TAP Vol 4 Issue 14 by Harborside Press LLC

Molecular Profiling of T-Cell Lymphomas

| Pemetrexed Maintenance in NSCLC

26, 30

| Future of Cancer Care

VOLUME 4, ISSUE 14

SEPTEMBER 1, 2013

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

World Cutaneous Malignancies Congress

ASCOPost.com

Will Funding for Lung Cancer Ever Improve?

Addressing the Key Clinical Questions in Advanced Melanoma By Caroline Helwick

By Apar Kishor Ganti, MD, MS, FACP

t the 3rd Annual World Cutaneous Malignancies Congress, in La Jolla, California, Steven J. O’Day, MD, Director of Clinical Research at the Beverly Hills Cancer Center and Adjunct Member of the John Wayne Cancer Institute, Los Angeles, addressed what he labeled the “key clinical questions” about metastatic melanoma in 2013.

More Complex Decisions “In the treatment of advanced melanoma, decision-making in the community is becoming more complex,” Dr. O’Day noted. “Conventional therapies have largely been ineffective. However, surgery remains an option for a subgroup of stage I� I� patients, high-dose interleukin (IL)2 [Proleukin] can still cure select patients, and there is still a limited role for chemotherapy and biochemotherapy, pri-

marily as a bridge to more effective treatments in patients with fast-growing disease.” But now, with the availability of immunotherapy and targeted agents, the focus has shifted to the optimal use of these compounds in the Steven J. O’Day, MD clinic. These drugs currently include (1) targeted T-cell immunotherapy with the anti-CTLA� agent ipilimumab (Yervoy) and the anti-PD-1 and anti-PD-L1 agents in clinical trials (nivolumab, lambrolizumab, MPDL3280A), and (2) targeted cancer cell pathway inhibitors, including BRAF inhibitors (vemurafenib [Zelboraf], dabrafenib [Tafinlar]), MEK inhibitors (trametinib

ung cancer is the most common cause of cancer-related death in the world. In the United States alone, an estimated 228,190 new cases of lung cancer and 159,�80 deaths from lung cancer will occur in 2013. These are alarming statistics when compared to the next four common causes of cancer-related deaths (colon, breast, pancreas, and prostate), which are estimated to account for 159,0�0 deaths combined.1 Since the declaration of the “War on Cancer” in 1971, the contrast between the changes in survival for lung cancer and the other cancers are even more disturbing. A comparison of the 5-year survival rates in 1975 and now reveals an improvement in prostate cancer from continued on page 91

continued on page 12

ASCO Annual Meeting

Access to and Appropriate Use of Oncology Drugs Called Into Question by ASCO Studies By Caroline Helwick

Dr. Ganti is Associate Professor in the Department of Medicine, VA Nebraska Western Iowa Health Care System, and in the Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha.

MORE IN THIS ISSUE

stantially over the past year. Rather, oncologists are adapting their practices to cope with it, often without guidance, according to surveys presented at the Annual Meeting. Richard L. Schilsky, MD, Chief Medical Officer of ASCO, relayed the results of an ASCO Drug Shortage Persists survey that sought to determine whether recent The shortage of oncology drugs has not eased sublegislative and regulatory efforts had ameliorated shortages.1 A subset of ASCO members from the United States were queried in October 2012 Permanent solutions [to the oncology (n = 390) and again in drug shortages] will require enhancing April 2013 (n = ��2). = ��2). = ��2). ��2). Results of the second survey the business model of generic drug suggested the situation manufacturing. has improved somewhat, —Richard L. Schilsky, MD but oncologists still need to substitute drugs and tudies presented at this year’s ASCO Annual Meeting suggest that despite the wealth of amazing oncolytics on the market, drug shortages persist, drug substitutions are common, off-label use of drugs occurs frequently, and patients find their costs burdensome.

Oncology Meetings Coverage International Lung Cancer Congress�� 3 ASCO Annual Meeting �� 5 World Cutaneous Malignancies Congress �� 10 Treatment Strategies in High-Risk Medulloblastoma �� 23 FDA Update �� 33 Fertility Rates in Childhood Cancer Survivors�� 34 Women in Oncology: Julie Vose, MD �� 43 Direct from ASCO �� 52–55

continued on page 72

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The ASCO Post | SEPTEMBER 1, 2013

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Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

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Associate Editors

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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

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 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 ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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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.

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

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 3

International Lung Cancer Congress Thoracic Oncology

Paul A. Bunn, Jr, MD, Offers Insights About a Hopeful Era in Lung Cancer Treatment By Caroline Helwick

he treatment of non–small cell lung cancer (NSCLC) is rapidly evolving as molecular targets are being refined and targeted drugs are designed to combat acquired resistance. In his State of the Art Lecture at the 1�th International Lung Cancer Congress, Dr. Bunn, Professor of Medicine and the James Dudley Chair in Cancer Research at the University of Colorado Cancer Center in Aurora, Executive Director of the International Association for the Study of Lung Cancer (IASLC), and former ASCO President, described current treatment of NSCLC and the promise posed by future approaches.

gists (CAP)/IASLC/Association for Molecular Pathology (AMP), and the National Comprehensive Cancer Network (NCCN). While platinum doublets are generally restricted to patients with performance status 0 to 2, oral tyrosine kinase inhibitors can

Treatment Recommendations

be considered for performance status 3, and thus, such patients should also undergo molecular testing. Histology is also a key determinant of therapy, as pemetrexed (Alimta) is indicated only for patients with nonsquamous histology, bevacizumab (Avastin) is also not indicated for squamous histology, and patients lacking the epidermal growth factor

Summarizing the current treatment algorithm, Dr. Bunn reminded oncologists that clinical features, histology, and molecular features must all be considered to select initial therapy. The need to perform molecular testing on essentially all patients is recommended in guidelines from ASCO, the College of American Patholo-

If you can’t assess the mutation status or confirm EGFR wild-type, give chemotherapy first. —Paul A. Bunn, Jr, MD

Target

Agent

Lead Investigator

MEK1

Trametinib

P. Jänne/G. Blumenschein

BRAF (V600E)

Dabrafenib

B. Johnson

BRAF (not V600E)

Trametinib

P. Jänne/G. Blumenschein

Dacomitinib

M. Kris

HER2

Neratinib + Temsirolimus

L. Gandhi

PIK3CA

Buparlisib

J. Engelman

Erlotinib + OSI906

C. Rudin

Erlotinib + MM121

L. Sequist

Rivantinib + erlotinib

J. Schiller, P. Jänne

KRAS

Trametinib

P. Jänne/G. Blumenschein

NRAS

Trametinib

P. Jänne/G. Blumenschein

MET amplification

Crizotinib

R. Camidge

ALK

Crizotinib

R. Camidge

ROS

Crizotinib

R. Camidge

RET

Cabozantinib

R. Camidge N. Rizvi

Courtesy of Paul A. Bunn, Jr, MD.

PROFILE 1007, which showed more than a doubling in progression-free survival with crizotinib, compared to docetaxel or pemetrexed, in the second-line setting. The results of the first-line randomized trial comparing crizotinib to a platinum doublet are still awaited.

Development of Resistance

Table 1: Lung Cancer Mutation Consortium Protocols Linked to Specific Molecular Abnormalities

EGFR

receptor (EGFR) mutation or ALK fusion should be treated with a platinum doublet, as they respond better to, and may live longer on, chemotherapy than an oral tyrosine kinase inhibitor. “This all means that performance

status, histology, and molecular features should be determined before you embark on treatment,” said Dr. Bunn. “Don’t start patients on tyrosine kinase inhibitors as first-line therapy in the absence of a driver abnormality. If you can’t assess the mutation status or confirm EGFR wild-type, give chemotherapy first.” For patients who show slow disease progression with changes in symptoms on a tyrosine kinase inhibitor, the unanswered question is whether to continue this drug or switch to chemotherapy. “In our clinic, we generally continue the tyrosine kinase inhibitor,” he said. A randomized clinical trial is currently evaluating this issue. If a patient on a tyrosine kinase inhibitor develops a single metastatic lesion that can be resected or irradiated, the patient can continue on the same drug, which can add another � to 10 months without progression. “Unfortunately, these drugs don’t cause complete remissions and don’t cure patients,” he acknowledged.

Targeting EGFR and ALK It is now well accepted that EGFR is not the only driver oncogene in NSCLC. Targeting of the ALK rearrangement with crizotinib (Xalkori) has made a substantial difference for the small subset of patients who have this abnormality. Accelerated approval for crizotinib required a follow-up randomized trial,

Half of EGFR-mutated tumors in patients treated with gefitinib (Iressa) or erlotinib (Tarceva) subsequently develop a secondary gatekeeper mutation, leading to acquired resistance to the tyrosine kinase inhibitors. Pharmaceutical companies are now investing in second- and third-generation agents that will bind to the secondary mutated pocket. The first-generation agents bind to activating EGFR mutations and the wild-type receptor alike but not to the T790M mutation. The second-generation drugs bind to other members of the HER family, and to some degree to T790M, with the best outcomes observed with the combination of afatinib (Gilotrif) plus cetuximab (Erbitux). The third-generation agents offer irreversible binding of activating EGFR and T790M mutations but not the wild-type receptor, which could mean far less skin toxicity and diarrhea. Several such compounds are in development, Dr. Bunn reported. For crizotinib, the mechanisms of resistance are similar, including the possible emergence of a second oncogenic driver in ALK-positive patients or a separate oncogenic driver in ALK-negative patients. Several second-generation ALK inhibitors in development are quite potent for the ALK gatekeeper mutations, producing extremely high response rates (about 75%). “Clearly, we will be seeing randomized controlled trials of these in the second-line setting after crizotinib failure and likely in the first-line setting compared to chemotherapy,” Dr. Bunn predicted. He added that ALK-positive patients are particularly sensitive to pemetrexed. Therefore, treatment with this agent after progression on crizotinib might be effective. The Southcontinued on page 4

The ASCO Post | SEPTEMBER 1, 2013

PAGE 4

Journal Spotlight Thoracic Oncology

Researchers Identify Gene Variations in Lung Cancer Patients That May Help Predict an Individual’s Treatment Response

esearchers at the Moffitt Cancer Center have identified four inherited genetic variants in patients with non–small cell lung cancer that can help predict survival and treatment response. Their findings, published in Carcinogenesis,1 could help lead to more personalized treatment options and improved outcomes for patients. The researchers analyzed DNA sequence variations in �51 patients with non–small cell lung cancer, paying close attention to 53 inflammationrelated genes. They found that four of the top 15 variants associated with survival were located on the TNFRSF10B gene. In the study, these variants increased the risk of death as much as �1%. The researchers also found that patients with these gene variations had a greater risk of death if their treatment plans included surgery without chemotherapy compared to patients who were treated with chemotherapy following surgery.

Potential Biomarker “There are few validated biomarkers that can predict survival or treatment response for patients with non– small cell lung cancer,” said study lead

Lung Cancer Treatment continued from page 3

west Oncology Group (SWOG) will conduct a randomized trial (SWOG1300) to evaluate pemetrexed alone or with continued crizotinib after progression.

More Oncogenes, Targets That said, two oncogenes do not describe the whole NSCLC tumor spectrum. The Lung Cancer Mutation Consortium is investigating more than a dozen molecular lesions and their biomarkers (Table 1) and have designed clinical trials for each,

author Matthew B. Schabath, PhD, Assistant Member of the Cancer Epidemiology Program at Moffitt. “Having a validated genetic biomarker based on inherited differences in our genes may allow physicians to determine the best treatments for an individual patient based on their unique genetics.” “Non–small cell lung cancer has an extremely poor 5-year survival rate. Only about 1�% of all patients survive for 5years and tragically, only about �% of patients with late-stage disease live longer than 5 years,” explained Dr. Schabath. “Part of the difficulty in treating lung cancer is the genetic diversity of patients and their tumors. Using a personalized medicine ap-

Part of the difficulty in treating lung cancer is the genetic diversity of patients and their tumors. Using a personalized medicine approach to match the best treatment option to a patient based on his or her genetics will lead to better outcomes. —Matthew B. Schabath, PhD

proach to match the best treatment option to a patient based on his or her genetics will lead to better outcomes.” The researchers noted that there has been no published data examining the association of these four specific

Genetics of Lung Cancer ■ Researchers analyzed DNA sequence variations in patients with non–small cell lung cancer and found that four of the top 15 variants associated with survival were located on TNFRSF10B.

■ These variants increased the risk of death as much as 41% in patients studied.

■ Patients with these variations had a greater risk of death if their treatment

plans included surgery without chemotherapy compared to patients who were treated with chemotherapy following surgery.

said Dr. Bunn. Nearly two-thirds of patients with adenocarcinomas have at least one driver mutation for which a drug is available. Median survival for patients who have a molecular driver and receive such targeted therapy in the Consortium studies is about 3.5 years.1 Immunotherapy also presents a promising new avenue of attack in NSCLC. In a phase I trial in 122 heavily pretreated NSCLC patients, the anti–programmed death (PD)-1 antibody BMS-93�558, a coinhibitory receptor expressed by activated

T cells, showed clinical activity at all dose levels.2 The overall response rate was 18%, and the progression-free survival rate at 2� weeks was 2�%. A trend for increased disease control was observed in tumors with squamous histology. At least two anti–PD-1 agents and two anti–PD-L1 agents (ie, blocking the ligand) are in development. “We don’t know if one is better than the other, or if one target is better, or if we can combine them, or if there is a biomarker, but we do know that responses are associated with all these drugs, and patients have had prolonged pro-

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variants on cancer risk or outcome, although studies have reported associations with other gene variants in the same gene family as TNFRSF10B. n Disclosure: The work was supported by funding from the State of Florida through the James & Esther King Biomedical Research Program (09KN-15), a National Institutes of Health SPORE grant (P50 CA119997), an American Cancer Society grant (93-032-13), and a grant from the National Cancer Institute (5 UC2 CA 1�8322-02).

Reference 1. Schabath MB, Giuliano AR, Thompson ZJ, et al: TNFRSF10B polymorphisms and haplotypes associated with increased risk of death in non-small cell lung cancer. Carcinogenesis. August 2, 2013 (early release online).

gression-free survival on them,” Dr. Bunn noted. n Disclosure: Dr. Bunn is a consultant for Amgen, Astellas, AstraZeneca, Bayer, BristolMyers Squibb, Boehringer Ingelheim, Celgene, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Lilly, Merck, Merck Serono, Merrimack, Myriad, Pfizer, Roche/Genentech, Sanofi, and Synta.

References 1. Kris MG, Oxnard GR, Johnson BE, et al. 2013 ASCO Annual Meeting. Abstract 8085. Presented June 1, 2013. 2. Brahmer JR, Horn L, Antonia S, et al. 2012 ASCO Annual Meeting. Abstract 7509. Presented June 2, 2012.

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 5

ASCO Annual Meeting Gynecologic Oncology

Olaparib Shows Robust Progression-Free Survival Benefit in Patients With BRCA Mutations By Alice Goodman

aintenance therapy with olaparib extended progression-free survival and the time to disease progression after a second subsequent therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation, according to an updated analysis of Study 19 presented at the 2013 ASCO Annual Meeting.1

Compelling Data “Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation, with a median improvement of �.9 months in [progression-free survival], a median improvement in [time

Jonathan Ledermann, BSc, MD, FRCP

to second disease progression] of 8.5 months, and an overall survival improvement of 3 months compared with placebo. As a result of these compelling data, phase III confirmatory trials will begin this year in [serous ovarian cancer] patients with a BRCA mutation,” stated presenting author Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology in the UCL Cancer Institute, University College London, and an Honorary Consultant Medical Oncologist at UCL Hospitals. He is Head of the Cancer Research UK & UCL Cancer Trials Centre, within UCL Cancer Institute. Study 19 enrolled 2�5 patients with serous ovarian cancer who responded to platinum-based chemotherapy to receive either maintenance olaparib at �00 mg twice daily or placebo. The primary analysis of Study 19, presented 2 years ago, found that olaparib maintenance therapy significantly extended progression-free survival in patients with serous ovarian cancer compared with placebo (P < .00001).2 However, an interim analysis showed no overall survival advantage for olapa-

rib maintenance. Dr. Ledermann explained that the presence of a BRCA mutation was not required for study entry, but a significant number of patients turned out to have a BRCA mutation. At baseline 97 of 2�5 patients (3�.�%) had a known BRCA mutation.

Subgroup Analysis A prespecified subgroup analysis of Study 19 showed that patients with a known BRCA mutation had improved survival on olaparib maintenance compared with placebo. To study further the effect of olaparib maintenance in patients with BRCA mutations, the investigators performed a retrospective analysis of germline BRCA mutation status in 280 patients who gave their consent (including the 97 with known BRCA status at baseline) using Myriad’s genetics assay. They also looked for somatic BRCA mutations within patients’ tumors (n = 209) using an assay from Foundation Medicine. A total of 13� patients had either a germline mutation or a somatic BRCA mutation, and 118 had wild-type BRCA (total number = 257, 9�%). In the updated efficacy analysis, in addition to the progression-free survival endpoint, the investigators assessed the time from randomization to time of the start of a second subsequent therapy for disease progression or death. In the 13� patients with BRCA mutations, a highly significant 82% reduction in risk of progression was observed for olaparib maintenance therapy (P < .00005). .00005). Median progression-free survival was 11.2 months with olaparib vs �.3 months with placebo. A significant but less robust advantage was also observed for olaparib in patients with wild-type BRCA (P = .007). For all patients, the updated analysis showed no overall survival difference for olaparib vs placebo. However, a trend toward improved overall survival was observed in the olaparib group with

EXPERT POINT OF VIEW

aul Sabbatini, MD, attending physician at Memorial Sloan-Kettering Cancer Center, New York, said that Study 19 is a well-designed study that showed PARP inhibition is a successful maintenance therapy for serous ovarian cancer that avoids the toxicity associated with continued cytotoxic chemotherapy. “Most importantly, the study shows that BRCA mutation is a robust biomarker for benefit of olaparib and will be appropriately used to guide phase III studies for this indication. However, this biomarker should Paul Sabbatini, MD not limit all future investigations with PARP inhibitors. For example, in breast cancer, PARP inhibition shows activity independent of BRCA status,” he noted. Dr. Sabbatini agreed with Dr. Ledermann that it is difficult to show a survival advantage for maintenance olaparib in this setting in patients treated with several subsequent lines of treatment. “Can we attribute an overall survival benefit to one intervention?” he asked. The timing of maintenance therapy is a crucial issue, Dr. Sabbatini continued. “This study shows the value of starting maintenance therapy after the primary chemotherapy, potentially avoiding the additive toxicity of combining PARP inhibition with paclitaxel and carboplatin.” This issue remains to be clarified by upcoming clinical trials. n Disclosure: Dr. Sabbatini reported no potential conflicts of interest.

a BRCA mutation at the time of analysis, with a 3-month difference. Longerterm analysis may show an overall survival difference, Dr. Ledermann noted. The time from randomization to progression after a second subsequent therapy also significantly favored olaparib maintenance therapy in the BRCAmutated patients (P = .00�3), .00�3), with median time to second progression of 23.8 vs 15.3 months, respectively. Time to second progression was also a median of 2.� months longer with olaparib in the wild-type patients.

Clinically Meaningful Benefit “This is a clinically meaningful benefit,” he said. The effect of olaparib carried on beyond progression in patients for whom a second subsequent therapy failed. Quality of life in patients with BRCA mutations was no different on either treatment arm.

Olaparib in Serous Ovarian Cancer ■ Maintenance therapy with the PARP inhibitor olaparib extended

progression-free survival in an overall analysis of patients with platinumsensitive relapsed serous ovarian cancer.

■ The benefit of olaparib was particularly robust in patients with a known BRCA mutation.

The study closed in 2012, and as of May of 2013, 2� of the original 2�5 patients remain on therapy—23 on olaparib and 3 on placebo. The tolerability of olaparib is similar in the patients with BRCA mutations and wild-type BRCA. The most common adverse events are low-grade nausea and fatigue. Dr. Ledermann said it is difficult to show a survival benefit in these patients who are treated with subsequent multiple lines of therapy. “Subsequent treatment gradually abrogates any differences between treatment arms that might exist early on. This doesn’t necessarily devalue the treatment,” he noted. n

Disclosure: Dr. Ledermann has received support for travel to meetings as well as supplementary financial support for investigator-led clinical trials from AstraZeneca.

References 1. Ledermann JA, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). 2013 ASCO Annual Meeting. Abstract 5505. Presented June 1, 2013. 2. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 3��:1382-1392, 2102.

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 10

World Cutaneous Malignancies Congress Dermatologic Oncology

Merkel Cell Carcinoma: Hints of Immune Mediation May Enhance Treatment Options By Caroline Helwick

storm” that involves viral infeccells appear exhausted. It’s important tion, integration mutation, and to understand this immune evasion, truncation mutation, perhaps in order to be able to harness the immediated by ultraviolet light or mune system for therapeutic use.” radiation, and blossoming into This is indeed supported by the recancer late in life as a result of cent findings of increased programmed immune suppression or senescell death ligand 1 (PD-L1) in Merkel cence. cell tumors with Merkel cell polyoma“The bottom line is that virus–specific CD8-positive T cells. [Merkel cell polyomavirus] ofThis probably represents an important Paul Nghiem, MD, PhD Shailender Bhatia, MD ten plays a role, but it’s not necmechanism of immune evasion by the erkel cell carcinoma is a rare but essary or sufficient for Merkel tumor cells, Dr. Nghiem said, suggestaggressive skin cancer with poor cell,” he said. “The question is, are the ing a role for the anti–programmed outcomes and suboptimal therapeutic viral oncoproteins recognized by the death (PD)-1/PD-L1 antibodies in options. With a ��% mortality rate, it is immune system?” treatment. three times more lethal than melanoma, Harnessing the immune system in Role of the Immune System and its reported incidence is rising. treating Merkel cell carcinoma will The immune system appears to be “Merkel cell carcinoma is a nasty be important, the speakers predicted. dysfunctional in the Merkel cell tumor cancer and we have zero FDA-apOngoing or planned immunotheramicroenvironment. There is downproved therapies for it. We are caupeutic efforts for treating the disease regulation of major histocompatibility tiously optimistic that this will change include adoptive cell therapy using complex class 1 on tumor cells, sparse in the next few years,” said Paul Merkel cell polyomavirus–specific T intratumoral CD8-positive T-cell inNghiem, MD, PhD, the Michael Piepcells; systemic therapy with ipilimfiltration, and immune exhaustion of korn Endowed Chair in Dermatology umab (Yervoy), anti–PD-1/PD-L1 tumor-infiltrating lymphocytes. “This Research at the University of Washingantibodies, and �-1BB (a T-cell actiton and Fred Hutchinson Cancer Research Center, Seattle. Dr. Nghiem Update on Merkel Cell Carcinoma and his colleague at the university and cancer center, Shailender Bhatia, ■ The Merkel cell polyomavirus is implicated in pathogenesis of Merkel cell MD, Assistant Professor of Medical carcinoma. Oncology, described emerging insights ■ The immune system is believed to play an important role, and evidence of into Merkel cell carcinoma at the 2013 a robust immune response is linked to improved survival. World Cutaneous Malignancies Congress in La Jolla, California. ■ New immunotherapeutic approaches are being investigated.

An Infectious Etiology? The fact that Merkel cell carcinoma occurs in the elderly and in immunosuppressed persons suggests an infectious origin. This hypothesis was strengthened in 2008 by the observed association between Merkel cell carcinoma and the genome of a previously unknown polyomavirus, now dubbed Merkel cell polyomavirus.1 Sequences of Merkel cell polyomavirus were detected in 80% of Merkel cell tumors, compared with 1�% of control skin tissue samples. The clonal pattern of chromosomal integration into Merkel cell carcinomas pointed to a contributing role for Merkel cell polyomavirus in the pathogenesis of the carcinoma. “However, while [Merkel cell polyomavirus] exists in the skin of most of us, only 1 in 3,000 persons will get [Merkel cell carcinoma],” Dr. Nghiem noted. He attributed this to a “perfect

provides a strong rationale for immunotherapy,” Dr. Bhatia said. Genes related to immune responsiveness are upregulated in Merkel cell carcinoma, and infiltration of CD8positive lymphocytes into the tumor is associated with improved survival. In a study of 1�� Merkel cell tumors, Dr. Nghiem and his team showed that patients who demonstrated robust intratumoral CD8-positive infiltration had 100% disease-specific survival, compared with �0% for those with sparse infiltration.2 “If CD8-positive cells have entered and moved at least one cell diameter away from a vessel, that is incredibly protective,” Dr. Nghiem noted. Dr. Bhatia added, “Unfortunately, the majority (~80%) of patients do not have these infiltrates. Even when there is infiltration, those

vator); and intratumoral injections with the toll-like receptor � agonist glucopyranosyl lipid adjuvant–stable emulsion (GLA-SE), interferon beta, and interleukin-12. Injections of interleukin-12 DNA, facilitated by electroporation, can regress not only the injected lesions but those at distant sites as well, with few side effects. Studies have shown that CD8-positive infiltration occurs in about 50% of patients after treatment, suggestive of a successful immune response, Dr. Bhatia added. The findings have also led to the development of a serum assay that monitors for recurrence by measuring the concentration of antibodies to the Merkel cell polyomavirus oncoprotein. The test is being validated and should become clinically available soon.

Proper Staging Is Important Meanwhile, lacking these novel approaches, clinicians need to understand some of the nuances of treating Merkel cell carcinoma with conventional approaches. Proper staging of disease is important, as one-third of clinically negative nodes are actually microscopically positive. “Stage IA patients still do not have a normal survival time. Even with early-stage disease there are reasons to be concerned,” Dr. Nghiem said. Dr. Bhatia agreed, noting that 35% of patients diagnosed with local disease die from Merkel cell carcinoma, despite its being potentially curable with surgery and radiotherapy. In an analysis of 5,823 Merkel cell carcinoma patients from the National Cancer Data Base, 5-year relative survival was 5�% (compared to matched controls).3 In the two-thirds of patients who presented with local disease only, even those with tumors ≤ 2 cm had only a ��% relative survival. “Sentinel lymph node biopsy results in more accurate staging, may have therapeutic implications, and should be considered in all patients,” Dr. Nghiem said. It may not be necessary when the procedure would not change management, when a falsenegative result would be more likely, or when prognostic data are not important to the patient. Additionally, the absence of positive surgical margins should not be falsely reassuring. “Disease can occur several centimeters away from the primary, so negative margins do not ensure a cure, and surgical treatment alone is often not a good plan,” he said. Excision, usually with radiotherapy, is the recommended local approach. With surgery alone, local recurrence is almost four times greater and regional recurrence is almost three times greater than when radiotherapy is also given.� But the risk of recurrence is important to determine. Five favorable features likely lower the need for adjuvant radiotherapy: primary tumor ≤ 1 cm, margins pathologically negative, lack of lymphovascular invasion in the primary, lack of profound immune suppression, and negative sentinel node biopsy. In the adjuvant setting, chemo-

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World Cutaneous Malignancies Congress Merkel Cell Carcinoma continued from page 10

therapy has not been shown to improve outcomes.

Salvage Therapy A number of approaches can palliate symptoms or serve as a bridge to enrollment in an immunotherapy trial. In stage I� disease, chemotherapy remains the standard of care. Although response rates may be high, they are seldom durable and progression-free survival is short. Toxicity can also be significant, especially in the elderly, and there is also the potential for im-

approach, especially if we can combine this with systemic immunotherapy.” n

Disclosure: Drs. Nghiem and Bhatia reported no potential conflicts of interest.

References 1. Feng H, Shuda M, Chang Y, et al: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:109�-1100, 2008.

2. Paulson KG, Iyer JG, Tegeder AR, et al: Transcriptome-wide studies of Merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29:1539-15��, 2011. 3. Lemos BD, Storer BE, Iyer JG, et al: Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma. J Am Acad Dermatol �3:751-7�1, 2010.

