TAP Vol 6 Issue 5 by Harborside Press LLC

Managing Bladder Cancer

6, 8–9

| Hypofractionated Breast Irradiation

20, 23, 24

| FDA Update

VOLUME 6, ISSUE 5

14, 66–67

MARCH 25, 2015

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

Genitourinary Cancers Symposium

Intensified Immunotherapy Encouraging in Chemotherapy-Naive Metastatic Prostate Cancer By Alice Goodman

merging evidence suggests that immunotherapy may play an important role in treating prostate cancer. In particular, preliminary results have shown that combining a new vaccine with ipilimumab (Yervoy) boosts overall survival in men with castration-resistant prostate cancer.1 A study comparing data from three independent trials of the vaccine won a Merit Award at the 2015 Genitourinary Cancers Symposium. Rilimogene galvacirepvec/rilimogene glafolivec (Prostvac) is a poxvirus-based, prostate-specific vaccine being developed by Bavarian Nordic in partnership with the National Cancer Institute (NCI). Ipilimumab, an immune checkpoint inhibitor, is approved for the treatment of melanoma and is being evaluated in a phase III trial in metastatic castration-resistant prostate cancer. “On the heels of the success of immunotherapy in metastatic melanoma, immunotherapy is an active area of study in prostate and other cancers. The approach in

this phase I study was to prime the immune cells with [the vaccine] and then intensify immunotherapy with ipilimumab to further enhance the immune response,” said lead author Harpreet Singh, MD, of the National Cancer Institute.

Two previous phase II trials by the same group looked at the vaccine alone and found an overall survival benefit in men with metastatic castration-resistant prostate cancer. The first trial, which included 125 men, found a median overall survival of 25.1 months. The second trial, which included 32 men, showed a median

ealth-care fraud is a long-standing problem in the United States, accounting for $75 billion in government expenses per year,1 while total spending on government healthcare programs is over $1 trillion. Two decades ago, the Department of Justice increased its efforts to combat health-care fraud. This change was stimulated by the Federal False Claims Act, a 1986 legislation that allows qui tam relators (commonly termed “whistle-blowers”) to receive up to 30% of financial recoveries from successfully concluded False Claims Act investigations. In 1996, the Federal Health Care Fraud and

continued on page 4

continued on page 97

Harpreet Singh, MD

Overall Survival Benefit

MORE IN THIS ISSUE

A Conversation With Hyman Muss, MD By Ronald Piana

ery system and will intensify the need for oncologists to be optimally trained to manage their older patients. Over the past 20 years, the oncology community has seen the development of geriatric programs and a focus on research in older cancer patients. To shed light on the state of geriatric oncology, The ASCO Post spoke with Hyman Muss, MD, a leader in the field.

The most important advance in geriatric oncology over the course of my career has been the recognition that older cancer patients need to be managed differently than their younger counterparts. —Hyman Muss, MD

Send your comments to editor@ASCOPost.com

Author affiliations on page 97. Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

Our Aging Population: Challenges in Caring for Older Patients With Cancer

Charles Bennett, MD, PhD, MPP

By Z. Kevin Lu, PhD, Brian Chen, JD, PhD, Zaina Qureshi, PhD, MPH, Oliver Sartor, MD, and Charles Bennett, MD, PhD, MPP

Geriatrics for the Oncologist

anaging older-aged cancer patients represents one of the major challenges to our health-care system. Caring for older cancer patients, with their frequent multiple morbidities and a variable health status, requires special integration of an oncologic and geriatric approach. Moreover, our aging population will pose serious challenges to an already overtaxed cancer deliv-

Health-Care Fraud and Abuse: Implications for Oncology

Practicing Like ‘Mini-Geriatricians’ During your career in geriatric oncology, what has been the most significant advance? Older patients, at least in affluent Western countries, are the majority of patients who have cancer, and the numbers are continuing to

Oncology Meetings Coverage Genitourinary Cancers Symposium �� 1, 3–6, 8–9 GI Cancers Symposium �� 16, 18–19 Richard ‘Buz’ Cooper, MD, on Health-Care Resources ��33 Inside the Black Box ��42 Direct From ASCO ��47–50 Five Questions to Guide Myeloma Care ��59 Issues With Herbal Supplements �� 76 Patient’s Corner: A Perspective ��89 David Hui, MD, MSc, on End-of-Life Care ��93

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A Harborside Press® Publication

The ASCO Post | MARCH 25, 2015

PAGE 2

Harborside Press® Publishing Staff

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Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

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John A. Fracchia, MD New York Urological Associates

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Associate Editors

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Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine Harold J. Burstein, MD Dana-Farber Cancer Institute

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

Robert W. Carlson, MD National Comprehensive Cancer Network

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

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

Jay S. Cooper, MD Maimonides Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

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Sarah McGullam, Web Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Regine M. Lombardo, Senior Graphic Designer Regine@harborsidepress.com Terri Caivano, Layout Artist Terri@harborsidepress.com Gail van Koot, Editorial Coordinator Gail@harborsidepress.com Elizabeth Janetschek, Editorial Assistant Elizabeth@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Jeannine Coronna, Vice President, Director of Operations Jeannine@harborsidepress.com

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The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January 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 subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2015 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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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 | MARCH 25, 2015

PAGE 3

Genitourinary Cancers Symposium Genitourinary Oncology

No Survival Benefit Reported With Docetaxel Added to Hormone Therapy in Metastatic Prostate Cancer By Alice Goodman

ocetaxel added to androgen-deprivation therapy did not improve overall survival over androgen-deprivation therapy alone in hormone-naive metastatic prostate cancer, according to an updated analysis of the GETUG-AFU 15 trial presented at the 2015 Genitourinary Cancers Symposium.1 In a retrospective analysis component of the trial, docetaxel

hazard ratio = 0.9 (0.7–1.2) for androgen-deprivation therapy plus docetaxel.

Results Differ From the CHAARTED Study These results differed from those of the E2805 CHAARTED study presented by Christopher Sweeney, MD, at the 2014 ASCO Annual Meeting.2 That

In a retrospective analysis, no improvement [in overall survival] was observed in patients with low-volume disease with the addition of docetaxel. —Gwenaelle Gravis, MD

provided an additional 14 months of survival overall and a 4-month difference in patients with high-volume disease, but neither was statistically significant. “We wanted to see whether docetaxel in an earlier setting could improve survival in metastatic cancer,” said presenting author Gwenaelle Gravis, MD, of the Institut Paoli-Calmettes, Marseille, France.

study showed a 17-month overall survival improvement with docetaxel added to androgen-deprivation therapy in men with high-volume disease, from 32.2 months to 49.2 months (P = .0006). “In this retrospective analysis of GETUG-AFU 15, the majority of patients were low volume, around 53%, and

■■ The results of the GETUG-AFU 15 study diverge from those of the E3805 CHAARTED study, which found a significant survival difference in high-volume metastatic prostate cancer when docetaxel was added to hormone therapy. ■■ Several factors may be responsible for this difference, including the fact that GETUF-AFU 15 was underpowered to detect a significant difference in survival in men with high-volume disease. ■■ Results of yet another trial in this setting are awaited, and then all three studies can be considered in determining the best course of treatment for hormone-sensitive chemotherapy-naive metastatic prostate cancer.

