Agency has approved a new manufacturer of a preservative-free formulation of methotrexate that is expected to further bolster supply and help avert a shortage of this lifesaving medicine. FDA expedited review of the application to help ad-

dress this potential shortage. FDA also recently issued draft guidance to industry on detailed requirements for both mandatory and voluntary notifications to the agency of issues that could result in a drug shortage or supply disrup-

tion. Increased awareness of the importance of early notification has

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%),

resulted in a sixfold increase in voluntary notifications by industry of potential shortages. In 2011, there were a total of 195 drug shortages prevented. Since the Executive Order last fall, FDA has prevented 114 drug shortages.

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thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ASCOPost.com | MARCH 15, 2012

PAGE 39

FDA Update

New Colonoscopy System Cleared by FDA

developer of endoscopy products based in New York and Kissing, Germany, invendo medical, announced that the company received 510(k) clearance by the FDA of the company’s new C20 colonoscopy system, including the SC20 single-use colonoscope.

The invendoscope SC20 has several features that are new to the field of colonoscopy: It is a single-use colonoscope with a working channel; it is not pushed or pulled but uses a computerassisted “gentle drive” technology; all endoscopic functions are performed

using a handheld device; and it reduces forces on the colon wall. A clinical trial with the company’s colonoscope demonstrated a > 98% cecal intubation rate, and lesions were detected in 41% of screening subjects. No device-related adverse

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical beneﬁt such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

events were observed during the study. The C20 colonoscopy system had already received CE mark in Europe. Clearance by FDA makes the new endoscope available for colon cancer screening in the United States.

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The ASCO Post | MARCH 15, 2012

PAGE 40

FDA Update

ODAC Votes against Denosumab to Delay Bone Metastasis in Men with Castration-resistant Prostate Cancer

he FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 that the risk-benefit ratio was insufficient for an expanded use of denosumab (Xgeva) to delay the spread

of prostate cancer to the bone in men with castration-resistant disease. The panel was not asked specifically whether it recommended approval for this expanded indication. The FDA

will make a final decision by April 26, 2012. According to the panel, the drug’s benefits were outweighed by the possibility of increased toxicity, particularly

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

osteonecrosis of the jaw, with longterm use. The patient representative was the only ODAC panelist to vote in favor of approval for the new indication.

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with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) Cosmos Communications 718.482.1800

ASCOPost.com | MARCH 15, 2012

PAGE 41

FDA Update

Ki-67 Image Analysis and Digital Read Applications Cleared

entana Medical Systems, Inc, received 510(k) clearance from the FDA for the Ventana Companion Algorithm Ki-67 (30-9) image analysis application used with the Ventana iScan Coreo Au scanner running Virtuoso software. Ven-

tana is currently the only company offering an FDA-cleared Ki-67 image analysis algorithm for determining Ki-67 expression levels in breast cancer patients. The Ki-67 protein is known to be an excellent marker for cellular prolif-

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

eration. The Ki-67 (30-9) application may assist pathologists in achieving objective and consistent Ki-67 interpretation and can provide quantitative results for images with hundreds or thousands of cells. Ventana also received FDA clear-

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures Cosmos Communications 718.482.1800

ance for the digital read application that allows the pathologist to interpret Ki-67 (30-9) stained slides as images on a computer monitor with the Ventana iScan Coreo Au scanner and Virtuoso software.

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The ASCO Post | MARCH 15, 2012

PAGE 42

FDA Update

First Urine-based Molecular Test to Gauge Need for Repeat Prostate Biopsies

en-Probe announced the FDA has approved its PROGENSA PCA3 (prostate cancer gene 3) assay, the first molecular test to help determine the need for repeat prostate biopsies in men who have had a previous negative biopsy. “Overexpression of the PCA3 gene is

highly specific to cancerous prostate tissue,” said John Wei, MD, MS, Professor of Urology at the University of Michigan Health System. “When evaluated with other risk factors, the PROGENSA PCA3 assay fills an important unmet clinical need by helping physicians identify which

(AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

men suspected of having prostate cancer should undergo a repeat prostate biopsy.” The PROGENSA PCA3 assay is indicated for use in conjunction with other patient information to aid in the decision for repeat biopsy in men 50 years of age or older who have had one or more

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146

previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on the current standard of care, before consideration of PROGENSA PCA3 assay results. A negative PROGENSA PCA3 assay result is associated with a decreased likelihood of a positive biopsy. A prostate biopsy is required to diagnose cancer. FDA approval of the PROGENSA PCA3 assay was based on a clinical study 495 eligible men enrolled at 14 clinical sites that began in August 2009 and concluded in May 2010. In the study, the PROGENSA PCA3 had a negative predictive value of 90%. The study only included men who were recommended for repeat biopsy. Therefore, the performance of the assay has not been established in men for whom a repeat biopsy was not already recommended. The PROGENSA PCA3 assay should not be used for men with atypical small acinar proliferation on their most recent biopsy.

■

FDA Drug Approvals, January–March 2012 ■■ Imatinib mesylate tablets

(Gleevec) approved for the adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive gastrointestinal stromal tumors (GIST). Accelerated approval for this indication was granted in December 2008.

■■ Vismodegib (Erivedge)

capsules approved for the treatment of metastatic basal cell carcinoma or locally advanced basal cell carcinoma in patients whose disease has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.003/PPI.003 09/11

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

■■ Axitinib tablets (Inlyta) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

■■ Glucarpidase injection

(Voraxaze) for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired SEE PAGE 72 renal function.

For more information, visit fda.gov.

Cosmos Communications 718.482.1800

ASCOPost.com | MARCH 15, 2012

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Hematology for the Oncologist

How I Work up the Patient with Thrombocytosis By Ayalew Tefferi, MD

hrombocytosis is defined as a platelet count greater than 400 × 109/L. In routine clinical practice, thrombocytosis is much more likely to be reactive (> 80% of cases) than primary. Reactive thrombocytosis is usually associated with infections, inflammation, trauma, hemolysis, metastatic cancer, the postsplenectomy state, or iron deficiency anemia. Causes of primary thrombocytosis include myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic syndrome/ myeloproliferative neoplasm overlap syndromes, and other myeloid malignancies. Congenital thrombocytosis is extremely rare and sometimes associated with germline mutations of thrombopoietin or its receptor (MPL). In managing the patient with thrombocytosis, one must first distinguish reactive from primary thrombocytosis. The presence of acute or subacute infection, a connective tissue disorder, vasculitis, hemolysis, active bleeding, recent surgery, history of splenectomy, or iron deficiency anemia favors the diagnosis of reactive thrombocytosis. The presence of chronic thrombocytosis, thrombohemorrhagic complications, microvascular symptoms, or splenomegaly favors the diagnosis of primary thrombo-

Hematology for the Oncologist

ematology for the Oncologist is guest edited by Ayalew Tefferi, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. The series is intended to provide guidance in managing hematologic issues that may present in your patients with cancer.

Ayalew Tefferi, MD

cytosis. However, clinical impression often requires confirmation through laboratory testing, which is also necessary to distinguish among the different causes of primary thrombocytosis (including essential thrombocythemia) (see diagnostic workup in Fig. 1). Below, I provide a stepwise approach to the laboratory evaluation of thrombocytosis.

Step 1: Review the complete blood count and order blood smear examination Complete blood count or blood smear clues for reactive thrombocytosis include presence of microcytic anemia (iron deficiency) or Howell-Jolly bodies (postsplenectomy state), which suggest thrombocytosis associated with surgical or functional hyposplenism. An increase in hematocrit or leukocyte count suggests myeloproliferative neoplasms, whereas presence of macrocytosis or leukoerythroblastic blood smear, or abnormal platelet morphology is consistent with clonal thrombocytosis. Microcytosis suggests iron deficiency anemia.

Step 2: Check serum ferritin and C-reactive protein The initial laboratory tests should include the measurement of serum ferritin concentration. A normal serum ferritin level excludes the possibility of iron deficiency anemia–associated reactive thrombocytosis. However, a low level does not exclude the possibility of clonal thrombocytosis. Increased C-reactive protein suggests but does not secure a diagnosis of reactive thrombocytosis associated with an occult inflammatory or malignant process.

Step 3: Screen for JAK2V617F JAK2V617F mutation screening is now part of the diagnostic workup for thrombocytosis, according to the World Health Organization (WHO) diagnostic criteria for essential thrombocythemia and polycythemia vera. However, peripheral blood mutation screening for JAK2V617F cannot substitute for bone marrow examination, since the mutation is not always detected in patients with essential thrombocythemia, where mutational frequency is estimated at 60%.

Bone marrow biopsy, cytogenetic studies, FISH for BCR-ABL1, and mutation screening for JAK2V617F BCR-ABL1-positive

JAK2V617F-positive

Chronic myelogenous leukemia

Use bone marrow morphology to distinguish essential thrombocythemia from other myeloid malignancy

Yes

Either other cytogenetic abnormalities present or histology consistent with myeloproliferative neoplasm

Use bone marrow morphology to distinguish essential thrombocythemia from other myeloid malignancy

Essential thrombocythemia unlikely

Fig. 1: A diagnostic algorithm for primary thrombocytosis.

Step 4: Bone marrow examination Bone marrow morphology appears normal in reactive thrombocytosis. In clonal thrombocythemia, bone marrow findings include increased numbers of megakaryocytes and other myeloid cells, abnormality in cell morphology, presence of megakaryocyte clusters, and reticulin fibrosis. In addition to morphologic analysis, bone marrow examination allows the performance of cytogenetic studies and special immunohistochemical stains. For example, the detection of a clonal cytogenetic abnormality is diagnostic of primary thrombocytosis. However, although some causes of primary thrombocytosis are always associated with an abnormal cytogenetic lesion (for example, chronic myelogenous leukemia [CML]), less than 5% of patients with essential thrombocythemia have detectable cytogenetic abnormalities. Essential thrombocythemia is currently defined as a persistent thrombocythemic state (platelet count ≥ 450 × 109/L) that is neither reactive nor associated with an otherwise defined myeloid malignancy (including polycythemia vera), primary myelofibrosis (including prefibrotic primary myelofibrosis), CML, and myelodysplastic syndromes. In this regard, it should be noted that CML, myelodysplastic syndromes, and prefibrotic primary myelofibrosis can all mimic essential thrombocythemia in their presentation. Therefore, before making a working

diagnosis of essential thrombocythemia, in the context of primary thrombocytosis, one must exclude CML not only by conventional cytogenetics but also by a fluorescence in situ hybridization (FISH) test for BCR/ABL1. Similarly, bone marrow histology should be carefully scrutinized for the presence of both trilineage dysplasia—which would suggest myelodysplastic syndromes—and intense marrow cellularity accompanied by atypical megakaryocytic hyperplasia—which would suggest prefibrotic primary myelofibrosis. Unlike essential thrombocythemia, prefibrotic primary myelofibrosis is often accompanied by elevated levels of serum lactate dehydrogenase level, increased peripheral blood CD34 cell count, and a leukoerythroblastic peripheral blood smear. The clinical relevance of distinguishing essential thrombocythemia from prefibrotic primary myelofibrosis has reently been demonstrated, where the latter was shown to be associated with significantly worse overall and leukemia-free survival.

Molecular Pathogenesis The first evidence of monoclonality in essential thrombocythemia was suggested in the early 1980s by clonality studies that utilized glucose-6-phosphate dehydrogenase (G6PD) isoenzyme analysis. These early observations were subsequently confirmed by X-linked DNA analysis. Unlike the situation for CML, the primary molecular abnormalcontinued on page 44

The ASCO Post | MARCH 15, 2012

PAGE 44

Hematology for the Oncologist Thoracic Oncology

Managing Thrombocytosis continued from page 43

ity in essential thrombocythemia has not been identified. In this regard, cytogenetic studies have been of limited value, because they are conducted in less than 5% of patients at diagnosis and are nonspecific. Both structural and numerical abnormalities involving many individual chromosomes (including trisomies 9 and 8, and long-arm deletions of chromosomes 5, 7, 13, 17, and 20) have been associated with essential thrombocythemia.

Summary The first step in approaching a patient with thrombocytosis is to entertain the possibility of reactive thrombocytosis, a process that has already been elaborated in a previous section. It is worth reiterating the value of mutation screening for JAK2V617F in distinguishing essential thrombocythemia from reactive thrombocytosis but not from other myeloproliferative neoplasms. In addition, rare cases of genetically defined essential thrombocythemia (eg, activating mutation of

Ayalew Tefferi, MD: How I Work up the Patient with Thrombocytosis ■■ Step 1: Review the complete

blood count and order blood smear examination.