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

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

37%

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Preradiotherapy 63% confirmed

1 week postradiotherapy Fig. 1: Single-fraction radiotherapy (8 Gy) for Merkel cell carcinoma has been effective with rapid-onset palliation and minimal toxicity. Photos courtesy of Shailender Bhatia, MD.

mune suppression. Pazopanib (�otrient) appears to be effective in some patients. When there is evidence of somatostatin receptor expression, somatostatin analogs may produce disease stabilization, without major side effects, Dr. Bhatia said. Radiotherapy can be effective as salvage treatment. At the University of Washington, a single-fraction 8-Gy approach has resulted in rapid-onset palliation after a convenient 1-day treatment (Fig. 1). In a study of 9 patients with 29 lesions, durable complete responses were achieved in 89% of lesions in patients who were not immunosuppressed and in 3�% of lesions among immunosuppressed patients.5 “Merkel cell is a radiosensitive tumor. When we use fractionated radiotherapy, it is possible that subsequent fractions may kill immune cells infiltrating into the tumors from the radiation,” he said. “A high-dose single fraction may be more immunogenic. It’s an exciting

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1 33% switched from CT + HT to HT alone‡ 4% switched from HT only to CT + HT ‡ • Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, and Uncover the Unexpected are registered trademarks of Genomic Health, Inc. © 2013 Genomic Health, Inc. All rights reserved. GHI10100_0712

�. Lewis KG, Weinstock MA, Weaver AL, et al: Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 1�2:�93-700, 200�. 5. Parvathaneni U, Iyer J, Nagase K, et al: Effective and durable palliation using a novel single fraction radiation therapy approach for Merkel cell carcinoma metastatic lesions (abstract). Int J Radiat Oncol Biol Phys 8�(suppl):S�31, 2012.

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World Cutaneous Malignancies Congress Advanced Melanoma continued from page 1

[Mekinist]), and their combination. In the application of these effective agents, Dr. O’Day said he considers the patient’s disease biology and metastatic presentation, molecular profile, involvement of the central nervous system, age, comorbidities, personal preferences, and goals of care, in an effort to truly personalize treatment.

Ipilimumab vs Vemurafenib Ipilimumab exerts a large benefit in a small subset of patients and often achieves durable disease control, but kinetically is associated with a slow response (3–� months) and carries autoimmune toxicity (though side effects are responsive to steroids). Approximately half of treated patients are alive at 1 year, and about one-third are alive at 2 years. “It is remarkable that blocking one important brake to the immune system gives long-term survival to one in four patients with widespread metastases,” he noted. He said the investigational anti-PD-1/PD-L1 agents will produce a more rapid response and will also be a less toxic form of immunotherapy.

BRAF inhibitors seems to be predominantly through MAP kinase reactivation. Therefore, the goal of blocking MEK with an oral agent “was an obvious choice,” he said. The MEK inhibitor trametinib has singleagent activity, though it is less than is seen with the BRAF inhibitors; its toxicity profile is probably less favorable, he added.

BRAF-Mutated vs Wild-Type In patients with BRAF-mutated disease, the questions to be answered include whether to start with an immunotherapeutic or targeted agent, how long to use targeted therapy once initiated, and whether to se-

‘Triple-Negative’ Melanoma For the patient whose tumor does not have mutations in BRAF, or even

This is a brave new world of immunotherapy. Using anti-PD-1/PD-L1 with ipilimumab in combination will improve this even further. —Steven J. O’Day, MD

quence or combine targeted agents and immunotherapy. In BRAF wildtype patients, the oncologist needs to determine if a rapid response is needed; if not, the question is whether to incorporate high-dose IL-2/adoptive cell therapy or move

New Focus in Melanoma Treatment ■ With the availability of immunotherapy and targeted agents, the focus in

melanoma treatment has shifted to the optimal use of these compounds, including ipilimumab, vemurafenib, dabrafenib, and trametinib, in the clinic.

■ Approval of the anti-PD-1/PD-L1 agents, including lambrolizumab and

nivolumab, is highly anticipated, and these clinical trials are a high priority.

�emurafenib and dabrafenib, on the other hand, exert a large benefit in almost 90% of BRAF-mutated patients and response occurs within days or weeks, but relapse is nearly uniform about � months after treatment initiation. Toxicity involves the skin and joints, and constitutional symptoms are not uncommon. The mechanism of resistance to

ing patients to immunotherapy is an important goal, he said. “I tend to reserve targeted treatment for patients who need a rapid response, with the goal of transitioning them to ipilimumab. And when I choose a targeted treatment, I am also now shifting to a BRAF/MEK inhibitor combination,” he said. Regardless of BRAF mutation status, there remains a need to identify the best way of targeting brain lesions and incorporating this treatment into the protocol, he said.

directly to ipilimumab therapy, he said. Dr. O’Day emphasized that while the BRAF inhibitors elicit a rapid response, the response is less durable than can be achieved with the anti-CTLA� agents, eg, ipilimumab, though response to ipilimumab can be slow. Due to the possibility of gaining a durable remission, bridg-

c-KIT (for which a drug such as imatinib [Gleevec] might be effective) or NRAS (for which a clinical trial might be appropriate), he decides between immunotherapy (ipilimumab or high-dose IL-2, possibly with adoptive cell therapy) or enrollment in a clinical trial of a front-line antiPD-1/PDL-1 agent. “The challenge in this group is the patient who presents very aggressively and may not be eligible for a trial,” he said. “It’s about how to bridge the patient for whom the kinetics of response to a drug won’t allow 3 to � months of waiting.” Bridging therapies include carboplatin/paclitaxel, paclitaxel/bevacizumab (Avastin)—perhaps with carboplatin—or biochemotherapy. Chemotherapy can work well in the short run, but the patient must ultimately be transitioned to immunotherapy.

Treatment in the Near Future The approval of the anti-PD-1/ PD-L1 agents is highly anticipated,

and these clinical trials are a high priority. Studies are evaluating various schedules of PD-1 antibodies compared with or in combination with ipilimumab. In a phase I trial, patients receiving the anti-PD-1 agent nivolumab had a median overall survival of almost 17 months, 1-year survival rate of �3%, and 2-year survival of �3%.1 Similarly, lambrolizumab, which recently received “breakthrough therapy” status from the FDA, had a median progression-free survival exceeding 7 months, and at 11 months, 81% of responders were still on treatment.2 Importantly, efficacy and safety were comparable between patients who had previously received ipilimumab and those naive to immunotherapy. The tumor control rate exceeds 50%, and the kinetics of response are better (1–3 months) with the anti-PD-1/PD-L1 agents, which makes them similar to the BRAF inhibitors, but with “remarkable” durability of disease control and less immune-related toxicity. Dr. O’Day predicted, therefore, that these drugs will “change the landscape” of advanced melanoma. “This is a brave new world of immunotherapy,” he commented. “Using antiPD-1/PD-L1 with ipilimumab in combination will improve this even further.” n

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

References 1. Topalian SL, Sznol M, Brahmer JR, et al: Nivolumab (anti-PD-1; BMS93�558; ONO-�538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial. 2013 ASCO Annual Meeting. Abstract 3002. Presented June 3, 2013. 2. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambrolizumab (MK-3�75, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 1, 2013.

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PAGE 14

JCO Spotlight Hematology

Molecular Profiling Improves Classification of Nodal Peripheral T-Cell Lymphomas By Matthew Stenger

he differential diagnosis of the most common peripheral T-cell lymphoma subtypes is difficult. In a diagnostic accuracy study reported in the Journal of Clinical Oncology, Pier Paolo Piccaluga, MD, PhD, of the University of Bologna, and colleagues in the European T-Cell Lymphoma Study Group and International Peripheral T-Cell Lymphoma Project assessed the ability of gene-expression profiles to identify peripheral T-cell lymphoma subtypes.1 They found that gene-expression profile–based molecular classifiers could distinguish angioimmunoblastic T-cell lymphoma and ALK-negative anaplastic large-cell lymphoma from peripheral T-cell lymphoma–not otherwise specified with a high degree of accuracy. The study involved 2�� peripheral T-cell lymphomas, including 158 peripheral T-cell lymphomas–not otherwise specified, �3 angioimmunoblastic T-cell lymphomas, and 23 ALK-negative anaplastic large-cell lymphomas. The gene-expression profile–based classification method was established on a support vector machine algorithm and the reference standard was an expert pathologic diagnosis according to WHO classification.

Predictive Accuracy The investigators first identified gene-expression profile–based molecular classifiers discriminating angioimmunoblastic T-cell lymphoma and ALKnegative anaplastic large-cell lymphoma from peripheral T-cell lymphoma–not otherwise specified in a training set. The molecular classifiers were developed in formalin-fixed paraffin-embedded samples and validated in both formalin-fixed paraffin-embedded and frozen tissues. In a training set, 208 genes distinguish-

ing peripheral T-cell lymphoma–not otherwise specified from angioimmunoblastic T-cell lymphoma and 1,133 genes distinguishing peripheral T-cell lymphoma–not otherwise specified from ALK-negative anaplastic large-cell lymphoma were identified. Pathway analysis showed that genes discriminating peripheral T-cell lymphoma–not otherwise specified from angioimmunoblastic T-cell lymphoma were particularly involved in lipid metabolism, DNA replication, and regulation of cell cycle and that genes differ-

ing that molecular classifiers of 38 and 53 genes for predictive models of angioimmunoblastic T-cell lymphoma and ALK-negative anaplastic large-cell lymphoma, respectively, could maintain the same accuracy. In an independent validation set, the angioimmunoblastic T-cell lymphoma prediction model had a positive predictive value of ��% and negative predictive value of 8�% for an overall diagnostic accuracy of 77% and the ALK-negative anaplastic largecell lymphoma model had a positive

Our findings support the usage of [a molecular classifier] as an additional tool in the diagnostic workup of nodal [peripheral T-cell lymphoma]. —Pier Paolo Piccaluga, MD, PhD, and colleagues

entially expressed in peripheral T-cell lymphoma–not otherwise specified vs ALK-negative anaplastic large-cell lymphoma were significantly involved in regulation of apoptosis, protein kinase cascade, and immune response. In an independent test set, the angioimmunoblastic T-cell lymphoma prediction model had a positive predictive value of 100% and negative predictive value of 98% for overall accuracy of 98%. The ALK-negative anaplastic large-cell lymphoma prediction model had a positive predictive value of 8�% and negative predictive value of 100% for overall accuracy of 98%. Molecular classifiers based on a smaller number of genes were identified, with discriminant analysis show-

Molecular Profiling of Peripheral T-Cell Lymphoma ■ Overall accuracy of the molecular classifiers was 98% and 77% for

angioimmunoblastic T-cell lymphoma and 98% and 93% for ALK-negative anaplastic large-cell lymphoma in test and validation sets, respectively.

■ A gene-expression profile–based molecular classifier improved the

prognostic stratification of patients with peripheral T-cell lymphoma.

■ The findings support the use of a molecular classifier as an additional tool in the diagnostic workup of nodal peripheral T-cell lymphoma.

predictive value of 73% and negative predictive value of 9�% for overall accuracy of 93%. In addition, the molecular classifier model identified as peripheral T-cell lymphoma–not otherwise specified several cases of the disease with a Tfollicular helper phenotype but lacking a morphology consistent with either angioimmunoblastic T-cell lymphoma or peripheral T-cell lymphoma–not otherwise specified follicular variant. This finding supports other evidence indicating that a subset of peripheral T-cell lymphoma–not otherwise specified shares a T-follicular helper derivation but is distinct from angioimmunoblastic T-cell lymphoma.

Prognostic Performance It was also found that the molecular classifier improved the prognostic stratification of patients with peripheral T-cell lymphoma. Based on patients with complete information available, median follow-up of living patients was 1,088 days, median overall survival for the entire population was ��9 days, and 3-year overall survival rates were ��% for patients with ALK-negative

anaplastic large-cell lymphoma, 1�% for those with angioimmunoblastic T-cell lymphoma, and 19% for those with peripheral T-cell lymphoma–not otherwise specified. With conventional histopathology, the difference in median overall survival between ALK-negative anaplastic large-cell lymphoma and peripheral T-cell lymphoma–not otherwise specified showed only a trend toward significance (1,�8� vs 395 days, P = .�2); when cases were reclassified according to gene-expression profile, the difference became significant (1,570 vs 391 days, P = .011). No differences in survival were noted when peripheral T-cell lymphoma–not otherwise specified was compared with angioimmunoblastic T-cell lymphoma. In addition, the molecular classifier categorized as peripheral T-cell lymphoma–not otherwise specified all 1� cases of peripheral T-cell lymphoma with strong CD30 expression but lack of typical anaplastic large-cell lymphoma morphology for which a consensus histopathologic diagnosis could not be reached. Overall survival in these patients was significantly worse than that of patients with ALK-negative anaplastic large-cell lymphoma (median, 1,570 vs 333 days, P = .02). The investigators stated, “[T]hese results indicate a remarkable diagnostic accuracy for the [gene-expression profile–based molecular classifier] in discriminating [angioimmunoblastic T-cell lymphoma] and ALK-negative [anaplastic large-cell lymphoma] from [peripheral T-cell lymphoma–not otherwise specified]…. Our findings support the usage of [a molecular classifier] as an additional tool in the diagnostic workup of nodal [peripheral T-cell lymphoma].” n

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

Reference 1. Piccaluga PP, Fuligni F, De Leo A, et al: Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: Results of a phase III diagnostic accuracy study. J Clin Oncol. July 15, 2013. See Commentary on page 15

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JCO Spotlight

Viewpoint: Molecular Profiling Improves Classification of Nodal Peripheral T-Cell Lymphomas By Steven M. Horwitz, MD

ne of the primary obstacles we face in caring for patients with peripheral T-cell lymphomas is a too often inadequate response to chemotherapy with low rates of progressionfree and overall survival.1 And while more intensive treatment programs and the availability of novel agents give a greater hope for success, the management of these lymphomas remains a significant challenge for clinicians.2 However, a frequently overlooked issue by clinicians—but one well understood by pathologists—is the difficulty in reliably making these diagnoses. In the International T-cell Project, in which four hematopathologists independently reviewed cases of T-cell lymphoma, a consensus diagnosis among these experts was reached in only 75% of patients with peripheral T-cell lymphoma–not otherwise specified.1 Much of the difficulty in reproducing diagnoses in cases of peripheral T-cell lymphoma stems from the need to interpret a constellation of features of histology, immunohistochemistry, and molecular diagnostics, which, unlike many B-cell lymphomas, can vary widely even within a specific T-cell lymphoma subtype.

system refined the prognostic accuracy among several particularly problematic/overlap areas in T-cell lymphoma: distinguishing subjects with peripheral T-cell lymphoma–not otherwise specified who have a follicular helper T-cell phenotype from angioimmunoblastic T-cell lymphoma, and distinguishing high CD30-expressing peripheral Tcell lymphoma–not otherwise specified from ALK-negative anaplastic large cell lymphoma.

Clinician’s Perspective From the clinician’s perspective, these results beg the question: Does this matter? The 3-year overall survival ratesl for patients in this series were 1�%, ��%,

be small, so these differences are more hypothesis-generating than conclusive regarding whether one drug is superior for a certain subtype than another. Nonetheless, pralatrexate (Folotyn), while active in many subtypes of T-cell lymphoma, seems to have stronger activity in peripheral T-cell lymphoma–not otherwise specified compared to angioimmunoblastic T-cell lymphoma, with response rates of 35% vs 8%.� In a recent phase II study, the investigational HDAC inhibitor belinostat produced a ��% response rate among those with angioimmunoblastic T-cell lymphoma (��%)—higher than in peripheral T-cell lymphoma– not otherwise specified (23%) and sig-

The study by Piccaluga and colleagues demonstrates a useful new tool to refine the diagnostic accuracy of T-cell lymphomas. Its development comes from an increased understanding of these lymphomas and gives us a glimpse into the not-too-distant future... —Steven M. Horwitz, MD

Molecular Profiling Strategy Piccaluga and colleagues report a study using molecular profiling to improve the classification of peripheral T-cell lymphoma.3 From the pathology side of management, this appears to be a clear advance. First off, they report high diagnostic accuracy in their geneexpression profile–based molecular classification among the most common T-cell lymphoma subtypes of peripheral T-cell lymphoma–not otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-negative anaplastic large cell lymphoma. This supports the concept that these subtypes represent distinct pathologic entities. Second, their classification system appears to be accurate and feasible from formalin-fixed paraffin-embedded tissue. As such, it has the potential to be clinically useful and more than just a research tool. And third, there are clues that their Dr. Horwitz is a medical oncologist at Memorial-Sloan Kettering Cancer Center, New York.

and 19% for patients with angioimmunoblastic T-cell lymphoma, ALK-negative anaplastic large cell lymphoma, and peripheral T-cell lymphoma–not otherwise specified, respectively. And while the addition of gene-expression profiling refined these diagnoses to allow some statistical significance, the median survival for each subtype is still less than 50% at 3 years, and we would still approach all these patients with full-course combination chemotherapy. So, at present this may be a better tool to reliably assign a subtype or to stratify patients for clinical trials than a necessity in routine practice.

Changing Approach However, there are clues that the “one size fits all” approach that we have used for T-cell lymphomas may be changing. As our experience with T-cell lymphomas grows, we are more frequently seeing differential responses to new agents among the T-cell lymphoma subtypes. The studies tend to

nificantly higher than in ALK-negative anaplastic large cell lymphoma (15%).5 Brentuximab vedotin (Adcetris) is approved based on an 8�% response rate in relapsed anaplastic large cell lymphoma, which universally expresses CD30.� However, it also showed activity in a small study among other types of Tcell lymphoma with varying degrees of CD30 expression, including responses in 50% of patients with angioimmunoblastic T-cell lymphoma and 25% with peripheral T-cell lymphoma–not otherwise specified.7 Other examples include the use of a highly targeted therapy such as crizotinib (Xalkori) in ALK-positive anaplastic large cell lymphoma and the empirically noted high response rates with L-asparaginase among NK/T-cell lymphomas.8,9

Conclusion The study by Piccaluga and colleagues demonstrates a useful new tool to refine the diagnostic accuracy of T-cell lymphomas. Its development

comes from an increased understanding of these lymphomas and gives us a glimpse into the not-too-distant future, when a greater knowledge of the molecular basis of these diseases may be routinely incorporated into the choice of therapies and hopefully lead to real benefits for our patients. n

Disclosure: Dr. Horwitz is a consultant for Celgene, Spectrum, Millennium, Amgen, Janssen. He has received research support from Celgene, Kiowa Hakko Kirin, Infinity Pharmaceuticals, Spectrum Pharmaceuticals, Seattle Genetics, and Millennium.

References 1. �ose J, Armitage J, Weisenburger D: International T-Cell Lymphoma Project: International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol 2�:�12�-�130, 2008. 2. d’Amore F, Relander T, Lauritzsen GF, et al: Up-front autologous stemcell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol 30:3093-3099, 2012. 3. Piccaluga PP, Fuligni F, De Leo A, et al: Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: Results of a phase III diagnostic accuracy study. J Clin Oncol 31:3019-3025, 2013. �. O’Connor OA, Pro B, Pinter-Brown L, et al: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: Results from the pivotal PROPEL study. J Clin Oncol 29:1182-1189, 2011. 5. Horwitz S, O’Connor O, Jurczak W, et al: Belinostat in angioimmunoblastic Tcell lymphoma: Results from the pivotal BELIEF trial. 12th International Conference on Malignant Lymphoma. Abstract 153. Presented June 22, 2013. �. Pro B, Advani R, Brice P, et al: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. J Clin Oncol 30:2190219�, 2012. 7. Oki Y, Horwitz S, Bartlett NL, et al: Safety and efficacy of brentuximab vedotin for treatment of relapsed or refractory mature t-/NK-cell lymphomas. 12th International Conference on Malignant Lymphoma. Abstract 152. Presented June 22, 2013. 8. Gambacorti-Passerini C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma (correspondence). N Engl J Med 3��:775-77�, 2011. 9. Matsumoto Y, Nomura K, KandaAkano Y, et al: Successful treatment with Erwinia L-asparaginase for recurrent natural killer/T cell lymphoma. Leuk Lymphoma ��:879–882, 2003.

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JCO Spotlight Hematology

Obinutuzumab Shows Activity in Relapsed/Refractory Diffuse Large B-cell Lymphoma or Mantle Cell Lymphoma and Indolent Non-Hodgkin Lymphoma By Matthew Stenger

binutuzumab is a type II, glycoengineered, humanized anti-CD20 monoclonal antibody. In the phase II GAUGUIN studies reported in the Journal of Clinical Oncology by Franck Andre Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille and Gilles A. Salles, MD, PhD, of Hospices Civils de Lyon–Université de Lyon and their colleagues, obinutuzumab exhibited encouraging clinical activity and an acceptable safety profile in patients with relapsed/refractory diffuse

large B-cell lymphoma or mantle cell lymphoma and in patients with relapsed/refractory indolent nonHodgkin lymphoma (NHL).

Study in Aggressive NHL In the study by Dr. Morschhauser and colleagues,1 �0 patients with relapsed/refractory diffuse large B-cell lymphoma (n = 25) or mantle cell lymphoma (n = 15) were randomly assigned to receive eight 21-day cycles of obinutuzumab infusion as a flat dose of �00 mg on days 1 and 8 of cycle 1 and day 1 of cycles 2 to

8 (�00/�00-mg group, n = 21) or 1,�00 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,�00/800-mg group, n = 19). The �00/�00-mg group consisted of 10 patients with diffuse large B-cell lymphoma and 11 with mantle cell lymphoma, and the 1,�00/800-mg group consisted of 15 with diffuse large B-cell lymphoma and � with mantle cell lymphoma. Thirteen patients (�2%) in the �00/�00mg group and 12 (�3%) in the 1,�00/800-mg group had rituximab (Rituxan)-refractory disease.

Responses The response rate at the end of treatment was 28%, including 32% in the 1,�00/800-mg group and 2�% in �00/�00-mg groups. Best overall response rates were 37% in the 1,�00/800-mg group and 2�% in the �00/�00-mg group. Responses were observed in 32% of patients with diffuse large B-cell lymphoma and in 27% of patients with mantle cell lymphoma, including 2 of � with mantle cell lymphoma in the 1,�00/800-mg group. Five of 25 rituximab-refractory continued on page 18

Can Obinutuzumab Benefit Patients With Rituximab-Refractory Non-Hodgkin Lymphoma? By Julie M. �ose, MD

binutuzumab is a glycoengineered type II antibody that differs from type I anti-CD20 antibodies by being associated with actin reorganization and adhesion followed by direct cell death.1 Obinutuzumab has been glycoengineered by reduction in fucose content of the Fc region, which increases its affinity for Fcγ receptors in effector cells and confers greater antibody-dependent cellular cytotoxicity compared with nonglycoengineered antibodies.2 In preclinical studies, obinutuzumab has been shown to be superior to rituximab (Rituxan) in xenograft lymphoma models.2

Clinical Trials Phase I clinical trials demonstrated the safety of obinutuzumab; however, higher doses appeared to be necessary to saturate the CD20 receptors.3 The two phase II studies recently reported in Journal of Clinical Oncology explored obinutuzumab treatment in relapsed/ refractory indolent or aggressive nonHodgkin lymphoma. The study by Morschhauser et al included �0 patients with relapsed/refractory diffuse large B-cell or mantle cell lymphoma with dose-level ranDr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center, Omaha.

domizations. Responses were observed in 32% of the diffuse large B-cell lymphoma group and 27% of the mantle cell lymphoma group. Although these are modest response rates, there were a few patients with responses lasting longer than 2 years.

Potential Therapeutic Improvement These studies provide an excellent example of taking an engineered molecule that demonstrates possibly superior attributes in the lab and translating it to human clinical trials, with potential to

These studies provide an excellent example of taking an engineered molecule that demonstrates possibly superior attributes in the lab and translating it to human clinical trials, with potential to improve upon our current therapies with other antiCD20 monoclonal antibodies. —Julie M. Vose, MD

The trial by Salles et al examined obinutuzumab in patients with relapsed/refractory indolent lymphoma. The response rate was higher in the indolent lymphoma patients, with a best response rate of ��% and a median duration of response of 17.2 months (range, 0.8–31.3 months). The toxicity in both trials was modest, with some infusion reactions and two episodes of tumor lysis syndrome. There were no treatment-related deaths in the studies.

improve upon our current therapies with other anti-CD20 monoclonal antibodies. Due to the mechanism of action including increased antibody-dependent cellular cytotoxicity, there was concern that obinutuzumab would have increased toxicity, including infusion reactions. However, the clinical trials to this point have not demonstrated such toxicities. Based upon these and other studies, an obinutuzumab dose of 1,000 mg for all cycles has been chosen and is being moved forward in current phase II and III trials.

Obinutuzumab is also now being tested in several combination trials with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for front-line treatment of diffuse large B-cell lymphoma and with bendamustine (Treanda) for rituximab-refractory follicular lymphoma. Additionally, specific subtypes of lymphoma may respond better to different anti-CD20 antibodies based upon Fcγ receptors or other tumor biology characteristics. Only prospective randomized trials will be able to demonstrate superiority of obinutuzumab to rituximab in any of these clinical situations. n Disclosure: Dr. �ose reported no potential conflicts of interest.

References 1. Alduaji W, Ivanov A, Honeychurch J, et al: Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosomemediated cell death in B-cell malignancies. Blood 117:�519-�529, 2011. 2. Mossner E, Brunker P, Moser S, et al: Increasing the efficacy of CD20 antibody therapy through the engineered direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115:�393-��02, 2010. 3. Menesses-Lorente G, Carlile D, Birkett J, et al: Pharmacokinetics of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant diseases (phase I/II study BO20999). Blood 11�:Abstract 1833, 2010.

What if you could use the body’s own T cells to combat Lung Cancer? With Immuno-Oncology it may be possible. Current approaches to lung cancer treatment include radiation, surgery and chemotherapy/targeted therapy, all of which are intended to target the tumor. Through our ongoing clinical program, BMS is investigating an entirely new way to treat lung cancer by targeting the immune system. Our research is focused on transforming the way tumor cells and the immune system communicate, including checkpoint pathways; we hope to find new ways to stop lung cancer from evading the immune system, thereby restoring the body’s natural ability to fight it. If you’re interested in learning more about BMS investigational studies in lung cancer, including a list of study sites, please visit BMS Study Connect to search for lung cancer studies near you. http://www.bms.com/studyconnect/Pages/Home.aspx

ONCUS13UB00863-02-01

06/13

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Leading the way

The ASCO Post | SEPTEMBER 1, 2013

PAGE 18

JCO Spotlight

Obinutuzumab continued from page 16

patients exhibited response, including � of 12 in the 1,�00/800-mg group. Overall, the median response duration was 9.8 months and > � months in rituximab-refractory patients. Median progression-free survival was 2.7 months (range, 0.2–32.7 months) in the 1,�00/800mg group and 2.� months (range, 0.3–32.7 months) in the �00/�00mg group.

Toxicity The most common adverse events were infusion-related reactions (75% of patients), which were considered manageable. The most common grade 3 or � adverse events were lymphopenia (15%; 1�% in the �00/�00mg group and 1�% in 1�00/800-mg group), anemia (10%; 1�% and 5%),

infusion-related reactions (8%; 10% and 5%), and thrombocytopenia (8%; 10% and 0%). Grade 3 or � tumor lysis syndrome occurred in two patients in the �00/�00-mg group. Grade 3 or � neutropenia occurred in one patient. There were no treatment-related deaths.

Study in Indolent NHL In the second study by Dr. Salles and colleagues,2 �0 patients with relapsed/refractory indolent NHL, including 3� with follicular lymphoma, were randomly assigned to the 1,�00/800-mg (n = 22, 20 with follicular lymphoma) or �00/�00mg (n = 18, 1� with follicular lymphoma) obinutuzumab regimens described above. Rituximab-refractory disease was present in 12 (�7%) of the �00/�00-mg patients and 10 (�5%) of the 1,�00/800-mg patients.

Obinutuzumab in Lymphoma ■ Obinutuzumab exhibited an acceptable safety profile in patients with

relapsed/refractory diffuse large B-cell lymphoma and mantle cell lymphoma and relapsed/refractory indolent non-Hodgkin lymphoma (NHL).

■ Phase III studies in aggressive and indolent NHL are underway using a dose regimen of 1,000 mg for all cycles with doses on day 1, 8, and 15 of cycle 1.