80% of patients in the androgen-deprivation therapy–alone arm received docetaxel after castration resistance. As distinct from the CHAARTED study, we found that the median overall survival was not significantly different,” she said. When patients in GETUG-AFU 15 were analyzed retrospectively according to disease volume, no significant difference was observed for low-volume disease between the two arms at a median follow-up of 81 months. Median overall survival was not reached with androgendeprivation therapy alone and was 83.1 months for androgen-deprivation therapy plus docetaxel. In the high-volume

disease group, median overall survival was 35.1 months vs 39 months, respectively. This represented a nonsignificant 4-month difference favoring docetaxel at a median follow-up of 84 months. In a multivariate analysis, prognostic factors included the extent of metastases (high or low volume) and the level of alkaline phosphatase at baseline were independant prognostic factors for survival. Treatment arm was not significant. There was no difference in overall survival in unselected patients with metastatic prostate cancer. In a retrospective analysis, no improvement was observed in patients continued on page 4

EXPERT POINT OF VIEW

Study Details GETUG-AFU 15 enrolled 385 patients between October 2004 and December 2008 and randomized them to receive either androgen-deprivation therapy plus docetaxel or androgen-deprivation therapy alone (luteinizing hormone-releasing hormone agonist or maximum androgen blockade or bilateral orchiectomy). The study was conducted at 30 centers (29 in France and 1 in Belgium). The patients’ median age was 63 years. Fifty-eight percent had a Gleason score of ≥ 8. Most cases were metastatic at diagnosis: 76% in the docetaxel arm and 67% in the androgen-deprivation therapy alone arm. The median followup was 50 months. In the original analysis, with a median follow-up of 50 months, the time to disease progression was prolonged in the docetaxel arm, but median survival was not significantly different, Dr. Gravis noted. In the updated analysis, with a median follow-up of 80+ months, median overall survival was 46.5 months (range = 39.1–60.6 months) for androgen-deprivation therapy alone vs 60.9 months (range = 46.1–71.4 months;

Updated Analysis of the GETUG-AFU 15 Trial

“G

ETUG-AFU 15 sought to improve outcomes in metastatic hormone-naive prostate cancer, but the study failed its primary objective,” noted formal discussant Eric J. Small, MD, of the University of California, San Francisco.

showed a highly statistically significant 13.6-month difference in survival with the addition of docetaxel to hormone therapy. This trial had more patients, and the benefit of early docetaxel was driven by high-volume patients, with no benefit in low-volume patients.

High-volume disease does worse than low-volume disease and should be treated with androgen-deprivation therapy plus docetaxel. —Eric J. Small, MD

In the overall analysis of this previously published trial, with no enrichment for any group, there was a 14-month difference in overall survival, which did not reach statistical significance, he reminded listeners. However, the CHAARTED study

Potential reasons for the overall survival difference between the two trials include one-third fewer highvolume patients in the GETUG-AFU 15 trial and no enrichment for highvolume patients, Dr. Small said. “The GETUG-AFU 15 trial is

underpowered, but results are directionally consistent with the ECOG CHAARTED trial, and the discrepancy between these trials can be explained,” he stated. “In summary, high-volume disease does worse than low-volume disease and should be treated with androgendeprivation therapy plus docetaxel. At this time, low-volume disease in hormone-sensitive prostate cancer should not be treated with docetaxel. Identification of biomarkers to predict which patients may benefit from docetaxel is a research priority,” Dr. Small said. Dr. Small looks forward to the results of the CALGB 90203 trial, which is comparing prostatectomy vs neoadjuvant androgen-deprivation therapy plus docetaxel followed by prostatectomy and includes correlative analysis of molecular tissue with clinical outcomes. n

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

The ASCO Post | MARCH 25, 2015

PAGE 4

Genitourinary Cancers Symposium Intensified Immunotherapy continued from page 1

overall survival of 26.6 months. Both trials demonstrated improved overall survival over that predicted by the Halabi nomogram (a model that uses historical data to estimate survival of prostate cancer patients after castration): The first study showed an 8.5-month im-

treated with the combination of the vaccine plus escalating doses of ipilimumab. Follow-up was about 80 months. The predicted survival of chemotherapy-naive patients with metastatic castration-resistant prostate cancer is 18.5 months on the Halabi nomogram, she said. The updated overall survival analysis showed a median overall sur-

These hypothesis-generating data suggest it is rational to combine vaccine and immunotherapy. Anti–PD-1 or anti–PD-L1 immunotherapies are of interest in this regard…. If we combine the vaccine with one of these agents, we may improve outcomes. —Harpreet Singh, MD

provement in median overall survival, and the second had a similar 9.1-month improvement in median overall survival compared with predicted survival, Dr. Singh told The ASCO Post.

vival of 31.3 months using the intensified immunotherapy approach. The most impressive results were seen in the group receiving the highest dose of ipilimumab (10 mg/kg) plus the vaccine: a

Immunotherapy in Advanced Prostate Cancer ■■ A new prostate-specific cancer vaccine (rilimogene galvacirepvec/ rilimogene glafolivec [Prostvac]) has been shown to improve survival in men with chemotherapy-naive metastatic prostate cancer. ■■ The new vaccine is undergoing phase III testing. ■■ Preliminary evidence suggests that combining the vaccine with an immune checkpoint inhibitor can further extend survival in chemotherapy-naive metastatic prostate cancer.

These studies led to an international phase III trial of the vaccine in men with metastatic castration-resistant prostate cancer and minimal symptoms who are chemotherapy-naive. That trial has just finished accrual. “It is clear that vaccine therapy alone improves overall survival,” Dr. Singh stated.

Phase I Trial She also presented updated phase I results of a study of 30 patients with metastatic castration-resistant prostate cancer (and baseline characteristics similar to those in the phase II trials)

Docetaxel Plus Hormone Therapy continued from page 3

with low-volume disease with the addition of docetaxel, and a nonsignificant difference of 4 months was observed in the high-volume disease group. Possible explanations for the difference between the current results and those in the CHAARTED study include

median overall survival of 37.2 months. “There is a tail in the curve. About 20% of these patients on the highest dose of ipilimumab are alive at 80 months,” Dr. Singh said.

Hypothesis-Generating Data “These hypothesis-generating data suggest it is rational to combine vaccine and immunotherapy. Anti–PD-1 or anti–PD-L1 immunotherapies [antibodies against programmed cell death protein 1 or its ligand] are of interest in this regard. They appear to have less toxicity than ipilimumab. If we combine the vaccine with one of these the increased use of salvage docetaxel in GETUG-AFU 15 and that the study was underpowered to detect a difference in the 183 patients with high-volume disease (91 on androgen-deprivation therapy alone and 92 on androgen-deprivation therapy plus docetaxel). When available, results of the STAMPEDE trial will be considered in the context of both CHAARTED and