■■ Step 2: Check serum ferritin and C-reactive protein.

■■ Step 3: Screen for JAK2V617F. ■■ Step 4: Perform bone marrow examination.

MPL) have been described and must be kept in mind while evaluating a patient with either a lifelong or family history of thrombocytosis. The second step in evaluating a patient with thrombocytosis is to confirm the diagnosis of essential thrombocythemia with a bone marrow examination and exclude the possibility of other myeloid disorders, including prefibrotic primary myelofibrosis. Although detailed analysis of megakaryocyte morphology might assist in distinguishing CML (dwarf megakaryocytes and not too many clusters) from essential thrombocythemia (giant megakaryocytes with cluster formation), cytogenetic studies or FISH for BCR/ABL1 should accompany bone marrow examination to rule out the possibility of CML. Mild reticulin fibrosis (grades 1 or 2) is detected in approximately 14% of patients with essential thrombocythemia at diagnosis and does not portend an unusual outcome. Clonal cytogenetic lesions in essential thrombocythemia are detected in < 5% of cases and are nonspecific.

■

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

Suggested Readings Barbui T, Thiele J, Passamonti F, et al: Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: An international study. J Clin Oncol 29:3179-3184, 2011. Tefferi A: Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 87:284-293, 2012.

Researchers Map Potential Genetic Origins, Pathways of Lung Cancer in Never-smokers

indings from a small study on potential gene mutations and pathway alterations that could lead to lung cancer in never-smokers were presented in a poster at the American Association for Cancer Research–International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held recently in San Diego, California. Timothy G. Whitsett, PhD, Senior Postdoctoral Fellow in the Cancer and Cell Biology Division at the Translational Genomics Research Institute (TGen), was lead author.1 Never-smokers account for 10% of lung cancer cases. “This is a very important subset of patients with lung cancer, and our research looks to identify pathways and genes that are potentially driving this form of cancer,” Dr. Whitsett said.

Study Details Dr. Whitsett and his colleagues looked at three female patients with adenocarcinoma: one never-smoker with early-stage disease, one never-smoker with late-stage disease, and, as a comparison, one smoker with early-stage disease. The team performed whole genome sequencing and whole transcriptome sequencing on each patient to identify gene mutations and pathway alterations that could have led to the development and progression of their specific lung cancers. “In the never-smoker with early-stage cancer, there were very few mutations in the genome, but when we looked at the whole transcriptome, we saw differences in gene expression,” Dr. Whitsett said.

In the never-smoker with late-stage disease, the researchers found mutations in “classic tumor-suppressor genes,” Dr. Whitsett said. He and his colleagues hypothesized that mutations of the tumorsuppressor genes might be a factor in late-stage lung cancer in never-smokers.

Genetic Profiles Whitsett and his colleagues reported that these never-smokers’ tumors lacked alterations in common genes associated with lung cancer such as EGFR, KRAS, and EML/ALK translocations. This finding makes these patients ideal cases for the discovery of new mutations that may drive lung adenocarcinomas in never-smokers, according to the researchers. Using whole genome sequencing and whole transcriptome sequencing to identify cancer origins “has become a way to really dive down into an individual tumor to try to understand the pathways that may be driving that tumor and identify what therapeutic interventions may be possible,” Dr. Whitsett said The researchers are now validating these findings in about 30 never-smokers with lung adenocarcinoma and about 60 clinically matched smokers with lung adenocarcinoma.

■

Reference 1. Whitsett TG, Sinari S, Sheff S, et al: Identification of key tumorigenic pathways in never-smoker lung adenocarcinoma patients using massively parallel DNA and RNA sequencing. AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer. Poster A43. Presented January 9, 2012.

Coming in Future Issues of The ASCO Post Important Oncology News from:

Plus:

■■ National Comprehensive Cancer Network 17th Annual Conference

■■ Original Columns and Perspectives from Oncology Leaders

■■ 2012 Gastrointestinal Cancers Symposium

■■ Conversations with Experts About Important Issues in Cancer Care

■■ 2012 Genitourinary Cancers Symposium ■■ American Association for Cancer Research 103rd Annual Meeting

■■ Special Features on Pain Management, Axillary Surgery, Cognitive Dysfunction, and more

Visit The ASCO Post online at ASCOPost.com.

CURRENTLY ENROLLING for METASTATIC PANCREATIC CANCER

A Randomized Phase III Study of Weekly ABI-007 Plus Gemcitabine Versus Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas Primary Objective To evaluate the efficacy of the combination of ABI-007 and gemcitabine versus gemcitabine alone in improving overall survival in patients with metastatic adenocarcinoma of the pancreas Key Eligibility Criteria* • Confirmed, measurable metastatic pancreatic adenocarcinoma diagnosed 6 weeks prior to randomization • ≥1 metastatic tumor measurable by CT scan • No prior therapy for treatment of metastatic disease • Karnofsky performance status ≥70 • No brain metastases • No prior malignancy in last 5 years

Albumin-bound Paclitaxel + Gemcitabine Arm† • Albumin-bound paclitaxel 125 mg/m2 IV weekly x 3 • Gemcitabine 1000 mg/m2 IV weekly x 3 • 28-day cycles N=842 Randomization (1:1) Gemcitabine Arm† • Cycle 1 (56-day cycle): Gemcitabine 1000 mg/m2 IV weekly x 7 • Cycles 2+ (28-day cycles): Gemcitabine 1000 mg/m2 IV weekly x 3

* Additional criteria apply. †

Patients continue treatment until disease progression or unacceptable toxicity, palliative radiotherapy to a target lesion is required, consent is withdrawn, or physician’s choice. End-of-study assessments will be performed for all patients who are removed from study.

Visit www.thempactstudy.com to learn more. Investigational use of paclitaxel protein-bound particles for injectable suspension (albumin-bound).

For more information, please contact Study Manager Tammy Davis at tadavis@celgene.com or call 910-791-2301.

The ASCO Post | MARCH 15, 2012

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News Hematology

Maintenance with Lenalidomide or Bortezomib Prolongs Remission in Elderly Patients with Multiple Myeloma By Caroline Helwick

he benefit of maintenance therapy in newly diagnosed multiple myeloma patients ineligible for stem cell transplant, such as the elderly, is still debated, though value appears to be emerging, according to studies presented at the 2011 American Society of Hematology (ASH) Annual Meeting. Maintenance therapy with either lenalidomide (Revlimid) or bortezomib (Velcade) delayed progression in clinical trials. An overall survival advantage was not yet evident, but in the bortezomib trial, median overall survival has not been reached in one arm.

Antonio Palumbo, MD

MM-015 Trial Italian investigators evaluated lenalidomide in 459 elderly, transplant-ineligible patients, with a median age of 71 years. The final results of the phase III MM-015 trial were presented by Antonio Palumbo, MD, of the University of Turin, Italy.1 “What is really changing in the

treatment paradigm is the concept of continuing treatment, moving from a fixed treatment to one incorporating continuous therapy,” Dr. Palumbo said. “Continuous treatment adds about 10 months of remission duration in elderly patients, and while no survival advantage has been shown, 3-year overall survival projected at 70% is certainly a good outcome.” MM-015 tested three treatment regimens. Two groups received induction therapy consisting of melphalan, prednisone, and lenalidomide (MPR). Half this group (n = 152) was placed on maintenance therapy with lenalidomide (MPR-R) given on days 1 to 21 every 28 days until progression, while the other half (n = 153) received no continuous therapy (MPR). A third group (n = 154) received only melphalan and prednisone as induction therapy and no maintenance (MP). The three-drug combination led to significantly more responses, “so MPR is better than MP when toxicity is not a problem…. But maintenance therapy provides the major difference,” Dr. Palumbo said. “You get a doubling in progression-free survival when you use continuous treatment,” he noted. Lenalidomide maintenance significantly extended progressionfree survival, from 14 months with MPR and 13 months with MP to 31

EXPERT POINT OF VIEW

avid S. Siegel, MD, PhD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, commented to The ASCO Post that essentially all patients with multiple myeloma could be candidates for maintenance therapy. “But I don’t know that we have established that maintenance therapy is unequivocably the right way to go,” he said. “These trials are not necessarily designed to David S. Siegel, MD, PhD answer that question in an absolute sense,” he noted. “It’s hard to do a trial that has a real survival endpoint,” which is what needs to be determined in order to understand the true benefit of continuing therapy, he said. Dr. Siegel does not use maintenance therapy in patients posttransplant, but he does continue patients on drug therapy indefinitely outside the context of transplant, he explained.

■

Disclosure: Dr. Siegel has been an advisor for Celgene and Millennium.

Maintenance Therapy in Patients with Multiple Myeloma ■■ In elderly patients not undergoing stem cell transplant, maintenance

therapy with lenalidomide or bortezomib prolongs remission, but has not yet been shown to increase survival.

■■ In the MM-015 trial, progression-free survival was doubled with

continuous treatment of lenalidomide after induction: 31 vs 14 months. Overall 4-year survival rates, however, were about 60% regardless of maintenance, and an increase in secondary cancers was observed among lenalidomide recipients.

■■ In the GEM2005MAS65 trial, maintenance therapy with bortezomib

increased complete response rates, from 24% after induction to 42%. Median progression-free survival was slightly higher in the bortezomib/ thalidomide arm than the bortezomib/prednisone arm, and overall survival at 5 years was 69% with this regimen.

months with MPR-R. The landmark analysis of all patients showed that lenalidomide maintenance resulted in a 66% reduction in progression (P < .001). “The advantage of maintenance was present in all patients, independent of age, grade, prognosis and so forth,” he noted. At 41 months median follow-up, however, no impact had been seen on overall survival. At 4 years, overall survival rates were 59% for MPR-R, 58% for MPR, and 58% for MP. These rates are significantly better than the typical 3-year average survival time, he noted, pointing out that a trend toward a survival benefit was observed in the 65- to 75-year-old age group. The major toxicity was neutropenia (grade 4 in 30% of patients). Grade 4 thrombocytopenia occurred in 5% of patients. “But as far as maintenance is concerned, thrombocytopenia and neutropenia rates were very rare,” he said. “Even in the frail elderly, toxicity is acceptable.”

Increase in Secondary Cancers Observed The downside of lenalidomide therapy in the study was the increased incidence of secondary cancers, though still rare. There were 12 cases of cancer among patients receiving maintenance lenalidomide, and 10 among patients receiving lenalidomide alone in the induction regimen, compared with 4 among patients who received only melphalan and prednisone. This amounted to incidence rates per 100 patient-

years of 3.04 with MPR-R, 2.57 with MPR, and 0.98 with MP. But Dr. Palumbo argued that this slight risk (about 5%) was far outweighed by lenalidomide’s benefit in delaying progression (about 75%), an opinion seconded by many specialists at the meeting.

Bortezomib-based Maintenance Strategy Bortezomib-based maintenance regimens may also optimize myeloma treatment in this group of patients, according to Maria-Victoria Mateos, MD, of the University Hospital of Salamanca, Spain. In the GEM2005MAS65 trial, conducted by the Spanish Myeloma Group, 260 elderly patients (median age 71) received induction therapy with bortezomib, melphalan, and prednisone (VMP) or bortezomib, thalidomide (Thalomid), and prednisone (VTP), after which 178 received one of two possible maintenance regimens: bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP).2 Maintenance therapy was bortezomib at 1.3 mg/m2 administered on days 1, 4, 8, and 11 every 3 months plus thalidomide at 50 mg/d (VT) or prednisone at 50 mg (VP) every 2 days up to 3 years. The study did not evaluate outcomes in patients who did not receive maintenance. Response rates were about 80% with either regimen. The current study determined whether maintenance therapy would upgrade these responscontinued on page 48

NOW APPROVED!

For more information, visit www.Erivedge.com

Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS Erivedge (vismodegib) capsule can result in embryo-fetal death or severe birth defects. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of Erivedge exposure through semen.

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555 Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on the following page.