Responses Response rates at the end of treatment were 55% in the 1,�00/800-mg group and 17% in the �00/�00-mg group, including response in 5 of 10 rituximab-refractory patients in the 1,�00/800-mg group and 1 of 12 in the �00/�00-mg group. Best overall response rates were ��% in the 1,�00/800-mg group and 33% in the �00/�00-mg group. Among patients with follicular lymphoma, response rates at the end of treatment were 50% in the 1,�00/800-mg group and 21% in the �00/�00-mg group, with best overall response rates of �0% and 3�%, respectively. The median response duration was 17.2 months (range, 0.8–31.3+ months) in all responders and 8.8 months in rituximab-refractory patients. Median progression-free survival was 11.9 months in the 1,�00/800mg group (range, 1.8–33.9+ months) and �.0 months in the �00/�00-mg group (range, 1.0–33.9+ months).

Toxicity The most common adverse events were infusion-related reactions (73% of patients), with two patients (9%) in the 1�00/800-mg group having grade 3 or � reactions. Overall, grade

3 or � adverse events occurred in four patients (22%) in the �00/�00-mg group and nine patients (�1%) in the 1,�00/800-mg group. Other grade 3 or � adverse events occurring in more than one patient were infection, lymphopenia, and neutropenia. No deaths occurred during treatment. Based on the encouraging activity observed in these studies and pharmacokinetic modeling, a simplified schedule using obinutuzumab 1,000 mg for all cycles, with doses on days 1, 8, and 15 of cycle 1, has been moved forward to phase III studies in both aggressive and indolent NHL. n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

References 1. Morschhauser FA, Cartron G, Thieblemont C, et al: Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. July 8, 2013 (early release online). 2. Salles GA, Morschhauser F, SolalCéligny P, et al: Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. July 8, 2013 (early release online).

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When hemoglobin falls...

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks. • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. • Use ESAs only for anemia from myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. • Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. • Control hypertension prior to initiating and during treatment with Aranesp®. • For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT *O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT %VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

i$FSFCSPWBTDVMBS EJTPSEFSTw FODPNQBTTFT $F/4 IFNPSSIBHFT BOE DFSFCSPWBTDVMBS BDDJEFOUT JTDIFNJD BOE IFNPSSIBHJD &WFOUT JO UIJT DBUFHPSZ NBZ BMTP CF JODMVEFE VOEFS iUISPNCPFNCPMJD BEWFSTF SFBDUJPOT w

Aranesp┬о EBSCFQPFUJO BMGB

Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 23

JCO Spotlight Neuro-oncology

No Event-Free Survival Difference With Chemotherapy Before vs After Radiotherapy in Children With High-Risk Medulloblastoma By Matthew Stenger

number of different strategies for combining chemotherapy and radiation therapy have been evaluated in the effort to improve survival in patients with high-risk medulloblastoma. In a trial (POG 9031) reported in Journal of Clinical Oncology, Nancy J. Tarbell, MD, of Massachusetts General Hospital, and colleagues in the Pediatric Oncology Group assessed the effects of chemotherapy before vs after radiotherapy following surgery in children with high-risk medulloblastoma.1 They found no difference in 5-year event-free survival with the two strategies.

Study Details In the trial, 22� patients aged 3 to 21 years with high-risk medulloblastoma were randomized after surgery to chemotherapy with three cycles of

The [event-free and overall survival] reported in this study compare favorably with other trials examining high-risk medulloblastoma. Preirradiation chemotherapy fails to confer a survival advantage over radiation before chemotherapy. —Nancy J. Tarbell, MD, and colleagues

cisplatin at 90 mg/m2 and etoposide at 150 mg/m2 over 7 weeks followed by radiotherapy (n = 112) = 112) 112) or radiotherapy followed by the same chemotherapy (n = 112). Patients were considered high risk if they had M1–� disease by modified Chang staging classification (see Table 1 on page 18), exhibited T3b/T� disease at time of surgery, or

had greater than 1.5 cm of residual tumor after surgery. Radiotherapy consisted of craniospinal irradiation of 35.2 to ��.0 Gy and posterior fossa boost of 53.2 to 5�.� Gy. All patients received consolidation chemotherapy consisting of vincristine and cyclophosphamide for 28 weeks. The median age was 7.8 3

years (range, 3.0–21.� years). The chemotherapy-first and radiotherapy-first groups were balanced for sex (55% and �2% male), race (79% and 7�% white), M stage (52% M0 in both groups), and T stage (3b or � in 73% and 70%); �0 patients in the chemotherapy-first group and 32 in the radiotherapy-first group were T3b/T� M0 with no residual disease.

Survival Outcomes Median follow-up was �.� years. Fiveyear event-free survival was ��.0% in the chemotherapy-first group and 70.0% in the radiotherapy-first group (P = .5�), and 5-year overall survival in the two groups was 73.1% and 7�.1% (P = .�7). There was no evidence of a difference in event-free survival between treatments after stratifying for stage. continued on page 24

Ongoing Progress in Treatment of Medulloblastoma By Karen J. Marcus, MD

rain tumors are the second most frequent pediatric malignancy. Medulloblastoma, a primitive cerebellar tumor of neuroectodermal origin, is the second most common brain tumor, accounting for 20% of childhood tumors of the central nervous system. Craniospinal radiotherapy has been the main curative modality, although the addition of chemotherapy has allowed children with standard-risk medulloblastoma to be successfully treated with lower doses of radiotherapy. Historically, children with highrisk medulloblastoma have a poor outcome, although more-recent clinical trials have attempted to improve outcome by intensifying therapy with systemic treatment.

trial in children with high-risk medulloblastoma testing chemotherapy given before vs after radiation therapy. There was no significant difference between

vival for these high-risk patients was encouraging, new biologic and molecular information is coming to light that can provide additional prognostic

Further insight into the biology of medulloblastoma, coupled with our knowledge of clinical factors and the results of studies such as this by Dr. Tarbell and colleagues, will allow us to devise and implement strategies for treatment that will continue to improve the outcome for all children with medulloblastoma. —Karen J. Marcus, MD

Encouraging Outcomes Dr. Tarbell and colleagues from the Pediatric Oncology Group reported in the Journal of Clinical Oncology the results of a prospective randomized Dr. Marcus is Division Chief, Pediatric Radiation Oncology, Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Brigham and Women’s Hospital, Harvard Medical School, Boston.

approaches in either 5-year event-free or overall survival. However, the outcomes for both approaches were encouraging. In this study, high-risk medulloblastoma was defined as M1–M� disease, meaning positive cerebrospinal fluid, metastatic disease in the brain, spine, or extraneural location, or residual local tumor of greater than 1.5 cm3. While the event-free and overall sur-

information and guide treatment in this setting—as in the settings of many other pediatric and adult malignancies.

Four Subtypes Molecular studies now classify medulloblastoma into four core subtypes based on gene-expression profiles: • Subtype 1 includes tumors with aberrations in the WNT signaling

pathway; these tend to occur in older children and adolescents and are associated with a very good outcome. • Subtype 2 tumors have aberrations in the sonic hedgehog pathway and tend to occur in children under 3 years of age, a population in which there is a favorable outcome. • Subtype 3 tumors are histologically either classic or large cell/anaplastic, have a variety of different genetic mutations including MYC amplification, and have the least favorable outcome compared to other subtypes. • Subtype � medulloblastomas are classic or large cell/anaplastic tumors with a CDK� amplification and other cytogenetic abnormalities. Their prognosis appears to be better than subtype 3 tumors. Further insight into the biology of medulloblastoma, coupled with our knowledge of clinical factors and the results of studies such as this by Dr. Tarbell and colleagues, will allow us to devise and implement strategies for treatment that will continue to improve the outcome for all children with medulloblastoma. n

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

The ASCO Post | SEPTEMBER 1, 2013

PAGE 24

JCO Spotlight

Medulloblastoma continued from page 23

In patients with M0 and residual disease after surgery, 5-year event-free survival was 59.�% in the chemotherapy-first group and �5.1% in the radiotherapy-first group (P = .�0). In patients with M+ and residual disease, 5-year eventfree survival was 51.2% and ��.0% (P = .20). Objective response rates in evaluable patients were ��% in the chemotherapy-first group and 8�% in the radiotherapy-first group (P = .01). There was no significant difference in 5-year event-free survival between patients in the chemotherapy-first group who achieved response and those who did not (73% vs 5�%, P = .1).

Patients with M0-1 disease received a median of 35.2 Gy craniospinal irradiation and 53.2 Gy to the posterior fossa, and patients with M2-3 disease received a median of �0 Gy craniospinal irradiation and 5�.� Gy to the posterior fossa, with these regimens not differing according to treatment group. The average overall radiotherapy treatment times were ��.3 days (standard deviation, 10.51 days) in the chemotherapy-first group and ��.8 days (standard deviation, 8.98 days) in the radiotherapyfirst group. Twenty-two patients in the chemotherapy-first group (20%) and 11 patients in the radiotherapyfirst group (10%) had more than 50 treatment days, with the difference approaching significance (P = .0�).

Chemotherapy/Radiotherapy Sequence in Medulloblastoma ■ There was no significant difference in event-free or overall survival between chemotherapy-first and radiotherapy-first groups.

■ There was no difference in event-free survival between treatments according to disease stage.

■ Event-free and overall survival reported in this study compare favorably with other trials in high-risk medulloblastoma.

M Stage Predicts Outcome On regression analysis, factors such as sex, race, and regimen were not significant predictors of event-free or overall survival, with M stage (see Table 1) being the only factor associated with outcome. The 5-year event-free survival rates were 22% for M� vs 70% for patients with M0, M1, M2, or M3 disease (P < .001). For M� patients, the

Table 1: Chang Staging System for Medulloblastoma T1

Tumor <3 cm in diameter

Tumor >3 cm in diameter

T3a

Tumor >3 cm in diameter with extension into aqueduct of Sylvius or foramen of Luschka

T3b

Tumor >3 cm in diameter with unequivocal extension into the brainstem

Tumor >3 cm in diameter with extension up past the aqueduct of Sylvius and/or down past the foramen magnum (ie, Beyond the posterior fossa)

No evidence of subarachnoid or hematogenous metastasis

Tumor cells found in cerebrospinal fluid

Intracranial tumor beyond primary site

Gross nodular seeding in spinal subarachnoid space

Metastasis outside the cerebrospinal axis (especially to bone marrow, bone)

Reprinted, with permission, from Chang CH, Housepian EM, Herbert C: An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351-1359, 1969.

relative risk for progression or relapse was four times higher (95% confidence interval [CI] = 1.9–8.9) vs patients with M0, M1, M2, or M3 disease, and the relative risk for death was �.3 times higher (95% CI = 2.0–9.� times). With regard to acute toxicity, there were more episodes of thrombocytopenia in the radiotherapy-first group, but toxicity was otherwise similar in the two groups. Treatment-induced disease included myelodysplastic syndrome in two patients and ossifying fibroma in one. The investigators concluded, “The [event-free and overall survival] reported in this study compare favorably with other trials examining high-risk medulloblastoma. Preirradiation chemotherapy fails to confer a survival advantage over radiation before chemotherapy.” n

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

Reference 1. Tarbell NJ, Friedman H, Polkinghorn WR, et al: High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol. July 15, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Steven J. O’Day, MD, on advanced melanoma see page 1

Paul Sabbatini, MD, on olaparib in patients with BRCA mutations see page 5

Pier Paolo Piccaluga, MD, PhD, on peripheral T-cell lymphomas see page 14

Michael P. Link, MD, on the future of cancer care see page 44

Barbara L. McAneny, MD, on community practice/health policy see page 63

Edward M. Schaeffer, MD, PhD, on active surveillance in prostate cancer see page 84

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JCO Spotlight Thoracic Oncology

Significant Improvement in Overall Survival Seen With Pemetrexed Maintenance After Pemetrexed/Cisplatin Induction in Patients With Advanced Nonsquamous NSCLC By Matthew Stenger

n the phase III PARAMOUNT trial, pemetrexed (Alimta) continuation maintenance therapy significantly reduced the risk of disease progression by 38% compared with placebo after pemetrexed/cisplatin induction in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). Final overall survival results were recently reported in the Journal of Clinical Oncology by Luis G. Paz-Ares, MD, of University Hospital �irgen del Rocío in Seville and colleagues, with pemetrexed maintenance being associated with a significant 22% reduction in risk of death.1 Updated safety results yielded no new findings, with drug-related grade 3 or � anemia, fatigue, and neutropenia being relatively infrequent but more common with pemetrexed.

patients, median overall survival was 13.9 months in the pemetrexed group and 11.0 months in the placebo group (hazard ratio [HR] = 0.78, P = .0195). One- and 2-year overall survival rates were 58% vs 32% and �5% vs 21%, respectively (both P < .05). Median overall survival from the time of induction was 1�.9 vs 1�.0 months (HR = 0.78, P = .0191). Hazard ratios for overall survival consistently favored pemetrexed for all patient subgroups (disease stage IIIB or I�, performance status at random-

Toxicity Pemetrexed maintenance was associated with significantly greater frequency of drug-related grade 3 or � anemia (�.�% vs 0.�%), neutropenia (5.8% vs 0%), and fatigue (�.7%

The decision to use maintenance therapy should be based on an individualized approach that includes patient-specific factors and wishes.

Trial Outcomes In the PARAMOUNT trial, 939 patients with advanced nonsquamous NSCLC received four cycles of pemetrexed/cisplatin induction therapy; 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were then randomly assigned to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles, n = 359) or placebo (n = 180). The mean number of maintenance cycles was 7.9 (range, 1–��) for pemetrexed patients and 5.0 (range, 1–38) for placebo patients. After a median follow-up of 12.5 months for all patients and 2�.3 months for surviving

additional therapy, with types of therapy being well matched between groups except for the more frequent use of docetaxel in the placebo group (�3% vs 32%). The majority of patients received an approved second-line treatment (either docetaxel or erlotinib [Tarceva]).

—Luis G. Paz-Ares, MD

ization, male or female, smoker or nonsmoker, age, and adenocarcinoma or other histology). Overall survival was numerically improved among patients with response on induction therapy (HR = 0.81, 95% confidence interval [CI] = 0.59–1.11) and those with stable disease on induction therapy (HR = 0.7�, 95% CI = 0.57–1.01); the study was not powered to detect differences between these subgroups. In total, ��% of pemetrexed patients and 72% of placebo patients received

Pemetrexed Maintenance in NSCLC ■ Pemetrexed maintenance reduced mortality risk by 22% compared with

placebo in patients with no progression and performance status of 0 or 1 after pemetrexed/cisplatin induction therapy.

■ Drug-related grade 3 or 4 anemia, neutropenia, and fatigue were

significantly more common with pemetrexed, although each had an incidence of < 7%.

vs 1.1%). The most frequent drugrelated grade 1 or 2 adverse events in the pemetrexed group were fatigue (17.5%), nausea (13.�%), and anemia (11.7%); grade 1 or 2 adverse events that were significantly more common with pemetrexed were anemia, neutropenia, leukopenia, increased AST, fatigue, nausea, vomiting, mucositis/ stomatitis in oral cavity, anorexia, eye watering, and fever. Treatment was discontinued due to potentially drug-related adverse events in 12.0% of pemetrexed patients and �.�% of placebo patients. Three deaths considered potentially drug-related occurred during maintenance treatment, due to pneumonia in one pemetrexed patient and sudden death–not otherwise specified and respiratory arrest in two placebo patients. There were no significant differences between patients receiving more

than six cycles of pemetrexed and those receiving fewer cycles with regard to toxicity of any grade or drug-related grade 3 or � laboratory toxicity; longer exposure was associated with a numeric increase in grade 3 or � neutropenia (9% vs �%, P = .0�2). Grade 3 or � infections occurred in 1.5% of patients receiving more than six cycles and 1.5% of those receiving six or fewer. The authors emphasized that since not all patients require maintenance therapy, as is shown by patients receiving placebo for multiple cycles without showing disease progression, additional studies are needed to identify patients who would benefit most from such treatment. They concluded, “Certainly, our understanding of optimal use of maintenance therapy will be furthered when several ongoing clinical trials are completed over the next few years. Then and now, the decision to use maintenance therapy should be based on an individualized approach that includes patient-specific factors and wishes. The results of the PARAMOUNT study provide evidence to direct those choices by providing new data on the benefits/risks of maintenance pemetrexed, supporting the use of continuation maintenance pemetrexed for patients with advanced nonsquamous NSCLC.” The study was supported by Eli Lilly. n Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Paz-Ares LG, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. July 8, 2013 (early release online). See Commentary on page 28

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A Phase III study of the pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in patients with HR+/HER2−, aromatase inhibitor-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor Postmenopausal women with HR+/HER2–, inoperable, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor (N≈615) Evidence of progression on or after mTOR inhibitor-based therapy No more than one prior line of chemotherapy for metastatic disease Archival tumor tissue for analysis of PI3K pathway activation

Molecular pre-screening*

ECOG Performance Status ≤2

Randomization (2:1)

Additional inclusion/exclusion criteria apply.

Buparlisib + fulvestrant

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival *Molecular pre-screening for PI3K activation status can occur at any time prior to randomization after obtaining pre-screening informed consent.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. For more information Contact your local Novartis representative. Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only). Visit www.clinicaltrials.gov (NCT01633060). Visit the PRI3M program website at www.pri3m.com or scan the QR code.

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 28

JCO Spotlight continued from page 26

Pemetrexed Maintenance in PARAMOUNT: Continuation Proves to Be a Strong Option for Advanced NSCLC, Although Not a Mandate By H. Jack West, MD

he PARAMOUNT trial1 represents an important landmark study of continuation maintenance therapy with pemetrexed (Alimta). While maintenance therapy gained a toehold in routine management of advanced non–small cell lung cancer (NSCLC) several years ago, the first trials that demonstrated a significant benefit for maintenance therapy employed a switch maintenance strategy. These trials were designed to switch patients to either pemetrexed in the JMEN trial2 or erlotinib (Tarceva) in the SATURN trial,3 with both demonstrating a significant improvement in progression-free and overall survival. (An underpowered trial demonstrated a significantly superior progression-free but not overall survival with early docetaxel after front-line gemicitabine/carboplatin.�) These trials led to pemetrexed and erlotinib each being approved as maintenance therapies for patients who hadn’t shown disease progression on first-line chemotherapy. Like the JMEN trial, which randomly assigned patients without disease progression after four cycles of a nonpemetrexed platinum-based doublet 2:1 to pemetrexed or placebo, PARAMOUNT pursued the same randomization, but only after all patients had demonstrated a response or stable disease after four cycles of cisplatin/pemetrexed. As in the JMEN trial with pemetrexed as switch maintenance, we now know that continuation maintenance with pemetrexed is also associated with a statistically and clinically significant improvement in progression-free and overall survival.

Study Limitations I consider these results to be impressive, but it’s also important to recognize that they don’t translate to a mandate to treat every eligible patient with maintenance therapy. Why not? Both the JMEN and SATURN trials suffered from (and also benefited from) a design that only administered the active drug at any time to about 80% of patients assigned to the placebo arm, thus compromising interpretation of the results—ie, the importance of Dr. West is Medical Director, Thoracic Oncology Program, Swedish Cancer Institute, Seattle.

maintenance therapy vs just receiving subsequent active therapy (or not). We therefore can’t know whether there is value in the timing of subsequent treatment or simply the access to it at all. The positive results from the PARAMOUNT trial convincingly demonstrate a comparable efficacy for maintenance chemotherapy. We don’t have a directly comparative trial of continuation vs switch maintenance therapy, but the PARAMOUNT data look every bit as good as the results from switch maintenance trials.

ticularly true with agents demonstrated to confer a survival benefit in previously treated patients with advanced NSCLC. However, this doesn’t mean that the treatment must necessarily be given immediately and without a break. There is no reason to believe that patients wouldn’t receive the exact same benefit if they resume a treatment like single-agent pemetrexed after a limited treatment break, whether that is defined as a fixed period of maybe 1 to 2 months or close follow-up with prompt reinitiation of treatment at an

Maintenance therapy strategies provide a reliable means for conferring that benefit, but there remains room for clinical judgment about whether an individual patient may be best served by continuation maintenance, switch maintenance, or a break from treatment. —H. Jack West, MD

The closest approximation we have available is the trial by Pérol et al,5 which randomly assigned patients who hadn’t shown progression after four cycles of cisplatin/gemcitabine to either continuation maintenance therapy with ongoing gemcitabine, switch maintenance erlotinib, or observation alone. Though not designed to directly compare continuation to switch maintenance therapy, the continuation maintenance therapy arm in the Pérol et al trial appeared numerically superior in the relative benefit in progression-free survival compared with observation alone, though neither arm demonstrated a significant improvement in overall survival.

Maximizing Benefit One very important point of this work is that both the PARAMOUNT and Pérol et al studies clearly illustrate that patients who haven’t demonstrated progression through first-line treatment can continue to benefit from the nonplatinum component well beyond an initial four cycles if it is likely to be tolerated well on an ongoing basis. This is par-

early sign of progression. To me, the real advantage of a maintenance approach is that it is the most reliable way to ensure that a patient actually receives the maximal benefit from the treatments available. It’s possible for disease to progress faster than anticipated, with patients missing an opportunity to receive subsequent therapy, but that doesn’t happen with a maintenance approach. Nevertheless, a treatment break may still be a very acceptable choice for individual patients. My personal view is that if continuation maintenance therapy is administered with an agent that is well-tolerated (as pemetrexed or, potentially, gemcitabine often is), then continuation maintenance therapy provides a way to maximize the benefit of further treatment without discarding a valuable therapy too early, and without initiating another treatment before it’s really needed. This is especially important because we don’t have an excess of treatments that remain effective in previously treated patients with advanced NSCLC. In contrast, I would be more inclined

to pursue switch maintenance therapy for people who haven’t shown progression and want, or are felt to need, maintenance therapy, but have experienced problematic, likely cumulative side effects from the first-line therapy.

Range of Options Maintenance therapy has become an established standard of care in the past several years. However, this setting after first-line therapy is one in which there remains a range of viable options. Collectively, the key trials on maintenance therapy illustrate very clearly that there is a striking benefit for effective subsequent therapy in patients who have not had progression after first-line therapy. Maintenance therapy strategies provide a reliable means for conferring that benefit, but there remains room for clinical judgment about whether an individual patient may be best served by continuation maintenance, switch maintenance, or a break from treatment. n

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

References 1. Paz-Ares L, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol July 8, 2013 (early release online). 2. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer. Lancet 37�:1�32-1��0, 2009. 3. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521-529, 2010. �. Fidias PM, Dakhil SR, Lyss AP, et al: Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 27:591-598, 2009. 5. Pérol M, Chouaid C, Pérol D, et al: Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 30:351�-352�, 2012.

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 29

Journal Spotlight Thoracic Oncology

Pattern in Lung Cancer Pathology May Predict Recurrence After Surgery

new study by thoracic surgeons and pathologists at Memorial Sloan-Kettering Cancer Center shows that a specific pattern found in the tumor pathology of some lung cancer patients is a strong predictor of recurrence. Knowing that this feature exists in a tumor’s pathology could be an important factor for physicians in guiding cancer treatment decisions. The study was published online in the Journal of the National Cancer Institute.1 According to the study’s authors, the findings offer the first scientific evidence that may not only help surgeons identify which patients are more likely to benefit from less radical lungsparing surgery, but which patients will benefit from more extensive surgery, potentially reducing the risk of lung cancer recurrence by 75%.

recurrence is high within the spared lobe of the lung. A lobectomy can reduce this chance of recurrence by 75%. If the micropapillary pattern is not

found, the surgeon can confidently perform lung-sparing surgery. n

Disclosure: For funding and author disclosures, visit jnci.oxfordjournals.org.

Reference 1. Nitadori J, Bograd AJ, Kadota K, et al: J Natl Cancer Inst. August 7, 2013 (early release online).

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Researchers retrospectively evaluated the clinical characteristics and pathology information of 73� patients who had surgery for early-stage adenocarcinoma and found that tumors in �0% of those patients exhibited an abnormal cell pattern strongly associated with cancer recurrence after surgery. No study to date has investigated the prognostic utility of this classification, called micropapillary morphology, for patients with small, early-stage lung adenocarcinomas. Currently there are no evidencebased criteria for choosing the most effective surgical approach for this group. The findings suggest that limited resection may not be appropriate for patients with the micropapillary pattern, as they were found to have a 3�% risk of the cancer returning within 5 years after lung-sparing surgery, or limited resection, in which the tumor is removed by minimally invasive means and lung function is preserved. In contrast, patients with the micropapillary pattern who underwent lobectomy had only a 12% incidence of recurrence over a 5-year period.

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Guiding Treatment Decisions The study observations may play a key role in deciding whether to perform lung-sparing surgery or lobectomy for patients with small lung adenocarcinomas. It currently takes an expert lung pathologist to identify the micropapillary pattern during an operation. If the surgeon performs lungsparing surgery in the presence of the micropapillary pattern, the chance of 1888 Berkshire Lane, Plymouth, MN 55441 | toll free: (877) 742-7177 | www.unitechmedicalinc.com

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PAGE 30

JCO Spotlight Thoracic Oncology

Bevacizumab/Pemetrexed Maintenance Increases Progression-Free Survival vs Bevacizumab Alone in Advanced Nonsquamous NSCLC By Matthew Stenger

aintenance therapy is associated with improved survival in non–small cell lung cancer (NSCLC), but few studies have compared active agents in this setting. In a phase III trial (A�APERL trial) reported in the Journal of Clinical Oncology by Fabrice Barlesi, MD, PhD, of Aix Marseille University–Assistance Publique Hôpitaux de Marseille, and colleagues, patients with advanced nonsquamous NSCLC who had disease control after first-line treatment with platinumbased chemotherapy plus bevacizumab (Avastin) had significantly prolonged progression-free survival with maintenance bevacizumab/pemetrexed (Alimta) compared with bevacizumab alone.1 Toxicity was increased with bevacizumab/pemetrexed, although no new safety signals were observed.

Study Details In this open-label multicenter trial, 37� patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/ m2, and pemetrexed 500 mg/m2 once every 3 weeks for four cycles. Of these, 2�9 (72%) achieved disease control

(response in 23% and stable disease in �9%) and 253 (�7%) were randomly assigned to receive maintenance bevacizumab 7.5 mg/kg alone (n = 125) or with pemetrexed 500 mg/m2 (n = 128) once every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from the time of randomization. For the bevacizumab/pemetrexed and bevacizumab groups, median age was �0 years in both (< �5 years for 70% of both), 58% and 57% of patients were male, Eastern Cooperative Oncology Group performance status at randomization was 0 or 1 in 98% and 9�%, 9�% and 89% had stage I� disease, 8�% and 92% had adenocar-

In patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant progression-free survival benefit compared with bevacizumab alone. —Fabrice Barlesi, MD, PhD

cinoma, 75% and 7�% were current or former smokers, 37% and 3�% had centrally located lung tumors, and 5% and �% had a cavitated tumor.

Maintenance Bevacizumab/Pemetrexed in Advanced NSCLC ■ Bevacizumab/pemetrexed maintenance prolonged progression-free

survival compared with bevacizumab alone in unselected patients with disease control after first-line platinum-based therapy plus bevacizumab.

■ Increased progression-free survival was seen in both patients with partial response and those with stable disease after induction therapy.

■ Bevacizumab/pemetrexed was associated with greater toxicity, but both regimens were generally well tolerated.

Prolonged Progression-Free Survival At a median follow-up of 8.1 months, progression-free survival from the time of randomization was 7.� months in the bevacizumab/ pemetrexed group vs 3.7 months in the bevacizumab group (hazard ratio [HR] = 0.�8, P < .001) in an analysis stratified by sex, smoking status, and induction response. The outcome was similar on stratified analysis of progression-free survival from first induction (median, 10.2 vs �.� months, HR = 0.50, P < .001). Pro-

Non–Small Cell Lung Cancer Maintenance Therapy: None, Single Agent, Multiple Agents? By Philip D. Bonomi, MD

arlesi et al have reported results of a randomized trial comparing bevacizumab (Avastin) vs pemetrexed (Alimta)/bevacizumab as maintenance therapy in patients with stage I� nonsquamous cell non–small cell lung cancer (NSCLC). It is important to consider their observations in relation to data from other maintenance trials and in relation to perceptions regarding maintenance therapy. Currently, opinions regarding maintenance therapy range from strong advocacy to nihilism based on the premises that treatment holidays are good and that outcome will be similar providing second-line therapy is initiated immediately upon identification of tumor progression. Prior Dr. Bonomi is Director of the Division of Hematology and Oncology at Rush University Medical Center, Chicago.

to addressing these divergent views, it is instructive to review data from the Barlesi et al study and from other trials.