EXPERT POINT OF VIEW

SCO Expert and GU News Planning Team Member, Charles Ryan, MD, of the University of California, San Franciso, Helen Diller Family Comprehensive Cancer Center, said the results presented by Singh et al at the 2015 Genitourinary Cancers Symposium were “encouraging” and that it makes sense to exploit two complementary arms of the immune system: The vaccine initiates or “jump starts” response to the tumor, and then active imCharles Ryan, MD munotherapy enhances the durability of response. Dr. Ryan noted that the Halabi nomogram was developed before the availability of newer therapies like abiraterone (Zytiga) and enzalutamide (Xtandi), so projected survival using that nomogram is probably not applicable in the modern era. The rilimogene galvacirepvec/rilimogene glafolivec (Prostvac) vaccine has several potential advantages over sipuleucel-T (Provenge), Dr. Ryan commented. “Prostvac is off the shelf, whereas sipuleucel-T relies on harvesting enough of the patient’s own immune cells. Thus, there is greater potential for a uniform product with Prostvac,” he said. “It is also possible that Prostvac will be less expensive, but that [remains to be seen].” Regarding the approach of combining the new vaccine with anti–PD-L1, Dr. Ryan said it is possible that an anti–PD-L1 agent would be safer than ipilimumab (Yervoy), “but this would require further validation in prostate cancer. Ipilimumab is better studied in prostate cancer than anti–PD-L1.” n Disclosure: Dr. Ryan reported no potential conflicts of interest.

agents, we may improve outcomes,” she stated. Many others in the field of prostate cancer are excited about the promise of immunotherapy. In the Genitourinary Cancers Symposium Daily News, L. Michael Glodé, MD, University of Colorado at Denver, wrote: “The remarkable advances recently reported in melanoma [with immunotherapies] … provide hope that we may be only in the earliest phase of truly effective treatment of metastatic prostate cancer, with

L. Michael Glodé, MD

GETUG-AFU 15 to determine the best course of treatment, she said. n

Disclosure: Dr. Gravis has served as a consultant or advisor to and traveled on behalf of Sanofi.

References 1. Gravis G, Boher JM, Joly F, et al: Androgen deprivation therapy plus docetaxel versus ADT alone for hormone-naive metastatic prostate cancer: Long-term analysis

the ultimate goal of long-term remissions or even immunologically driven ‘cure.’”2 Dr. Glodé called the trial results reported by Dr. Singh “promising” and suggested that using the new vaccine could be more cost-effective than sipuleucel-T (Provenge), a vaccine approved in the predocetaxel setting. n

Disclosure: Dr. Singh reported no potential conflicts of interest. Dr. Glodé and colleagues received research funding for the phase II trial of Prostvac from Bavarian Nordic.

References 1. Singh H, Madan RA, Dahut WL, et al: Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer. 2015 Genitourinary Cancers Symposium. Abstract 172. Presented February 26, 2015. 2. Glodé LM: Immunotherapy for prostate cancer: Past, present, and future. 2015 Genitourinary Cancers Symposium Daily News, February 27, 2015.

of the GETUG-AFU 15 phase III trial. 2015 Genitourinary Cancers Symposium. Abstract 140. Presented February 26, 2015. 2. Sweeney C, Chen, Y-H, Carducci MA, et al: Impact on overall survival with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: An ECOG-led phase III randomized trial. 2014 ASCO Annual Meeting. Abstract LBA2.

ASCOPost.com | MARCH 25, 2015

PAGE 5

Genitourinary Cancers Symposium Genitourinary Oncology

High-Dose Radiotherapy Provides Meaningful Improvements in Localized Prostate Cancer—But Not Increased Survival Yet By Alice Goodman

igh-dose radiotherapy failed to improve overall survival at 7 years compared with standard-dose radiotherapy in men with stage II localized prostate cancer. However, the high-dose schedule had several advantages, including improved rates of local tumor control and distant metastasis, according to the

79.2-Gy dose of three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy improved overall survival compared with the standard 3D-CRT or intensity-modulated radiotherapy dose of 70.2 Gy. The 79.2-Gy dose was chosen for the trial because it had been previ-

Dose escalation did not significantly decrease the rate of death from prostate cancer. However, dose escalation does offer some valuable outcomes, just not improvement in survival. —Jeff M. Michalski, MD

results of the phase III Radiation Therapy Oncology Group (RTOG) 0126 study1 presented at the 2015 Genitourinary Cancers Symposium. “We were disappointed that we failed to see an improvement in overall survival,” said lead author Jeff M. Michalski, MD, of Washington University School of Medicine, St. Louis. “Dose escalation did not significantly decrease the rate of death from prostate cancer. However, dose escalation does offer some valuable outcomes, just not improvement in survival,” he added.

Study Details At a median follow-up of 7 years, the 5-year overall survival rates were 88% and 89% in the high-dose and standard radiotherapy arms, respectively, and 10-year overall survival rates were 67% and 66% in the high-dose and standard arms, respectively. These differences were not statistically significant. RTOG 0126 evaluated whether a

ously identified as feasible and associated with fewer side effects than other dose schedules, Dr. Michalski said. A total of 1,532 patients were randomized 1:1 to receive either 44 fractions of high-dose radiotherapy or 39 fractions of standard radiotherapy. The median age of patients was 69 years, and 66% received 3D-CRT. No patient received hormone therapy.

Meaningful Improvements High-dose radiotherapy did show improvements over standard therapy regarding the rates of biochemical failure, distant metastasis, and time to local tumor progression. Ten-year rates of biochemical failure were 30% and 45% in the high-dose and standard radiotherapy arms, respectively (P < .0001). Ten-year rates of time to local tumor progression were 4% and 8% in the high-dose and standard radiotherapy arms, respectively (P = .0059), and the

High-Dose Radiotherapy in Localized Prostate Cancer ■■ At a median follow-up of 7 years, high-dose radiotherapy did not improve survival over standard-dose radiotherapy in stage II localized prostate cancer, according to a phase III RTOG trial. ■■ High-dose radiotherapy did improve the rates of local tumor control and distant metastasis. ■■ Experts say that with longer follow-up, a survival difference may emerge. ■■ Dose escalation has become common practice now in this setting.

EXPERT POINT OF VIEW

ommenting on this study, formal discussant D. Andrew Loblaw, MD, a radiation oncologist at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada, said: “The trial showed that after a median follow-up of 7.0 years, there were no differences in overall survival between the two groups. This, however, is not surprising given the follow-up; one wouldn’t expect to see a difference in survival until at least a median of 13 years of follow-up. There was a clinically significant difference in biochemical disease-free survival, local tumor control, and a trend toward improvement in time to metastatic disease, all favoring the higher-dose group.” Dr. Loblaw acknowledged the higher risk of moderate gastrointestinal and genitourinary toxicities associated with the higher-dose group. “The chance

We’ll have to wait another 7 years to see whether this study can address the question of whether five additional externalbeam treatments improve overall survival. —D. Andrew Loblaw, MD

of serious side effects in the high-dose group was only nominally higher in the gastrointestinal realm,” he said. “Overall, this study is consistent with the five other randomized dose-escalated external-beam studies—data that have already changed practice. Although very well conducted, we’ll have to wait another 7 years to see whether this study can address the question of whether five additional external-beam treatments improve overall survival,” Dr. Loblaw stated. Dose escalation has already entered the realm of clinical practice. According to Dr. Loblaw, in both Canada and Europe, doses higher than 74 Gy are standard, as per guidelines. “In the United States, the National Comprehensive Cancer Network Guidelines don’t specify dose, but all of the physicians I have interacted with offer dose escalation,” he said. Disclosure: Dr. Loblaw reported no potential conflicts of interest.