The ASCO Post | MARCH 15, 2012

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News

Maintenance Therapy in Elderly Myeloma Patients continued from page 46

es and confer a benefit in terms of progression-free and overall survival. “Toxicity was very low with maintenance,” Dr. Mateos noted. VT was associated with more peripheral neuropathy (9% vs 3%), but in all but

one patient this was worsening—not emergent—neuropathy. Maintenance therapy greatly increased the number of complete responses. For the whole population, after a median of 20 months of maintenance, complete responses increased from 24% after induction to 42%. After induction, complete response rates

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

were similar between VMP and VTP, but slightly more additional complete responses were achieved with VT maintenance (46% vs 39%), Dr. Mateos reported. At 46 months follow-up, median progression-free survival was slightly higher with VT maintenance—39 vs 32 months with VP—and this was

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

not influenced by the induction regimen. Overall survival has not been reached with VT SEE PAGE 72 maintenance, with 69% of patients alive at 5 years and 60% alive after treatment with VP. But for patients with high-risk cytogenetics (20% of the population), neither maintenance regimen could overcome the poor prognosis. Median progression-free survival was 26 months and median overall survival was 50 months, with no differences seen between the regimens.

■

Disclosure: Dr. Palumbo reported receiving honoraria from Celgene. Dr. Mateos reported receiving honoraria from Millennium Pharmaceuticals, Janssen, and Celgene.

References 1. Palumbo A, Adam Z, Kropff M, et al: A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone followed by continuous lenalidomide maintenance in patients ≥ 65 years with newly diagnosed multiple myeloma: Updated results for patients aged 65 to 75 years enrolled in MM-015. 2011 American Society of Hematology Annual Meeting. Abstract 475. Presented December 12, 2011. 2. Mateos M-V, Oriol A, Teruel A-I, et al: Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly myeloma patients included in the GEM2005MAS65 Spanish randomized trial. American Society of Hematology Annual Meeting. Abstract 477. Presented December 12, 2011.

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PAGE 49

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Context May Affect Benefit of Adjuvant Clodronate in Breast Cancer By Susan London

benefit of the oral bisphosphonate clodronate when used as adjuvant therapy for early breast cancer may depend on factors such as the endpoint assessed and patient age, suggests the randomized B-34 trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP).

endpoint, finding no significant gain in disease-free survival with clodronate vs placebo, investigators reported at the San Antonio Breast Cancer Symposium.1 But in the subset of women aged 50 years or older, there were 26% to 39% reductions in the risks of recurrence and metastases with clodronate.

Clodronate in Breast Cancer ■■ In NSABP B-34, the bisphosphonate clodronate produced low rates of toxicity and adverse events.

■■ At a median of 8.4 years, disease-free survival rates were statistically similar among clodronate and placebo recipients.

■■ Among women aged 50 years or older, clodronate conferred a

marginally better recurrence-free interval, and a significantly better bone metastasis–free interval and nonbone metastasis–free interval.

Vicious Cycle?

Alexander H.G. Paterson, MD

The trial, conducted among 3,323 women, failed to meet its primary

These findings add to accumulating evidence that suggests it may be time to modify the vicious-cycle hypothesis of bone metastases, whereby cancer cells and bone cells mutually drive each other in promoting bone resorption, according to lead investigator Alexander H.G. Paterson, MD, who is an investigator with the NSABP in Pittsburgh and a Professor at the University of Calgary in Canada.

In “the new vicious cycle, cancer accelerates osteoclast function and bone destruction—I think we agree on [that],” he said. “However, inhibition of osteoclast function with bisphosphonates has an effect on cancer growth in older women but little effect in premenopausal women.”

Disparities between Trials The overall B-34 findings differ

from those of another adjuvant clodronate trial, which found a reduced risk of bone metastases.2 The disparity is likely due to differences in endpoints and patients, speculated Dr. Paterson. Several components of disease-free survival—contralateral breast cancers, second primaries, and death from any cause—“may not have a direct relcontinued on page 50

Risk Stratification of BRCA Mutation Carriers May Help Guide Follow-up By Susan London

atient and tumor characteristics can stratify women with breast cancer and a BRCA mutation into groups having different risks of contralateral disease, which may help tailor follow-up, suggests a study of more than 5,000 women in the Netherlands. Confirming findings of other studies, the study found that the cumulative 10-year risk of developing cancer in the other breast was significantly higher for BRCA mutation carriers than for noncarriers, according to results reported at the 2011 San Antonio Breast Cancer Symposium.1 However, age and tumor receptor status had modifying effects, enabling splitting of the carriers into subgroups having very different risks.

Study Background “Studies show that certain subgroups of women [with a BRCA mutation] who have already had cancers are also at risk for developing a second new

cancer in their other breast, much more so than survivors who do not carry the mutation,” said Alexandra J. van den Broek, MSc, a doctoral candidate at the Netherlands Cancer Institute. “Our study is, as far as we know, the first study showing that within certain carriers of BRCA mutations, subgroups with an increased or decreased risk for contralateral breast cancer can be made.”   Researchers surveyed 5,061 women diagnosed with unilateral, invasive breast cancer at 10 hospitals in the Netherlands. A total of 211 women (4.2%) were carriers of the BRCA1 or BRCA2 mutation. Overall, at a median of 8.4 years of follow-up, 8.6% of participants developed contralateral breast cancer.  Ms. Van den Broek and colleagues found that the overall 10-year risk for developing contralateral breast cancer in noncarriers was 6.0%, whereas risk for carriers was 17.9%. For carriers diagnosed with their first

BRCA Mutation and Risk of Contralateral Disease ■■ In a Dutch study of more than 5,000 patients with breast cancer, survivors with a BRCA1 or BRCA2 mutation had a more than 10% greater risk for developing cancer in their other breast.

■■ Age at diagnosis and triple-negative or estrogen receptor status of the first cancer further affected risk.

■■ Guidelines should be amended to consider these factors when counseling women with the mutation.

breast cancer when younger than 40 years, the 10-year risk for contralateral breast cancer jumped to 26.0%. For carriers between the ages of 40 and 50 years at first diagnosis, the risk was 11.6%. In addition, mutation carriers with a triple-negative first tumor had a 10-year cumulative contralateral breast cancer risk of 18.9%, compared with 11.2% among carriers with a non–triple-negative first tumor.

Important for Counseling Although these numbers can be overwhelming to carriers who have already survived breast cancer, Ms. van den Broek said it is crucial to know who is most at risk and by how much. “Guidelines for prophylactic measures and screening in the follow-up of patients with breast cancer carrying the BRCA1 or BRCA2 mutation are important to provide patients with the best information and counseling,” she said. “If these results are confirmed, [it will be] possible to personalize the guidelines for these specific subgroups.” The next step will be to confirm the results in larger studies and to look at other factors that define subgroups of patients with an increased or decreased risk for CBC.

Clinically Useful Information This is “really clinically useful information,” commented Laura J.

Laura J. Esserman, MD

Esserman, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center during the question-and-answer period. “Modeling studies have suggested that BRCA2 carriers, particularly at older ages, don’t benefit very much, certainly not much in terms of survival, from prophylactic mastectomy,” Dr. Esserman noted. Given the study’s results for women aged 40 to 50, “I think this would support that the benefit of prophylactic mastectomy would be quite small” in older BRCA2 mutation carriers.

■

Disclosure: Ms. van den Broek and Dr. Esserman reported no potential conflicts of interest.

Reference 1. van den Broek AJ, Schmidt MK, Tollenaar RAEM, et al: The risk of contralateral breast cancer in BRCA1/2 carriers compared to non-BRCA1/2 carriers in an unselected cohort. San Antonio Breast Cancer Symposium. Abstract S4-2. Presented December 8, 2011.

The ASCO Post | MARCH 15, 2012

PAGE 50

News

Clodronate in Breast Cancer continued from page 49

evance for an agent that has its prime effect on bone,” he explained. Additionally, the B-34 patients had “earlier breast cancer and lower rates of events, and the majority were over the age of 50.” “I’ve stated my concerns all the way through this trial” regarding the choice of primary endpoint and its possible weakening of the ability to assess secondary endpoints, concurred Trevor J. Powles, PhD, of the Royal Marsden Hospital, London, who was lead investigator on the earlier clodronate trial. “Clodronate may be different from zoledronate because we are looking at an agent [for which] we really have no evidence that it does anything but work on bone.”

Trevor J. Powles, PhD

Clinical Impact Session moderator Julie R. Gralow, MD, Director of Breast Oncology at the University of Washington, Seattle, questioned what the new B-34 findings mean for clinical care. “Clodronate is approved in Canada, but it’s not approved in the U.S. Are you going to start using it when you go home?” she asked Dr. Paterson.

“I think we have to start thinking about this,” he replied. “It’s an easy treatment, it’s oral, it seems to have an effect in older women and at low toxicity. We’ve now got four trials showing the same direction. There are differences in the patients, and you are going to get differences in the statistics. But they are all pointing in the same direction—that is, benefit in older patients.” In an interview, Dr. Gralow further noted that data from bisphosphonate trials are gradually sorting out a possible role for these agents in adjuvant therapy, which may ultimately lead to less intensive treatment for some patients. There is “clearly something going on with age, estrogen status, and bone resorption,” she agreed. Additionally, trials such as AZURE3 suggest that bisphosphonates may have less benefit in patients given chemotherapy, possibly because that therapy already prevents many recurrences. “We have to figure out the population [who benefit],” Dr. Gralow commented. “I’d like to back off on giving chemo … if we can figure out who the bisphosphonates really work in—is it a group that doesn’t get chemo? A group that is postmenopausal or has a high bone resorption state?”

Study Details In the B-34 trial, women with early breast cancer, regardless of receipt of chemotherapy and/or tamoxifen, were assigned in balanced fashion to 3 years of treatment with clodronate or placebo. They predominantly were aged 50 years or older (64%),

had node-negative disease (75%), and had tumors with hormone receptors (78%). The time on assigned treatment was significantly shorter in the clodronate group than in the placebo group. Overall, 40% of patients did not complete 3 years of treatment. “The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy,” Dr. Paterson noted. “Compliance might have been better if we had started a little later.” The incidence of grade 3 or higher toxicity was similar with clodronate and placebo (20% and 22%). There was a single case of possible osteonecrosis of the jaw with clodronate.

Julie R. Gralow, MD

nonskeletal metastases with clodronate increased in “stepwise” fashion with age, further pointing to a role for the “estrogen micromilieu,” according to Dr. Paterson.

■

Key Findings

Disclosure: Dr. Gralow receives research support from Amgen, Novartis, and Roche. Dr. Paterson has been a consultant for Amgen and receives clinical trials funding from Amgen. Dr. Powles reported no potential conflicts of interest.

With a median follow-up of 8.4 years, the rate of disease-free survival was statistically indistinguishable between groups. Overall, 17.3% of women in the clodronate group and 18.8% of women in the placebo group had an event. In terms of secondary endpoints, the clodronate group had a significantly longer nonbone metastasis–free interval (HR = 0.74), Dr. Paterson reported. Analyses among predefined subgroups showed no significant improvement in disease-free survival with clodronate. But among women aged 50 years or older at diagnosis, the drug conferred a marginally better recurrence-free interval (HR = 0.76) and a significantly better bone metastasis–free interval (HR = 0.61) and nonbone metastasis–free interval (HR = 0.63). In post hoc analyses, relative reductions in risks of skeletal metastases and

References 1. Paterson AHG, Anderson SJ, Lembersky BC, et al: NSABP protocol B-34: A clinical trial comparing adSEE PAGE 72 juvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/ortamoxifen or no therapy—final analysis. San Antonio Breast Cancer Symposium. Abstract S2-3. Presented December 7, 2011. 2. Powles T, Paterson A, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8(2):R13, 2006. 3. Coleman RE, Marshall H, Cameron D, et al: AZURE Investigators. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:13961405, 2011.

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ADCETRIS is the ﬁrst approved CD30directed antibody-drug conjugate (ADC)

Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • H L in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • S ystemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

A therapeutic alternative for relapsed patients

73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.1

Contraindication Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.1

Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.1

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS is an ADC designed to target cells expressing CD301

Antibody The antibody, brentuximab, specific for CD301

Cytotoxic agent

Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1

The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1

CD30 is prevalent in both HL and sALCL2 • B inding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • B inding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1

Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials: • 102 patients with HL who relapsed after ASCT1

Neutropenia Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1

• 58 patients with relapsed sALCL1

Tumor lysis syndrome

ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1

Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1

Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3

Progressive multifocal leukoencephalopathy (PML) JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.1

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.