Increasing Interest in Maintenance Chemotherapy Prior to 2009, results of relatively small randomized trials in patients with stage I� NSCLC did not provide a clear answer regarding the role of maintenance chemotherapy. A metaanalysis that included 13 randomized maintenance therapy trials and 3,027 patients provided some clarification. This analysis showed superior progression-free survival (hazard ratio [HR] = 0.75, P = .0001) and superior overall survival (HR = 0.92, P = .03) in patients treated with maintenance chemotherapy. Comparison of newer treatments (third-generation regimens) vs older regimens revealed su-

perior progression-free survival with third-generation regimens (P = .003). Although the survival benefit was marginal and adverse events were more frequent in patients receiving maintenance chemotherapy, there was increased interest in studying maintenance therapy, particularly with newer chemotherapeutic agents. Docetaxel was the first drug tested in this setting. The design of the docetaxel study was based on the hypothesis that switching to a different drug as maintenance therapy might be cytotoxic for tumor cells that were resistant to the induction regimen. Treatment-naive patients with stage I� NSCLC were randomly assigned to immediate vs delayed docetaxel following treatment with four cycles of first-line gemcitabine/cisplatin, providing disease was controlled at completion of first-line treatment. Progression-free survival was supe-

rior in patients treated with immediate docetaxel, and, despite a trend for superior overall survival in patients treated with immediate docetaxel, the survival difference was not significant.

Pemetrexed Trials Subsequently, pemetrexed maintenance therapy was tested in two randomized studies. Like the docetaxel maintenance trial, the first pemetrexed study tested a switch maintenance strategy. In this trial, patients with stage I� NSCLC were treated initially with a nonpemetrexed platinum doublet. Patients who achieved objective tumor regression or stable disease after four cycles of firstline therapy were randomly assigned to pemetrexed maintenance or placebo. Both progression-free survival (HR = 0.50, P = .001) and overall survival (HR = 0.79, P = .012) were signifcontinued on page 31

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 31

JCO Spotlight

gression-free survival was prolonged in the bevacizumab/pemetrexed group both among patients with partial response (8.� vs 3.9 months, HR = 0.�2, P < .001) and those with stable disease (�.8 vs 3.3 months, HR = 0.�3, P = .03�) after induction, and progression-free survival benefit also extended across age, performance status, and smoking history subgroups. After progression, 39% of patients

NSCLC Maintenance Therapy continued from page 30

icantly prolonged in patients receiving pemetrexed maintenance. Subset analysis revealed that the benefit was limited to patients with non–squamous cell lung cancer with hazard ratios of 0.�� (P < .0001) for progression-free survival and 0.70 (P = .002) for overall survival. In addition, there was a significant interaction difference for treatment by histology (P = .033). The subsequent pemetrexed maintenance trial evaluated the concept of continuation maintenance. Based on the observation in the previous trial that treatment benefit was limited to patients with non–squamous cell cancers, patients with squamous cell histology were excluded. It is noteworthy that this is the largest maintenance trial in this setting and that the population of patients with nonsquamous disease constitutes a relatively large group of patients. In the first study, 72% (�81/��3) of the patients had nonsquamous histology. In the second trial, 939 patients were enrolled and received four cycles of pemetrexed/carboplatin. Then, 539 patients were randomly assigned to maintenance pemetrexed vs placebo, providing there was no evidence of tumor progression. Outcomes were similar to results from the prior maintenance trial, with progression-free survival (HR = 0.50, P < .0001) and overall survival (HR = 0.79, P = .012) being longer in patients treated with pemetrexed continuation maintenance.

Bevacizumab vs Pemetrexed/ Bevacizumab Maintenance Barlesi et al designed a randomized trial in which patients with nonsquamous NSCLC and disease control after four cycles of pemetrexed/cisplatin plus bevacizumab were randomly assigned to bevacizumab vs pemetrexed/

in the bevacizumab/pemetrexed group and 57% of those in the bevacizumab group received subsequent treatment, with the most common being tyrosine kinase inhibitors (2�% and 33%) and taxanes (12% and 28%).

Overall Survival and Response Rates Median overall survival from randomization was not yet reached in bevacizumab maintenance. The induction regimen was given to 37� patients, and 253 were subsequently randomly assigned to maintenance therapy. Progression-free survival was significantly longer in patients who received pemetrexed/bevacizumab maintenance (HR = 0.��, P < .001). Although there was a trend for superior overall survival with pemetrexed/bevacizumab (HR = 0.75, P = .219), the study was not powered to to address overall survival.

Role of Pemetrexed/ Carboplatin/Bevacizumab If Barlesi et al’s trial design had compared maintenance pemetrexed vs pemetrexed/carboplatin, it would have provided important information regarding the role of bevacizumab

the bevacizumab/pemetrexed group and 12.8 months in the bevacizumab group (HR = 0.75, P = .219). After median follow-up of 10.9 months from time of first induction, median overall survival was not reached in the bevacizumab/pemetrexed group and 15.7 months in the bevacizumab group (HR = 0.75, P < .23). The best overall response rates (all partial responses) during the induction and maintenance period doublets improves overall survival, the accompanying editorial contended that survival benefit is limited to the combination of bevacizumab with paclitaxel/ carboplatin. The triplet regimen consisting of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/ bevacizumab has been evaluated by Barlesi et al and two additional groups of investigators. Each group observed acceptable toxicity during induction and maintenance phases with this regimen. Patel et al’s trial compared pemetrexed/carboplatin/ bevacizumab followed by pemetrexed/bevacizumab maintenance vs paclitaxel/carboplatin/ bevacizumab followed by bevacizumab maintenance. Survival was the primary

The objective of maintenance therapy in patients with stage IV NSCLC should be improved overall survival without excessive toxicity and with acceptable cost. —Philip D. Bonomi, MD

maintenance. In a large trial comparing paclitaxel/carboplatin/bevacizumab followed by bevacizumab maintenance vs paclitaxel/carboplatin, superior survival was observed in patients treated with the bevacizumab regimen. It has been assumed that bevacizumab maintenance contributed to the survival advantage of the triplet regimen. However, the survival impact of maintenance bevacizumab has not been addressed in a randomized trial. In addition to the maintenance question, the role of bevacizumab with nonpaclitaxel regimens is not clear. While a recent meta-analysis suggested that adding bevacizumab to platinum

endpoint of this study. While superior progression-free survival was observed with the pemetrexed regimen, overall survival was not significantly different. These results suggested that inclusion of bevacizumab maintenance might be necessary for the pemetrexed regimen to achieve similar efficacy to the paclitaxel/bevacizumab regimen. However, results from a smaller randomized trial presented at the 2013 ASCO meeting showed similar survival with pemetrexed/carboplatin followed by maintenance pemetrexed compared to paclitaxel/carboplatin/bevacizumab followed by bevacizumab maintenance. Although not powered to address sur-

were 55.5% in the bevacizumab/ pemetrexed group and 50.0% in the bevacizumab group (P = .878). Median duration of response (9.2 vs 5.7 months, P = .00�) and median duration of disease control (7.8 vs �.9 months, P < .001) were significantly longer in the bevacizumab/pemetrexed group. A preliminary analysis of health-related quality of life found no significant differences between Continued on page 32

vival, the study suggests that combining bevacizumab with pemetrexed/ carboplatin may not add benefit.

Closing Thoughts In summary, the objective of maintenance therapy in patients with stage I� NSCLC should be improved overall survival without excessive toxicity and with acceptable cost. Maintenance pemetrexed alone, bevacizumab alone, and pemetrexed/bevacizumab are associated with acceptable toxicity. Although some physicians do not embrace maintenance pemetrexed because mandatory crossover to pemetrexed was not required in the two trials discussed, these large randomized placebo-controlled trials provide convincing evidence that switch or continuation pemetrexed maintenance after a platinum doublet significantly prolongs overall survival. Does adding bevacizumab to pemetrexed maintenance improve survival? The Barlesi et al trial comparing bevacizumab vs pemetrexed/bevacizumab maintenance and another study testing bevacizumab vs pemetrexed maintenance were not powered to address overall survival. In addition, interpretation of maintenance treatment effect in two trials that tested a paclitaxel/ bevacizumab–containing regimen vs a pemetrexed regimen might be confounded by a potentially more favorable interaction of bevacizumab with paclitaxel. The ongoing Eastern Cooperative Oncology Group (ECOG) E5508 trial, in which non–squamous cell NSCLC patients are randomly assigned to bevacizumab vs pemetrexed vs pemetrexed/bevacizumab after completion of four cycles of paclitaxel/carboplatin/bevacizumab, will have important clinical and economic implications for maintenance therapy. n Disclosure: Dr. Bonomi reported no potential conflicts of interest.

The ASCO Post | SEPTEMBER 1, 2013

PAGE 32

JCO Spotlight

NSCLC Maintenance Therapy continued from page 31

patients in the maintenance arms; full quality-of-life results are to be reported elsewhere.

Toxicity Any grade, grade ≥ 3, and serious adverse events were more common with bevacizumab/pemetrexed maintenance. The most common adverse events of any grade during maintenance treatment were nausea (23% and 12%), hypertension (22% and 18%), and asthenia (1�% and 8%); hemoptysis of any grade occurred in 2.�% and 1.7% of patents. Grade ≥ 3 adverse events occurred in 38% of bevacizumab/pemetrexed patients and 22% of bevacizumab patients, including hematologic toxicities in 10% and 0% and nonhematologic toxicities in 31% and 22%; the most common were neutropenia (5.�%), hypertension (�.8%), and anemia (3.2%) in the bevacizumab/pemetrexed group and hypertension and dyspnea (2.5% each) in the bevacizumab group. There were no cases of grade ≥ 3 pulmonary hemorrhage in either group, and no treatment-related deaths were observed. Serious hematologic adverse events occurred in 1.�% of the bevacizumab/ pemetrexed group and in 0% of the bevacizumab group, and serious nonhematologic adverse events occurred in 17% and 13%, respectively; the most common events were pneumonia (1.�%) and pulmonary embolism (0.8%) in the bevacizumab/pemetrexed group and pulmonary embolism (1.7%) in the bevacizumab group. Adverse events

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.

led to discontinuation of bevacizumab in 9% of the bevacizumab group and to discontinuation of bevacizumab in 18% and pemetrexed in 17% of the bevacizumab/pemetrexed group. The investigators concluded, “In an unselected population of patients with nonsquamous NSCLC who had achieved disease control

with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant progressionfree survival benefit compared with bevacizumab alone. The combination was well tolerated.” n Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Barlesi F, Scherpereel A, Rittmeyer A, et al: Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non–small-cell lung cancer: A�APERL (MO22089). J Clin Oncol. July 8, 2013 (early release online).

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ASCOPost.com | SEPTEMBER 1, 2013

PAGE 33

FDA Update

FDA Approves First Rapid Diagnostic Test to Detect Both HIV-1 Antigen and HIV-1/2 Antibodies

he U.S. Food and Drug Administration (FDA) approved the first rapid human immunodeficiency virus (HI�) test for the si-

multaneous detection of HI�-1 p2� antigen as well as antibodies to both HI�-1 and HI�-2 in human serum, plasma, and venous or fingerstick

whole blood specimens. Approved for use as an aid in the diagnosis of HI�-1 and HI�-2 infection, the Alere Determine HI�-1/2 Ag/Ab

Combo test is also the first FDAapproved test that independently distinguishes results for HI�-1 p2�

antigen and HI� antibodies in a single test. The test can be used by trained professionals in outreach settings to identify HI�-infected individuals who might not be able to be tested in traditional health care settings. The test does not distinguish between antibodies to HI�-1 and HI�-2, and is not intended to be used for screening of blood donors.

Earlier Detection Possible

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Detection of HI�-1 antigen permits earlier detection of HI�-1 infection than is possible by testing for HI�-1 antibodies alone. The test can distinguish acute HI�-1 infection from established HI�-1 infection when the blood specimen is positive for HI�-1 p2� antigen but is negative for HI�-1 and HI�-2 antibodies. “This test helps diagnose HI� infection at an earlier time in outreach settings, allowing individuals to seek medical care sooner,” said Karen Midthun, MD, Director of the FDA’s Center for Biologics Evaluation and Research. “Earlier diagnosis may also help to reduce additional HI� transmission.” HI� infection can result in the development of acquired immune deficiency syndrome, or AIDS. HI� damages the body’s defense mechanisms by destroying specific blood cells, called CD�+ T cells, which are crucial to helping the body fight diseases. Two types of HI� have been identified, HI�-1 and HI�-2. HI�-1 is responsible for most HI� infections throughout the world. HI�-2 is found primarily in West Africa; however, cases of HI�-2 infection have been reported in North America and Europe. The Alere Determine HI�-1/2 Ag/Ab Combo test is manufactured by Orgenics, Ltd, of Yavne, Israel. n

The ASCO Post | SEPTEMBER 1, 2013

PAGE 34

Journal Spotlight Survivorship

Fertility Rates in Childhood Cancer Survivors Suggest Strategies for Follow-up Care By Caroline McNeil

hildhood cancer survivors with clinical infertility have a good chance of achieving pregnancy, according to new findings from the Childhood Cancer Survivor Study (CCSS).

Study Background As a group, women who survive childhood cancer are known to have lower fertility rates. This study, however, focused on survivors with functioning ovaries who wanted to get pregnant, comparing them to a control group of sisters of childhood cancer survivors. The survivors were more likely to have clinical infertility, meaning they had tried to get pregnant for at least a year without success. However, 64% of the survivors with clinical infertility eventually conceived, about the same rate as women in the general

of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and senior author of the study. “It’s important to get infertility experts involved earlier rather than later,” she said. “That’s one important message from this study.” Published recently in Lancet Oncology,1 the study included 3,531 women who had been diagnosed with cancer before age 21 and 1,366 sibling survivors, all participants in the ongoing, multicenter CCSS. The researchers used questionnaires to gather data on participants’ infertility, medical treatment for infertility, and time to first pregnancy.

Treatment Gap A second important message from the study concerns infertility treatment. Among participants with clinical infertility, about the same

It’s important to get infertility experts involved earlier rather than later. That’s one important message from this study. —Lisa R. Diller, MD

population with clinical infertility. The results challenge the common view that childhood cancer survivors who have trouble getting pregnant are likely to be infertile. Moreover, these findings suggest strategies that may optimize a survivor’s chances of getting pregnant. The survivors with clinical infertility were younger on the whole than those in the sibling control group with clinical infertility, and infertility increased with age as expected in both groups. Overall, 13% of survivors had clinical infertility compared to 8% of the sisters. The gap was especially wide at younger ages. That suggests survivors could benefit from infertility counseling and treatment in their 20s, rather than waiting as many women do until they are in their 30s or older, said Lisa R. Diller, MD, Chief Medical Officer

proportion of survivors and controls (~70%) sought help from infertility specialists. However, significantly fewer survivors received drug treatments commonly prescribed for infertility; 42% of these survivors received drugs, compared to 75% of their siblings. That finding came as a surprise. “We have no idea why…. It’s kind of a mystery,” said Elizabeth Ginsburg, MD, Medical Director of Assisted Reproductive Technologies at Brigham and Women’s Hospital, Boston, and a coauthor of the study. Possibly the women themselves declined drugs because of past medical experiences, she conjectured. Or they and their doctors may have been concerned about comorbidities, such as the heart problems that can result from anthracycline use. Dr. Ginsburg said that in the

Elizabeth Ginsburg, MD

Brigham and Women’s survivorship clinic, patients ask two main questions about infertility treatments: Could their cancer treatments have put future offspring at risk of birth defects or other problems? And would the infertility treatment increase their own risk of cancer recurrence? There’s no evidence to suggest that the answer is yes to either of these questions, she said, but it is still a common concern. “Whatever the specific reason, there seems to be generally more trepidation on the part of cancer survivors,” she said. There is also the possibility of low expectations on the part of providers. “My guess is that people just think it’s not going to work,” said Dr. Diller. “Without this data in front of you, you might think there was no chance. The study gives you a cohort to which you can compare your individual patient.” Dr. Ginsburg agreed: “We’re hoping that as more studies like this one appear, there will be greater awareness that it’s better to address fertility issues early and that survivors can benefit from treatment,” she said. Perhaps the most important group to reach with the new data are

Susan Lindemulder, MD

the youngest adult survivors, those in their early 20s. In the survivorship clinic at Oregon Health and Science University (OHSU)/Doernbecher

Children’s Hospital, providers routinely discuss fertility whether the patient brings it up or not, said Susan Lindemulder, MD, who leads the clinic. Also routinely, they offer referrals to OHSU’s reproductive endocrinology department. “But it’s a minority who choose to do that,” said Dr. Lindemulder. “One of the mental barriers is that these young survivors are not ready to have children. We have a very frank discussion and tell them not to follow societal norms [waiting until their 30s], but it’s still hard for them to get beyond their current priorities in life, especially the young 20s.”

Richard A. Anderson, MD, PhD

Early Collaboration The findings also highlight the importance of early collaboration between oncologists and reproductive medicine experts in order to preserve fertility, according to Richard A. Anderson, MD, PhD, Professor of Clinical Reproductive Science and Head of Obstetrics and Gynaecology at the MRC Center for Reproductive Health, University of Edinburgh, who wrote an editorial accompanying the study.2 “Fertility preservation is now part of mainstream fertility treatment,” he writes, “but requires seamless links between oncologists and reproductive medicine.” For girls who have reached puberty, it is possible to collect and freeze oocytes. But for younger patients, the only option is collecting and freezing ovarian tissue for future implantation, a still experimental procedure performed only in the research setting. The new findings also reinforce the importance of coordination between oncologists and physicians continued on page 38

DECODE metastatic melanoma. EXTEND survival. The first BRAF inhibitor shown to significantly extend overall survival (OS) vs dacarbazine in BRAF V600E (+) patients with unresectable or metastatic melanoma.*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

*Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF速 (vemurafenib) tablets 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

EXTEND SURVIVAL Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60 Not reached

7.9

40 20 0

ZELBORAF (n=337)

6 8 OS (months)

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Learn more at Zelboraf.com/SURVIVAL

Significant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response with ZELBORAF vs 5.5% with dacarbazine (95% CI; 41.6%-55.2% vs 2.8%-9.3%; P<0.001) There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade 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 required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed June 24, 2013. 2. 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. 3. Data on file. Genentech, Inc.

The ASCO Post | SEPTEMBER 1, 2013

PAGE 38

Journal Spotlight

Fertility Rates continued from page 34

who provide follow-up care to cancer survivors. Many large cancer centers have follow-up programs for survivors, but eventually most patients transition as adults to a primary care physician. Some centers have transition programs that support both

the primary care physician and the patient. Typically, a treatment summary and a survivorship care plan are prepared for each patient. Still, many young adult survivors are lost to follow-up. “That is sort of a Pandora’s box,” said Dr. Lindemulder. “It’s Safety:7" the classic young adult thing—they feel indestructible.

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. 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 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily. Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure. ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine. Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade Grade All Grade All All Other Malignancies Grades 3a Grades 3 Grades 3a (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies. Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can 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)].

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. 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.

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

0 24 0

8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

<1 22 <1

0 <1 1

0 <1 0

30 24 14

8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, 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 Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

Reference 1. Barton SE, Najita JS, Ginsburg ES, et al: Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 14:873-881, 2013. 2. Anderson RA: Infertility in women after childhood cancer. Lancet Oncol 14:797798, 2013.

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

Disclosure: The study was funded by the National Cancer Institute, American Lebanese Syrian Associated Charities, and Swim Across America.

7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

33 45 23 24 9 8 19 5 14

21 24 10

follow-up care to adult primary care: www.survivorshipguidelines.org. “If we can incorporate the data from the current study into the guidelines, it could help change practice no matter where the care is taking place,” Dr. Diller said. n

Safety:10"

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

Later, around age 30, it’s different, they are finding us.” She and her colleagues talk with colleges and universities and local pediatricians to try to reach these youngest adults. Another effort to help survivors get the care they need is the Children’s Oncology Group’s guidelines for the transition from childhood cancer

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

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

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 39

Issues in Oncology Technology

Integrating Genomic Sequencing Into Clinical Care

Six studies are underway to determine the medical, ethical, and financial feasibility of the routine mapping of patients’ genes. By Jo Cavallo

lthough the price of next-generation genomic sequencing is coming way down, making it available to more people interested in determining their risk for disease, figuring out how to interpret the results and applying that information in the routine medical care of individual patients remains a complex issue, especially for diseases like cancer. What diseases or individual susceptibilities will be most usefully addressed by genomic sequencing and how physicians—many of whom are unfamiliar with interpreting largescale genomic data—can incorporate that data into real-world clinical applications is the subject of the Clinical Sequencing Exploratory Research (CSER) program, which was launched by the National Human Genome Research Institute in 2011. The program is designed to study the methods needed to integrate whole-genome and whole-exome sequencing into the clinical care setting and explore the ethical and psychosocial issues raised by applying personal genomic data to medical care, including the implications of reporting unintended findings. The program will also seek to identify best practices and develop methods on how best to disseminate the information to physicians and patients. To accomplish these goals, last year, CSER began awarding multimillion-dollar 4-year grants to a consortium of clinicians, researchers, bioinformaticians, and ethicists at six institutions. The academic centers and their areas of investigation include Baylor College of Medicine, Houston (Incorporation of Genomic Sequencing Into Pediatric Cancer Care); Brigham and Women’s Hospital, Boston (Integration of Whole Genome Sequencing Into Clinical Medicine); Children’s Hospital of Philadelphia (Applying Genomic Sequencing in Pediatrics); Dana-Farber Cancer Institute, Boston (The Use of Whole-Exome Sequencing to Guide the Care of Cancer Patients); University of North Carolina, Chapel Hill (NC GENES [ncgenes.org], which is establishing best practices to guide implementation of genom-

ic technologies to improve human health); and the University of Washington, Seattle (Clinical Sequencing in Cancer: Clinical, Ethical, and Technological Studies). These clinical sequencing projects will be divided into three areas:

team studying integration of wholegenome sequencing into clinical medicine. “Our challenge is to set up a process to orient and train physicians in this sequencing technology, which they didn’t learn in medical school, and give them the tools and

In addition to wanting to know how useful data from whole-exome sequencing is to clinicians, we also want to know if the information transforms their ability to guide clinical trial enrollment. —Levi Garraway, MD, PhD

integrating genomic sequencing into patient care, sequencing and analyzing the data, and studying the experiences of physicians and patients.

Determining the Right Amount of Knowledge “Before DNA sequencing becomes widely accessible to physicians or directly to patients through commercial laboratories, we are interested in learning what we find when looking at the genome of a generally healthy adult or an adult with a specific disease—in our case, cardiomyopathy—and ask the question, how will physicians and patients understand and use this type of information in health care?” said Denise M. Lautenbach, MS, Genetic Counselor and Project Manager of MedSeq Project, Brigham

Denise M. Lautenbach, MS

and Women’s Hospital and Harvard Medical School, Division of Genetics, in Boston, and a member of the

resources to navigate this information with their patients.” The study at Dana-Farber Cancer Institute is investigating the creation of a workable model for the integration of clinical sequencing into cancer care, as well as examining patient preferences for the type of data they want to receive. The study researchers are in the process of sequencing the whole exomes of 400 patients with solid tumor cancers, primarily lung and colon cancer, to determine, in part, the usefulness of generating whole-exome level sequencing data. (In contrast, several academic cancer centers are sequencing just targeted mutation or gene panels.) Enrollment began earlier this year and currently there are nearly 50 patients in the study. The Broad Institute of MIT and Harvard will do the exome sequencing and both Broad and Dana-Farber will review the data. The patients are asked at the time of consent about whether they want to receive incidental results—for example, information about a gene that predicts an increased risk for Alzheimer’s disease—and the experiences of those patients who opted in to receive the information will be assessed. Patients will also be given the opportunity to have genetic counseling at any point during the study. About 27 oncologists will also be surveyed

about their experiences receiving and using the data. “In addition to wanting to know how useful data from whole-exome sequencing is to clinicians, we also want to know if the information transforms their ability to guide clinical trial enrollment. We’re trying to understand if having all this information is a good or a bad thing or somewhere in-between,” said Levi Garraway, MD, PhD, Associate Professor of Medicine, Harvard Medical School and Dana-Farber Cancer Institute and co–lead investigator of the whole-exome sequencing study.

Dividing Mutations Into Actionable Strategies To help answer that question, Dr. Garraway’s group is developing a strategy to place sequencing data into two-tier mutation categories. “The top tier of information would include actionable mutations like EGFR with MET amplification. The second tier would also include information that is potentially actionable based on literature showing these genes are linked to druggable pathways,” said Dr. Garraway. “Some oncologists may look at the top tier and say ‘If I don’t see anything interesting in the data, I’m not going to use the information.’ Others might say, ‘I’ve run out of options for my patient so I’m going to dig deeper into the data because it may help me find a clinical trial that I wouldn’t have thought of before,’” he said. The study will also evaluate the psychological impact on patients of having this level of genomic detail. “We presume that having genetic information is a good thing, but it may not be. Or if the information is presented and reported in the wrong way, it may end up being confusing and overwhelming and cause patients more anxiety rather than be empowering for them,” said Dr. Garraway.

Factoring in Cost In addition to learning about the medical impact—and benefit—of whole-genome and whole-exome sequencing, the CSER projects are also continued on page 40

The ASCO Post | SEPTEMBER 1, 2013

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Issues in Oncology

Genomic Sequencing continued from page 39

investigating the economic impact of the ubiquitous use of this type of screening on a health-care system already buckling under the weight of soaring costs. “Even as the cost of whole-genome sequencing comes down, there is still the cost of manpower to interpret, report, and update the results,” said Ms. Lautenbach. “One of the big questions in the field of genetics is about whether we are going to provide too much information to our

physicians or information that is so uncertain it necessitates additional tests to follow-up on the results to rule out a diagnosis or to look into something just to be safe, and spend a lot of money in the process. No one knows the answer to that.” Conversely, widespread use of genomic sequencing will also enable oncologists to personalize treatment, reducing both the use of highcost drugs that are ineffective against the cancer cell’s molecular pathway and potentially serious side effects warranting additional treatment.

It could also change the way clinical trials are designed, streamlining a cumbersome process, and limiting a drug’s failure rate, perhaps reducing the cost of a clinical trial. “We appreciate that cancer has to be thought of as many, many rare diseases, and that means that you can’t think of cancer the same way you thought of it in the old days when you had a phase III trial of 1,000 patients with lung cancer. Now we have to think about how to become nimble and use sequencing to recognize that, for example, a given tumor

isn’t simply ‘lung adenocarcinoma.’ Perhaps it is lung adeonocarcinoma that has a KRAS mutation, STK11 mutation, or other relevant genetic changes, and we must use that information to target treatment,” said Dr. Garraway. Although the CSER studies are scheduled to end in 4 years, some of the findings will be published in medical journals ahead of that date. n

Disclosure: Ms. Lautenbach reported no potential conflicts of interest. Dr. Garraway is a founder, consultant, and equity holder in Foundation Medicine, a company building a genomic-based diagnostic product.