10-year rates of distant metastasis were 5% and 8% in the high-dose and standard arms, respectively (P = .026). Less salvage therapy was used in the high-dose radiotherapy arm (13.5% vs 20.6%, P = .0002). High-dose radiotherapy incurred greater late toxicity, including grade 2 or higher gastrointestinal and genitourinary adverse events. Dr. Michalski said there are strategies that can reduce these side effects such as intensity-modulated radiotherapy and careful attention to rectal dosimetry. Further study is planned to test

dose-escalated therapy. The RTOG 0815 trial, completing accrual, will evaluate dose-escalated radiotherapy with or without a short course of androgendeprivation therapy. n Disclosure: Dr. Michalski reported no potential conflicts of interest.

Reference 1. Michalski JM, Moughan J, Purdy J, et al: A randomized trial of 79.2 Gy versus 70.2 Gy radiation therapy for localized prostate cancer. 2015 Genitourinary Cancers Symposium. Abstract 4. Presented February 26, 2015.

The ASCO Post | MARCH 25, 2015

PAGE 6

Genitourinary Cancers Symposium Genitourinary Oncology

Antiangiogenesis Plus Chemotherapy Pursued in Advanced Bladder Cancer By Alice Goodman

wo separate phase II studies lend support to the concept of antiangiogenesis in advanced bladder cancer. The combination of an antiangiogenic agent and chemotherapy may fulfill an unmet need in this disease, the studies suggest. Both studies were presented at the 2015 Genitourinary Cancers Symposium. The first study offered proof of concept for using the combination of pazopanib (Votrient) and weekly paclitaxel.1 However, for now GlaxoSmithKline has halted the development of pazopanib for bladder cancer. The second study was positive for the combination of ramucirumab (Cyramza) and docetaxel, and a phase III study comparing that combination with docetaxel alone has been mounted in the second-line setting. “We are moving forward with the antiangiogenic approach [in bladder cancer]. These studies provide proof of concept that the target is worthy of pursuit,” said Matthew Galsky, MD, Director of Genitourinary Medical Oncology at Icahn School of Medicine at Mount Sinai, New York, who was not involved in either of these trials. Dr. Galsky said that the first randomized phase III trial of antiangio-

Matthew Galsky, MD

genic therapies in this setting, CALGB 90601, has completed accrual and is ongoing. That trial is comparing gemcitabine/cisplatin plus or minus bevacizumab (Avastin). “We are waiting for results of this trial. In addition, there may be other antiangiogenic drugs that will be found useful,” he added.

Paclitaxel Plus Pazopanib “Although platinum-based combination chemotherapy achieves good responses in metastatic bladder cancer, patients will recur, and effective treatment is an unmet need,” stated lead author of the phase II study Sandy Srinivas, MD, Stanford University School of Medicine, Palo Alto, California. “Many drugs have been tested in metastatic disease, but none is approved in the United States,” she added. The combination of pazopanib plus weekly paclitaxel achieved high response

Sandy Srinivas, MD

rates and was tolerable. Based on the positive results, a phase III trial was mounted. In August 2014, GlaxoSmithKline halted development of pazopanib, leaving the combination treatment in limbo. It is possible that another drug company will pick this up and go forward, but for now, that is unknown. The phase II study combined pazopanib with weekly paclitaxel, based on data suggesting that this combination would be effective. Patients with pretreated recurrent urothelial cancer were included in the study (n = 32). The median age was 67 years; patients were predominately male; 34% had upper tract tumors; 50% had two prior chemotherapy regimens; 28% had liver metastases. The median time from the last chemotherapy was less than 3 months in more than 50% of patients. A two-stage design called for stopping the trial if no response was observed in the first nine patients, but

EXPERT POINT OF VIEW

ormal discussant of both trials, Jonathan Rosenberg, MD, of the Genitourinary Division at Memorial Sloan Kettering Cancer Center in New York, agreed that both studies move the field of antiangiogenesis in advanced bladder cancer forward. “The very high overall response rates in the pazopanib plus paclitaxel study have not been seen in the second-line setting. The progressionJonathan Rosenberg, MD free survival is also quite good. This study shows that the combination of chemotherapy and antiangiogenesis inhibition may play a role in bladder cancer. Tolerability is an issue, since the majority of patients required dose reductions and 44% needed growth factor support,” Dr. Rosenberg said. The second study had positive results, and the combination of ramucirumab plus docetaxel will be studied in phase III. “In this study, the median progression-free survival was very respectable,” Dr. Rosenberg continued. “Both studies were done in previously treated metastatic bladder cancer. There is reason to be hopeful that antiangiogenesis plus chemotherapy will turn out to be a valid option in a disease with no approved therapies,” concluded Dr. Rosenberg. n Disclosure: Dr. Rosenberg has served as a consultant to Eli Lilly.

that did not happen. The most common adverse events included fatigue, diarrhea, nausea/vomiting, and neuropathy. There were few grade 3 and 4 adverse events. Febrile neutropenia occurred in 6%, and 44% of patients required growth factor support. The overall response rate was 50%; there were 3 complete responses, 12

Ramucirumab reduced the risk of disease progression by 61% compared with docetaxel. —Daniel Petrylak, MD

■■ Phase II studies in this setting showed encouraging response rates and progression-free survival for separate combinations of an antiangiogenic agent plus chemotherapy.

unconfirmed partial responses, and 11 confirmed partial responses. These response rates are encouraging compared with expected response rates in this setting, Dr. Srinivas said. One patient is still alive 55 months later, she added. Responses were seen in both highand low-risk patients. Dose modifications of pazopanib were employed in the majority of patients.

■■ Both trials support further study of antiangiogenic therapies and chemotherapy.

Ramucirumab Plus Docetaxel

Treating Advanced Bladder Cancer ■■ In the United States, there are no approved drugs for metastatic bladder cancer that has progressed on first-line platinum-based chemotherapy, and thus it represents an unmet need.

■■ The phase III RANGE study should shed some light on this issue.

provement in progression-free survival with ramucirumab plus docetaxel as second-line therapy for advanced metastatic urothelial carcinoma,2 supporting further evaluation of this combination. “These patients have limited therapeutic options,” said lead author Daniel Petrylak, MD, Yale University Cancer Center, New Haven, Connecticut.

Interim results of a randomized phase II trial showed significant im-

“Interim results of the phase II trial support the initiation of a phase III registration trial called RANGE. This study will compare docetaxel and ramucirumab vs docetaxel plus placebo in locally advanced or unresectable or metastatic urothelial cancer that has progressed on first-line platinum therapy,” he told listeners. The open-label, multicenter, phase II trial conducted in the United States and Canada randomized 139 patients to one of three arms: docetaxel with ramucontinued on page 8

Residual disease in myeloma goes deep.1-5 shouldn’t we stRive to go deepeR? Even after achieving complete response, myeloma cells can persist.1-5 It’s time to reconsider the way we approach myeloma: Growing evidence supports using a long-term treatment approach for continuous disease suppression and improved outcomes.6-8 Proteasomes regulate intracellular protein degradation. Their inhibition induces endoplasmic reticulum stress within myeloma cells and impacts support mechanisms within the bone marrow microenvironment.9-11 At Takeda, we’re committed to achieving a deeper understanding of multiple myeloma and helping to address the challenges patients face today and tomorrow.