ADCETRIS induced complete and partial remissions in clinical trials1 Efﬁcacy in relapsed patients1

Relapsed HL

Relapsed sALCL

Median treatment duration: 27 weeks

Median treatment duration: 24 weeks

(N = 102)

Duration of response in months

Response, % (95% CI)

Complete remission (CR) Partial remission (PR) Objective response rate (ORR)

(N = 58)

Median (95% CI)

Range

20.5

1.4-21.9+

(23-42)

(12.0-NE*)

3.5

(32-49)

(2.2-4.1)

1.3-18.7

6.7

(65-83)

(4.0-14.8)

Duration of response in months

Response, % (95% CI)

1.3-21.9+

Median (95% CI)

Range

13.2

0.7-15.9+

(44-70)

(10.8-NE*)

2.1

(18-41)

(1.3-5.7)

0.1-15.8+

12.6

(77-95)

(5.7-NE*)

0.1-15.9+

*Not estimable. +Follow-up was ongoing at the time of data submission.

• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 7 2% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4

Adverse reactions occurring in ≥20% of patients regardless of causality1 HL (N = 102)

sALCL (N = 58)

% of patients

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

Neutropenia

Peripheral sensory neuropathy

Fatigue

Nausea

Anemia

Upper respiratory tract infection

Diarrhea

Pyrexia

Rash

Thrombocytopenia

Cough

Vomiting

Adverse Reaction

• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1

Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1 Recommended dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes every 3 weeks1 • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete blood counts should be monitored prior to each dose of ADCETRIS1

Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 – 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 – 3% discontinued due to peripheral motor neuropathy1

Monitor patients for PN and institute dose modiﬁcation accordingly1 New or worsening Grade 2 or 3

old dose until PN improves to Grade 1 or baseline and then H restart at 1.2 mg/kg

Grade 4

Discontinue ADCETRIS

Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)

Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors

Hold dose until resolution to baseline or Grade 2 or lower Consider growth factor support for subsequent cycles Discontinue or reduce dose to 1.2 mg/kg

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent page. Please see full Prescribing Information at ADCETRIS.com. REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504. US/BV/2011/0029b

855.4SEAGEN (855.473.2436) SeaGenSecure.com

ASCOPost.com | MARCH 15, 2012

PAGE 55

Expert’s Corner American Association for Cancer Research

Research Funding Key to Continued Progress in Cancer Care A Conversation with Judy Garber, MD, MPH By Ronald Piana

merican Association for Cancer Research (AACR) President and ASCO member Judy Garber, MD, MPH, recently spoke with The ASCO Post

Project Origins

about the findings of AACR’s landmark Cancer Progress Report,1 In addition, she offered her perspective on the current and future state of cancer research.

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial inﬁltration and/or inﬂammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is conﬁrmed.

Stevens-Johnson syndrome

What was the genesis of the Progress Report? It started as an idea to commemo-

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in speciﬁc populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and ﬁndings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

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

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufﬁcient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufﬁcient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efﬁcacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The inﬂuence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The inﬂuence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and ﬁndings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including signiﬁcantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

General dosing information

Dose modiﬁcation

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150

Judy Garber, MD, MPH

rate the anniversary of the National Cancer Act of 1971, and to summarize the progress over the ensuing decades. Then–AACR President Elizabeth Blackburn, PhD, and a group of people from various sectors of the community began with a think tank of sorts, from which a working group coalesced. An e-mail Q&A, categorizing the most important discoveries and challenges in cancer research and care, was sent to a larger group of AACR members. A series of comments and drafts were circulated, and the working group, along with AACR staff and leadership, hammered all the data into the finished report.

Moving Research Forward The Progress Report cited the need for more and better computational and statistical tools to aggregate and stimulate the data into clinical action. Where are we in regard to filling that need? We already have many of the analytic and statistical tools needed to move research forward. For instance, there are ongoing large-scale genomic analyses and informational projects that require computational biology efforts. Fortunately there are people with these special statistical and computational skills to move state-of-theart research forward; the problem is that there are not enough of them. Every research center in the nation faces the same dilemma—how to find more bright people doing large-set data analyses to turn their talents toward cancer biology. We need to recruit people internationally and from different disciplines such as engineering and aerospace who think in terms of massive data sets and are willing to use those skills to drill down into oncontinued on page 56

The ASCO Post | MARCH 15, 2012

PAGE 56

Expert’s Corner

Judy Garber, MD, MPH continued from page 55

cology data and give us the answers we need.

Behavior-related Cancers The Progress Report notes that more than 50% of all cancer cases are behavior-related. Are we learning how to address that staggering statistic in ways that will substantially decrease preventable cancers? For one thing, as the Progress Report pointed out, the reduction in tobacco use in this nation over the past several decades is a remarkable accomplishment. That said, we still have a long way to go. As a scientific community, we have struggled to find creative methods of prevention that engage people in a way that is meaningful on a long-term basis. Other behaviors remain more difficult to modify. For example, it is a complex challenge to educate the public regarding sustained dietary modifications and even more difficult to address our national epidemic of obesity for many health reasons, of which cancer prevention is only one. We have not really tackled recreational sun exposure and continue to struggle to make occupational and environmental exposures national priorities. For those exposures that individuals can self-regulate, more research is needed to finds ways to maximize behavior modiSEE PAGE 72 fication.

Cancer Resarch in Hard Economic Times The Progress Report’s call for more research funding has an almost desperate tone. Do you think cancer research is in jeopardy? Cutting-edge clinical research

calls for very expensive technology, but we need these technologies to increase the pace of progress. Since the National Cancer Act was signed into law in 1971, we haven’t faced a real cut in cancer research funding. Yes, we’ve had functional cuts—that is, even if the research budget remained flat we have incrementally lost purchasing power due to inflation and increasing operational costs. However, we’re now facing an 11% cut to cancer research funding, and more

Convincing Policymakers How do we meet that need in an era of declining NIH and NCI budgets? To begin with, by being more persuasive. Many leaders from AACR and ASCO participated in last year’s Hill Day—an annual day of meetings with members of Congress and congressional aides to emphasize the importance of increased federal funding for cancer research. What we were told by members of Congress is that we are not marketing the full force of cancer

Our extensive research has brought us to a level of scientific knowledge by which we finally understand the nature of our enemies—the more than 200 diseases that we call “cancer”—and increasingly are finding ways to defeat them. —Judy Garber, MD, MPH

cuts are on the table. That means fewer grants, which translates into slower progress. To put this in perspective, it’s worth noting that NIH allocates approximately 60% of its budget to research, compared with 15% in the private sector. Many people do not understand that the newest and best treatments often originate from basic and translational discoveries that are made when researchers across the investigative spectrum—basic, clinical, and translational—work together. We need the whole team to make progress at the rapid rates our patients need and deserve. We want to offer our patients the most effective and least toxic treatments, and we can actually see these new therapies coming out of the pipeline. Unfortunately, without the necessary funding, that progress is going to slow to a trickle.

research very well. Many people in Congress don’t truly understand what the NCI does; they think all the money stays in Bethesda, not realizing that funding research has a positive impact in their hometowns. Moreover, cancer research funding has a positive economic impact on local economies by bringing in high-value employment opportunities and support industries. Policymakers don’t quite grasp the concept that all the progress we’ve made developing lifesaving treatments being delivered in community practices across the country are the result of 40 years of cancer research. We’ve come to a paradox of sorts, because policymakers don’t want cancer progress to slow down, but they also are reluctant to pay for it during a time of economic challenges. So it’s become part of our job to elucidate the overall benefits of invest-

The ASCO Post Like us on Facebook facebook.com/TheASCOPost

ment in cancer research, not just on Capitol Hill, but also to the general public. After all, cancer affects everyone across the nation.

Bottom Line What is the most important takeaway message from the Progress Report? I’d say it’s the emphasis on how federally funded research for cancer has had a tremendous payoff in lives extended and saved. Our extensive research has brought us to a level of scientific knowledge by which we finally understand the nature of our enemies—the more than 200 diseases that we call “cancer”—and increasingly are finding ways to defeat them. As a result, we are currently at a defining moment in our ability to detect, prevent, manage, and cure cancers. We have evidence that the new, targeted drugs work just as we anticipated they would. And the energy from this progress should be directed at removing cancer as a major health threat. To turn that goal into reality, the AACR respectfully recommends that Congress provide the NIH and NCI with annual budget increases of at least 5% above the biomedical inflation rate. Without investment in research, we risk stalling the exponential progress we have already made.

■

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

Reference 1. American Association for Cancer Research: AACR Cancer Progress Report 2011: Transforming Patient Care through Innovation. Available at www.cancerprogressreport.org. Accessed January 23, 2012. For more on the AACR’s efforts to impress upon Congress the need to increase cancer research funding, see page 58

Now Enrolling

The Medical Division at Lilly Oncology is currently enrolling patients in a phase 3 trial of the VEGF receptor-2 antagonist ramucirumab (IMC-1121B)

REACH*: A Second-line Hepatocellular Carcinoma (HCC) Trial

Randomization

• H CC after progression on or intolerance to first-line sorafenib • C hild-Pugh score of <9 (Child-Pugh A or B [B7 or B8]) • A t least 1 measurable or evaluable viable lesion not previously treated with locoregional therapy

N=~544

Best supportive care + blinded ramucirumab 8 mg/kg IV infusion every 2 weeks

Best supportive care + blinded placebo 8 mg/kg IV infusion every 2 weeks

Treat until progressive disease, intolerable toxicity, noncompliance, withdrawal of consent, or investigator decision

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

• P atient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life

• Immunogenicity of ramucirumab

For further information, please contact ImClone Systems by e-mail at ClinicalTrials@imclone.com or visit www.clinicaltrials.gov (identifier number NCT01140347). Note that, for an investigator to participate, the study must be approved by the investigator’s country competent health authority. Ramucirumab (IMC-1121B) is an investigational new drug. The safety and efficacy of ramucirumab have not been established for the use under investigation. There is no guarantee that ramucirumab will receive regulatory approval and become commercially available for the use under investigation.

* REACH: A Multicenter, Randomized, Double-blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma Following First-line Therapy With Sorafenib

The ASCO Post | MARCH 15, 2012

PAGE 58

News American Association for Cancer Research

AACR Urges Congress to Maintain, Preferably Increase, Cancer Research Funding By Margot J. Fromer

ecember 23, 2011, marked the 40th anniversary of the National Cancer Act. To mark that occasion, on February 2, the American Association for Cancer Research (AACR) held a Congressional briefing, attended by about 100 legislative aides, to remind Congress that the war on cancer is far from over. Significant strides have been made, said Margaret Foti, PhD, MD (hc), CEO of AACR, and the era of personalized medicine promises renewed hope. But the research needed to turn that hope into reality costs

Margaret Foti, MD, PhD

a fortune. Dr. Foti added that 12 million cancer survivors are alive today because of Congress’s strong bipartisan support of cancer research. Two of those supporters, Rep. Brian Bilbray (R-CA) and Rep. Rosa DeLauro (D-CT), spoke briefly to confirm their continued belief in the funding effort. Both have been touched personally by cancer: Rep. Bilbray’s daughter is undergoing treatment for malignant melanoma, and Rep. DeLauro is a long-time survivor of ovarian cancer.

View from the Front Line Judy E. Garber, MD, Director of the Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and AACR President, said, “Nearly every treatment I can offer as a clinician has been discovered in the past 40 years—almost all, at least in part, because of the extraordinary commitment by Congress. We have been able to decrease cancer deaths by 21% in men and 12.4% in women since 1990, and the average 5-year survival rate is 68% for adults and 80% for children.” She said that as a result of the publicly funded Human Genome Project, more than 290 cancer-related genes

have been discovered. “But knowing that these genes exist and contribute to the cause of cancer is not nearly enough. We need to learn how tumor environment regulates cell behavior, and how that environment supports tumor growth. We need to better understand metastasis, one of the thorniest problems in cancer research, and interaction with the immune system.”