Melanoma

Journal Spotlight

Enhanced Treatment, Surveillance Needed for Patients With BRAF-Mutant Melanoma to Prevent Secondary Cancers

esearchers at Moffitt Cancer Center suggest secondary cancers seen in melanoma patients who are being treated for a BRAF gene mutation may require new strategies, such as enhanced surveillance and combining BRAF inhibitor therapy with other inhibitors, especially as they become

Risk of Secondary Malignancies However, a type of cellular signaling that occurs as a result of inhibiting BRAF may leave patients susceptible to secondary malignancies, such as squamous cell carcinoma, RAS-mutant leukemia and colorectal cancer, and

These secondary cancers emerge because BRAF inhibitors can activate tumor growth pathways in cells with genetic changes. —Keiran S. Smalley, PhD

more widely used. They discussed this topic in a review article published in Nature Reviews Clinical Oncology.1 The BRAF gene is mutated in about half of all cases of melanoma, as well as other cancers, and the mutant protein can be successfully deactivated by BRAF inhibitor drugs. The development and therapeutic use of BRAF inhibitors to treat patients in advanced stages of BRAFmutant melanoma is a prime example of a successful targeted therapy. FDA-approved BRAF inhibitors are widely used in metastatic melanoma with much success, and their use is expanding to other tumor types and is being tested in earlier stages of melanoma.

the development of gastric and colonic polyps. “These secondary cancers emerge because BRAF inhibitors can activate tumor growth pathways in cells with genetic changes,” explained coauthor Keiran S. Smalley, PhD, Assistant Member of the Cancer Biology and Evolution Program at Moffitt. “When the BRAF inhibitor signaling activates a biological pathway called MAPK, secondary cancers can emerge.” The Moffitt investigators refer to the development of secondary cancers in this setting as a case of paradoxical activation. “The paradoxical activation of MAPK signaling was an unexpected

observation that emerged as BRAF inhibitors were being developed,” commented study coauthor Geoffrey T. Gibney, MD, Assistant Member of the Chemical Biology and Molecular Medicine Program at Moffitt. “Combination therapies using BRAF inhibitors and other inhibitors are being considered to prevent paradoxical activation of MAPK pathways.”

inhibitors has often been lacking. They also added that BRAF-mutant melanoma patients with a family history of colorectal cancer may require more than the usual screening if BRAF-inhibitor therapy is necessary.

Possible Role of Combination Therapy A possible combination therapy to lessen the risk of paradoxical activation and the emergence of secondary malignancies is combining BRAF inhibitors with other inhibitors. One option is an MEK inhibitor, which inhibits the mitogen-activated protein kinase enzymes used to therapeutically affect the MAPK pathway that is often overactive in cancers.

Vernon K. Sondak, MD

“Despite the concerns, the development of BRAF inhibitors is a major milestone in treating patients with BRAF-mutant melanoma,” concluded study coauthor Vernon K. Sondak, MD, who is Chair of the Cutaneous Oncology Program at Moffitt. “With surveillance and carefully designed drug combinations, the future for patients with BRAF-mutant melanoma and other malignancies looks increasingly optimistic.” n

Disclosure: For full disclosures of the study authors, visit www.nature.com. Geoffrey T. Gibney, MD

However, this combination does not eliminate all secondary cancers. The researchers note that extended follow-up for patients showing long-term responses to BRAF

Reference 1. Gibney GT, Messina JL, Fedorenko IV, et al: Paradoxical oncogenesis— the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 10:390-399, 2013.

Coming soon

Another option in short-acting G-CSF therapy » FDA approved Brought to you by Teva—a global leader experienced in developing and manufacturing biologics. Teva has a substantial portfolio of more than 50 oncology products in the US.

Learn more at GRANIXhcp.com Indication » GRANIXTM is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatmentemergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Prescribing Information on adjacent page.

The ASCO Post | SEPTEMBER 1, 2013

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Journal Spotlight Prostate Cancer

Study Suggests Low-Grade Prostate Cancers May Not Progress Over Time By Jo Cavallo

ata analyzed from a large cohort study of men diagnosed with prostate cancer found that prostate cancer aggressiveness may be established when the tumor is formed and not changed over time. The researchers of the study,

Kathryn L. Penney, ScD, Instructor in the Department of Medicine at Harvard Medical School and Associate Epidemiologist at Brigham and Women’s Hospital, and colleagues compared data from 420 participants recruited to the Physi-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

cians’ Health Study and 787 participants recruited to the ongoing Health Professionals Follow-up Study. All of the men were diagnosed with prostate cancer between 1982 and 2004 and treated with prostatectomy.

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

The researchers determined that after the first introduction of widespread prostate-specific antigen (PSA) screening, the proportion of patients diagnosed

Kathryn L. Penney, ScD

with advanced-stage cancers was reduced by more than sixfold in 22 years, but that the proportion diagnosed with high Gleason-grade cancers did not change substantially. The findings suggest that low-grade prostate cancers do not progress to higher grade over time. The study is published in Cancer Research.1

Pre-PSA vs PSA Eras To compare the distribution of grade and clinical stage across the pre-PSA and PSA screening eras, the researchers divided the data into four time periods based on when the participants received a diagnosis and treatment: 1982–1993, 1993–1996, 1996–2000, and 2000–2004. They found that the number of men who had undergone PSA screening increased from 42% in 1994 to 81% in 2000, and that the number of late-stage cancers decreased from 19.9% in the 1982-1993 group to only 3% in the 2000–2004 group, reflecting an 85% decrease in stage at diagnosis. However, there was just a moderate decrease in high Gleason grade cancers, from 25.3% in the 1982–1993 group to 17.6% in the 2000–2004 group, reflecting a 30% decrease. Further analysis of the data found that the moderate decrease in high Gleason grade cancers was not because progression to more aggressive disease was prevented through screening, but because of an increased diagnosis of low-grade disease that would not have been detected without PSA screening. n Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Penney KL, et al: Cancer Res. August 15, 2013 (early release online).

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 43

Women in Oncology Dr. Julie Vose Finds the Best of Both Worlds—Patient Care and Cutting-Edge Research—in Academic Medicine By Ronald Piana

Julie M. Vose, MD, MBA

ulie M. Vose, MD, MBA, is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center. She grew up in Mitchell, South Dakota, a small town nestled on the banks of the James River. Mitchell is home to the Corn Palace, which pays homage to the agricultural heritage of South Dakota—a state so vast and scarcely populated that it averages only 10 people per square mile.

Early Interest in Science Dr. Vose’s father was a pathologist; he nurtured his daughter’s early interest in science by helping her with

her chemistry projects. “During the summers while I was in high school, I worked in my father’s laboratory. That’s really how I first became interested in medicine, looking through the microscope at cancer cells. My mother was a nurse, so I grew up in a healthcare environment,” said Dr. Vose. After high school, Dr. Vose went to South Dakota State University, where she majored in medical technology, which is preparation to work in a medical laboratory. Toward the end of her training, however, Dr. Vose decided she wanted to become a doctor. “After graduating from South Dakota State, I moved to Omaha and enrolled in the University of Nebraska Medical School. During my junior and senior years, I began doing chart review research with Dr. James Armitage. That was when I first became interested in lymphoma,” said Dr. Vose. Dr. Vose did her fellowship and internship in internal medicine at the University of Nebraska Medical Center. “I continued doing research and clinical trial work with Dr. Armitage, who became a terrific mentor. During that time, I became even more fascinated by lymphoma, hematologic malignancies, and stem cell transplan-

Julie M. Vose, MD, MBA TITLE: Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center, Omaha MEDICAL DEGREE: MD, University of Nebraska Medical Center BUSINESS DEGREE: MBA in Health Administration, University of Colorado Business School RESEARCH INTERESTS: New therapies for Hodgkin disease, non-Hodgkin lymphoma, multiple myeloma, and chronic lymphocytic leukemia, including stem cell transplantation, immunotherapy, and other novel agents CAREER HIGHLIGHTS AND HONORS: Member, ASCO Board of Directors (2010–2013); Fellow, ASCO (elected 2013); Co-Chair, Lymphoma Steering Committee, National Cancer Institute (2009–2014); Member FDA Oncologic Advisory Board (2011–2014); Chair, Publications Committee, ASCO (2009–2010); Carol Bell Cancer Research Award, Eppley Cancer Center (2009); UNMC Department of Internal Medicine Career Investigator (2009); UNMC Distinguished Scientist Award (2008); UNMC Department of Internal Medicine Clinical Research Award (2000); Lymphoma Research Foundation’s Evelyn Hoffman Memorial Award for Excellence in Lymphoma Research (2000); Fellow, American College of Physicians (elected 1997)

tation,” said Dr. Vose. Asked what she felt were the major advances during her career, Dr. Vose said, “The development of filgrastim [Neupogen] was a big step in lymphoma treatment because it allowed us to deliver effective chemotherapy drugs more successfully. And in lymphoma specifically, it would be the development of rituximab [Rituxan], which hugely modified the way we deliver therapy in that disease.” She added, “Then, more recently, there is the ongoing work in gene expression, which may guide the development of individualized therapy for lymphoma patients.”

Delicate Balance As Chief of Hematology/Oncology at the University of Nebraska Medical Center, a large part of Dr. Vose’s energy is spent in administrative work. “I’m in charge of 19 faculty members and about 100 other employees. Managing a group of this size takes up about 40% of my time,” said Dr. Vose. Despite her hefty administrative workload, Dr. Vose is still very active in the clinic, spending about 30% of her time tending to patients with lymphoma and multiple myeloma. “The rest of my time is spent on clinical research. It’s always a delicate balance with funding, so we do a mix of investigator-initiated trials, cooperative group trials, and clinical trials from pharmaceutical companies,” said Dr. Vose. Asked why she chose a career in academic medicine, Dr. Vose said, “I like working in academic medicine because it’s the best of both worlds. I get to administer cutting-edge treatments and take care of patients and also conduct research to find new ways to treat them. An added benefit is to be able to teach the next generation of cancer care providers.”

Forward-Looking Mission Dr. Vose noted that that the University of Nebraska Medical Center is one of the leading centers for treatment and transplant for patients with lymphoma and other blood cancers, and is constantly recruiting new faculty and scientists. In order to keep pace with this vibrant pattern of growth,

Dr. Vose said they are currently constructing a new cancer campus that includes a research tower featuring state-of-the-art laboratories and advanced technology. In addition to the cancer research tower, the cancer campus will have comprehensive outpatient clinical facilities, a 108-bed cancer hospital, and space for further expansion. For an oncologist deeply engaged in cutting-edge research, it is a dream come true to be part of an institution with such a forward-looking mission. However, oncology is about caring for patients with cancer, and Dr. Vose stressed that her institution is peopleoriented. “The people are so friendly and outgoing, which is hugely important in that it creates a warm and supportive environment for our patients. Helping patients get through their journey with cancer in such a supportive place like the University of Nebraska is incredibly rewarding.” Dr. Vose has led numerous clinical trials and published widely. Her research has led her to be an advisor and member of several advisory boards, and she was elected to the ASCO Board of Directors. Her 3-year term ended in June. She was also recently awarded with the designation of Fellow of ASCO (FASCO), which recognizes ASCO members for their longterm service to ASCO.

Overarching Challenge After a long and illustrious career that has seen cancer victories but has also been tempered by the frustrating slowness of progress in many cancers, is Dr. Vose optimistic for the future? “The advances in recent years have come from our understanding of cancer on the molecular level, which, for instance, has helped us develop therapies that directly attack lymphoma cells. But the overarching challenge we face today is one of quality, cost, and efficiency. We weren’t taught that in medical school,” she said. “To ensure that we’ll have the resources to continue our vital work in clinical trials and research, we need to find ways to become more efficient. It’s already part of the new culture, so I think the future in oncology is promising,” Dr. Vose concluded. n

The ASCO Post | SEPTEMBER 1, 2013

PAGE 44

Future of Oncology ASCO Examines the Future of Cancer Care Over the Next 2 Decades By Jo Cavallo

hile the many scientific advances over the past 50 years have led to improved outcomes for millions of patients with cancer—increasing the number of survivors from just 3 million in the 1970s to nearly 14 million today—the next 20 years promise to bring even greater opportunities to improve the lives of people diagnosed with cancer. They will also bring unprecedented challenges, according to a report published by ASCO, Shaping the Future of Oncology: Envisioning Cancer Care in 2030.1

paradigm of the practice of oncology was rapidly changing,” said Michael P. Link, MD, Past President of ASCO and a leader in the development of ASCO’s Shaping the Future of Oncology vision statement. “We thought it was important to anticipate how oncology care might change over the next 20 years, so we can be better prepared and more proactive,” he continued. Dr. Link is the Lydia J. Lee Professor in Pediatric Cancer at Stanford University School of Medicine.

Key Drivers of Change

Changing Role of Oncologists

To help identify the issues that will have the greatest impact on oncology care and prepare oncologists and patients to meet these challenges, in 2011, ASCO’s Board of Directors sought the advice of physician volunteers from ASCO’s committees, as well as thought leaders in a variety of fields, including clinical research, information technology, and public health-care policy. As a result of those conversations, the Board identified the following three key drivers of change that will transform cancer care over the next 2 decades: • “Big Data,” the transformation of cancer care through health information technology • Cancer “panomics,” the complex combination of patient-specific characteristics that drive the development of cancer, response to therapy, and long-term toxicities. Improved appreciation of these factors and the growing understanding of the biology of cancer will finally make precision medicine a reality and take targeted therapy to an entirely new level. • Delivering value. The unsustainable cost increases in new cancer agents and health care in general are leading to a growing focus on cost-effectiveness and “value” in health care. “ASCO realized the impending challenges we face, such as physician shortages, increasingly complex health-care reimbursement, and the rising costs of health care. But what really began to concern us was the accelerated pace of the development and use of genomics and how we treat cancer. We began to see that the whole

In the area of Big Data, by 2030, ASCO anticipates that the field of

ogy workforce capacity. Oncologists may need to reserve their focus for patients with difficult or complex cancers and transition more routine care to other members of the patient’s care team,” said Dr. Link.

Better Care Through Cancer Panomics Panomics will be the driving force behind the majority of cancer care, enabling providers to personalize treatment for each patient. By 2030, according to the report, most cancers will be molecularly well understood and highly treatable, combination targeted therapy will be the standard of care for most cancers, and validated

We [ASCO] need to hear from our members about what they are seeing, doing, and reading. We want to know whether they think the information we presented is realistic. —Michael P. Link, MD

oncology will be able to draw on advances in health information technology, including ASCO’s CancerLinQ, to bring together vast quantities of real-world data. Oncologists will be in a position to analyze and share data on all patients with cancer, including their molecular profiles, comorbidities, treatments, clinical outcomes, and long-term side effects. In addition, the huge body of observational data will enable investigators to formulate immediate practice-changing conclusions. Clinical guidelines will be transformed into living, “crowd-sourced” documents that are more detailed and accurate. Big Data and its ability to provide accurate clinical care decision support quickly will enhance oncologists’ ability to develop patient treatment plans, manage care teams, collaborate with primary care providers on how to manage the health of cancer survivors transitioned to their care, and guide treatment of complex cancer cases, according to the report. “We anticipate the coming wave of cancer will outstrip the current oncol-

biomarkers will help identify many patients at risk of developing cancer, enabling providers to blunt its development through early treatment or prevention strategies. However, the ability to narrowly define cancer by patient-specific characteristics will mean that treatments will have to be tested in various combinations among small, molecularly defined patient populations, potentially making the development of new therapies and implementation of clinical trials prohibitively expensive. To solve this problem, ASCO speculates that research sponsors and the U.S. Food and Drug Administration will need to initiate trial designs and endpoints that can lead to rapid drug approval. In addition, CancerLinQ and other rapid-learning systems will aid researchers in corroborating the findings of smaller, faster clinical trials, and drug companies will collaborate on drug development.

Value-Driven Care The exploding rise in healthcare spending in the United

States—$2.6 trillion in 2010 and projected to reach $4.5 trillion in 20202— is leading to changes in the way health care, including cancer care, will be delivered and in determining what constitutes value. According to the report, two major challenges in oncology loom: Oncology care professionals will need to adapt to demands for greater quality, efficiency, and transparency in care provided. And the oncology community will need to address the spiraling cost of new cancer therapies, especially as novel therapies are tested and administered in combinations of two or more drugs. With many new agents costing $100,000 for a course of treatment, combination therapies could be priced out of reach for many patients, threatening both access to care and the sustainability of cancer drug development. To meet these challenges, new payment models that promote quality and value will be needed. To ensure that value will be the driver of oncology care practice, ASCO’s Quality Oncology Practice Initiative (QOPI) and rapidlearning systems, such as CancerLinQ, will enable providers to know how their care compares with established guidelines and the care received by patients in other practices. Moreover, oncology providers will be compensated according to their ability to demonstrate value and quality as determined by approaches developed by their peers, by patients, and by payers. In addition, medical school, residency, and CME programs will include emphasis on quality measurement, data analysis, staff management, and other skills physicians will need to succeed under new practice models. Quality ratings for oncologists and oncology practices will be publicly available, allowing patients to judge potential providers for themselves. Through guidelines and insights gained through CancerLinQ, cancer care quality and cost-effectiveness will become more consistent across regions and institutions.

Starting the Dialogue The picture of oncology in 2030 as presented in ASCO’s vision statement was carefully researched, but Dr. Link emphasizes that this is only a projection. It offers a starting point for ongocontinued on page 45

ASCOPost.com | SEPTEMBER 1, 2013

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JCO Spotlight Head and Neck Cancer

Meta-Analysis: Addition of Taxane to Cisplatin/5-FU Induction Improves Outcome in Locally Advanced Head and Neck Cancers By Matthew Stenger

isplatin plus fluorouracil (5-FU) induction chemotherapy has been compared with taxane (docetaxel or paclitaxel), cisplatin, and 5-FU in randomized trials in locoregionally advanced head and neck cancers. An updated individual patient data meta-analysis reported in the Journal of Clinical Oncology by Pierre Blanchard, MD, and colleagues in the Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction Project, Collaborative Group was performed to compare outcomes with taxane/cisplatin/5-FU vs cisplatin/5-FU induction therapy in this setting.1 Taxane/cisplatin/5-FU was associated with significant improvements in overall survival, progression-free survival, locoregional failure, and distant failure.

Improved Overall Survival The analysis included five randomized trials representing 1,772 patients with locoregionally advanced head and neck cancers, with updated individual patient data being retrieved for all trials. Patients had a mean age of 56 years, and most were male (90%) and had ECOG performance status of 0 or 1 (99%). Most tumors were locally advanced (T3-T4 in 85%, N2-3 in 62%); 39% of the tumors arose in the oropharynx and 25% in the hypopharynx. Median follow-up was 4.9 years. The hazard ratio (HR) for death for taxane/cisplatin/5-FU vs cisplatin/5FU was 0.79 (95% confidence interval [CI] = 0.70–0.89, P < .001), with an absolute overall survival benefit of 7.4% at 5 years for taxane/cisplatin/5FU (35.0% vs 42.4%). Heterogeneity was significant (P = .08, I2 = 51%) and related to one trial; after exclusion of this trial, there was no heterogene-

Future of Oncology continued from page 44

ing dialogue among ASCO members. “We want to see if there are areas that we haven’t thought of and addressed. We need to hear from our members about what they are seeing, doing, and reading. We want to know whether they think the information we presented is realistic. We especially want to hear from younger members who are going to be around in 2030 about what they think is necessary, both to meet the

ity (P = .99, I2 = 0%) and the hazard ratio for death was 0.72 (95% CI = 0.630.83). There was no interaction between treatment effect and patient covariates of age, sex, performance status, tumor stage, or site. The difference in overall survival was related to a reduction of head and neck cancer mortality in favor of taxane/ cisplatin/5-FU (HR = 0.74, 95% CI = 0.65–0.84, P < .001), with an absolute difference at 5 years of 9.3% (50.8% vs 60.1%). No significant difference in noncancer mortality was observed (HR = 1.12, 95% CI = 0.82–1.51, P = .47).

Induction Therapy for Head and Neck Cancer ■ Taxane/cisplatin/fluorouracil (5-FU) induction was associated with

significantly better overall survival compared with cisplatin/5-FU in patients with locally advanced head and neck cancers.

■ Taxane/cisplatin/5-FU induction was also associated with significant

improvements in progression-free survival, locoregional failure, and distant failure.

and distant failure, with a hazard ratio of 0.63 (95% CI = 0.45–0.89, P = .009) and an absolute benefit of 6.4% at 5 years (13.7% vs 20.1%). There was no heterogeneity between trials for progression-free survival, locoregional

Although induction [taxane/cisplatin/5-FU] is superior to [cisplatin/5-FU] in terms of [overall survival, progression-free survival], and locoregional and distant control, its precise role compared with upfront [chemoradiotherapy] in the management of locoregionally advanced head and neck squamous cell carcinomas remains to be defined. —Pierre Blanchard, MD, and colleagues

Improved Progression-Free Survival, Locoregional and Distant Failure Taxane/cisplatin/5-FU induction was also associated with significant improvements in: progression-free survival, with a hazard ratio of 0.78 (95% CI = 0.69-0.87, P < .001) and an absolute benefit at 5 years of 7.1% (28.4% vs 35.5%); locoregional failure, with a hazard ratio of 0.79 (95% CI = 0.66– 0.94, P = .007) and an absolute benefit of 7.4% at 5 years (44.2% vs 51.6%); challenges of our future and to make things better,” said Dr. Link.

Getting Your Input How realistic is the vision presented in ASCO’s Shaping the Future of Oncology: Envisioning Cancer Care in 2030? Is this the future that you want to see? What more or what else should oncologists strive to achieve for their patients? What role should ASCO play in the changing paradigm in oncology care? These are some of the issues ASCO

failure, and distant failure analyses. Compliance with concomitant chemotherapy differed significantly (P = .02) between taxane/cisplatin/5FU and cisplatin/5-FU for trials with planned chemoradiotherapy, with more patients in the taxane/cisplatin/5-FU arms receiving the concomitant chemotherapy as planned (49% vs 43%) and fewer not receiving any chemotherapy (31% vs 38%). Compliance with radiation therapy was also significantly better in the taxane/cisplatin/5-FU arms, with would like to address with its members. To read and download a copy of the complete vision document, go to www.asco.org/about-asco/asco-vision. To post comments on the information presented in the document, log onto asco.org/vision. “We need the expertise of our members. We want to see how we can improve the suggestions in the vision document. Then ASCO can begin to work on addressing the issues we will confont,” said Dr. Link. n

73% starting the planned therapy vs 67% in the cisplatin/5-FU arms (P = .004). Although no data on tumor response were collected, the investigators posited that these differences might be attributable to a higher response rate with taxane/cisplatin/5-FU, with fewer cisplatin/5-FU patients being candidates by protocol for radiation therapy or concomitant treatment. Among patients who started chemoradiotherapy, there was no difference in compliance with concomitant chemotherapy. The investigators concluded: “Although induction [taxane/cisplatin/5FU] is superior to [cisplatin/5-FU] in terms of [overall survival, progressionfree survival], and locoregional and distant control, its precise role compared with upfront [chemoradiotherapy] in the management of locoregionally advanced head and neck squamous cell carcinomas remains to be defined.” n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Blanchard P, Bourhis J, Lacas B, et al: Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: An individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 31:2854-2860, 2013.

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

References 1. American Society of Clinical Oncology: Shaping the Future of Oncology: Envisioning Cancer Care in 2030. Available at http://www.asco.org/about-asco/ asco-vision. Accessed August 6, 2013. 2. Centers for Medicare & Medicaid Services, Office of the Actuary: National Health Expenditure Data, 2012 release. Available at www.cms.gov. Accessed August 6, 2013.

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can 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 using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. 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. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reactiona

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. 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. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. 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. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 49

Journal Spotlight Integrative Oncology

American Ginseng Improves Cancer-Related Fatigue By Matthew Stenger

n a collaborative phase III trial of the North Central Cancer Treatment Group and Mayo Clinic (N07C2) reported in Journal of the National Cancer Institute by Debra L. Barton, RN, PhD, AOCN, FAAN, of the Mayo Clinic and colleagues, patients with cancer-related fatigue were treated with Wisconsin ginseng (a common type of American ginseng) or placebo.1 Fatigue was significantly reduced in ginseng recipients at 8 weeks, and no discernible toxicities were associated with ginseng treatment.

Study Details In this double-blind multi-institution study, 341 patients with cancer-

related fatigue received 2,000 mg of Wisconsin ginseng in two daily doses (n = 171) or placebo (n = 170) for 8 weeks. Fatigue was defined as a score of ≥ 4 on a scale on which 0 indicates no fatigue and 10 indicates fatigue “as bad as it can be.” Patients with all cancers, other than brain or central nervous system lymphoma, who were undergoing or had undergone curative treatment and who had been diagnosed within the past 2 years were eligible for the study. Those currently receiving cancer treatment could not be scheduled to change treatment status during the trial. Patients could not be receiving systemic steroids, opioids, prior/current ginseng, or other

[A]lthough this study provides support for the use of American ginseng to ameliorate [cancer-related fatigue], more research is necessary to understand its role and how to maximize its positive effects. —Debra L. Barton, RN, PhD, AOCN, FAAN, and colleagues

agents for fatigue. The primary endpoint was change from baseline in the general subscale of the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF) at 4 weeks. There were no significant differ-

ences between the ginseng and placebo groups at baseline for age (mean, 55 and 56 years), sex (81% and 75% female), race (91% and 92% white), menopausal status (22% and 18% premenopausal), type of cancer (breast continued on page 50

Ginseng in the Spotlight T:13.5”

By Ollie Minton, MB, BS, PhD, FRCP

read the study by Barton and colleagues in Journal of the National Cancer Institute with great interest. Ginseng seems potentially to be one treatment for cancer-related fatigue, a poorly understood but debilitating symptom that patients experience during and after treatment.1 I am impressed that the authors have not only built on phase II trial data to power a full trial, but have also published the study in one of the major cancer journals. It is rightfully in the spotlight, as nearly all patients undergoing cancer treatment feel the major effects of fatigue. We also know that experiencing higher-than-average fatigue on treatment puts a patient at higher risk of long-term fatigue after completion of successful treatment—for up to years afterwards.2 We must be able to offer patients potential interventions and guidance upon completion of treatment. This need not be limited to drugs and could include exercise, especially in cancer survivors. However, as patient groups have pointed out, in the maelstrom of treatment, this is not always practical. A pill to be taken offers an easier solution to reduce fatigue—ginseng may be the pill we reach for. Dr. Minton is Consultant and Honorary Senior Lecturer in Palliative Medicine, St. George’s, University of London, UK.

Isolated Finding I would not want to overplay the results of this trial—it is one isolated finding. In comparison, although there have been negative trials of psychostimulants, psychostimulant treatment maintains a moderate

from prolonged use, however unlikely it may be. In addition, as ginseng is not a drug per se and is not regulated to the same degree, preparations will differ. This is an important practical aspect, as even the authors struggled to obtain

My ongoing query (shared with the authors) concerns what ginseng is doing to ameliorate fatigue— especially given that there was not a significant difference between groups in the primary endpoint of fatigue at 4 weeks. —Ollie Minton, MB, BS, PhD, FRCP

positive effect on meta-analysis.3 It is too early based on one trial—which, as the authors state, has a low effect size—to dismiss all pharmacologic alternatives. My ongoing query (shared with the authors) concerns what ginseng is doing to ameliorate fatigue—especially given that there was not a significant difference between groups in the primary endpoint of fatigue at 4 weeks. Also, while toxicities experienced may have been minimal, this does not preclude longer-term harm

the same preparation as that used in the preceding phase II study. There is a clear suggestion of a dose-response effect, which will need to be explored in conjunction with our understanding of the mechanisms of fatigue.4

Recommendations I would feel able to recommend ginseng to my patients, knowing its limitations. However, I would be clear that the exact formulation needs to be carefully examined. Herbal remedies are not without potential harm, and it

will be vital to exclude other “natural” ingredients in a mixture. I also don’t know how American ginseng availability would affect wider use. I would want to be reassured that this is a class effect of ginseng going forward. I would make the following recommendations for future research: (1) Use different formulations of ginseng and measure inflammatory markers to correlate to clinical outcomes; and (2) Separate out the on-treatment and long-term survivor populations to identify the distinct roles of acute and chronic fatigue. n

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

References 1. Minton O, Berger A, Barsevick A, et al: Cancer-related fatigue and its impact on functioning. Cancer 119:2124-2130, 2013. 2. Minton O, Stone P: How common is fatigue in disease-free breast cancer survivors? A systematic review of the literature. Breast Cancer Res Treat 112:5-13, 2008. 3. Minton O, Richardson A, Sharpe M, et al: Psychostimulants for the management of cancer-related fatigue: A systematic review and meta-analysis. J Pain Symptom Manage 41:761-767, 2011. 4. Minton O, Stone PC: Review: The use of proteomics as a research methodology for studying cancer-related fatigue: A review. Palliat Med 24:310-316, 2010.