ReFeRenCes: 1. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540-2547. 2. Paiva B, Vidriales MB, Cerveró J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023. 3. Biran N, Ely S, Chari A. Controversies in the assessment of minimal residual disease in multiple myeloma: clinical significance of minimal residual disease negativity using highly sensitive techniques [published online ahead of print September 16, 2014]. Curr Hematol Malig Rep. doi:10.1007/s11899-014-0237-y. 4. Munshi NC, Anderson KC. Minimal residual disease in multiple myeloma. J Clin Oncol. 2013;31(20):2523-2526. 5. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079. 6. Palumbo A, Niesvizky R. Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Leuk Res. 2012;36(suppl 1):S19-S26. 7. Girnius S, Munshi NC. Challenges in multiple myeloma diagnosis and treatment. Leuk Suppl. 2013;2(suppl):S3-S9. 8. Palumbo A, Gay F, Musto P, et al. Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints. J Clin Oncol. 32:5s, 2014 (suppl; abstr 8515). 9. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4(5):349-360. 10. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034-2042. 11. Borrello I. Can we change the disease biology of multiple myeloma? Leuk Res. 2012;36(suppl 1):S3-S12. Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. Other trademarks are the property of their respective owners. Copyright © 2015, Millennium Pharmaceuticals, Inc.

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The ASCO Post | MARCH 25, 2015

PAGE 8

Genitourinary Cancers Symposium Genitourinary Oncology

Adjuvant Chemotherapy Favored in Locally Advanced Bladder Cancer Not Treated With Neoadjuvant Therapy By Alice Goodman

large observational study presented at the 2015 Genitourinary Cancers Symposium in Orlando, Florida, found that adjuvant chemotherapy extended the likelihood of survival in locally advanced bladder cancer compared with observation alone.1 Using three different approaches to propensity scores adjustment for confounders, the authors found that adjuvant chemotherapy was associated with a 28% to 31% higher probability of survival in patients with locally advanced bladder cancer, postcystectomy, compared to observation alone. “In a real-world population, adju-

The best available evidence supports use of neoadjuvant therapy in this setting. These data lend more support to consider adjuvant chemotherapy in appropriate patients who have not received neoadjuvant chemotherapy. —Matthew D. Galsky, MD

vant chemotherapy provided a survival benefit in patients with locally advanced bladder cancer who had not been treated

with neoadjuvant chemotherapy. This level 2 evidence lends support to the use of adjuvant chemotherapy in locally

EXPERT POINT OF VIEW

ommenting on the study presented by Galsky et al at the Genitourinary Cancers Symposium, Matthew I. Milowsky, MD, Section Chief, Genitourinary Cancer, at the

tremely important contribution to the existing literature,” he stated. “Comparative effectiveness studies are one mechanism by which to answer clinically important questions that we have

It is likely the right time to stop asking for another randomized clinical trial and recommend the use of adjuvant cisplatin-based chemotherapy in appropriately selected patients. —Matthew I. Milowsky, MD

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, agreed with Dr. Galsky that it is unlikely that we will ever have an appropriately powered, prospective clinical trial to define the role of adjuvant therapy in bladder cancer. “The study by Galsky et al is an ex-

been unable to adequately address with randomized clinical trials.”

Further Considerations Addressing some of the study’s limitations, Dr. Milowsky said: “Although the National Cancer Database has limitations, it is a robust

source of hospital registry data, representing approximately 70% of newly diagnosed cancer cases nationwide. The authors’ use of propensity score matching to determine the treatment effect while accounting for variables that predict for receiving the treatment and multiple imputation analysis to account for incomplete data significantly strengthens their findings.” He added, “The conclusion that adjuvant chemotherapy was associated with an improvement in survival in patients with ≥ pT3 and/or pNpositive bladder cancer with a hazard ratio of 0.72 is strikingly similar to the benefit that has been seen in metaanalyses and retrospective series. It is likely the right time to stop asking for another randomized clinical trial and recommend the use of adjuvant cisplatin-based chemotherapy in appropriately selected patients.” Disclosure: Dr. Milowsky reported no potential conflicts of interest.

advanced bladder cancer patients who have not received neoadjuvant chemotherapy—the current standard of care,” said lead author Matthew D. Galsky, MD, Associate Professor of Medicine and Urology at The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York. “These data can help inform shared decision-making.”

Poor Accrual Dr. Galsky told the The ASCO Post that three recent randomized trials of adjuvant chemotherapy in this setting have had poor rates of accrual. Of a total of 1,610 planned patients, only 620 (39%) enrolled in these trials. “I think accrual was poor, at least in part, because doctors think they know the answer. However, doctors are split on this issue, and so are trial results, so doctors may be biased toward favoring the results of one trial or another,” Dr. Galsky said. In addition, the guidelines are split on this issue. The National Comprehensive Cancer Network Guidelines advocate for adjuvant chemotherapy (category 2B recommendation) for patients who have not received neoadjuvant therapy, whereas the European Association of Urology recommends against it. “There are no sufficiently powered randomized trials to answer this question, and historical experience suggests such a trial cannot be done. We conducted our population-based observational study to provide the next level of evidence,” Dr. Galsky said.

Study Details The study was based on 5,653 patients with locally advanced urothelial bladder cancer enrolled on the National continued on page 9

Antiangiogenesis Plus Chemotherapy continued from page 6

cirumab, docetaxel with icrucumab, or docetaxel alone. Patients were treated until disease progression. The icrucu mab arm failed to show any meaningful benefit, and that drug is not expected to be pursued further in bladder cancer. At an interim analysis, median progression-free survival was 22 weeks with ramucirumab plus docetaxel and 10.4 weeks with docetaxel alone. Sub-

group analysis showed that all groups benefited from the combination. Overall survival in the ramucirumab plus docetaxel arm was more than 11 months at the time of the analysis, but survival data are not yet mature. Again, this is considered to be better than that expected from historic controls. “Ramucirumab reduced the risk of disease progression by 61% compared with docetaxel,” Dr. Petrylak said. Toxicities that occurred in more than 5% of patients on the combination

arm were fatigue, febrile neutropenia, pneumonia, diarrhea, and stomatitis. n Disclosure: Dr. Galsky has received research funding from Bristol-Myers Squibb, Novartis, Dendreon, Celgene, and Janssen; is on the adisory board of Merck, Lilly, Novartis, and Astellas; has served as a consultant for BioMotiv; and has stock in Dual Therapeutics. Dr. Srinivas reported no potential conflicts of interest. Dr. Petrylak has served as a consultant or advisor to and received research funding from Eli Lilly and Co, Genentech, and Sanofi and has travelled on behalf of Genentech and Sanofi.

References 1. Srinivas S, Narayanan S, Harshman LC, et al: Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer. 2015 Genitourinary Cancers Symposium. Abstract 294. Presented February 27, 2015. 2. Petrylak DP, Tagawa ST, Kohli M, et al: Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma. 2015 Genitourinary Cancers Symposium. Abstract 295. Presented February 27, 2015.

ASCOPost.com | MARCH 25, 2015

PAGE 9

Genitourinary Cancers Symposium Locally Advanced Bladder Cancer continued from page 8

Cancer Database who were treated with radical cystectomy between 2003 and 2007: 4,360 were treated with observation after surgery, and 1,293 received adjuvant chemotherapy. These patients had not received neoadjuvant chemotherapy or radiation to the primary tumor. Patients in the adjuvant chemotherapy group received multiagent chemotherapy within 90 days of surgery. The authors found that patients with positive lymph nodes were about twice as likely to receive adjuvant chemotherapy, and those with private insurance were 1.3 times more likely to be treated with adjuvant chemotherapy. In addition to the main analysis, a subset analysis found that adjuvant chemotherapy was favored over observation for all subsets, including age, gender, nodal status, and number of involved nodes. Study limitations included its retrospective design, the lack of details on the type of chemotherapy, and no details on cancer-specific survival.