Personalized Medicine Is the Future Cancer treatment is moving away from the one-size-fits-all model to more “personalized” medicine, in which the unique molecular components of a patient’s tumor dictate the most efficacious therapy. “We used to think that the organ from which the cancer derived defined treatment, but as a result of technology used to sequence cancer genomes, we now understand that many of the exploitable targets in a cancer are defined by the intrinsic factors that drive that specific tu-

Keith Flaherty, MD

a drug discovered by systematically searching for mutations associated with a particular cancer—like finding a needle in a haystack, he said. Clinical trials compared vemurafenib with the standard of care and confirmed that the drug reduces disease progression by 74% and the risk of death by 63%. It received FDA approval in August 2011. Unfortunately, said Dr. Flaherty, “The average time to disease progression is about 6 months. Our recent findings suggest that ipilumumab (Yervoy) should be combined with

Because of inflation and the increasing costs of research and technology, NIH has essentially lost about 13% of its purchasing power over the past 8 years. This creates dire peril. —Geoffrey M. Wahl, PhD

mor’s development,” said Dr. Garber. The challenge, she said, is to develop new drugs designed specifically to block identified malfunctions. So far, FDA has approved 32 such agents. Keith Flaherty, MD, Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, said that genetic screening has revealed that about half of all melanoma patients carry a mutation of a specific RAF gene, called BRAF. Of these, he continued, almost all (90%) have a mutation known as BRAF V600E, which causes the BRAF protein to continually activate its signaling network, causing cancer. Dr. Flaherty and his colleagues developed vemurafenib (Zelboraf ), which inhibits overactive BRAF V600E, thus blocking its ability to cause cancer. It is the first example of

vemurafenib, but we worry that giving ipilumumab after vemurafenib would not be a good idea.” Since the same mutation found in melanoma patients occurs in other types of cancer (thyroid, ovarian, colorectal, and prostate tumors), other uses for vemurafenib may be found.

Another Dramatic New Treatment Roslyn Milstein Meyer, PhD, Assistant Clinical Professor of Psychiatry, Yale University School of Medicine, was already gravely ill when she was diagnosed with stage IV malignant melanoma at age 56. Her oncologist suggested an NIH trial for adoptive immunotherapy using tumor-infiltrating lymphocytes. “The investigators planned to remove my malignant lymph node and isolate lymphocytes that at-

tacked the tumor. They would then clone these cells into the billions and return them to me,” Dr. Meyer explained. “Unfortunately, they were unable to grow the cells for tumor-infiltrating lymphocyte treatment [this happens to about 40% of patients], but as we were waiting for the cells to grow, I was put on high-dose interleukin-2 [IL-2, Proleukin]. This is a tough treatment with only a 10% to 20% response rate. I was one of the lucky ones, and my tumors began to shrink.” Dr. Meyer hoped this would turn into a cure, but it did not, and over the next 3 years, she “rode a roller coaster of recurrence.” But she persevered because she believed that the longer she lived, the more likely she would be to find a successful treatment. And she did. Three years after diagnosis, Dr. Meyer was the first person to receive a variation of the attempted first tumor-infiltrating lymphocyte treatment. A total of 84.6 billion cells were infused back into her body along with more IL-2. Several months later, all tumors but one had disappeared. That one was excised. “It’s been more than 3 years now, and I continue to have no signs of cancer,” said Dr. Meyer.

Funding as an Investment Geoffrey M. Wahl, PhD, Professor in the Gene Expression Laboratory, Salk Institute, and a Past President of AACR, said that cancer research funding should provide a significant return on the investment: improved health, economic growth, and increased competitiveness. Cancer is this nation’s most expensive illness. According to AACR figures, in 2010, about $264 billion was spent on cancer health-care costs: $103 billion for direct medical costs, $21 billion for lost productivity due to illness, and $140 billion for lost productivity due to premature death. Since 2003, when Congress doubled NIH’s budget, appropriations for NIH and NCI have remained essentially flat. This year, the increase is only $299 million—well below the inflation rate. Because of inflation and the increasing costs of research and technology, NIH has essentially lost

ASCOPost.com | MARCH 15, 2012

PAGE 59

News

about 13% of its purchasing power over the past 8 years. This creates dire peril, said Dr. Wahl. It ought to be increased by at least 5% over the inflation rate. Dr. Wahl also noted the bleak outlook for young cancer researchers. “As grant money and academic opportunities dry up, talented scientists become discouraged and leave the field—or they don’t enter it at all. If we do not maintain a robust workforce, and if cancer research is no longer attractive to young people, we will lose our competitive edge,” he said. “In fact it’s already happening. It used to be that when foreign scientists came to this country for doctoral and postdoc training, they wanted to stay. Now they can’t wait to go back home, where jobs are plentiful and funding is adequate and assured.” According to AACR, investment in NIH research creates jobs and economic growth, as illustrated by the following data: ■■ It is the largest medical research

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com. Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

agency in the country, with projects conducted by 325,000 scientists at more than 3,000 institutions. ■■ The federal investment has had a 150% multiplier effect; that is, it led to creation of 487,900 jobs and generated $68 billion in new economic activity. ■■ The $3.8 billion invested in the Hu-

man Genome Project from 1988 to 2003 had a $796 billion economic impact and generated $244 billion in personal income. It supported 310,000 jobs.

■

Disclosure: Dr. Flaherty has served as a member of advisory boards for Roche/ Genentech. Drs. Garber, Foti, Meyer, and Wahl reported no potential conflicts of interest.

The ASCO Post Watch future issues for important news from key oncology meetings. Visit www. ASCOPost.com

The ASCO Post | MARCH 15, 2012

PAGE 60

News

Some Patients Using Complementary and Alternative Therapies May Be Receiving ‘Parallel’ Rather Than Integrative Care By Charlotte Bath

ost patients with cancer receiving complementary and alternative medicine do so not as part of integrative care, but rather as “parallel care,” according to Lynda Balneaves, RN, PhD, Associate Professor, University of British Columbia, School of Nursing in Vancouver. Dr. Balneaves is lead investigator of a study analyzing data from interviews with patients in Canada and the United States. “For most individuals, true integration is not occurring. Complementary/alternative medicine and conventional care are being provided in parallel systems by health professionals who are not consulting each other,” she reported at the Eighth International Society for Integrative Oncology (SIO) Conference, during a moderated abstracts session entitled Best of SIO. “There has been a real push in this field to get away from using the [complementary and alternative medicine] terminology, and instead go to integrative oncology,” Dr. Balneaves said in a follow-up interview with The ASCO Post. But integrative oncology “is not happening in reality,” she said, “unless you are at a very specialized clinic.”

Widespread Use of Complementary Medicine Dr. Balneaves cited recent data showing that up to 40% of people living with cancer in America and Europe report using some form of complementary medicine, but only 3% to 5% of patients use only alternative medicine and decline conventional therapy. “This suggests that people are using complementary medicine and conventional cancer care together, in

Lynda Balneaves, RN, PhD

what we hope would be an integrative manner,” Dr. Balneaves said. “But is it truly occurring in an integrative manner? Not really, according to information obtained from interviews with 34 patients—23 with breast cancer and 11 with prostate cancer—in Canada and the United States. The patients were interviewed every 2 to 3 months over a 1-year period. The study was a secondary analysis within a larger international study, the PATH study, lead by Marja Verhoef, PhD, from the University of Calgary.

other chronic conditions.” Participants were recruited through cancer clinics and at community settings such as natural health food stores, and through the website of the Complementary Medicine Education and Outcomes (CAMEO) Program of the British Columbia Cancer Agency (www.bccancer.bc.ca/cameo). Gary Deng, MD, PhD

Motivating Factors Patients expressed several different motivating factors for using complementary and alternative therapies. “Many people expressed a belief that

This study is important because it is a qualitative study. Not everything we do in oncology can be subjected to the research methodology of randomized controlled trials. Qualitative studies can reveal special information that is helpful to clinical practice. —Gary Deng, MD, PhD

‘Like an Orchestra’ “This study is important because it is a qualitative study,” noted session moderator Gary Deng, MD, PhD, of Memorial Sloan-Kettering Cancer Center, and President of the Society for Integrative Oncology. “Not everything we do in oncology can be subjected to the research methodology of randomized controlled trials. Qualitative studies can reveal special information that is helpful to clinical practice.” Patients expressed a clear preference, Dr. Balneaves said, “to have complementary and conventional care combined.” She noted that one woman described integrative care as “like an orchestra. Everyone is working together and there is synergy.” Dr. Balneaves further explained, “People were not just drawing from a naive sense of using complementary medicine. These were people who had previous experience of using complementary medicine for overall health or

chemotherapy was equated to poison. As a consequence, they were looking for alternatives that would be more natural and more amenable to their well-being,” Dr. Balneaves said. “There were some clear recommendations by health professionals within the conventional setting to use specific supplements,” mostly from health professionals in the United States, she added. “Social support was huge,” she said. “The majority of people were creating a treatment plan based on what their fellow survivors were using” and what they were hearing about in support groups. Some people said that they felt let down after conventional treatment ended, but used complementary/alternative medicine to fill the void, saying, “I’ve now created a protocol for myself.”

Barriers to Integration One of the chief barriers to integrative care was lack of dialogue among

conventional practitioners, complementary/alternative medicine providers, and patients. “When people tried to negotiate integration of their care, they were blocked by conventional health professionals,” Dr. Balneaves reported. Patients experienced “distress and anxiety” from not being able to have discussions with their conventional providers, Dr. Balneaves added. In some cases, this caused patients to abandon complementary/alternative therapy, even if it was perceived to be working. This lack of dialogue can also impair the patient-provider relationship, she said. “My sense from the data is that patients are saying, ‘It’s my responsibility and I have to live with my decision,’ but they really would like to get the conventional provider’s perspective,” Dr. Balneaves commented. “They’d like to ask, ‘What do you know about this? Is it safe? Do you have any data about it? Will it work?’ And they are not even getting to that point of a dialogue.” Cost can also be a barrier. There are integrative care clinics, she said, “but you can only go there if you can afford it. That’s not integration either.” Dr. Balneaves’ abstract concludes, “Until these barriers are addressed through professional processes of communication, education, and health policy, integrative oncology will remain a concept ‘just on paper’ and not a reality within cancer care settings.”

■

Disclosure: Drs. Balneaves and Deng reported no potential conflicts of interest.

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

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

DECODE

metastatic melanoma

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

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

EXTEND

survival

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

P<0.0001

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

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

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

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

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

zelboraf.com

The ASCO Post | MARCH 15, 2012

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News Hematology

ASH 2011 Presentations Include Novel Agents and New Strategies in Leukemia, Lymphoma, and Myeloma By Alice Goodman

ttendees at the 53rd Annual Meeting of the American Society of Hematology (ASH), held recently in in San Diego, were able to

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

coverage from the meeting, many other presentations merit attention, including the following noteworthy reports.

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

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

A novel inhibitor of B-cell receptor signaling achieved high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia (CLL) who were refractory to at least two previous treatments, according to updated results of a phase Ib/II study presented by Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston.1 This agent, PCI-32765, represents the first in class of Bruton’s tyrosine kinase (Btk) inhibitors.

Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

Novel Target for B-cell CLL

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

Susan O’Brien, MD

“Given the increased efficacy over time seen with this agent, its lack of toxicity, and its lack of myelosuppression, these drugs promise to change the paradigm for the treatment of CLL,” Dr. O’Brien said at a press conference. Phase III trials are planned. Btk is a protein essential for CLL cell survival and proliferation that mediates B-cell receptor signaling involved in normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B cells. An earlier analysis of the multicenter phase Ib/II study showed good activity and tolerability in SEE PAGE 72 61 patients with relapsed/refractory CLL after at least two prior therapies. At the ASH meeting, Dr. O’Brien presented longer-term follow-up of the study, with a median follow-up of 10.2 months for patients receiving a 420-mg daily dose of PCI32765 and 6.5 months for those given an 840-mg daily dose. Objective response rates in the 420mg cohort increased from 48% after 6 months of follow-up to 67% at 10 months; objective response rate in the 840-mg cohort was 68% at 6.5 months Safety:10"

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

choose from a wide range of interesting and important sessions exploring hematologicSafety:7" malignancies. In addition to The ASCO Post’s regular news

ASCOPost.com | MARCH 15, 2012

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News

median follow-up. Nodal partial response was seen in 23% of patients (> 50% reduction in aggregate lymph node size), with residual lymphocytosis. Objective response rate appeared to be independent of molecular risk features. The treatment is well tolerated. Two patients discontinued PCI-32765 because of adverse events, and six patients had dose reductions. Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis were the most frequently reported side effects. Only 5% (3/61) have had disease progression on PCI-32765; 6-month progression-free survival was 92% in the 420-mg cohort and 90% in the 840-mg cohort.