The ASCO Post | SEPTEMBER 1, 2013

PAGE 50

Journal Spotlight

Ginseng for Fatigue continued from page 49

in 64% and 57%, colon in 12% and 10%), or proportions currently receiving cancer treatment (49% in both groups). Somewhat more patients in the ginseng group were taking sleep aids (25% vs 17%). There were no significant differences between the two groups in baseline scores for MFSI-SF subscales or total score.

in 3% of ginseng patients and 2% of placebo patients, vomiting in 1% and 1%, insomnia on 6% and 7%, anxiety in 2% and 3%, and agitation in 1% and 2%. All of these adverse events were moderate except for severe insomnia in one patient in each group. As noted by the authors, preclinical data suggest that ginseng may act

by downregulating inflammatory pathways, thereby decreasing inflammation, and modulating cortisol and the impact of chronic stress on the hypothalamic pituitary adrenal axis. Among the active ingredients in ginseng, the most important appears to be ginsensosides, and it is important to note that amounts and strengths

of ginsensosides vary among species and batches of ginseng. Preclinical data indicate that American ginseng does not interfere with tamoxifen, doxorubicin, cyclophosphamide, paclitaxel, fluorouracil, or methotrexate. Some data indicate that the herb is synergistic with these agents against MCF-7 breast

Fatigue Significantly Reduced at 8 Weeks At 4 weeks, mean (standard deviation) changes from baseline in the general subscale of the MFSI-SF were 14.4 points (27.1) in the ginseng group (n = 147 evaluable) and 8.2 points (24.8) in the placebo group (n = 153 evaluable; P = .07). At 8 weeks, changes were 20 points (27) in the ginseng group (n = 138 evaluable) and 10.3 points (26.1) in the placebo group (n = 133 evaluable; P = .003). Among patients currently undergoing cancer therapy, ginseng was associated with significant improvement in fatigue at both 4 weeks (P = .02) and 8 weeks (P = .01). More patients had a positive response to ginseng and more had a strong clinical benefit (≥ 30% improvement) compared with placebo. With regard to secondary endpoints, significant improvements in ginseng patients were observed at 8 weeks in the MFSI-SF physical subscale, MFSI-SF total score, and the Profile of Mood States (POMS) fatigue inertia subscale. No differences between groups were observed on the MFSI-SF mental, emotional, or vigor subscales or POMS vigor activity subscale.

What if you could help the immune system respond to cancer cells? PD-L1 expression helps tumor cells evade the immune system programmed death-ligand 1 (PD-L1), which binds to the PD-1 and B7.1 receptors on Tumor expression of

T cells, deactivates T-cell–mediated cytotoxicity. This inhibits the immune system and allows the tumor to continue to grow.1 Nearly all cancer types show increased expression of PD-L1.2

PD-1

Inactivated T cell

PD-L1 TCR

No Appreciable Toxicity Only five toxicities with a greater than 1% incidence were attributed to study treatments, consisting of nausea

Ginseng for Cancer-Related Fatigue

B7.1

MHC

Tumor cell

PD-L1

■ Ginseng significantly reduced fatigue at 8 weeks compared with placebo in patients with cancer-related fatigue.

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307-314. 3. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129-1132.

■ The relative benefit of ginseng was greater among patients currently receiving cancer therapy.

■ Ginseng was not associated

with any discernible toxicities.

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 51

Journal Spotlight

cancer cell lines. The investigators concluded: “Data from this study support that American ginseng has activity against [cancer-related fatigue] but that clinically meaningful results may not be realized until 2 months after starting ginseng…. [A]lthough this study provides support for the

use of American ginseng to ameliorate [cancer-related fatigue], more research is necessary to understand its role and how to maximize its positive effects. It would, however, be reasonable for a cancer survivor to try American ginseng for fatigue, taking into consideration that there are no other pharmacologic agents

known to be effective.” n

Disclosure: For study funding information, visit jnci.oxfordjournals.org.

Reference 1. Barton DL, Liu H, Dakhil SR, et al: Wisconsin ginseng (Panax quinquefolius) to improve cancer-related fatigue. J Natl Cancer Inst. July 13, 2013.

More Integrative Oncology For additional information about ginseng and its potential for use in treating cancer-related fatigue, see page 76 in this issue of The ASCO Post.

Contact

The ASCO Post

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Blocking PD-L1 may restore the body’s adaptive immune response

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

Genentech is investigating the strategy of inhibiting the interaction between tumor-expressed PD-L1 and its receptors

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

on T cells; blocking this interaction may restore the body’s adaptive immune system to respond to cancer cells.1 Research is also under way to validate PD-L1 as a potential biomarker for cancer immunotherapy.3

Activated T cell

B7.1

TCR

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 52

Direct from ASCO

Philanthropy Spotlight

Conquer Cancer Foundation Donor and ASCO Member Denis Hammond, MD: Spreading the Word to Help Conquer Cancer

ncology care professionals answer hundreds of questions from patients and their families every day. Over the course of months and years doctors and nurses address everything from medical questions about drug regimens and side effects, to personal questions about how cancer may affect work or sexuality, to existential questions about death, dying, and survivorship. Sometimes, a cancer diagnosis or treatment will raise a different and very specific kind of question: How can I help? How can I make a difference in the fight against cancer for myself and for other patients with cancer and their families? Naturally, many patients turn to the cancer experts in their lives with this important question, seeking guidance about which of the many worthy organizations working to improve the lives of people with cancer they can support to make the biggest difference for someone like them in the future. There are, of course, many possible answers to that question, but when it was posed to Denis Hammond, MD, on a phone call last year, one particular organization came to mind: the Conquer Cancer Foundation.

sequent years I have been increasingly impressed with the results of the Foundation’s work. I have seen young investigators who received YIAs [Conquer Cancer Foundation of ASCO Young Investigator Awards] go on to produce groundbreaking research. The Foundation has also supported the activities of community oncologists in research and quality improvement. So that work has more directly affected me

lifesaving care for his wife, eventually curing her lymphoma, and providing attentive follow-up during her survival, including early diagnosis and treatment of subsequent bladder cancer, which was a side effect of her treatment. Mr. Simpson uses the word “super” to describe the level of care his wife received, specifically citing Dr. Hammond’s good advice and how he consistently “gave his full attention to everybody.”

It is unusual that a small contributor such as myself can feel directly connected to the benefits of his/her charitable giving. Happily, with the Foundation I feel that I can see the payoff of my donations in many concrete ways. —Denis Hammond, MD

in my clinical practice,” he said. “It is unusual that a small contributor such as myself can feel directly connected to the benefits of his/her

Although Mrs. Simpson remained in remission from her lymphoma, she subsequently developed lung cancer and in 2012 passed away

charitable giving. Happily, with the Foundation I feel that I can see the payoff of my donations in many concrete ways,” he said. Dr. Hammond met Jackson and Susan Simpson in 1990 when Susan was diagnosed with advanced lymphoma. Mr. Simpson credits Dr. Hammond with providing excellent,

from that malignancy. After his wife’s passing, Mr. Simpson turned to his wife’s oncologist once again for advice, looking for, as he puts it “help with going to the right place.” “I called him and I said ‘Denis, I’d like to make sure I’m not spreading my money around and doing very little’” he recalled.

A Doctor’s Advice Dr. Hammond has practiced oncology at New Hampshire Oncology-Hematology PA, for more than 30 years and has been a member of ASCO for nearly that long and a donor and supporter of the Conquer Cancer Foundation since it was first founded by ASCO as the ASCO Foundation in 1999. “At that time, I felt it was important to demonstrate to corporate donors that ASCO membership was enthusiastic about the work of the Foundation,” he said. “Over “Over “Over the sub-

“I suggested the Conquer Cancer Foundation,” said Dr. Hammond. Mr. Simpson recalls that Dr. Hammond discussed some other organizations with him during that conversation as well—the Jimmy Fund, Exeter Hospital, where Mrs. Simpson was treated—but the Conquer Cancer Foundation stood out. “He thought of you immediately,” he said.

Making a Difference by Supporting Young Researchers Since that phone call, Mr. Simpson has joined Dr. Hammond as a Conquer Cancer Foundation donor, but it wasn’t until later that Dr. Hammond would learn of the impact that their brief conversation had on the careers of several young researchers hoping to attend the ASCO Annual Meeting. Mr. Simpson chose to specifically designate his philanthropic support in Susan’s memory to Conquer Cancer Foundation of ASCO Merit Awards. Merit Awards recognize outstanding cancer research performed by young investigators, and provide financial support so recipients can travel and present their work at an ASCO meeting. “They’re a good way to try to help at the basic level, getting people interested and working on cancer research,” said Mr. Simpson. For Dr. Hammond, this outcome is welcome news. “I am delighted that my introduction of Mr. Simpson to the Foundation seems to have been fruitful for both parties,” he said. To learn more about the Conquer Cancer Foundation and to make a donation, visit www.ConquerCancerFoundation.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | SEPTEMBER 1, 2013

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Direct from ASCO

Legislative Endorsement Update From ASCO

SCO recently announced its endorsement of the Tobacco Tax Equity Act of 2014 (S. 194), which would close tax loopholes that allow tobacco companies to avoid the federal cigarette tax by making taxes on pipe tobacco equivalent to cigarette tobacco. “Raising tobacco taxes is one of the most effective ways to reduce

whom are being hit with significant out-of-pocket costs as many insurers only cover cancer drugs in intravenous form. “The cost sharing burdens im-

posed on patients for oral cancer drugs can create insurmountable financial barriers to optimal treatment and may increase the total cost of care,” Dr. Hudis said.

Palliative Care and Hospice Education and Training Act Lastly, ASCO is supporting legislation (S. 641) that addresses continued on page 54

Clifford A. Hudis, MD, FACP

tobacco use, especially among youth,” said ASCO President Clifford A. Hudis, MD, FACP, in an endorsement letter. “Reducing tobacco use is one of the most effective ways of preventing cancer, and therefore ASCO supports your efforts to achieve parity among all tobacco products as a way to reduce tobacco consumption of all kinds.” The bill’s sponsor, Sen. Richard Durbin (D-Illinois), also argued that the bill would reduce federal spending on some medical programs because higher prices on tobacco products would dissuade people from smoking, thus lowering medical expenses from health problems related to tobacco use, such as cancer.

Cancer Drug Coverage Parity Act ASCO has also endorsed the Cancer Drug Coverage Parity Act of 2013 (H.R. 1801), bipartisan federal legislation that would require private health insurance plans offering intravenous chemotherapy benefits to provide parity for orally administered and selfinjectable anticancer medications. Sponsored by Reps. Brian Higgins (D-New York) and Peter King (RNew York), the bill would greatly reduce financial burdens placed on patients with cancer, many of

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 54

Direct from ASCO

ASCO Challenges Its Members to Double Their Impact During the Month of September All Gifts to the Conquer Cancer Foundation Will Be Matched

or the entire month of September, donors to the Conquer Cancer Foundation of the American Society of Clinical Oncology have the opportunity to double their impact through a matching gift from

an anonymous individual donor. From September 1 to 30, 2013, all donations—whether made online, through the mail, or via the Foundation’s new peer-to-peer fundraising platform #WeConquerCancer— will be matched, doubling critical support for oncology research and education. The match also features a unique benefit to donors. Unlike many matching gifts, where the match-

ing funds support the philanthropic goals of the matching donor, in this case the matching funds will support the programs supported by the original gift. This means that during the month of September, a $500 gift to the Foundation’s Grants & Awards Program will become a $1,000 gift to the Grants & Awards Program, and a $1,000 gift to support International Programs will become a $2,000 gift in support of International Programs, allowing donors to double their impact in precisely the method of their choosing.

beat that goal yet again and then some. This September the Foundation is challenging its supporters to raise $50,000 or more to maximize the impact of this special matched gift to help conquer cancer. Donations can be made online at www.conquercancerfoundation. org/donate. Questions about the match can be directed to support@ conquercancerfoundation.org or

by calling 571-483-1700. The Conquer Cancer Foundation is 501(c)3 charitable organization dedicated to building a world free from the fear of cancer through funding breakthrough cancer research and sharing cutting-edge cancer information. n © 2013. American Society of Clinical Oncology. All rights reserved.

Goal of $50,000 During last year’s September matching challenge, generous Conquer Cancer Foundation donors blew through the $20,000 goal by the second week of the month. This year donors are being challenged to

What the Latest Breast Cancer News Means for Patients Legislative Update continued from page 53

the growing demand for palliative care, an essential yet underutilized component of high-quality cancer care. The bill, Palliative Care and Hospice Education and Training Act (PCHETA), sponsored by Sen. Ron Wyden (D-Oregon), would begin to address a growing national need for palliative care. The legislation would create up to 24 Palliative Care Education Centers at medical schools across the country to expand interdisciplinary training, as well as establish fellowships that would provide faculty in medical schools and other health profession schools short-term intensive courses focused on palliative care. ASCO believes that oncologists must take a strong leadership role in helping implement PCHETA once enacted. ASCO has demonstrated longstanding leadership in fostering

the delivery of palliative care in the oncology setting. The Society has issued several policy statements advocating for palliative care to be a part of comprehensive cancer care; developed numerous educational and training initiatives (including a published curriculum) to improve palliative care skills in the oncology workforce; integrated palliative care into its clinical practice recommendations and quality improvement programs; and sponsored many young researchers to investigate palliative care topics. ASCO encourages its members to take action and urge their elected officials to support these bills. Visit the ACT Network (www. asco.org/actnetwork) to learn how you can advocate for these important pieces of legislation. n © 2013. American Society of Clinical Oncology. All rights reserved.

irect your patients to www .cancer.net/breastsymposium to read patient-friendly summa-

Symposium and provide a list of questions to ask their doctors and additional resources to learn more. Also, your patients can listen to a podcast of the Symposium highlights online or download it at www.cancer.net/podcasts. n

ries that explain the research highlighted at the 2013 Breast Cancer

Save the Date ASCO’s Quality Care Symposium November 1-2, 2013 Manchester Grand Hyatt San Diego, California

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 55

Direct from ASCO

ASCO University® Appoints First Editor-in-Chief

SCO has appointed Daniel G. Haller, MD, as the first Editorin-Chief of ASCO University ®, an eLearning center designed to serve as the educational home for physicians, nurses, advanced practice providers, and patient educators at every stage of their careers. As head of the editorial board, Dr. Haller will provide oversight and leadership to ensure that ASCO University’s portfolio of educational products

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

and services maintain high quality support for oncology professionals’ lifelong learning needs. Dr. Haller—a widely recognized researcher in gastrointestinal malignancies, a respected editor, and longtime ASCO member and volunteer—currently serves as Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and as an attending physician at

5 most-accessed Top 10Top most-accessed articles recently in published articles published 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343 by Kevin S. Hughes, et al

Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer by José Baselga, et al

International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease by Evangelos Terpos, et al

Radiation Treatments After Breast-Conserving Therapy for Elderly Patients by Benjamin D. Smith, et al

Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study by Frédéric Amant, et al

Daniel G. Haller, MD

the Hospital of the University of Pennsylvania. Among the various roles he has had within ASCO, Dr. Haller served as Editor-in-Chief of the Journal of Clinical Oncology from 2001 to 2011. According to Dr. Haller, his experience with academic journals provides him with a strong foundation for his new role working with ASCO University’s editorial board. Dr. Haller’s goals for his 3-year term, which began in March 2013, include improving the quality of existing products; developing new products, when appropriate; and keeping an “ear to the ground to find out what people want,” enabling ASCO University to respond to oncology professionals’ needs.

Wide Range of Offerings ASCO University currently offers courses on a wide variety of cancer types and topics, including courses designed to assist those preparing for certification or enrolled in maintenance of certification; ASCO Tumor Boards, monthly multidisciplinary presentations that explore evidence relating to case scenarios; oncology literature reviews; the Meeting Library, with materials from ASCO’s Annual Meeting and thematic meetings; and the Oncology Slide Library, with more than 80,000 slides developed from ASCO content and from presenters at ASCO’s Annual Meeting and thematic meetings. In addition, ASCO University

recently released the 3rd edition of ASCO-SEP—a comprehensive, CME-accredited program designed to help medical providers assess and improve their level of knowledge in various areas of oncology. All courses are accessible online, as well as through digital notepads and smartphones, and content may be downloaded from iTunes University. Dr. Haller notes that, during his tenure as Editor-in-Chief, he will ensure that ASCO University stays “ahead of the curve,” providing educational materials in a variety of formats to meet the needs of today’s busy health-care providers who rely heavily on digital notepads, electronic readers, and smartphones to access information. ASCO University’s commitment to that goal is already evident. For example, the latest edition of ASCO-SEP is available as an eBook that is compatible with iPhone, iPad, iPod, Kindle, and Nook devices. And individuals can access the Online Question Bank and ASCO Flashcards, a digital flash cards app, to test their knowledge.

Associate Editors Dr. Haller will be supported in his new role by seven Associate Editors: Aditya Bardia, MD, of Massachusetts General Hospital; Quyen Chu, MD, of Louisiana State University Health Sciences Center; Jill Gilbert, MD, of Vanderbilt University; David Graham, MD, of Carle Clinic Association; Heather Hylton, PA-C, of Memorial SloanKettering Cancer Center; Benjamin Levy, MD, of Beth Israel Hospital; and Bhoomi Mehrotra, MD, of St. Francis Hospital. In addition, ASCO’s Integrated Media & Technology Committee will continue to provide oversight for ASCO University. n © 2013. American Society of Clinical Oncology. All rights reserved.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (N=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (N=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A Phase II, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

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

The ASCO Post | SEPTEMBER 1, 2013

PAGE 60

Awards Hematology

ASH Announces 2013 Honorific Award Recipients

he American Society of Hematology (ASH) announced the seven scientists who have received 2013 Honorific Awards for their significant contributions to the understanding and treatment of hematologic diseases.

The Honorific Awards are the Society’s most prestigious awards. This year’s awards will be presented at the 55th ASH Annual Meeting, which will take place December 7–10, 2013, in New Orleans.

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Wallace H. Coulter Award for Lifetime Achievement in Hematology ASH will present the Society’s highest honor, the 2013 Wallace H. Coulter Award for Lifetime Achievement in

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

Hematology, to Professor Sir David Weatherall, MD, of the University of Oxford for his more than 50-year career in hematology combining seminal discoveries, visionary translational research leadership, and a passion for

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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Awards

Professor Sir David Weatherall, MD

• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

global health initiatives that have together helped improve clinical care for thousands throughout the developing world. Sir David has paved the way for other physicians and scientists in refining the understanding of inherited blood disorders, particularly thalassemias and tropical diseases. In a groundbreaking 1965 report, Sir David and colleague

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

John Clegg identified imbalanced globin chain production as the cause of thalassemia, a discovery that was essential to developing improved treatments and designing disease prevention efforts.

Henry M. Stratton Medal The Society will recognize Nancy Andrews, MD, PhD, Dean of

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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 Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

Nancy Andrews, MD, PhD

continued on page 62

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Awards

ASH 2013 Honorific Awards continued from page 61

Duke University School of Medicine, and Elaine Jaffe, MD, of the National Cancer Institute at the National Institutes of Health, with the 2013 Henry M. Stratton Medal. Dr. Andrews, the recipient of the 2013 Stratton Medal for Basic Research,

8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

Elaine Jaffe, MD

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

is also Vice Chancellor for Academic Affairs at Duke University. She is recognized as a leader in the study of molecular biology of iron metabolism and made several critical discoveries early in her career central to the understanding of erythropoiesis. Dr. Jaffe, the recipient of the 2013 Stratton Medal for Clinical/Transla-

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

tional Research, is Head of the Hematopathology Section of the Laboratory of Pathology in the Intramural Program of the National Cancer Institute (NCI). Dr. Jaffe is widely known for her work regarding the pathophysiology and prognosis of malignant lymphomas.

William Dameshak Prize ASH will present the 2013 William Dameshek Prize to Andrew S. Weyrich, PhD, of The University of Utah for his research on the cellular and molecular causes of blood clots.

Andrew S. Weyrich, PhD

Dr. Weyrich is Professor of Pathology and Internal Medicine at The University of Utah. Among his major contributions to platelet biology research, Dr. Weyrich has successfully identified the mRNA splicing and translational mechanisms that allow platelets to respond to environmental changes.

E. Donnall Thomas Lecture and Prize ASH will honor Katherine A. High, MD, of the Howard Hughes Medical Institute and The Children’s Hospital of

Katherine A. High, MD

Philadelphia with the 2013 E. Donnall Thomas Lecture and Prize for her unparalleled work to identify the molecular basis of hemophilia and to develop novel genetic therapies to treat the disorder.

Ernest Beutler Lecture and Prize ASH will honor Kenneth Kaushansky, MD, of Stony Brook University and David J. Kuter, MD, DPhil, of the Massachusetts General Hospital continued on page 71

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Expert’s Corner

Combining Community Practice and Health Policy Advocacy A Conversation With Barbara L. McAneny, MD By Ronald Piana munity practice over an academic career.

Barbara L. McAneny, MD

arbara L. McAneny, MD, is a board-certified medical oncologist/hematologist with a robust community practice in Albuquerque, New Mexico. Dr. McAneny, who has held many leadership roles in oncology associations, became a delegate to the American Medical Association (AMA) from ASCO in 2002, was elected to the Board of Trustees in 2010 and most recently was elected Chair-Elect to the Board of Trustees for the AMA. The ASCO Post recently spoke with Dr. McAneny about her ongoing work in the clinic and the policy arena, and her new position at the AMA.

Origins and Early Career Are you a native of New Mexico? No, I’m from the Midwest. I was born in Missouri, and I grew up in southern Illinois. I went to the University of Minnesota in 1973 and graduated from the University of Iowa College of Medicine in 1977. I finally figured out that not everyone in the country endures 7 months of winter, so I decided to move to the Southwest. I fell in love with New Mexico. Why did you choose oncology as a profession? When I was going through my internal medicine residency at the University of Iowa College of Medicine, I learned that I loved taking care of patients with cancer, which is the simple reason I decided to become an oncologist. I also learned that my skills were in relating to patients and delivering hands-on cancer care, not in writing papers, so that is the reason I decided on com-

Please tell the readers about your early days in practice. After my fellowship at the University of New Mexico in oncology and hematology, I cofounded a private practice with Dr. Clark Haskins, which evolved into the New Mexico Hematology/Oncology Consultants. In 2002, we built the New Mexico Cancer Center, a freestanding physician-owned multidisciplinary clinic handling medical oncology, radiation oncology, imaging, and clinical trials. We have an on-site pharmacy as well, so it is a full-service oncology clinic.

Making Strides in Prevention You have championed numerous health-related issues such as reduction/avoidance of tobacco use. In what other ways can cancer prevention be improved? Prevention is the perfect example of where oncology needs to partner with other specialties. Oncologists pride themselves on being multi-

my comments before the committee with this statement: I am here to ask you to decrease my business by onethird by making it harder for people to become addicted to tobacco. That got policymakers’ attention because nobody goes in front of a legislature and pleads for help in decreasing their business. So oncologists can truly have a potent voice when we choose to use it for the public good. But we need to be aware that political change is a long, incremental process during which you need to build consensus and educate the population. Thanks to the Clean Indoor Air Act, smoking in buildings is no longer allowed in New Mexico, so the work certainly paid off.

Innovation Grant You were awarded a grant from the Centers for Medicare & Medicaid to test how oncology practices in the community could provide better, more cost-effective care. Please share that experience with our readers. Over the years at New Mexico Oncology, we figured out that using

I started my career wanting to take care of every cancer patient in the world. When I realized that wasn’t possible, I began working on public health issues because I see that as being able to positively affect the lives of multitudes of patients with cancer. —Barbara L. McAneny, MD

disciplinary, but we only see people after the cancer is diagnosed, when prevention is meaningless. If we are going to make strides in prevention, we’ll need to work hand-in-hand with our overworked primary care colleagues to help facilitate the inclusion of cancer screening, smoking cessation, and obesity into their practices so they can have those vital conversations with their patients. We also need to make ourselves available to talk with the public. When I present at a legislative hearing, I want to make sure the message is taken seriously. For instance, when I was working on New Mexico’s Clean Indoor Air Act, I opened

an aggressive approach to managing cancer side effects prevents a huge amount of unnecessary emergency room visits and hospitalizations. We also extended our office hours to accommodate after-hours patients and put in place a system that encourages patients to call us before making any other decision, such as racing to the ER. It certainly makes more sense to see a community oncologist than to sit in an ER next to someone with pneumonia for 5 hours while waiting to see a doctor who is not trained in oncologic side-effect care. In another efficiency-minded step, we shredded our paper charts

in 2002 and went completely electronic. I now realize how much money we’re saving the system by the processes we put into place. So prior to the grant, I had a template of cost-effective care delivery. In 2012, I was awarded a $19.8 million Center for Medicare and Medicaid Innovation (CMMI) grant to test how oncology private practices could provide better care for patients with cancer at a lower cost. To accomplish that, I created a small company called Innovative Oncology Business Solutions in which we will try to replicate the care and cost-saving practices that we initiated at the New Mexico Cancer Center in six other practices across the United States. We are documenting that our measures and interventions are providing betterquality, cost-effective care in terms of real outcomes. The data gathered at the seven sites involved in our pilot program are important for the oncology community, not only because we’re seeing better outcomes, but also in light of the cost savings component. In today’s setting, we need to figure out how to care for the growing patient population on a very tight budget. There’s simply no more money out there, and we need to keep our patients healthier and avoid preventable clinical scenarios that erode our precious resources.

Balancing Public Health and Clinical Roles Please describe your recent appointment as Chair-Elect, Board of Trustees, of AMA, particularly as it pertains to oncology. The AMA is hugely relevant to the oncology community’s success moving forward. We need to be part of the AMA’s “big tent.” It is the house of medicine where all specialties and subspecialties gather and work together on all the issues that affect our patients and us. It is a great honor to be the Chair-Elect of the AMA. In June 2014, I will become Chair of the Board. We direct the vision and direction of the AMA, which is to promote the art continued on page 66

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Expert’s Corner

Barbara L. McAneny, MD continued from page 63

and science of medicine and the betterment of public health. How do you balance the clinic with the myriad public health issues you undertake? I have a busy clinical schedule, so

I save my evenings and weekends for everything else, which includes answering hundreds of e-mails, hours of conference calls to map out strategies, and writing grant proposals. I started my career wanting to take care of every cancer patient in the world. When I realized that wasn’t possible, I began working on

public health issues because I see that as being able to positively affect the lives of multitudes of patients with cancer. Your work covers such a broad medical canvas; please share a bit about your patient care activities. Our group serves a very diverse

patient population across the state, including some of New Mexico’s most underserved. A clinic that means a lot to me is our Gallup Clinic in the heart of the Navajo Nation. Many of these people live on less than $20,000 per year and have no running water or electricity. We are the only cancer providers for

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Expertâ&#x20AC;&#x2122;s Corner

120 square miles. For many of these patients, a tank of gas is cost-prohibitive, so they would not be able to travel long distances for their care. I leave for this clinic on Thursday morning and return on Friday evening, staying over at a small motel in Gallup. I take care of patients that otherwise probably would not have their cancers

treated. It means a huge amount to me. Anyone who works in public health programs of any stripe needs to ground him or herself in a clinic that provides care to the underserved. It reminds us of why we became doctors in the first place. There are vulnerable patients out there whose lives you can affect in a very positive way.

State Medical Societies Do you have any closing thoughts? Oncologists tend to forget how important their state medical societies are, particularly if one wants to further issues critical to the community. The state medical societies are a tremendous vehicle for gathering voices and sending a collective mes-

sage to local policymakers, and the AMA can affect national policy. So I urge my colleagues across the country to make use of this resource and become involved in issues that further the goals of delivering high-quality, cost-effective care to our patients. n Disclosure: Dr. McAneny reported no potential conflicts of interest.