Closing Thoughts “The best available evidence supports use of neoadjuvant therapy in this setting. Our data lend more support to consider adjuvant chemotherapy in appropriate patients who have not received neoadjuvant chemotherapy,” Dr. Galsky stated. Whether adjuvant chemotherapy should be used to treat a patient who

has had neoadjuvant chemotherapy and has residual cancer in the tumor specimen is an issue not addressed by the current study. n Disclosure: Dr. Galsky has received research funding from Bristol Myers, Novartis, Dendreon, Celgene, and Janssen; is on the adisory board of Merck, Lilly, Novartis, and Astellas; has served as a consultant for

BioMotiv; and has stock in Dual Therapeutics.

Reference 1. Galsky MD, Stensland K, Moshier EL, et al: Comparative effectiveness of adjuvant chemotherapy versus observation in patients with ≥ pT3 and/or pN+ bladder cancer. 2015 Genitourinary Cancers Symposium. Abstract 292. Presented February 27, 2015.

Role of Adjuvant Chemotherapy in Bladder Cancer ■■ Guidelines differ on the appropriate use of adjuvant chemotherapy in locally advanced bladder cancer patients who have not received neoadjuvant chemotherapy— the current standard of care. ■■ Randomized trials to address this issue have had poor accrual and are underpowered. ■■ In the absence of level 1 data, a large, real-world, observational study tackled this issue and found that adjuvant therapy is likely to extend survival over observation alone in this setting by at least 28%. ■■ This study provides level 2 evidence that can be used in shared decision-making between patients and physicians.

The ASCO Post Wants to Hear From You

Write to The ASCO Post at editor@ASCOPost.com

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The ASCO Post | MARCH 25, 2015

PAGE 10

Announcements

AACR Names Nancy E. Davidson, MD, President-Elect for 2015–2016 By Jo Cavallo

he American Association for Cancer Research (AACR) has announced the election of Nancy E. Davidson, MD, Director of the University of Pittsburgh Cancer Institute and UPMC Cancer-

Center in Pittsburgh, as its PresidentElect for 2015–2016. Dr. Davidson will officially become President-Elect at the AACR Annual Meeting 2015 in Philadelphia, April 18–22. She will start her

presidential term in April 2016. Dr. Davidson has focused her career on clinical and translational breast cancer research, cancer biology and treatment, and the role of apoptosis and mecha-

nisms of epigenetic regulation of gene expression of the estrogen receptor alpha (ESR1) gene in breast cancer treatment. “We are delighted that Dr. Davidson has been elected to serve as the next

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ASCOPost.com | MARCH 25, 2015

PAGE 11

Announcements

AACR President-Elect,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR, in a statement. “She is an acknowledged expert in breast cancer research whose clinical and translational work has had a profound impact on the lives of patients. Dr. Davidson will lead the association with much energy and dedication, and

it will be an honor to work with her to make further strides in our mission to prevent and cure all cancers.”

Exciting Time in Cancer Research “With deaths from cancer declining and the number of cancer survivors on the rise, this is an exciting time in cancer

research and care,” said Dr. Davidson in a statement. “I am honored to be given the opportunity to work with AACR and its members on our singular focus to advance scientific discoveries that can translate to exceptional patient care.” Dr. Davidson is also Distinguished Professor of Medicine and Pharmacology and Chemical Biology, Associate Vice

I am honored to be given the opportunity to work with AACR and its members on our singular focus to advance scientific discoveries that can translate to exceptional patient care. —Nancy E. Davidson, MD

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Chancellor for Cancer Research, Hillman Professor of Oncology, and Professor at the Clinical and Translational Science Institute at the University of Pittsburgh and Adjunct Professor of Oncology at Johns Hopkins University School of Medicine in Baltimore. Dr. Davidson is known for her studies involving the role of hormones and the estrogen receptor in breast carcinogens that have defined the molecular mechanisms driving the disease, as well as for her efforts to establish novel therapeutic approaches for patients who fail to respond to common treatment modalities. Dr. Davidson has led clinical trials investigating chemotherapy and endocrine-related therapies for treating premenopausal breast cancer and has increased the understanding of the potential of angiogenesis inhibitors, such as bevacizumab (Avastin), in the treatment of metastatic breast cancer.

A Formidable Career Dr. Davidson has been recognized for her work in breast cancer research with many awards throughout her career, including ASCO’s Gianni Bonadonna Breast Cancer Award, the AACR Women in Cancer Research Charlotte Friend Memorial Lectureship, the Potamkin Award from the Pennsylvania Breast Cancer Coalition, the Distinguished Alumna Award from Johns Hopkins University Alumni Association, and the Rosaline E. Franklin Award for Women in Science from the National Cancer Institute. Dr. Davidson is an elected member of the Institute of Medicine, the Assocontinued on page 12

The ASCO Post | MARCH 25, 2015

PAGE 12

Announcements

Winship Cancer Institute of Emory University Names New Chief Medical Officer and Chief Quality Officer

agar Lonial, MD, has been named Chief Medical Officer at Winship Cancer Institute of Emory University and Charles A. Staley, MD, has been named Chief Quality Officer, according to an announcement recently released by the Cancer Institute. Both physicians join Winship’s senior leadership team and will advance Winship’s clinical programs and services within all of its facilities. Dr. Lonial, Professor and Executive Vice Chair of Emory’s Department of Hematology and Medical Oncology, is an internationally recognized authority in the management and research related to B-cell malignancies, including multiple myeloma. As Chief Medical Officer of Winship, Dr. Lonial will oversee all

clinical care initiatives impacting both clinicians and patients. Dr. Staley, Professor and Director of Emory’s Division of Surgical Oncology, specializes in the management of

patients with gastrointestinal cancers. He previously served as Winship’s Chief Medical Officer andS:6.75” in this new role will assume responsibility for the institute’s quality improvement processes across

all disciplines and campuses. “I can’t think of two physicians who are better suited to take on the critical leadership roles of Winship’s Chief Medical Officer and Chief Quality Of-

AACR Names President continued from page 11

ciation of American Physicians, and the American College of Physicians. Dr. Davidson is a Past President of ASCO and currently serves as a member of the scientific advisory committee of Break-

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Dr. Davidson will lead the association with much energy and dedication, and it will be an honor to work with her to make further strides in our mission to prevent and cure all cancers. —Margaret Foti, PhD, MD (hc)

through Breast Cancer and the scientific advisory board of the V Foundation for Cancer Research. The AACR, whose mission is to prevent and cure cancer through research, education, communication, and collaboration, has more than 35,000 members in 101 countries. n

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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Announcements

7.5”

15”

Charles A. Staley, MD

Sagar Lonial, MD

ficer,” said Walter J. Curran, Jr, MD, Winship’s Executive Director. Dr. Lonial and Dr. Staley will collaborate on tracking and improving patient services andS:6.75” satisfaction, as well as focusing on cancer outcomes at Winship.n

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

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

HR=0.28 95% CI: 0.19, 0.40 P<0.0001

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median

4.0 4.0

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months months

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219 111

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Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