Continuous Lenalidomide in Transplant-ineligible Myeloma Continuous lenalidomide (Revlimid) in combination with melphalan and prednisone (MPR-R) improved progression-free survival with a trend toward improved overall survival compared with MPR alone (melphalan, prednisone, lenalidomide induction without subsequent lenalidomide) in an interim analysis of a randomized, double-blind, phase III study (MM015) of patients with newly diagnosed, transplant-ineligible multiple myeloma.2 Lenalidomide is not approved for this indication. The study randomly assigned 459 patients to MPR-R, MPR followed by placebo, or MP plus placebo followed by placebo. In patients aged 65 to 75 years, median progression-free survival for MPR-R was 31 months, compared with 12 months in the MP arm (P < .0001), representing a 70% reduction in risk of progression for continuous lenalidomide vs MP in this setting. Induction with MPR alone achieved a progression-free survival benefit of 15 months vs 12 months for MP (P = .006). A trend toward improved overall survival was observed for MPR-R vs MP; 4-year overall survival was 69% for MPR-R vs 58% with MP. Safety with maintenance lenalidomide was acceptable, with no evidence of cumulative toxicity. Rates of secondary primary malignancies related to treatment were 4% with MPR-R, 2.6% with MPR, and 1% with MP. “These rates [of secondary primary malignancies] are below the expected rates in myeloma,” said lead author Antonio Palumbo, MD,

Chief of the Myeloma Unit, University of Torino, Torino, Italy.

Quizartinib: New FLT3 Inhibitor Updated interim results of a phase II open-label monotherapy efficacy study of quizartinib (AC220), a new FLT3 inhibitor, suggest that this drug can achieve clinically meaningful responses in patients with both refractory and relapsed FLT3/ITD-positive acute myeloid leukemia.3 In an exploratory analysis, many patients who were treated with this agent were able to go on to hematopoietic stem cell transplant (HSCT). The analysis included 62 patients treated with quizartinib once daily in continuous 28-day cycles until relapse, drug intolerance, or elective HSCT. Cohort 1 consisted of 26 patients aged 60 or older relapsed/refractory to first-line chemotherapy; cohort 2 comprised 36 patients aged 18 or older relapsed/refractory to second-line

Antonio Palumbo, MD

chemotherapy or HSCT. Overall composite complete remission (including those with incomplete platelet or absolute neutrophil count recovery) rate was 46% in cohort 1 and 36% in cohort 2. Partial remission rates were 15% and 22%, respectively. Overall survival was longest in patients who achieved composite complete remission (median of 34.1 weeks). “These encouraging efficacy results and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib in mono- and combination therapy,” said lead author Jorge Cortes, MD, MD Anderson Cancer Center, Houston. This study was singled out by Martin Tallman, MD, Chief of the leukemia service at Memorial SloanKettering Cancer Center in New York, as important in acute myleoid leukemia. “Quizartinib is the newest FLT3 inhibitor to be introduced for acute myeloid leukemia. It is one of the first

Research Highlights from ASH ■■ A first-in-class Bruton’s tyrosine kinase inhibitor showed impressive activity and no myelotoxicity in patients with chronic lymphocytic leukemia refractory to other treatments.

■■ Continuous lenalidomide maintenance therapy following treatment with MPR (melphalan, prednisone, and lenalidomide) improved survival in patients with newly diagnosed transplant-ineligible multiple myeloma compared with MPR and MP without lenalidomide maintenance.

■■ Early studies suggest that quizartinib (AC220) could be the first FLT3 inhibitor to achieve meaningful clinical responses in acute myeloid leukemia.

■■ New agents are urgently needed to improve depth of response and make more patients with peripheral T-cell lymphoma eligible for potentially curative transplantation.

ones to induce complete response as a single agent,” he stated.

Poor Outcomes for Peripheral T-cell Lymphomas For the majority of patients with relapsed/refractory peripheral T-cell lymphomas (PTCL), outcomes are poor with systemic chemotherapy, characterized by brief remissions at

Jorge Cortes, MD

Martin Tallman, MD

best. A population-based study at the British Columbia Cancer Agency evaluated the spectrum of survival of patients with in relapsed and refractory PTCL in an effort to have a historical comparison to gauge the effectiveness of emerging novel therapies. With a median follow-up of surviving patients of 4 years, the researchers demonstrated that the majority of patients have a very short overall survival of 5.7 months and in many instances are too ill to receive any further therapy. No surprisingly, those patients that ultimately receive high-dose chemotherapy and transplantation have an improved outcome.4 In a multivariate analysis, familiar International Prognostic Index (IPI) factors such as elevated lactate dehydrogenase, poor performance status (> 2), and the number of extranodal sites > 2 were identified as prognostic factors for poor survival. A separate

evaluation of patients with long-term survival (> 2 years) in the absence of transplant demonstrated that these individuals were more likely to have had a late relapse, skin-only relapse, good performance status (0 or 1), and a low IPI score (0 to 2).

■

Disclosure: Dr. Cortes receives research support from Ambit. Dr. Palumbo has received honoraria from Celgene. Dr. O’Brien receives research support from and is a consultant to Pharmacyclics.

References 1. O’Brien S, Burger JA, Blum KA, et al: The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Follow-up of a phase Ib/II study. 53rd Annual Meeting of the American Society of Hematology. Abstract 983. Presented December 13, 2011. 2. Palumbo A, Adam Z, Kropff M, et al: A phase 3 study evaluating the efficacy and safety of lenalidomide (Len) combined with melphalan and prednisone followed by continuous lenalidomide maintenance (MPR-R) in patients (pts) ≥ 65 years (yrs) with newly diagnosed multiple myeloma (NDMM): Updated results for pts aged 65-75 yrs enrolled in MM-015. 53rd Annual Meeting of the American Society of Hematology. Abstract 475. Presented December 12, 2011. 3. Cortes J, Pearl AE, Smith CC, et al: A phase II open-label, AC220 monotherapy efficacy study in patients with refractory/ relapsed FLT3-ITD positive acute myeloid leukemia: updated interim results. 53rd Annual Meeting of the American Society of Hematology. Abstract 2576. Presented December 11, 2011. 4. Mak V, Connors JM, Klasa R, et al: Survival of peripheral T-cell lymphomas patients following relapse: Spectrum of disease and rare long-term survivors. 53rd Annual Meeting of the American Society of Hematology. Abstract 96. Presented December 11, 2011.

The ASCO Post | MARCH 15, 2012

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Calendar

2012 Oncology Meetings MARCH Hematology/Oncology Pharmacy Association 8th Annual Meeting March 21-24 • Orlando, Florida For more information: www.hoparx.org 65th Society of Surgical Oncology Annual Meeting March 21-24 • Orlando, Florida For more information: www.surgonc.org Society of Interventional Radiology 37th Annual Meeting March 24-29.San Francisco, California For more information: www.sirmeeting.org

3rd European Lung Cancer Conference April 18-21 • Geneva, Switzerland For more information: www.esmo.org

ONS 37th Annual Congress May 3-6 • New Orleans, Louisiana For more information: www.ons.org

Diagnosis and Treatment of Advanced Forms of Prostate Cancer, Bladder Cancer and Kidney Cancer April 20-21 • Kiev, Ukraine For more information: http://nbscience.com

State of the Art Techniques in IMRT, IGRT, SBRT, Proton and Brachytherapy May 4-6 • Las Vegas, Nevada For more information: www.astro.org

Organisation for Oncology and Translational Research 8th Annual Conference April 20-21 • Kyoto, Japan For more information: www.ootr-institute.org/

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

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

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

APRIL ASTRO Spring Refresher Course April 13-15 • Chicago, Illinois For more information: www.astro.org 35th National Conference on Breast Cancer April 13-15 • Hollywood, Florida For more information: www.acr.org

3rd International Video Workshop on Radical Surgery in Gynaecological Oncology April 26-28 • Prague, Czech Republic For more information: www.ivw2012.cz 8th European Oncology Nursing Society Spring Convention April 26-27 • Geneva, Switzerland For more information: www.ecco-org.eu American Radium Society Annual Meeting April 28-May 2 • Las Vegas, Nevada For more information: www.americanradiumsociety.org American Roentgen Ray Society Annual Meeting April 29-May 4 • Vancouver, Canada For more information: www.arrs.org

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

AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org Keystone Symposia: The Role of Inflammation during Carcinogenesis May 20-25 • Dublin, Ireland For more information: www.keystonesymposia.org

JUNE ASCO Annual ’12 Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org Cambridge Healthtech Institute’s 10th Annual Meeting: Next-Gen Kinase Inhibitors June 4-6 • Cambridge, Massachusetts For more information: www.healthtech.com ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org Melanocytes and Melanoma: From Basic Science to Clinical Applications June 18-20 • Malmö, Sweden For more information: www.melanoma2012.org

MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

JULY Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma 13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

AUGUST Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org

continued on page 68

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

NEW TREATMENTS ARE URGENTLY NEEDED.

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

Merck Oncology

The ASCO Post | MARCH 15, 2012

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Calendar 2012 Oncology Calendar continued from page 66 10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com UICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec, Canada For more information: www.worldcancercongress.org

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

OCTOBER ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org 14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer 44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org 32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

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

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer

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

NOVEMBER

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

2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

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

Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org

Pan Pacific

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

Lymphoma Conference

Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com 12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

2012

Tuesday-Friday

July 17-20, 2012 Hyatt Regency Maui Resort & Spa Lahaina, Maui, Hawaii

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

Conference Directors James O. Armitage, MD

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

Julie M. Vose, MD, MBA

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

CALL FOR ABSTRACTS: April 16, 2012

IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

Scan code with your smartphone to learn more!

unmc.edu/panpacificlymphoma

ASCOPost.com | MARCH 15, 2012

PAGE 69

In the News

Adolescents and Young Adults with Cancer: A Distinct Population of Patients Who Need to Be Treated Differently By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

ancer among adolescents and young adults has been in the news lately for a number of reasons. These include reports on the CBS Evening News and elsewhere that survival rates have not improved for cancer patients in the 15 to 39 age group and several segments on the PBS NewsHour on cancer in teens. The PBS blog, The Rundown,1 noted that as former Chair of the Children’s Cancer Group, Archie SEE PAGE 72 Bleyer, MD, was “one of the first to sound the alarm that teens were being ‘left behind’ in the research and medical oncology community at a critical time in their lives.” In an interview with The ASCO Post, Dr. Bleyer explained that in 1970s, when the War on Cancer was declared in the United States, survival was poorer among older patients and in children. “So we concentrated on their cancers, and there’s been tremendous progress. But as we concentrated on the youngest of our patients and older adults, we left behind the adolescents and the young adults,” Dr. Bleyer said.

Turning Point “It’s starting to turn around, but it’s still got a long way to go,” he added. Dr. Bleyer is currently Clinical Research Professor at Oregon Health and Science University (OHSU) in Portland and a consultant and Chair of the Institutional Review Board at St. Charles Health System in Bend, Oregon. “A major turning point in the idea of focusing on these patients under 40,” according to Brandon Hayes-Lattin, MD, was the Report of the Adolescent and Young Adult Oncology Progress Review Group, published by the NCI in 2006.2 That report identified several factors limiting progress against cancer in adolescents and young adults (AYA), including restricted access to

care, delayed diagnosis, and inconsistency in treatment and follow-up care. Last year, ASCO launched its Focus Under Forty™ program to address disparities in survival rates and focus on specific challenges of diagnosing and treating adolescents and young adults with cancer. Dr. Hayes-Lattin is a member of the task force that planned the curriculum for Focus Under Forty and Senior Medical Advisor for LIVESTRONG, which helped develop the program. A bone marrow transplant physician, Dr. Hayes is also Medical Director of the Adolescent and Young Adults Oncology Program and Associate Professor, Division of Hematology and Oncology, at the OHSU Knight Cancer Institute.

Creating a Home “What we have seen in the past year are major strides in awareness of the unique cancers and the unique issues that young adults face. The opportunity that is before us now is how to organize and institutionalize that interest and that awareness,” Dr. Hayes-Lattin said. The Teenage Cancer Trust Units in the United Kingdom have given a home for where to act on these issues,” he added. “In the United States, we have made great progress in awareness and now we would really like to step it up and make progress in creating a home for this [adolescent and young adult] work to happen.” The Teenage Cancer Trust operates teen cancer centers in the United Kingdom that have benefited from the promotion and fundraising efforts of Roger Daltrey and Pete Townsend of the rock group, The Who. These efforts were highlighted by the PBS NewsHour, which noted that the Daltrey/Townsend Teen and Young Adult Cancer Program is expanding to the United States, with the first site scheduled to open in California as part of the UCLA Health Systems. “There is great interest in creating these unique young adult spaces,” Dr. Hayes-Lattin said. “We have space within our inpatient cancer ward that is an AYA room,” and includes a Wii gaming device and treadmill. OHSU also has a consult service that reaches out to identify AYA patients with cancer being treated in the pediatric or adult facilities there, and then offers them medical consults and resources specific to adolescents and young adults.