American Medical Association Board of Trustees Ardis Dee Hoven, MD, President, Internal Medicine/ Infectious Disease Robert M. Wah, MD, President-elect, Reproductive Endocrinology/Obstetrics & Gynecology Jeremy A. Lazarus, MD, Immediate Past President, Psychiatry Andrew W. Gurman, MD, Speaker, Orthopedic Surgery Susan R. Bailey, MD, Vice Speaker, Allergy, Asthma and Immunology/Pediatrics David O. Barbe, MD, MHA, Chair, Family Practice Barbara L. McAneny, MD, Chair-elect, Oncology Steven J. Stack, MD, Immediate Past Chair, Emergency Medicine Carl A. Sirio, MD, Secretary, Internal Medicine Members Stephen R. Permut, MD Joseph P. Annis, MD Maya A. Babu, MD, MBA Julie K. Goonewardene Gerald E. Harmon, MD Patrice A. Harris, MD William E. Kobler, MD Mary Anne McCaffree, MD Albert J. Osbahr III, MD Ryan J. Ribeira Georgia A. Tuttle, MD Monica C. Wehby, MD

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2013

2013 Oncology Meetings September Georgia Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet.org/cme Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information: www.tops-tennessee.com Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org

Minnesota Society of Clinical Oncology - MSCO Fall Membership Conference September 10 • Minneapolis, Minnesota For more information: www.msco-minnesota.com 2013 Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 • Denver, Colorado For more informaton: www.icaac.org Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com 9th Scientific Meeting of the Australasian Society for Breast Disease September 12-14 • Cairns, Queensland, Australia For more information: www.asbd. org.au International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/

NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org The Art and Science of the New Melanoma Landscape September 27-28 • Houston, Texas For more information: www. ProvaEducation.com/Melanoma ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences ASH Consultative Hematology Course September 27 • Chicago, Illinois For more information: www.hematology.org Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences

Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications October 3-6 • San Diego, California For more information: www.aacr.org Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www.globalbiomarkersconsortium. com Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org

17th Annual Interdisciplinary Conference on Supportive Care, Hospice, and Palliative Medicine October 11-12 • Houston, Texas For more information: www.mdanderson.org/ conferences 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/ Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html 9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/ 2nd Annual Oncology Clinical Development Congress October 14-15 • Manchester, United Kingdom For more information: www. oncologyclinicaldevelopmentcongress.com International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ ASCOv2/About+ASCO/ International+Affairs/Internationa l+Clinical+Trials+Workshops International Stereotactic Radiotherapy Conference October 19-20 • Houston, Texas For more information: www.mdanderson.org/ conferences 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in continued on page 70

What if we could harness the potential of the immune system to fight cancer? With immuno-oncology, it may be possible. Immuno-oncology is a rapidly evolving field of research that focuses on working directly on the immune system to fight cancer.1 At Bristol-Myers Squibb, we are committed to researching and developing innovative treatments that harness the potential of the immune system to help patients fight cancer.

Bristol-Myers Squibb is leading the way in immuno-oncology. To find out more about our cutting-edge immuno-oncology research, visit BMSImmunoOncology.com. For information on investigational studies, including study sites, visit BMSStudyConnect.com. References: 1. Borghaei H, Smith MR, Campbell KS. Immunotherapy of cancer. Eur J Pharmacol. 2009; 625(1-3): 41â&#x20AC;&#x201C;54.

Leading the way ÂŠ2013 Bristol-Myers Squibb Company.

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2013

2013 Oncology Meetings continued from page 68

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013 • Boston, Massachusetts For more information: www.aacr.org 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 International Society of Geriatric Oncology Congress October 24-26 • Copenhagen, Denmark For more information: www.siog.org

Twelfth Annual International Conference on Frontiers in Cancer Prevention Research October 27-30, 2013 • National Harbor, Maryland For more information: www.aacr.org 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/ Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

New York Lung Cancer Symposium

9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/

Academy of Oncology Nurse

Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

For more information: www.gotoper.com/conferences

Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw

11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences

November 9 • New York, New York

Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

JANUARY 24–26, 2014

Renaissance Vinoy St. Petersburg • St. Petersburg, FL

Chair: Pamela Hallquist Viale • Co-Chairs: Sandra E. Kurtin and Wendy H. Vogel

advancedpractitioner.com/jadprolive

For more information: www.hematology.org

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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Awards

ASH 2013 Honorific Awards

Sciences and Dean of the School of Medicine at Stony Brook University. His research focuses on hematopoiesis, cloning, and characterizing many of the growth factor receptors that drive basic blood cell production. Dr. Kuter, the recipient of

continued from page 62

Cancer Center with the 2013 Ernest Beutler Lecture and Prize for their significant advances in the discovery of thrombopoietin. Dr. Kaushansky, the recipient of the 2013 Ernest Beutler Prize in Basic Science, is Senior Vice President of Health

Kenneth Kaushansky, MD

David J. Kuter, MD, DPhil

the 2013 Ernest Beutler Prize in Translational Research and Clinical Science, is the Director of the Mass General Cancer Hospital Center for Hematology and a Professor of Medicine at Harvard Medical School. Dr. Kuter is renowned for translating the understanding of cytokine signaling in megakaryopoiesis into clinical practice. n

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ASCO Annual Meeting Issues in Oncology

Oncology Drugs continued from page 1

make other adaptations. While 59% of respondents reported being aware of ongoing drug shortages in their community, this number was slightly higher—70%—last fall, according to Dr. Schilsky. Forty percent felt the drug shortage has not been resolved: 17% believed the shortage is worse now, 16% considered it unchanged, and 9% noticed improvements for some drugs but worsening for others. Furthermore, oncologists expressed growing concern over the shortage of drugs used in supportive care, such as antiemetics, pain medications, and basic intravenous fluids and electrolytes.

Most Physicians Still Feel the Pinch In a separate survey of 250 oncologists/hematologists, 83% reported encountering shortages of curative and palliative chemotherapy agents in recent months, and these shortages frequently affected the quality and cost of patient care.2 “Drug shortages are affecting the treatment of curable malignancies. We don’t know the extent to which adaptations forced by these shortages led to adverse clinical outcomes for patients,” said Keerthi Gogineni, MD, of the University of Pennsylvania, Philadelphia, at a press briefing. “We were surprised by the large number of oncologists who had to make changes in how they care for patients due to drug shortages,” she added.

83% of patients, according to the respondents. To adapt, physicians changed the treatment regimen (78%), substituted drugs part way through therapy (77%), delayed treatment (43%), “rationed” treatment (37%), omitted doses (29%), reduced doses (20%), and referred patients to other practices (17%). Most providers (70%) indicated they lacked institutional recommendations on these measures. Nearly 60% of physicians substituted more expensive agents when cheaper generics were not available. This included levoleucovorin (Fusilev) for leucovorin; capecitabine (Xeloda) for 5-FU; and nab-paclitaxel (Abraxane) for paclitaxel. For one cycle of chemotherapy for colorectal cancer, levoleucovorin costs about 30 times that of leucovorin and capecitabine is 140 times more expensive than 5-FU, Dr. Gogineni pointed out. In addition, clinical trial enrollment is suffering, according to both speakers. In Dr. Gogineni’s survey, 13% of respondents said shortages prevented enrollment or completion of clinical trials. According to Dr. Schilsky, 23 protocols of the Cancer and Leukemia Group B (CALGB) clinical trials group have been affected by drug shortages. The CALGB has recommended delaying registration of new patients, borrowing drugs from neighboring institutions, substituting alternative drugs, and omitting drugs in short supply as possible actions that an institution could take if faced with a drug shortage for patients on protocol. While the U.S. Food and Drug Administration (FDA) has stopgap measures in place to ease the situation, Dr. Schilsky indicated that “permanent solutions will require enhancing the business model of generic drug manufacturing.”

Drug Costs for Unapproved Compounds

Keerthi Gogineni, MD

The survey was distributed to 454 randomly selected ASCO members, and 214 responses from March 2012 to March 2013 were analyzed. Shortages were most commonly reported for leucovorin, liposomal doxorubicin, fluorouracil (5-FU), bleomycin, and cytarabine, and these and other shortages compromised the delivery of standard chemotherapy in

A significant proportion of cancer patients receive treatments that are neither FDA-approved nor endorsed by the compendia of the National Comprehensive Cancer Network (NCCN). The Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 1998 to 2008 also indicated that 18% of drug costs go toward unapproved drugs.3 “We found a lot of off-label use,” said Dawn L. Hershman, MD, MS, of Columbia University, New York. The study of 42,634 patients with

Dawn L. Hershman, MD, MS

metastatic breast, ovarian, lung, colon, and prostate cancer and multiple myeloma found the following number of unapproved drugs being used (ie, neither FDA-approved nor NCCN-endorsed): 20 in breast cancer, 8 in colon cancer, 8 in lung cancer, 18 in multiple myeloma, 28 in ovarian cancer, 33 in prostate cancer, and 13 in uterine cancer. The percentage of patients receiving only an approved drug was just 55%, meaning that 45% of patients received a drug that was not FDA-approved. Variability was high by tumor type, with multiple myeloma patients the most likely to receive an unapproved drug (80%) and colon cancer patients the least likely (10%). The pattern was consistent across the 10-year time period, Dr. Hershman reported. Altogether, 70% of unapproved drugs were NCCN endorsed. The mean number of unapproved drugs was 1.5 per patient. “The bulk of unapproved drugs are, however, compendia-approved, and this is reassuring because we think the compendia are appropriate,” she said. About half the compendia-supported drugs were eventually FDA-approved, but those that did not become FDAapproved were not deleted from the compendia and continued to be used. A breakdown of the cost according to appropriate use revealed that nearly $150 million was reimbursed for drugs that were neither FDA-approved nor compendia-supported, primarily for

Monika K. Krzyzanowska, MD, MPH

the treatment of multiple myeloma and prostate cancer. “We didn’t think we would find any

unapproved use of drugs. We thought regulations were in place to stop that,” she commented. Monika K. Krzyzanowska, MD, MPH, of the Princess Margaret Cancer Center, Toronto, discussed the study and noted that some off-label use is not completely “inappropriate”—for example, in rare cases where there is little evidence to guide practice or prior to approval of a drug for which evidence of benefit has just emerged. In some cases, however, drugs are used in a disease for which they have not been well studied. But clearly, oncologists are not “choosing wisely” in all circumstances, she said. “Greater scrutiny of off-label use is needed, especially for diseases or drugs where there is a high prevalence of inappropriate prescribing, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial, such as in patients with advanced cancer and poor performance status.”

Financial Distress Felt by Patients In a Duke University survey, 17% of insured cancer patients reported “high” or “overwhelming” financial distress, but only 25% of this group brought this to the attention of their oncologist.4 “Even insured cancer patients may

S. Yousuf Zafar, MD

experience considerable financial distress, but little has been known about whether patients want to include cost discussions in treatment decisionmaking,” said S. Yousuf Zafar, MD, of Duke Cancer Institute. “We found a disconnect between a desire to talk about cost and actually having this discussion,” he observed. The analysis by Duke University researchers was a cross-sectional study of 300 insured adults with solid tumors treated for at least 1 month. Participants were surveyed in person and were asked about financial distress, out-of-pocket costs, discussion about continued on page 74

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The ASCO Post | SEPTEMBER 1, 2013

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ASCO Annual Meeting Oncology Drugs continued from page 72

costs with their physician, and aspects of decision-making. The average patient was a married 60-year-old with at least a high school education and household income of $60,000. Fifty-five percent had private insurance and 36% had Medicare. Colorectal cancer was the most common diagnosis, and threequarters of patients had advanced disease. Patients responded to eight questions on a 10-point scale, such as “Do you have stress related to your financial situation?” “Are you living paycheck to paycheck?” and “Could you handle an $8,000 financial emergency?” High or overwhelming financial distress was reported by 17% of pa-

tients. About half of all respondents expressed a desire to talk about cost with their oncologist, but only 19% actually engaged in a cost discussion. Of those who did, 57% said this resulted in decreased expenses. Interestingly, approximately onethird of patients believed they might receive inferior care should they express a concern over costs. “The fact that many patients said they wanted the best care regardless of cost carries the implication that patients link cost to quality, and if they broach the topic of cost they might receive lesser quality care,” he suggested. Twenty percent believed financial issues were “not my doctor’s job” or matters where “my doctor can’t help,” while 10% were “embarrassed” to bring up the topic. However, 21%

said cost should “always be taken into account.” In an exploratory analysis, white race and high level of distress were significantly associated with likelihood of discussing costs. The fact that the majority of patients who actually have cost discussions find them helpful indicates there are “false barriers” to these discussions, Dr. Zafar maintained. “We need to at least identify patients at greatest risk for financial distress. We might not have all the answers, but broaching the topic can go a long way.” n Disclosure: Drs. Schilsky, Hershman, and Zafar reported no potential conflicts of interest. Dr. Gogineni has received research funding from Pfizer. Dr. Krzyzanowska has an uncompensated consultant or advisory role with Bayer/Onyx, has received honoraria from AstraZeneca, Novartis, and Sanofi,

and has received research funding from AstraZeneca and Exelixis.

References 1. Schilsky RL: Improvising when standard therapy is not available. 2013 ASCO Annual Meeting. Abstract CRA6510. Presented June 4, 2013. 2. Emanuel EJ, Shuman D, Chinn D, et al: Impact of oncology drug shortages. 2013 ASCO Annual Meeting. Abstract CRA6510. Presented June 4, 2013. 3. Hershman DL, Neugut AI, Buono D, et al: Off-label and compendia use of chemotherapy in patients with metastatic cancer. 2013 ASCO Annual Meeting. Abstract 6509. Presented June 4, 2013. 4. Zafar Y, Abernethy AP, Tulsky FA, et al: Financial distress, communication, and cancer treatment decision-making: Does cost matter? 2013 ASCO Annual Meeting. Abstract 6506. Presented June 3, 2013.

Journal Spotlight

Family Members of Children With Cancer Are Also at Risk for the Disease By Jo Cavallo

arents and siblings of children with cancer have between a two- and four-times increased risk of developing cancer than first-degree relatives with no childhood cancer patients, according to a study published in the International Journal of Cancer.1 The study, led by Joshua Schiffman, MD, Medical Director of the

Study Details The researchers examined the family medical history of 4,482 children age 18 or younger diagnosed with cancer over a 43-year period to determine the cancer risk in their relatives and compared the information to matched population controls.

Not all children’s cancers are hereditary, but the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5% to 10% generally cited in adult hereditary cancers, and likely even more than 20%. —Joshua Schiffman, MD

Huntsman Cancer Institute’s High Risk Pediatric Cancer Clinic, used data from the Utah Population Database to broadly examine the risk of all types of cancer in relatives of children with cancer.

The researchers found that firstdegree relatives, primarily siblings, of pediatric cases faced a twofold increased risk of a cancer diagnosis before the age of 19, which extended

to their second-degree relatives (P < 10-4, respectively). In addition, firstdegree relatives of children diagnosed before the age of 5 had a 3.6-fold increased risk of developing pediatric cancer (P < 10-7), second-degree relatives of under age 5 cancer patients had a 2.5-fold risk (P < 10-4), and third-degree relatives were at a twofold risk (P < 10-3). The researchers also assessed known inherited genetic syndromes in adult relatives of the pediatric cancer patients and found that cancers associated with Li-Fraumeni Syndrome appeared to be driving the increased risk to relatives in families with a history of cancer. “Not all children’s cancers are hereditary, but the numbers in this study suggest that the proportion of hereditary childhood cancers may be significantly higher than the 5% to 10% generally cited in adult hereditary cancers, and likely even more than 20%,” said Dr. Schiffman in a statement.

Collecting Family Medical Histories on Multiple Generations Although childhood cancers are rare occurrences, the researchers recommend that physicians collect three generations of family medical history for all newly diagnosed pediatric cancer patients and refer family members with a history of early-onset cancers in children or adults for genetic counseling. In addition, parents of children diagnosed with cancer before the age of 5 with a family history of cancer should be told of the potential increased cancer risk to other children in the family. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Curtin K, Smith KR, Fraser A, et al: Familial risk of childhood cancer and tumors in the li-fraumeni spectrum in the utah population database: Implications for genetic evaluation in pediatric practice. Int J Cancer. June 12, 2013 (early release online).

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Journal Spotlight Gynecologic Oncology

Role of Epithelial-to-Mesenchymal Transition in Ovarian Cancer By Jo Cavallo

n a study of ovarian cancer cells taken from patients, scientists from Georgia Institute of Technology have confirmed that metastasizing cancer cells have a different molecular structure from primary tumor cells and display genetic signatures consistent with epithelial-to-mesenchymal transition. Although histologic examination of 14 matched sets of primary ovary and metastatic omentum ovarian tissue taken from 7 cancer patients found no morphologic distinction between the matched sets of primary and metastatic samples, gene expression profiling (Affymetrix, U133) clearly distinguished two classes of metastatic samples, reported the researchers. One class displayed expression patterns statistically indistinguishable from primary samples isolated from the same patients, while a second class displayed expression patterns significantly different from primary samples, said the researchers. Further analysis focusing on genes previously associated with epithelial-to-mesenchymal transition clearly distinguished the primary from metastatic samples in all but one patient. The study results were published in the Journal of Ovarian Research.1

cer cells are very different from those comprising the primary tumor and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.” n

Disclosure: For full disclosures of the study authors, visit www.ovarianresearch.com.

Reference 1. Lili LN, Matyunina LV, Walker LD,

et al: Molecular profiling supports the role of epithelial-to-mesenchymal transition (EMT) in ovarian cancer metastasis. J Ovarian Res. July 10, 2013 (early release online).

Is your cancer therapy

SPECIFIC, ADAPTABLE, DURABLE? and

New Chemotherapies Needed Although previous laboratory studies in cell cultures and animals suggested that metastasizing cancer cells undergo a major molecular change as they leave the primary tumor site and travel to distant sites, making them more resistance to chemotherapy that is effective on the primary tumor, there was no confirmation that this epithelial-to-mesenchymal transition process took place in human tissue samples. The researchers concluded that their results are consistent with a role of epithelial-to-mesenchymal transition in most, if not all, ovarian cancer metastases and demonstrate that identical morphologies between primary and metastatic cancer samples are insufficient to negate a role of epithelialto-mesenchymal transition in the metastatic process. In a statement, Benedict Benigno, MD, one of the study authors and Director of Gynecological Oncology at Northside Hospital in Atlanta, said, “These results clearly indicate that metastasizing ovarian can-

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to

FightCancerWithImmunotherapy.com

The ASCO Post | SEPTEMBER 1, 2013

PAGE 76

Integrative Oncology By Jyothirmai Gubili, MS, Editor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center

Ginseng Scientific name: Panax ginseng Common names: Chinese ginseng, ren shen, Korean ginseng, red ginseng

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose ginseng for this issue because it is increasingly being used by cancer patients. Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial SloanKettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, LAc, Memorial SloanKettering Cancer Center.

Overview

Panax ginseng is a slow-growing perennial plant indigenous to Northeast Asia. The root is treasured for its

medicinal properties and has a history spanning several centuries. Traditional Chinese Medicine practitioners believe that ginseng promotes Yang (eg, male, hot, and positive) qualities. It is used, often in herbal formulas, as a revitalizing agent to improve strength, stamina, and endurance, and to treat

fatigue, cardiovascular disorders, diabetes, sexual dysfunction, and cancer. Ginseng is available in health food stores in the form of tablets, capsules, extracts, teas, and creams for external use. Although fresh ginseng root is sometimes chewed and preserved in wine for consumption, it is marketed primarily in dried form, either whole or sliced. Panax ginseng should not be confused with American ginseng or Siberian ginseng, which have different medicinal properties. Also, because ginseng is expensive, adulteration with morphologic fakes and cheaper products is common.

The Science

Ginsenosides, the saponin glycosides present in ginseng root and other

Guest Editor

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc. Barrie R. Cassileth, MS, PhD org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. parts of the plant, are thought to be responsible for ginseng’s medicinal effects.1 Recent studies indicate that they

OF NOTE Epidemiologic data from studies conducted in Asia suggest that Panax ginseng may have anticancer potential. However, such effects have not yet been confirmed in clinical trials. also have anticancer properties in vitro.2 P ginseng has been used effectively to treat erectile dysfunction.3 It may also increase the hypoglycemic effects of insulin and sulfonylureas as well as reduce

insulin resistance in type II diabetic patients4 and enhance immune response.5,6 Data from an epidemiologic study showed that ginseng improved survival and quality of life in breast cancer patients.7 Also, consumption of a ginseng extract was associated with a reduction in the incidence of all cancers in casecontrolled epidemiologic studies.8,9 Because ginseng showed estrogenic activity in vitro,10 patients with hormone-sensitive cancers should avoid taking it until definitive clinical data become available.

Adverse Effects

Dry mouth, tachycardia, nausea, vomiting, diarrhea, insomnia, and nervousness have been reported fol-

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs www.mskcc.

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 77

Integrative Oncology lowing use of ginseng.1 A 26-year-old male without a history of mental illness became manic after chronic consumption of P ginseng capsules. His symptoms, including irritability, insomnia, flight of ideas, and rapid speech, resolved following discontinuation of the supplement.11 Gynecomastia has been reported in a 12-year-old boy after ingesting ginseng extract for bodybuilding.12

Herb-Drug Interactions

Insulin and sulfonylureas: P ginseng can increase the hypoglycemic effects of insulin and sulfonylureas.4 Anticoagulants: P ginseng may antagonize the effects of anticoagulants.13 Imatinib: In combination with imatinib (Gleevec), P ginseng may increase the risk of hepatotoxicity.14 Raltegravir: Elevated plasma levels of raltegravir (Isentress), an antiretroviral drug, were reported in a patient following concurrent use of raltegravir and ginseng.15 n References 1. Attele AS, Wu JA, Yuan CS: Ginseng pharmacology: Multiple constituents and multiple actions. Biochem Pharmacol 58:1685-1693, 1999. 2. He BC, Gao JL, Luo X, et al: Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ßcatenin signaling. Int J Oncol 38:437-445, 2011. 3. de Andrade E, de Mesquita AA, Claro Jde A, et al: Study of the efficacy of Korean Red Ginseng in the treatment of erectile dysfunction. Asian J Androl 9:241-244, 2007. 4. Ma SW, Benzie IF, Chu TT, et al: Effect of Panax ginseng supplementation on biomarkers of glucose tolerance, antioxidant status and oxidative stress in type 2 diabetic subjects: Results of a placebo-controlled human intervention trial. Diabetes Obes Metab 10:1125-1127, 2008. 5. Cho YK, Sung H, Lee HJ, et al: Longterm intake of Korean red ginseng in HIV1-infected patients: Development of resistance mutation to zidovudine is delayed. Int Immunopharmacol 1:1295-305, 2001. 6. Scaglione F, Cattaneo G, Alessandria M, et al: Efficacy and safety of the standardized ginseng extract G115 for potentiating vaccination against common cold and-or influenza syndrome. Drugs Exp Clin Res 22:65-72, 1996. 7. Cui Y, Shu XO, Gao YT, et al: Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol 163:645-653, 2006. 8. Shin HR, Kim JY, Yun TK, et al: The cancer-preventive potential of Panax ginseng: A review of human and experimental evidence. Cancer Causes Control 11:565576, 2000.

9. Yun TK, Choi SY: Non-organ specific cancer prevention of ginseng: A prospective study in Korea. Int J Epidemiol 27:359-364, 1998. 10. Lee Y, Jin Y, Lim W, et al: A ginsenoside-Rh1, a component of ginseng saponin, activates estrogen receptor in human breast carcinoma MCF-7 cells. J Steroid Biochem Mol Biol 84:463-468, 2003. 11. Engelberg D, McCutcheon A, Wise-

man S: A case of ginseng-induced mania. J Clin Psychopharmacol 21:535-536, 2001. 12. Kakisaka Y, Ohara T, Tozawa H, et al: Panax ginseng: A newly identified cause of gynecomastia. Tohoku J Exp Med 228:143145, 2012. 13. Lee SH, Ahn YM, Ahn SY, et al: Interaction between warfarin and Panax ginseng in ischemic stroke patients. J Altern Complement Med 14:715-721, 2008.

14. Bilgi N, Bell K, Ananthakrishnan AN, et al: Imatinib and Panax ginseng: A potential interaction resulting in liver toxicity. Ann Pharmacother 44:926-928, 2010. 15. Mateo-Carrasco H, Gálvez-Contreras MC, Fernández-Ginés FD, et al: Elevated liver enzymes resulting from an interaction between raltegravir and Panax ginseng: A case report and brief review. Drug Metabol Drug Interact 27:171-175, 2012.

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-2: A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Trebananib (AMG 386) With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

Trebananib15 mg/kg IV QW + PLD 50 mg/m2 IV Q4W

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

R A N D O M I Z A T I O N

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Key Inclusion Criteria: • Subjects must have had one to three prior chemotherapeutic regimens • Radiographically documented disease progression either on or following the last dose of prior chemotherapeutic regimen • ECOG performance status of 0 or 1

Key Inclusion Criteria: • FIGO Stages III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin • No prior use of any anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer • ECOG performance status of 0 or 1

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2009-017946-30 • www.ClinicalTrials.gov (NCT01281254)

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2011-001112-53 • www.ClinicalTrials.gov (NCT01493505)

The ASCO Post | SEPTEMBER 1, 2013

PAGE 78

Patient’s Corner Survivorship

I’m Not the Person I Was Before Cancer

A diagnosis of non-Hodgkin lymphoma has taught me the value of loving myself. By Cindy Johnson, as told to Jo Cavallo

’ve been the caretaker for my husband Will since he suffered three strokes in March 2011, followed by a diagnosis of leukemia a few months later. Now, our roles have reversed, and Will is taking care of me as I go through treatment for stage III follicular nonHodgkin lymphoma (NHL). It’s been a difficult transition from caretaker to patient, but our mutual dependency has brought us closer.

locks of hair in the shower drain or on the bathroom floor. I discovered that losing my hair was no big deal. I think the most troubling side effect so far has been chemotherapy-induced premature menopause

[Having cancer has] taught me not to worry so much about how I look or what other people think of me…. I’ve learned that what really matters is not what people can see on the outside— it’s what is going on inside.

Getting Used to the Idea My cancer was diagnosed just a few months ago, and I’m still getting used to the idea of having an incurable disease. My oncologist believes that I will go into remission after I finish my regimen of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone), and my latest PET scan shows that the treatment has already shrunk swollen lymph nodes in my neck and abdomen, although an enlarged lymph node pressing against my kidney remains unchanged. When I first found out that I had cancer, like many women, I was concerned about losing my hair during treatment. Long and blond, my hair was always a source of pride. So before I started chemotherapy, I got a buzz cut to avoid the shock of seeing long

have to perform, like cleaning out the peripherally inserted central catheter (PICC) line in my arm and making sure to securely wrap it in plastic before I take a shower. Or not knowing from one day to the next which foods

—Cindy Johnson

and the attendant hot flashes and emotional roller coaster caused by fluctuating hormone levels. I wasn’t prepared for that.

Living With Cancer There are so many aspects of having cancer that most healthy people don’t understand. It’s not just that the first day of chemo is hard and you feel exhausted for days afterward, or that suddenly you can’t feel your fingers because they are numb from peripheral neuropathy—another R-CHOP side effect. It’s all the daily rituals I

might turn on me. With cancer, every day is a new experience. Still, having cancer has also been a blessing in some ways. It’s taught me not to worry so much about how I look or what other people think of me. Since my diagnosis, some friends have stayed away because they are fearful of seeing me as this new person going through cancer treatment. But I’ve learned that what really matters is not what people can see on the outside—it’s what is going on inside. I have a respect and love for myself I didn’t have before my diagnosis, and I value myself more. I listen

to my body, and on those days when I’m feeling exhausted, I rest and don’t push myself to do more than I can.

Facing the Future I’m fortunate because I have a wonderful oncologist who carefully explains in language I can understand the course of my lymphoma and what I can expect in the future in terms of recurrence. The day I was diagnosed with NHL, I was admitted to the hospital so I could start chemotherapy the next day. Everything was happening so quickly, there was no time to think or make the mental adjustment of going from being a healthy person to a person with cancer. If my oncologist hadn’t taken the time to answer all my questions and reassure me that I would be fine, I would have been terrified. Instead he made me feel secure and able to cope with what was happening to me. Except for worrying about what I will do when Will passes away—he has end-stage congestive heart failure— and I no longer have his support, I have no fear about my disease. I don’t know what each day will bring, but I’m proud to say that I’m a cancer survivor. n Cindy Johnson is a history professor at Cisco College in Cisco, Texas.