SIGNOFF

31 3

Months

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

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The ASCO Post | MARCH 25, 2015

PAGE 14

FDA Update

Priority Review Granted for Trabectedin in Advanced Soft-Tissue Sarcoma

he U.S. Food and Drug Administration (FDA) has granted Priority Review for the New Drug Application (NDA) for trabectedin to treat patients with advanced soft-tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, who have received prior chemo-

therapy including an anthracycline. The NDA for trabectedin was submitted to the FDA on November 24, 2014. Trabectedin is a novel, multimodal, synthetically produced antitumor agent—originally derived from the sea squirt Ecteinascidia turbinata—that pre-

vents tumor cells from multiplying. The filing is based on the phase III

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

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randomized, open-label study ET743SAR-3007. This trial is evaluating the safety and efficacy of trabectedin vs dacarbazine for the treatment of patients with advanced liposarcoma and leiomyosarcoma. Results will be presented at a later date. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia. 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain. 5 Palmar-plantar erythrodysesthesia syndrome. 1

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Journal Spotlight Genetics/Genomics

Gastric, Breast Cancer Risk in Carriers of CDH1 Gene Mutations

n a new study,1 more precise estimates of age-associated risks of gastric and breast cancer were derived for carriers of the CDH1 gene mutation, a cancer-predisposing gene that is abnormal in families meeting criteria for clinically defined hereditary diffuse gastric cancer (HDGC).

David G. Huntsman, MD, of the British Columbia Cancer Agency, and colleagues tested for CDH1 germline mutations in 183 new families with HDGC. Penetrance S:6.75” (the proportion of people with a gene mutation who will show clinical disease) was derived from

75 mutation-positive families from this and other study groups, comprising 3,858 individuals. Germline DNA from 144 HDGC families without the CDH1 mutations also was screened for 55 cancer-associated genes, to determine if other genes are associated with HDGC. David G. Huntsman, MD

PROD ED AE/AS CW CD AD

James M. Ford, MD

should be considered the new standard for genetic counseling, and will be included in the next International Gastric Cancer Linkage Consortium guidelines.… The study provides a major advance. Further clinical and genetic research is necessary to identify more biomarkers and better methods of screening individuals at high risk,” he concluded. n DATE

SIGNOFF

References 1. Hansford S, Kaurah P, Li-Chang H, et al: Hereditary diffuse gastric cancer syndrome. JAMA Oncol. February 12, 2015 (early release online). 2. Ford JM: Hereditary gastric cancer. JAMA Oncol. February 12, 2015 (early release online).

Disk

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In a related editorial,2 James M. Ford, MD, of the Stanford University School of Medicine, said, “The study by Dr. Huntsman and colleagues assembles the largest group of genetically defined HDGC families to date (75 families, comprising 3,858 individuals) to determine agespecific penetrance of gastric and breast cancer. These updated risk assessments S:9.75”

Stage 2: Systolic ≥160 mmHg or Diastolic ≥100 mmHg

Placebo N=1073 (%) 15

‘Major Advance’

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are 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 COMETRIQ, 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. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

The authors identified 31 distinct CDH1 mutations in 34 of 183 families (19%). They estimate that by age 80, the cumulative incidence of gastric cancer is 70% for men and 56% for women, with a risk of breast cancer for women of 42%. They also identified candidate mutations in 16 of 144 probands (the person who is the starting point in a family being studied). “These data should assist in the genetic counseling and management of at-risk individuals from CDH1-positive HDGC families,” the study concludes.

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

PharmaGraphics

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

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Gastrointestinal Cancers Symposium Infectious Disease

Many Cancer Patients at Risk for Hepatitis B Virus Reactivation By Caroline Helwick

“I

n 2015, no cancer patients should be cured of their malignancy only to die of reactivation of hepatitis B virus (HBV),” according to Anna S. Lok, MD, the Alice Lohrman Andrews Research Professor in Hepatology and Director of Clinical Hepatology at the University of Michigan, Ann Arbor. “I recommend screening all patients before starting on chemotherapy. Assess the risk of HBV reactivation, and if the risk is moderate or high, start prophylaxis as soon as possible,” Dr. Lok told attendees at the 2015 Gastrointestinal Cancers Symposium. “Some oncologists argue that not all patients with reactivation will have a bad outcome and ask whether we can just monitor patients and start antivirals on demand [ie, upon signs of reactivation],” she said. “But we don’t always catch things in time, and in multiple studies, outcomes for prophylaxis are better than for treatment on demand,” she explained. Gregory J. Gores, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota, moderated the session and commented on Dr. Lok’s presenta-

Gregory J. Gores, MD

tion. “There are probably a dozen different guidelines from multiple societies on the issue of HBV reactivation. The program committee of this meeting selected Dr. Lok to give her perspective because of her depth of knowledge in this topic and her pragmatic approach.”

Understanding HBV Reactivation The reactivation of HBV is an abrupt increase in viral replication in a person with chronic or past HBV infection. Reactivation can occur in persons who are surface antigen–positive (HBsAg+) or surface antigen–negative (HBsAg–) and core antibody–positive (antiHBc+) with or without surface antibody. Many patients have normal levels

limus (Afinitor), and transarterial chemoembolization with cytotoxic drugs, can cause HBV reactivation.

Special Concerns Rituximab creates the most concern, as it carries a more than fivefold increased risk for HBV reactivation vs other regimens among HBsAg–/anti-HBc+ patients. Also concerning is the potential for delayed reactivation, up to 2 years fol-

I recommend screening all patients before starting on chemotherapy. Assess the risk of HBV reactivation, and if the risk is moderate or high, start prophylaxis as soon as possible. —Anna S. Lok, MD

of liver enzymes and undetectable HBV DNA at baseline, but chemotherapy leads to immunosuppression and its sequelae: increases in HBV DNA, elevations in liver enzymes, and in some cases development of acute liver failure, and even death. Control of HBV by the host immune response becomes weakened in the setting of immunosuppressive therapy, allowing HBV to replicate at a faster rate. It has been most extensively studied in lymphoma (with the use of the anti-CD20 antibody rituximab [Rituxan]), but it also occurs with other chemotherapy agents, corticosteroids alone (in high enough doses), biologics (antitumor necrosis factor-alpha [TNF] agents, interleukin-17, anti-CTLA4), and more classic immunosuppressive agents such as methotrexate. According to case reports, even some molecularly targeted agents, including tyrosine kinase inhibitors, the mTOR inhibitor evero-

lowing discontinuation of rituximab. Reports of 109 fatalities from HBV reactivation associated with rituximab led the U.S. Food and Drug Administration (FDA) to issue a warning in 2013 and a recommendation that all patients receiving this drug be screened at baseline for HBsAg and anti-HBc, that those testing positive be monitored during and after treatment, and that antiviral prophylaxis be considered. Patients should remain on prophylaxis for 1 year after treatment ends. Another special group includes patients with hepatocellular carcinoma, who should definitely receive an antiviral, according to Dr. Lok, “because they have underlying liver disease that led to the cancer and the data have shown that hepatocellular carcinoma patients on an antiviral have less recurrence and better survival. In this case, there are other rationales for the antiviral, not just for prevention of reactivation.” Male gender and elevated HBV

Table: Risk-Based Prevention of HBV Reactivation Risk

HBsAg+

HBsAg–, anti-HBc+

Antiviral Therapy

High

Chemotherapy, anti-CD20 or antiCD56 treatment; IST for transplantation; steroids in combination with other IST

Chemotherapy for hematologic malignancies, anti-CD20 or antiCD56 treatment

Prophylaxis

Moderate

Anti-TNF treatment, maintenance low-dose steroids; other IST without steroid

Chemotherapy for solid tumors; IST for transplantation; steroids in combination with other IST

Prophylaxis or ondemand (monitor)

Low

Steroids alone for a few days

Anti-TNF, maintenance low-dose steroid, other IST without steroid

No prophylaxis

HBc = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; IST = immunosuppressive therapy.