Expect and Ask Questions about Sex and Fertility Preservation

hat most concerns the adolescent and young adult population? “If they are worried about anything, it is sex and having families,” according to Archie Bleyer, MD. Years ago, he said, “oncologists were so worried about just getting them in remission, treating their cancers, and getting them to survive, that the idea of the cured person having a child and being fertile was given a low priority. Now, although we are still struggling with this in terms of getting it applied universally, at least there’s an awareness that Archie Bleyer, MD before you start chemotherapy or radiation that could make that patient infertile,” methods for preserving fertility should be discussed. For males, sperm banking, and for females, embryo cryopreservation “are the available standard-of-care options for fertility preservation,” Brandon Hayes-Lattin, MD, reported. “For women, other methods are increasingly being used—techniques that some groups would still classify as experimental, but that have generated healthy pregnancies. These options include egg cryopreservation and even ovarian tissue cryopreservation.” Dr. Hayes-Lattin was diagnosed with testicular cancer at age 28, when he was a resident. “I was already planning to go into oncology,” said Dr. Hayes-Lattin, who later completed an oncology-hematology fellowship, “but it certainly changed my awareness and perception of not just the medical side, but all the related needs,” such as considering the use of a sperm bank, he said. “Fertility preservation was not something I had really thought much about. I had a young family, and all of a sudden, I had to think about things like life insurance in ways that I had never really paid much attention to before. I became acutely aware of and more interested in these more psychological and practical concerns.”

Create Supportive Environment It is “absolutely fair game” to ask young adults about lifestyle issues, according to Dr. Hayes-Lattin. “The key is to be open and create an atmosphere that encourages young people to talk about topics such as sex, drugs, and alcohol use, how cancer and its treatment are affecting them medically and psychologically, or whatever is potentially a barrier to them getting the best cancer treatment they need.” Physicians “need to know about what the patient is doing to him or herself—or wants to do to him Brandon Hayes-Lattin, MD or herself—and the potential adverse interactions that can make the therapy worse, more toxic, or less effective, or complicate treatment and create other serious outcomes,” Dr. Bleyer said. “Those issues have to be addressed.”

■

“Increasingly, although still sparingly, centers are developing their own adolescent and young adult programs,” Dr. Bleyer said. “There are still too few of them, but there are areas of the country that are well served.”

Different Set of Cancers Adolescents and young adults have a different set of cancers, not necessarily those that have benefited most from re-

search advances (see Fig.1 on page 71). Dr. Bleyer identified the types of cancers mostly likely to affect AYAs as breast, lymphoma, melanoma, sarcoma, thyroid cancer, and gonadal cancer (testicular for males and cervical carcinoma and ovarian stromal cell tumors for females). Specific types of cancers may present differently in adolescents and young adults than they do in younger or older continued on page 71

ASCOPost.com | MARCH 15, 2012

PAGE 71

In the News

Adolescents and Young Adults with Cancer continued from page 69

patients. “The best example in terms of cancer in an older person that affects a young person differently might be breast cancer,” Dr. Hayes-Lattin said. “A young woman with breast cancer is more likely than an older woman to have a breast cancer that does not have hormone receptors, that is estrogen receptor– and progesterone receptor– negative. And that has direct implications. It means that hormonal therapy really doesn’t have a role in treatment and maintenance for those women.”

Delayed Diagnosis Because the cancers are different, the signs and symptoms can be different and overlooked by physicians, who may have a low index of suspicion for cancer in the adolescent and young adult population, or by the young people themselves, who may see themselves as invulnerable to serious disease. Adolescents and young adults may, however, be more vulnerable to peer pressure, Dr. Bleyer noted. “There may be a symptom or a sign of a medical problem that should be addressed, but peer pressure favors an attitude suggesting, ‘Don’t be a wimp. Get over it.’ So they don’t bring their problem for medical attention.” In addition, adolescents may be embarrassed to talk about symptoms that in-

volve sexual organs. Being uninsured “also leads to delayed diagnosis,” Dr. Bleyer noted. “With the Affordable Care Act, 2.5 million more young adults are now on insurance, but we’ve still got a long way to go.”

Social Support Venues “To not be involved with the psychosocial needs of older adolescents and young adults, which are so distinctly different, would make any other efforts almost impossible to achieve,” Dr. Bleyer said. “There is such a need to understand the social, sexual, and personality needs of young adults, that without being really attentive to that, we are not going to make much more progress.” OHSU runs a support group for young adults aged 15 to 39. “That support group is run by our hospital, but we also partner with both local and national organizations that provide support and social interaction,” Dr. Hayes-Lattin explained. These include groups that host social events, kayaking, hiking, and other types of trips. “So we try to come up with a menu of young adult relevant supports—some of them are official social work–facilitated support groups, and some are more young adult social interaction programs.” “An increasing number of support venues have been available on the Internet,” Dr. Bleyer said. “And for this

100%

80%

60%

40%

20%

12%

Other

4% 4% 5%

Brain Tumors Leukemia Colorectal Cancer

Testis Cancer

Thyroid

10%

Female Genital

10%

Sarcoma

Ovary and Uterine Cervix

Bone and Soft Tissue

11%

Melanoma

13%

Lymphoma

15%

Breast

Hodgkin and Non-Hodgkin

0% Fig. 1: Relative incidence of types of cancer in patients aged 15 to 39 years, based on Surveillance Epidemiology and End Results data. Courtesy of Archie Bleyer, MD.

Should ‘AYA’ Be an Oncology Subspecialty?

he lag in improvement in survival rates for adolescents and young adults (AYAs) with cancer and a greater awareness of the unique issues they face has prompted discussion about whether “AYA” should become a new oncology subspecialty.1 “Yes and no,” according to Archie Bleyer, MD. “I am going to say more yes than no, given that evidence suggests there are now programs trying to develop that approach. In fact, there are now fellowships in AYA oncology,” he noted. “I don’t know that it will ever get to the point where it will be a recognized, national discipline. But I do think there will be centers of excellence that will have the AYA oncology discipline, with training programs and graduates who will go on to focus on that age group for their careers,” he said. “I certainly support the idea of specialized training for providers who see a lot of young adults,” Brandon Hayes-Lattin, MD, stated. “I think it is still a dream to think that there would be a subspecialty—that there would be an AYA oncologist. But I think that at least in the short term, we have demonstrated the need for specialized training.”

■

Reference 1. Williams BA: Teen with cancer getting tailor-made care. The Record, January 7, 2012. Available at www.northjersey.com. Accessed February 27, 2012.

age group, that is more helpful than any others.” Groups hosting such websites include the Young Survival Coalition for young women with breast cancer (www.youngsurvival.org), Planet Cancer (www.planetcancer.org), and LIVESTRONG (www.livestrong.org).

Lowest Participation Rate for Clinical Trials “The age group that participates least in clinical trials is between 15 and 40 years old. Less than 2% of those patients are on clinical trials at any time during their cancer experience. That, of course, means more than 98% are never on a clinical trial,” Dr. Bleyer said. “The main problem right now is lack of clinical trials” for the cancers affecting the adolescent and young adult population, he explained. “For the trials we do have, there is still a lower rate of participation than is seen in other age groups. Some of that is because of insurance issues, with patients unable to afford the care at a comprehensive cancer center. Some of it is because of a lack of ability to travel, stay in hotels, or get off from work or school.” Added to that are psychosocial issues related to feeling so different already and “then having to go somewhere else and be almost isolated from their peers.” Oncologists may need to think outside standard age ranges when it comes to referring adolescent and young adult patients to clinical trials, Dr. Hayes-Lattin advised. Pediatric trials may accept patients up to age 30 or 35. In some cases, adult clinical trials have age cutoffs at 18 years old just because

the consent processes are different for under and over 18, Dr. Hayes-Lattin said. “It is a barrier that has existed that hasn’t been challenged enough. Pediatric oncologists consent to younger patients on trials safely and effectively all the time.” This low participation rate in clinical trials has consequences. “First of all, almost everything we’ve learned about treating cancer has come from clinical research and clinical trials,” Dr. Bleyer said. Lack of clinical research among the adolescent and young adult population means “we are not going to be able to learn what we need to do to help them,” he continued. “Second, with clinical trials come the biological specimens to study the problem in the laboratory and to learn more about the basic biology and what might work for therapy,” he added. “So we’ve got the combination of lack of specimens, lack of clinical trials, and thereby less progress.”

■

Disclosure: Drs. Bleyer and Hayes-Lattin reported no potential conflicts of interest.

References 1. Kane J: Teens dealing with cancer find an ally in The Who’s Daltrey. The Rundown, January 11, 2012. Available at www. pbs.org/newshour/rundown. Accessed February 27, 2012. 2. Adolescent and Young Adult Oncology Progress Review Group: Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer. National Cancer Institute, LIVESTRONG Young Adult Alliance, 2006. Available at http://planning.cancer. gov. Accessed February 27, 2012.

The ASCO Post | MARCH 15, 2012

PAGE 72

Patient’s Corner Breast Cancer

Surviving Cancer Means Making Many Difficult Decisions By AnneMarie Ciccarella, as told to Jo Cavallo

he best advice I received after getting a diagnosis of stage I invasive lobular carcinoma in my left breast was from my radiologist, who told me, “Remember, be your own best advocate.” Those words have stayed with me through my 6-year struggle with breast cancer and its aftermath.

Extraordinary Steps I was 49 when I got my diagnosis and was immediately confronted with a difficult decision. Because my mother had been diagnosed with breast cancer 20 years earlier, when she was 49, I thought before I make any treatment decisions I should get a BRCA gene test. But even before I got the results, when I learned that with my type of breast cancer there was a chance the disease might already be in my other breast, I opted for a contralateral prophylactic mastectomy plus eight rounds of the chemotherapy regimen CMF (cyclophosphamide, methotrexate, and fluorouracil). My decision may seem extreme, given that the cancer had been found early and hadn’t spread to my lymph nodes. But when a pathology report of my right breast showed several areas of cellular atypia, I knew I had made the right choice. Still, coping with all these issues beforehand wasn’t easy. The word “mutilation” kept coming into my head, and I wished desperately that someone—my oncologist or someone else on my medical team— would just tell me what to do. Of

course, only I could decide what was right for me. Only I could be my own best advocate. The next medical decision was taken out of my hands. When my genetic test results showed mutations of unknown significance on both my BRCA1 and BRCA2 genes, the genetic doctor strongly suggested that I should have a prophylactic oophorectomy to prevent the possibility of my developing ovarian cancer. Since I was on letrozole anyway, there was no logical reason for me to keep my ovaries, and I had the surgery. My main goal for the course of action I

vances will derail any possibility that this will be her genetic fate.

Taking Advocacy to the Next Level To learn more about our family’s specific risk factors for breast cancer and to keep up-to-date on new research and treatments being developed to fight this disease, I’ve joined the Susan Love/Avon Army of Women. I work with breast cancer organizations throughout my state to encourage all women to join the Army of Women, whose goal is to find ways to prevent breast cancer.

The bottom line is that women need to understand the risks and benefits of their cancer treatment, and physicians need to explain those risks and benefits in language their patients can understand. —AnneMarie Ciccarella

followed was to reduce my risk factors for cancer recurrence as much as possible, even if it meant taking extraordinary steps like removing body parts. In August 2007, just 2 months after I had finished my surgeries and chemotherapy, my mother was diagnosed with a second primary cancer in her other breast. In 2010, my 42-year-old sister was diagnosed with breast cancer. Now, I’m worried about what might lie ahead for my 26-year-old daughter, Stephanie, even as I’m hopeful that medical ad-

I’ve also become active in educating women about one of the least recognized and talked about side effects of chemotherapy—chemobrain, a cognitive condition I only learned about recently, even though I’ve felt its effects for years. An an accountant by profession, soon after undergoing chemotherapy I began noticing that I had difficulty performing even the simplest calculations, and recalling common words was often beyond my grasp. Over the years, I’ve even lost my ability to multitask and have had to learn to concentrate

AnneMarie Ciccarella

on doing one thing at a time to prevent becoming mentally overloaded and frustrated. Had I known developing chemobrain was a possibility, I would have insisted on a neuropsychological evaluation before starting my treatment so I could compare the difference in my cognition before and after therapy. To help other cancer survivors learn about this devastating side effect and give them a place to talk about their experiences coping with the problem, I’ve launched a chemobrain blog (http:// chemo-brain.blogspot.com/p/who-isam.html). The bottom line is that women need to understand the risks and benefits of their cancer treatment, and physicians need to explain those risks and benefits in language their patients can understand. And most of all, a woman with cancer needs to be her own best advocate.