Don’t Miss These Important Reports in This Issue of The ASCO Post Paul A. Bunn, Jr, MD, on lung cancer see page 3

Julie M. Vose, MD, on obinutuzumab in NHL see page 16

Karen J. Marcus, MD, on treating medulloblastoma see page 23

H. Jack West, MD, on the PARAMOUNT trial in NSCLC see page 28

Philip D. Bonomi, MD, on the AVAPERL trial in NSCLC see page 30

Debra L. Barton, RN, PhD, AOCN, FAAN, on American ginseng see page 49

Visit The ASCO Post online at ASCOPost.com

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 84

In the News Genitourinary Oncology

Active Surveillance of Very Low-Risk Prostate Cancer Might Not Be Suitable Option for African American Men By Charlotte Bath

frican American men with prostate cancer that meets current criteria for very low-risk disease might actually be harboring larger and more aggressive tumors that make active surveillance a less viable option, according to the results of a study published online in the Journal of Clinical Oncology1 ( JCO) and reported in the public and medical press. “This study offers the most conclusive evidence to date that broad application of active surveillance recommendations and associated outcomes may not be suitable for African Americans,” stated the study’s corresponding author, Edward M. Schaeffer, MD, PhD, Associate Professor of Urology and Oncology at the Johns Hopkins University School of Medicine in Baltimore, Co-Director of the Prostate Cancer Multidisciplinary Clinic at the Johns Hopkins Hospital, and Director of Global Urologic Services for Johns Hopkins Medicine International. “What we learned in doing this study,” Dr. Schaeffer told The ASCO Post, “is that most active surveillance protocols from large institutions and most active surveillance studies have

a limited number of non-Caucasian patients.” The study “supports earlier studies that suggested the outcomes for African American men are not

work (NCCN) criteria for very lowrisk prostate cancer.3 “These were men who would be candidates for active surveillance but chose an active inter-

The tumors in the African American men are in a different location that is harder to biopsy, and they are actually almost twice as big on average as the tumors in Caucasians. —Edward M. Schaeffer, MD, PhD

equivalent to the outcomes for Caucasian men in active surveillance, or put another way, outcomes for African American men with very low-risk prostate cancer are not equivalent to Caucasian men with very low-risk prostate cancer,” he said.

More Adverse Pathology The study involved 1,801 men (1,473 white men, 256 African American men, and 72 others) who met National Comprehensive Cancer Net-

vention with surgery. That is important to be clear about,” Dr. Schaeffer stressed. Preoperative characteristics among the men were similar, although African American men had slightly worse Charlson comorbidity scores. Because the men did have surgery, investigators were able to evaluate pathologic findings and oncologic outcomes. What they found was that African American men considered to be at very low-risk of prostate cancer had more adverse

Expect Questions From Patients About Active Surveillance

hile National Comprehensive Cancer Network (NCCN) practice guidelines for prostate cancer advise that active surveillance is usually appropriate for men with very low-risk prostate cancer and a life expectancy ≤ 20 years, a Johns Hopkins study suggests that outcomes for African American men considering active surveillance are not equivalent to those in Caucasian men who meet the NCCN criteria for very low-risk disease. This discrepancy may prompt questions from patients considering their options for prostate cancer. African American men considering active surveillance “should be counseled that their disease-free outcomes may not parallel currently published oncologic outcomes from large [active surveillance] cohorts,” stated the study authors.

“The important point is not to say that active surveillance is right or wrong for African American men, but it is important to highlight that there is a discrepancy in the outcomes for African American vs Caucasian men,” the study’s corresponding author, Edward M. Schaeffer, MD, PhD, told The ASCO Post. “We are basing a lot of our advice about expected outcomes on series that are predominantly Caucasian men. That is a previously unrecognized deficiency that we have to address.”

Race-Based Risk Tables Researchers at Johns Hopkins University School of Medicine are addressing the issue by developing risk assessment tables for men of different races diagnosed with prostate cancer. “The idea would be that if an African American or a young white man

came to the clinic, we would be able to determine—based on risk factors that we now believe should include race—the ‘riskiness’ of his cancer,” Dr. Schaeffer said. These race-based risk tables are currently in the review phase, Dr. Schaeffer noted. Still in the development phase are modified criteria that African American men can use to determine whether to choose active surveillance or more immediate treatment. For African American men who are considering active surveillance, “we highly recommend magnetic resonance imaging (MRI),” Dr. Schaeffer said. “An MRI of the prostate will be able to help us image these tumors that might have been missed on biopsy. That is the premise. Whether or not that is going to be effective will have to be studied prospectively.” n

pathologic features at the time of radical prostatectomy and poorer oncologic outcomes. African American men had a lower rate of organ-confined cancers (87.9% vs 91.0% for white men, P = .004) and a higher rate of positive surgical margins (9.8% vs 5.9%, P = .02). African American men were more likely to have disease upgrading (27.3% vs 14.4% for white men, P < .001). “Furthermore, African Americans demonstrated a significantly higher hazard of biochemical recurrence [4.0% vs 1.4%, log-rank P = .004],” according to the study report, and adverse pathologic findings were more common in African American patients (14.1% vs 7.7% for white patients, P = .001). “On multivariable analysis, [African American] race was an independent predictor of adverse pathologic features [odds ratio [OR] = 3.23, P = .03] and pathologic upgrading [OR = 2.26, P = .03],” the investigators reported.

Survival Differences Anticipated At a median follow-up of 3 years (2 years for African American patients and 4 years for white patients), there were no differences in metastasis-free, cancer-specific, or overall survival, but Dr. Schaeffer noted that longer follow-up is needed. The Cancer of the Prostate Risk Assessment PostSurgical scoring system (CAPRA-S) score “assesses the likelihood of the cancer coming back, and CAPRA-S scores are statistically higher in African American men than in Caucasians,” he said. CAPRA-S is “a validated predictor of biochemical recurrence that ranges from 0 to 12 points based on serum PSA, pathologic Gleason pattern, lymph node involvement, extracapsular extension, seminal vesicle invasion, and positive surgical margins. We defined increased/ higher recurrence risk in this cohort as a CAPRA-S ≥ 3, which is associated with a 27.2% or higher 5-year risk of recurrence,” the investigators explained in the study report. The results showed that a CAPRA-S > 3 was significantly higher in African American men (14.8% vs 6.9% for

ASCOPost.com | SEPTEMBER 1, 2013

PAGE 85

In the News

white men, P < .001). “So I would anticipate that we would over time see more cases of metastases in the African American cohort, and we didn’t see them because our follow-up was not long enough to capture those events,” Dr. Schaeffer said.

More Anterior Tumors In another study, published simultaneously, Dr. Schaeffer’s research team performed a detailed pathologic analysis of the men in the JCO paper.2 Detailed examination of surgical specimens showed that African American men had higher total tumor volume than white men, were more likely to have multiple tumor nodules, and more likely to have the dominant nodule located in the anterior aspect of the prostate gland. “That anterior location is not easily sampled by a standard prostate biopsy,” Dr. Schaeffer noted. “In the African American men, the tumors were in an entirely different location than in the Caucasian men,” he said. “We believe that there is a biologic reason for this anatomic difference. Our research team is actively exploring several potential mechanisms.” Based on these findings, “we are working on understanding biologically why these tumors develop in a different locations as well as on potential modifications to biopsy templates for African American men,” Dr. Schaeffer said.

Not Universal Rejection Dr. Schaeffer noted that since the study published in JCO “is a retrospective analysis from a single institution, the results should not support universal rejection of active surveillance, but rather, should promote further studies to address whether alternate modes of race-specific surveillance should be used to ensure parity.” He said that he has shared findings with a prostate cancer active surveillance group at the University of California, San Francisco, and “they are investigating whether or not these observations hold true in their group as well.” Dr. Schaeffer also credited colleagues from the University of Miami. “They were the first people to report on African American men in active surveillance, and they have shown similar findings, although it was in a small number of men,” he said. “I think this study certainly suggests that differing outcomes for men with prostate cancer of different races

should really be explored more,” Dr. Schaeffer stated. “We are not saying that this is something that should universally be adopted, but we really look forward to and are encouraged by other investigators confirming our results.” n Disclosure: Dr. Schaeffer reported no potential conflicts of interest.

References 1. Sundi D, Ross AE, Humphreys EB, et al: African American men with very low–risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: Should active surveillance still be an option for them? J Clin Oncol. June 17, 2013 (early release online). 2. Sundi D, Kryvenko ON, Carter HB, et

al: Pathologic examination of radical prostatectomies in men with very low-risk disease at biopsy reveals distinct zonal distribution of cancer in African American men. J Urol. June 13, 2013 (early release online). 3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate cancer, version 4.2013. Available at www.nccn.org. Accessed August 14, 2013.

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The ASCO Post | SEPTEMBER 1, 2013

PAGE 86

Perspective Thoracic Oncology

Role of Erlotinib in EGFR Wild-Type Lung Cancer By Pasi A. Jänne, MD, PhD

welcomed Matthew Stenger’s Journal Spotlight on the TAILOR trial in the August 15 issue of The ASCO Post (“Docetaxel Superior to Erlotinib in Second-Line Treatment of Advanced Non–Small Cell Lung Cancer With Wild-Type EGFR”). The

line chemotherapy had failed were allocated to receive either erlotinib or placebo. Patients were enrolled in this trial at a time when we did not yet appreciate the existence of EGFR mutations and their associated sensitivity to EGFR kinase inhibitors.

Most patients with a good performance status, who have failed first-line therapy, who seek the opinion of an oncologist want to know their best therapeutic option, not whether the proposed treatment is superior to no treatment. —Pasi A. Jänne, MD, PhD

trial was recently published online in Lancet Oncology,1 and addresses important questions about the role of erlotinib (Tarceva) in second-line therapy for non–small cell lung cancer (NSCLC). An epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor, erlotinib was first approved by the U.S. Food and Drug Administration (FDA) as an anticancer therapy in 2004. This approval was based on the BR.21 randomized trial, wherein patients with NSCLC in whom first- or secondPasi A. Jänne, MD, PhD, is Director, Lowe Center for Thoracic Oncology, Scientific Director, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

In the 9 years since the discovery of EGFR mutations, science and medicine has advanced. We now routinely test for EGFR mutations and treat patients with EGFR tyrosine kinase inhibitors instead of chemotherapy when an EGFR mutation is identified. In fact, erlotinib was just recently approved by the FDA for the treatment of first-line EGFR mutant NSCLC.

EGFR Wild-Type Given the increased use of erlotinib in EGFR mutant NSCLC patients, the question of its benefits in patients who do not have EGFR mutations has gained increasing attention. A retrospective analysis of the BR.21 study suggested that even among patients without an EGFR mutation, there was

still a benefit of receiving erlotinib compared to placebo.2 However, most NSCLC patients with a good performance status, who have failed firstline therapy, who seek the opinion of an oncologist want to know their best therapeutic option, not whether the proposed treatment is superior to no treatment. The TAILOR trial addresses this question specifically for EGFR wildtype patients. The data from the trial demonstrate that docetaxel is more effective than erlotinib in EGFR wildtype. Patients treated with docetaxel had a significantly higher response rate and progression-free survival and a numerically longer overall survival than those assigned to receive erlotinib.

Study Implications What are the implications of this study? Certainly if the only molecular genotyping test that has been performed is an EGFR mutation test, then patients with EGFR wild-type NSCLC should preferentially receive doctaxel as their second-line therapy. Whether the same findings would apply to other chemotherapies is unknown. However, it is important to recognize that NSCLC patients are no longer divided into EGFR mutant or wild-type groups. In fact, tumors that do not harbor EGFR mutations may harbor other genomic alterations such as rearrangements in ALK, RET, or ROS1 or mutations in BRAF or ERRB2—many of which are alterations for which there are either approved targeted therapies (crizotinib [Xalkori] for ALK rearrangements) or agents in clinical de-

velopment. Hence, it is far more critical to extend molecular genotyping to go beyond EGFR mutation testing, to find the most effective therapy for our patients based on their tumor’s genomic profile. Do the results of the TAILOR trial suggest that patients not harboring an EGFR mutation will never benefit from erlotinib? Three percent of patients had a partial response to erlotinib, and it is possible that there are determinants other than EGFR mutations of erlotinib efficacy that have yet to be fully validated. Potential biomarkers include EGFR amplification and/or presence of EGFR ligands. However, given the low response rate, these are likely to exist in only a minority of EGFR wild-type NSCLC patients. Future studies will be needed to identify this subset of EGFR wild-type NSCLC patients and to determine the effectiveness of erlotinib compared to docetaxel. n References 1. Garassino MC, Martelli O, Broggini M, et al: Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small cell lung cancer and wild-type EGFR tumours (TAILOR): A randomized controlled trial. Lancet Oncol. July 22, 2013 (early release online). 2. Zhu CQ, da Cunha SG, Ding K, et al: Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 26:4268-4275, 2008.

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Are You Ready for the Boards? Prepare with ASCO’s Interactive Board Reviews Fall Session

About the SeSSionS:

WhAt’S CoveRed?

ASCO’s Interactive Board Reviews are designed for those preparing for the ABIM Med/Heme Onc Certification examination, MOC examination, or simply looking for selfassessment opportunities.

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october 9, 2013 (6-8 pm ET) > GI (Colorectal) Cancers > Breast Cancer > Genitourinary Cancers

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> GI (Non-Colorectal) Cancers

october 23, 2013 (6-8 pm ET) > Hematologic Malignancies

ReceIve AcceSS to Full cAptuReS oF Both lIve SeSSIonS And the ABIlItY to eARn cMe cRedIt.

> Lung Cancer

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PAGE 88

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Nodal Metastases More Likely if Tumors Have Breast Cancer Stem and Progenitor Cells With PI3K/Akt Signaling Defects Patients with breast tumors in which breast cancer stem and progenitor cells have a genetic abnormality of the PI3K/ Akt signaling pathway are more likely to have lymph node metastases, according to a study in JAMA Surgery. “These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer,” the researchers reported. “Molecular profiling of [breast cancer stem and progenitor cells] may identify patients who would likely benefit from PI3K/ Akt inhibitors, which are being tested in clinical trials.” The study involved 30 women with invasive ductal carcinoma of the breast exceeding 1.0 cm. “Solid-tissue breast specimens were collected at the time of mastectomy or lumpectomy before any adjuvant treatment,” the investigators explained. “Following tissue analysis, medical records were reviewed, and additional data were compiled retrospectively for each patient.” Positive lymph nodes were identified in six patients and micrometastatic deposits, defined as < 0.2-cm metastatic focus of tumor, in another six. Patients with macroscopic lymph node metastases had axillary lymph node dissection, but patients with only

micrometastatic disease did not. Of the 30 tumors, 10 had breast cancer stem and progenitor cells with AKT1, HRAS, or PIK3CA mutations.

Significant Correlation The investigators found a statistically significant correlation between the presence of breast cancer stem and progenitor cell mutations and axillary lymph node metastases (P = .02). “This significance was more pronounced when micrometastatic disease was included (P = .001),” the researchers stated. Of the 10 patients with breast cancer stem and progenitor cell mutations, 3 had disease progression following chemotherapy, hormone therapy, and a trastuzumab (Herceptin) regimen. Two of those patients died of disease, and one had brain metastases. None of the patients with breast cancer stem and progenitor cells without mutations had evidence of disease. The mean follow-up was 29 months for patients with breast cancer stem and progenitor cell mutations and 19 months for those without such mutations, and the authors noted the difference was statistically significant (P = .001). “While axillary lymph node metastases are known to correlate with tumor size, [breast cancer stem cell and progenitor cell] mutation in this study was an independent predictor of lymph node metastasis,” the authors wrote. “Because 4 of 20 patients (20%) without [such] mutations had axillary lymph node metastases, a PI3K/

Akt mutation in [breast cancer stem and progenitor cells] may not be a requirement for axillary lymph node metastases. However, a significant correlation was found between the two factors, with 9 of 10 patients (90%) with [breast cancer stem and progenitor cell] mutations having nodal metastases. Five of 10 patients (50%) with [breast cancer stem and progenitor cell] mutations had axillary lymph node macrometastatic disease, and an additional 4 of 10 patients (40%) had micrometastatic disease.” The authors concluded that the results of the study “support concomitant evaluation of [breast cancer stem and progenitor cells] along with assessment of the breast cancer overall.” Donovan CA, et al: JAMA Surgery. July 24, 2013 (early release online).

Long-Term Current Use of Calcium Channel Blockers Is Associated With Higher Risk of Breast Cancer Long-term use of a calcium channel blocker to treat hypertension is associated with higher breast cancer risk, according to a report published online by JAMA Internal Medicine. Researchers evaluated associations between various classes of hypertensives, the most commonly prescribed class of medication in the United States, and the two most common histologic types of breast cancer, invasive ductal and invasive lobular breast cancer, but only found an association for calcium channel blockers. Other antihypertensive medications—diuretics, beta-blockers, and angiotensin II antagonists— were not associated with increased breast cancer risk The population-based study in the three-county Seattle–Puget Sound metropolitan area included women aged 55 to 74 years, 880 with invasive ductal breast cancer, 1,027 with invasive lobular breast cancer, and 856 who did not have cancer and served as controls. Those who were currently using calcium channel blockers and had done so for 10 or more years had higher risks of ductal breast cancer (odds ratio [OR] = 2.4, P = .04 for trend) and lobular breast cancer (OR = 2.6, P = .01 for trend). These associations did not vary according to estrogen receptor status. In addition, the relationship did not vary much based on the type of calcium channel blockers used (short-

acting vs long-acting or dihydropyridines vs non-dihydropyridines).

First Study to Find Link “While some studies have suggested a positive association between calcium channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms,” the researchers concluded. “Given these results, should the use of [calcium channel blockers] be discontinued once a patient has taken them for 9.9 years? The answer is no, because these data are from an observational study, which cannot prove causality and by itself cannot make a case for change in clinical practice,” Patricia F. Coogan, ScD, of the Slone Epidemiology Center at Boston University wrote in an accompanying commentary. “Should the results be dismissed as random noise emanating from an observational study? The answer is no, because the data make a convincing case that the hypothesis that long-term [calcium channel blockers] use increases the risk of breast cancer is worthy of being pursued,” she continued. “In conclusion, the present study provides valid evidence supporting the hypothesis that long-term [calcium channel blocker] use increases the risk of breast cancer. If true, the hypothesis has significant clinical and public health implications.… If the 2- to 3-fold increase in risk found in this study is confirmed, long-term [calcium channel blocker] use would take its place as one of the major modifiable risk factors for breast cancer. Thus it is important that efforts be made to replicate the findings.” Li CI, et al: JAMA Internal Medicine. August 5 (early release online). Coogan PF, JAMA Internal Medicine. August 5 (early release online).

ENDOMETRIAL CANCER ‘Best-Ever’ Published Prognostic Factor for EarlyStage Type 1 Endometrial Cancer Immunohistochemical demonstration of the L1 cell adhesion molecule (L1CAM; CD171) “has been shown

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In the Literature

to be the best-ever published prognostic factor” in Federation Internationale de Gynecologie et d’Obstetrique (FIGO) stage I, type I endometrial cancers “and shows clear superiority over the standardly used multifactor risk score,” researchers concluded after conducting a retrospective multicenter cohort study. “Of the 1,021 investigated type I endometrial cancers, 17.7% were rated L1CAM-positive in this study. L1CAM expression in 10% or more of the tumor cells was associated with an overwhelming increase in the likelihood of distal or local recurrence and moreover was independently related to poor overall survival,” the researchers reported in the Journal of the National Cancer Institute. While only 2.9% of L1CAM-negative cancers recurred during follow-up, 51.4% of the L1CAM-positive cancers did. “Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Logrank P < .001),” the results showed. “Multivariable analyses revealed an increase in the likelihood of recurrence [hazard ratio [HR] = 16.33, 95% confidence interval [CI] = 10.55–25.28] and death [HR = 15.01, 95% CI = 9.28–24.26],” the authors reported. “In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree identified L1CAM as the best variable for predicting recurrence [sensitivity = 0.74, specificity = 0.91] and death [sensitivity = 0.77, specificity = 0.89],” they added. The authors called for routine immunohistochemical L1CAM determination for all type I endometrial cancers. “It is worth noting that L1CAM-based risk assessment can be obtained from curettage material before major surgery. However, the reliability of this procedure, especially for sampling errors, requires validation in prospective approaches,” the researchers wrote. “The most intriguing question is what treatment is most beneficial for patients with L1CAM-positive type I endometrial cancers,” the investigators noted. They speculated that chemotherapy could be the most valid option and that another promising approach could be a fully humanized anti-L1CAM antibody currently being developed for clinical use. Zeimet AG, et al: J Natl Cancer Inst 105:1142-1150, 2013.

PROSTATE CANCER Printed and Web-Based Decision Aids Improved Informed Decision-Making but Didn’t Alter Screening Amid conflicting recommendations for prostate cancer screening

and mixed messages communicated to the public about screening effectiveness, decision aids can assist men in making informed choices. A comparison of two different types of decision aids, one print-based and one Web-based, found that both appear to improve patients’ informed decisionmaking about prostate cancer screen-

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ing up to 13 months later, but do not appear to affect actual screening rates, according to a study published in JAMA Internal Medicine. A total of 1,893 men were randomly assigned to receive a print-based decision aid, a Web-based interactive decision aid, or usual care. The mean age continued on page 90

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In the Literature

Emerging Clinical Data continued from page 89

was 56.9 years, and 23.8% of the men had a high school education or less. A slight majority (56.2%) were white, 39.9% were African American, and 3.9% were characterized as other. More than 86.3% had been screened for prostate cancer, almost 60% in the last year.

The decision aids had identical content and were geared to an eighth-grade reading level. Content included introductory material about the prostate, a description of screening and possible results, and information about treatment options, risks, and adverse effects. Also included were a review of prostate cancer risk

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factors and encouragement to discuss screening with a physician (but not instructions to make an immediate appointment), a 10-item values clarification tool, and resources for more information. The Web material also featured voice-overs, animation, graphics, and an interactive values clarification tool. Researchers mea-

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sured the participants’ prostate cancer knowledge, decisional conflict, decisional satisfaction, and whether participants had prostate cancer screening. At 1- and 13-month follow-up, both decision aids resulted in significantly improved prostate cancer knowledge and reduced decisional conflict compared with usual care. At 1 month, high satisfaction was reported by significantly more print (60.4%) than Web participants (52.2%) and significantly more Web and print than usual care participants. At 13 months, differences in the proportion of men reporting high satisfaction among print participants (55.7%) compared with Web participants (50.4%) and those receiving usual care (49.8%) was not significant. Screening rates at 13 months did not differ significantly among groups. “The clinical implications of this study include the potential” for these two different types of decision aids “to be easily adopted in real-world practice settings,” the authors wrote. The decision aids “offer neutrality,” since they did not influence the screening decision in either direction compared with usual care, and this “allows patients and providers to individualize the decision,” the authors added. Now that the decision aids have demonstrated beneficial effects, these aids need to be delivered to patients in a systematic manner, the researchers advised. “Possible avenues include personal health records, distribution in health-care provider offices, or via the websites of large health-care organizations.” An accompanying commentary noted that “the lessons of prostate cancer screening should cause us to reexamine our tendency to adopt new screening technologies before obtaining high-quality evidence about the magnitude of benefits and harms. Specifically, we should consider implementing policies that help offset our collective propensity to emphasize potential benefits of cancer screening and deemphasize (or completely ignore) potential harms.” n Taylor KL, et al: JAMA Internal Medicine. July 29, 2013 (early release online). Reuland DS, Pignone M: JAMA Internal Medicine. July 29, 2013 (early release online).

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Perspective

Funding for Lung Cancer continued from page 1

69% to 99.8%, in breast cancer from 75% to 89%, in colorectal cancer from 51% to 67%, and in bladder cancer from 74% to 80%. In contrast, the survival rate in lung cancer has moved from 13% to a mere 16%.

Paucity of Funding A major reason for this lack of improvement is the paucity of funding for lung cancer research. Progress in the treatment of most malignancies has resulted from rigorous scientific research. Funding agencies have for the most part ignored lung cancer. Data from the National Cancer Institute (NCI), Department of Defense (DoD), and Centers for Disease Control and Prevention (CDC) reveal that the amount of money spent per death from cancer for the fiscal year 2012 was $17,835 for breast cancer, compared to $1,378 for lung cancer. This represents a greater than 10-fold increased spending per breast cancer death compared to each lung cancer death. A look at the total funding for these malignancies is just as alarming. Between 2008 and 2010, the NCI spent $1,803.3 million on breast cancer research compared to $776.4 million on lung cancer research.2 This disparity is not unique to the United States. In the United Kingdom, in 2012, breast cancer research received £40.8 million; leukemia, £31.6 million; million; colon cancer, £24.5 mil milmillion; prostate cancer, £20.9 million; and lung cancer, the cause of the highest number of cancer-related deaths, a paltry £14.8 million million million in research funding. When funding per death from cancer is evaluated, breast cancer received approximately £3,500, whereas lung cancer received just over £400 per death.3 Many individuals will spend more annually on round-trip airfares than either the United States or the

United Kingdom spends on research per lung cancer death.

Reasons for Disparities The reasons for these disparities are unclear. Some may argue that the goal of these federal agencies is to fund the most advanced research, irrespective of what type of cancer is being studied. Here, lung cancer is at a significant disadvantage compared to breast cancer. Since breast cancer has enjoyed a higher level of funding for a long period of time, it has attracted more researchers

in Dallas found that both explicit and implicit attitudes were significantly more negative toward lung cancer than breast cancer.4 As a society, are we justified in vilifying this large group of individuals? Less than half a century ago, society endorsed these same habits that are so vehemently criticized today. While smoking cessation is of paramount importance, the majority of lung cancers occur in individuals who have quit smoking. When these individuals ask for help to combat this deadly disease,

Winning the war against cancer will not become a reality until lung cancer is defeated. —Apar Kishor Ganti, MD, MS, FACP

and has enjoyed more success, thereby raising the quality of research as well. Another argument is that since the molecular pathways are similar for many cancers, results from the study of a pathway in one cancer would be applicable to another malignancy as well. But as recent studies have shown, what is true for the role of the EGFR-targeting antibody cetuximab (Erbitux) in colon cancer is not necessarily true in lung cancer. Thus, tumor-specific research is warranted. Lung cancer has long been seen as a cigarette-smoking–related illness, and the stigma of smoking has contributed to the public perception of patients with lung cancer—the impression is that because these individuals smoked, they brought this upon themselves. A recent 1,700-person study by Dr. Joan Schiller at the University of Texas Southwestern Medical Center

we must not turn our backs on them. Finding ways to combat this disease will also save money currently spent on taking care of the complications of lung cancer and its treatment.

were categorized as a separate disease, lung cancer in nonsmokers would be the sixth leading cause of cancerrelated deaths following lung cancer in smokers, colon, breast, pancreas, and prostate cancer. Clearly, the argument that patients with lung cancer brought it on themselves and therefore do not deserve sympathy is simiilar to comparing them to obese patients with cancer and does not hold much credibility.

Closing Thoughts Another reason for lack of funding may be the paucity of long-term survivors who can raise lung cancer awareness in the society and also be passionate advocates for increased funding support. Breast cancer survivors have raised billions of dollars through fundraisers, awareness campaigns, races, and galas. They have convinced large companies to contribute a percentage of sales toward breast cancer research. This increased funding for research has led to dramatic improvements in results for patients with breast cancer, and it stands to reason that the same could be true for lung cancer. Winning the war against cancer will not become a reality until lung cancer is defeated. n

Rising Incidence in Nonsmokers

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

The incidence of lung cancer in nonsmokers is increasing worldwide. Understanding of the genetics of lung cancer has led to identification of the same driver mutations in some lung cancers diagnosed in former smokers as seen in never-smokers. Presumably these individuals would have developed lung cancer even if they had never smoked. Approximately 15% of patients in the United States with lung cancer are in this category. Lung cancer accounts for almost 23,000 deaths annually among nonsmokers in the United States. If this

References 1. American Cancer Society: Cancer Facts & Figures 2013. Available at www. cancer.org. Accessed August 13, 2013. 2. NCI Office of Budget and Finance: 2012 Fact Book. Available at obf.cancer. gov. Accessed August 13, 2013. 3. National Cancer Research Institute: CaRD 2012. Available at www.ncri.org. uk/default.asp?s=1&p=3&ss=6. 4. Schiller JH, Bowden CJ, Mills J, et al: Explicit and implicit attitudes toward lung cancer, relative to breast cancer. 2013 ASCO Annual Meeting. Abstract 8017. Presented June 3, 2013.

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