■

AnneMarie Ciccarella lives in Glen Head, New York. Letter to the Editor

USING QR CODES

Cost of Cancer Therapy: The Elephant in the Room?

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

The code will scan automatically.

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

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

am distressed by your coverage of innovative therapies, such as dual HER2 blockade (see The ASCO Post, January 1, 2012, and Supplement to February 15, 2012), without mentioning that these therapies will never be costeffective given the current pricing of the agents involved. If we wish to maintain our credibility as the arbiters of appropriate cancer therapy, we cannot continue to ignore the elephant in the room. ASCO has to come out strongly in favor of negotiated pricing for new

cancer drugs rather than the current “take it or leave it” system. The current SEE PAGE 72 cost structure of new drugs is unsustainable, and we, as leaders, need to say it, and say it loudly.

■

—Michael J Kraut, MD Medical Director, Oncology Providence Cancer Institute Southfield, Michigan

ASCOPost.com | MARCH 15, 2012

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In the Literature

Emerging Clinical Data on Cancer Management COLON CANCER Survival Advantage of Oxaliplatin Extends to Diverse Group of Patients The survival advantage conferred by adding oxaliplatin to adjuvant chemotherapy with fluorouracil (5-FU), as previously shown in randomized controlled trials, extends to patients in the general population, including older and minority group patients and those with higher comorbidity. These results, reported in the Journal of the National Cancer Institute, were obtained by comparing data for 4,060 patients from five observational sources to pooled data for 8,292 patients from five randomized controlled trials. “To mirror the trial cohorts, we restricted our analyses to patients diagnosed before age 75 years,” the researchers noted. “The survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings,” the researchers stated. The 3-year overall survival for patients receiving oxaliplatin was 86% for the randomized controlled trials and ranged from 79% to 88%

for the observational sources. “The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity,” the authors remarked.

Veterans Administration hospitals,” the researchers reported. “In summary, our analyses suggest that the benefit of oxaliplatin evident in clinical trials appears to manifest in day-to-day practice,” they concluded. “Physicians and patients should be reassured from our findings that oxaliplatin is associated with marginally but consistently superior survival for patients diagnosed before age 75 years in community settings.” Sanoff HK, et al: J Nat Cancer Inst 104:211-227, 2012.

TREATMENT-RELATED MORTALITY VEGFR Tyrosine Kinase Inhibitors Linked to Increased Risk of Fatal Adverse Events A meta-analysis of 10 randomized controlled trials involving 4,679 patients showed that the use of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors was associated with an increased risk of fatal adverse events. “The crude incidence of [fatal adverse events] in patients treated with a VEGFR [tyrosine kinase inhibitor] was 1.5% compared with 0.7% in patients from placebo/ control arms.” However, despite the relatively low adverse event rate, the risk of developing a fatal adverse event was more than twofold higher among patients treated with VEGFR tyrosine kinase inhibitors vs patients treated in placebo/control arms, researchers reported in the Journal of Clinical Oncology. The studies were culled from a search of MEDLINE and PubMed databases for articles published from January 1996 through February 2011. The studies could involve patients with any type of primary tumor but were limited to trials of FDA-approved VEGFR tyrosine kinase inhibitors, as of February 2011, the researchers noted. These agents were sorafenib (Nexavar), approved for renal cell and hepatocellular carcinoma, sunitinib (Sutent), approved for renal cell carcinoma and gastrointestinal stromal tumor, and pazopanib (Votrient), approved for renal cell carcinoma. Subgroup analysis found no difference in the rate of fatal adverse events between different VEGFR tyrosine kinase inhibi-

tors or tumor types. For the incidence of fatal adverse events, all tyrosine kinase inhibitor SEE PAGE 72 treatment arms were included, representing a total of 2,461 patients, the researchers reported. Hemorrhage was the most frequently occurring fatal adverse event reported in four trials and resulted in 19 deaths, or 47.5% of all study deaths. Myocardial infarction was the second most common fatal adverse event reported in five trials, representing 15% of study deaths. Other less frequent fatal adverse events were abnormal hepatic function or failure (n = 4), sepsis (n = 3), congestive heart failure (n = 2), and, resulting in 1 death each, ischemic stroke, pulmonary embolism, dehydration, and sudden death.

Relative Risks The highest incidence of fatal adverse events occurred in a phase III trial of sorafenib in renal cell carcinoma. Overall, 19 deaths occurred in the six sorafenib trials, compared to 7 deaths in the three sunitinib trials, and 1 death in the single pazopanib trial. “This may be a result of the larger proportion of patients enrolled in sorafenib trials (62% of all patients in the analysis) rather than a unique property compared with the related molecules sunitinib and pazopanib,” the authors stated, noting that there were no statistically significant differences in relative risks. “All of these drugs antagonize the intracellular domain of the VEGFR and block the downstream signaling. In addition, all three drugs have similar toxicity class-effect profiles,” the researchers added. Despite the current findings, the authors’ concluded, all three drugs benefit the overall population of patients with renal cell carcinoma, hepatocellular carcinoma, or gastrointestinal stromal tumor “by improving patients’ outcome and should continue to be offered to these patients. However, as this class of drugs gains greater clinical use, practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes.”

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Schutz FAB, et al: J Clin Oncol. February 6, 2012 (early release online).

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PAGE 75

Perspective

Geriatric Oncology continued from page 1

Early Efforts in a New Field The traditional way in which cancer is studied—ie, clinical trials focusing on younger, healthier patients—has left us with a void in the data needed to manage older patients in an evidencedbased fashion. These trials often fail to establish the validity of cancer treatment in the elderly, and may also fail to provide information related to the long-term complications of treatment, including decline in function.2 Among the first to recognize this issue was Dr. Rosemary Yancik, who in 1981 organized a symposium sponsored by the National Cancer Institute and the National Institute on Aging. The conference reached a number of conclusions and set a research agenda, as described in the 1983 monograph, “Perspectives on Prevention and Treatment of Cancer in the Elderly.”3 In his 1988 ASCO Presidential Address, subsequently published in the Journal of Clinical Oncology, Dr. B.J. Kennedy also encouraged the study of aging and cancer.4 He stated, “[O]ur society need not ration how we will treat our disadvantaged members, but should continue to seek those preventive and positive measures that can shorten our later period of morbidity. A very major cancer load will persist well into the 21st century, even if the attempts at prevention are eventually a total success. There is a developing knowledge on aging. Care of the older person needs to be part of medical education and oncology education. Research will help attain a desirable quality of life with aging and a reduced morbidity.” Drs. Yancik and Kennedy pointed us in the right direction, but their goals have proven to be somewhat elusive.

Important Strides Since these publications, studies of older patients with cancer have revealed a significant amount of important clinical information. This growing body of knowledge has included the degree and severity of comorbidity and its effect on treatment, the role of polypharmacy, and the various social and financial problems facing older patients with cancer. The underrepresentation of older patients in clinical trials has been amply documented.5 The adverse outcomes of inadequate dosing and supportive care in both curative and palliative treatments have been demonstrated in numerous treatment settings. Even when clinical trials are available, barriers to participation of older patients have been

shown to be primarily due to physician reluctance due to fear of toxicity, limited expectation of benefit, or ageism. Important strides have been made in the evaluation of older patients through various methodologies of geriatric assessment. The comprehensive geriatric assessment (CGA), developed by geriatricians, is a multidisciplinary evaluation of the older patient encompassing several important clinical domains.6 Researchers in this area have shown that traditional measures of performance in oncology are not adequate in older patients and that geriatric-specific measures (ie, activities of daily living, instrumental activities of daily living) have a much greater predictive value.7 Recent advances in the assessment of geriatric oncology pa-

phasizing Geriatric Oncology, and has established a Geriatric Oncology track. The International Society of Geriatric Oncology (SIOG), with headquarters in Switzerland, has implemented a number of task forces to evaluate the current literature in geriatric oncology and to make treatment recommendations. Its annual meeting is a forum for updates and discussions about moving the field forward. The National Comprehensive Cancer Network (NCCN) has published practice guidelines for Senior Adult Oncology. The Cancer and Aging Research Group have been particularly productive in the development of geriatric assessment. A major milestone is the Journal of Geriatric Oncology, which began publication in 2010.

As older patients become the majority of the patients we evaluate and treat, they need to become the focus of our endeavors. Our elders deserve nothing less. —Stuart M. Lichtman, MD

tients were reported with the publication of two important trials.8,9 These newer assessment tools need to be validated in prospective trials, but they appear to be predictive and easy to administer.

Professional Organization Activities Some oncology professional societies and organizations have shown a major interest in Geriatric Oncology. In 1995, the Cancer and Leukemia Group B (CALGB) organized a Cancer in the Elderly Committee.10 The formation of this committee has led to a number of completed and published studies in barriers to participation, supportive care, and cancer therapeutics. The newly formed Alliance of CALGB, the North Central Cancer Treatment Group (NCCTG), and the American College of Surgeons Oncology Group (ACOSOG) will strengthen this committee. The Gynecologic Oncology Group (GOG) recently formed an Elderly Task Force and has initiated a clinical trial in ovarian cancer (GOG 273). ASCO sponsored a clinical practice forum in 2000, “Cancer Care in the Older Patient,” as part of its Curriculum Series and has incorporated geriatrics in the ASCO University program. The Annual Meeting has included numerous Education Sessions, Clinical Science Symposia, and oral presentations em-

Further Changes Needed Despite all of the changes that have taken place in the past few years, there is still much that needs to be done. There needs to be improvement in the assessment of the older patient to allow clinicians to make appropriate treatment decisions. An easily administered, predictable measure is critical. Practical treatment questions include whether adjuvant therapy is appropriate based on potential benefit of treatment vs predicted survival; what is the best palliative regimen; and when is best supportive care appropriate. Clinical trial participation needs to be encouraged. Clinical trial design, statistical analysis, and trial reporting need to incorporate the specific needs of older patients and provide practical information for the clinician. Endpoints need to be practical in the elderly—for example, maintenance of independence, avoiding functional decline, and time without symptoms. The publication of large trials in which older patients have participated should give age-associated data, a practice that is still lacking.11

An Evolving Society American society has evolved over the past few decades in terms of how we view aging. An age of 65 years is, for the most part, no longer considered elderly. People are often very active into their

70s and 80s. Chronologic age should not be the sole parameter used in treatment decisions. Physicians caring for older patients need to be educated about these very important issues. Older patients should be systematically evaluated to the degree necessary to make evidence-based decisions. In addition, studies in the basic sciences, including the biology of aging, need to be explored. As older patients become the majority of the patients we evaluate and treat, they need to become the focus of our endeavors. Our elders deserve nothing less.

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

References 1. Edwards BK, Howe HL, Ries LA, et al: Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94:2766-2792, 2002. 2. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293:1073-1081, 2005. 3. Yancik R (ed): Perspectives on Prevention and Treatment of Cancer in the Elderly. New York, Raven Press, 1983. 4. Kennedy BJ: Aging and cancer. J Clin Oncol 6:1903-1911, 1988. 5. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999. 6. Cohen HJ, Feussner JR, Weinberger M, et al: A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 346:905-912, 2002. 7. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582-1587, 1998. 8. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 29:3457-3465, 2011. 9. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. November 9, 2011 (early release online). 10. Cohen HJ, Muss HB: The Cancer and Leukemia Group B Cancer in the Elderly Committee: Addressing a major cancer need. Clin Cancer Res 12(11 Pt 2):3606s-3611s, 2006. 11. Lichtman SM: Call for changes in clinical trial reporting of older patients with cancer. J Clin Oncol. February 13, 2012 (early release online). Adapted, in part, from Lichtman SM, Balducci L, Aapro M: Geriatric oncology: A field coming of age. J Clin Oncol 25:1821-1823, 2007.

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