DNA at baseline indicate greater susceptibility to reactivation. An increased risk is also associated with high-intensity immunosuppressive therapy and conditioning regimens prior to bone marrow transplant, immunosuppressive therapy after solid organ transplant, high-dose steroids, and anthracyclines. HBsAg+ patients are more at risk than HBsAg–/anti-HBc+ patients.

Reactivation Seen in at Least 30% of HBsAg+ Patients Determining the incidence of treatment-associated HBV reactivation is difficult, because clinical trials tend to exclude patients with HBV infection. “But when drugs are used in the real world, problems arise, and we have little data to guide our management,” Dr. Lok indicated. In lymphoma patients, from whom most of the data come, Dr. Lok documented HBV-related hepatitis in almost half of HBsAg+ patients and in 4% of HBsAg–/anti-HBc+ patients. This “seemingly trivial” increase in enzymes triggered nonfatal liver failure in 4% and death in 4% of HBsAg+ patients.1 In a systematic review of patients receiving chemotherapy for various malignancies, HBV reactivation was observed in 38.7%, leading to hepatitis in 33%, liver failure in 13%, and death in 5.5% of patients who did not receive antiviral prophylaxis.2 Another study of HBsAg+ patients observed reactivation in 30%, including 58% with lymphoma and 25% with other malignancies.3

Optimizing Prophylaxis Among the five FDA-approved nucleoside/nucleotide analogs (dosed once daily) are lamivudine (Epivir), adefovir (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka), and tenofovir (Viread). Most of the data on prophylaxis are on lamivudine, the first of these agents approved. A systematic review,2 involving 275 treated patients and 475 controls, showed that lamivudine reduced HBV reactivation and HBV-related hepatitis by 79% to 100%, reduced HBV-related liver failure by 100%, and reduced HBVrelated deaths by 80% to 100%. Lamivudine-treated patients also were less likely to die of cancer, since chemotherapy interruption is less likely when reactivation is prevented, Dr. Lok noted. The preferred agents are now entecavir and tenofovir, as they are the continued on page 18

MARCH IS

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31 ACTS to raise awareness of multiple myeloma.

@Celgene_Myeloma #mmaware MULTIPLE MYELOMA NEVER GIVES UP. BUT NEITHER DO WE.™ Celgene.com/NeverGiveUp

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Gastrointestinal Cancers Symposium Hepatitis B Virus continued from page 16

Algorithm to Guide Prophylaxis

most potent viral suppressors and the least likely to cause drug resistance. In a recent randomized, controlled trial of rituximab-treated patients, entecavir was significantly more effective than lamivudine in HBsAg+ patients in terms of HBV reactivation (6.6% vs 30%, P = .001), HBV-related hepatitis (0% vs 13.3%, P = .003), and chemotherapy disruption (1.6% vs 18.3%, P = .002).4

An algorithm recently coauthored by Dr. Lok can guide clinicians in the prevention of HBV reactivation.5 It calls for all cancer patients to be screened before starting treatment and classifies patients as (1) HBsAg+; (2) HBsAg–, anti-HBc+; and (3) HBsAg–, anti-HBc–. Risk within the first two groups is further stratified by HBV DNA levels.

Reactivation of Hepatitis B Virus in Patients With Cancer ■■ The immunosuppressive effects of anticancer agents put patients at risk for reactivation of hepatitis B virus (HBV). ■■ All cancer patients should be screened for HBV infection, and risk for reactivation of HBV should be assessed. ■■ Patients at moderate to high risk of HBV reactivation should receive antiviral prophylaxis, preferably with entecavir and tenofovir, before starting treatment for cancer. ■■ Rituximab is associated with the highest risk of HBV reactivation among chemotherapy treatments.

For HBsAg+ and HBsAg–/anti-HBc+ patients, those considered at high-risk (see table on page 16) should receive a prophylactic antiviral; moderate-risk patients can receive prophylaxis or be monitored and receive on-demand antivirals; low-risk patients can receive usual care, as can the third group. For patients with undetectable or very low levels of HBV DNA, Dr. Lok does not advocate delaying chemotherapy. However, this step may be wise for patients with high levels, “because once patients are immunosuppressed, the response to the antiviral appears to be less robust,” she noted. n

Disclosure: Dr. Lok has held consulting or advisory roles for Gilead Sciences and GlaxoSmithKline and has received research funding from Gilead Sciences and Bristol-Myers Squibb. Dr. Gore reported no potential conflicts of interest.

References 1. Lok AS, Liang RH, Chiu EK, et al: Reactivation of hepatitis B virus replica-

tion in patients receiving cytotoxic therapy: Report of a prospective study. Gastroenterology 100:182-188, 1991. 2. Loomba R, Rowley A, Wesley R, et al: Systematic review: The effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148:519-528, 2008. 3. Yeo W, Zee B, Zhong S, et al: Comprehensive analysis of risk factors associating with hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 90:1306-1311, 2004. 4. Huang H, Li X, Zhu J, et al: Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: A randomized clinical trial. JAMA 312:25212530, 2014. 5. Hwang JP, Lok AS: Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol 11:209-219, 2014.

Optimal Timing of Rectal Surgery: 60 Days or Less Post Chemoradiation Therapy By Caroline Helwick

or the treatment of locally advanced rectal cancer, the optimal timing between the end of neoadjuvant chemoradiation therapy and surgical resection appears to be 60 days, according to an analysis of the National Cancer Database presented at the 2015 Gastrointestinal Cancers Symposium.1 An interval of 60 days or less was associated with a higher likelihood of pathologic complete response. A longer interval did not further increase response and, in fact, was associated with higher risks of positive margins and mortality, reported Jonathan C. Salo, MD, a surgical oncologist at the Levine Cancer Institute at Carolinas Medical Center, Charlotte, North Carolina. “Several retrospective studies have shown that pathologic complete response rates increase with increasing radiation-surgery interval. Most retrospec-

tive studies have shown no difference in overall mortality with longer radiationsurgery interval, compared with a shorter interval, and some have even shown

tains 30 million records; and provides staging, treatment, and survival data. They examined data from 6,805 patients diagnosed with rectal adenocarcinoma

Surgical margins were a highly powerful prognostic indicator, as was postoperative length of stay. —Jonathan C. Salo, MD

improved survival in patients who had a longer interval,” Dr. Salo said. Dr. Salo and colleagues assessed patients in the National Cancer Database, which represents 70% of newly diagnosed cancer patients in the United States; con-

National Cancer Database Analysis on Timing of Rectal Surgery ■■ Analysis of the National Cancer Database (2004–2006) found the optimal time between neoadjuvant chemoradiation therapy and surgery is around 60 days for most patients. ■■ Much shorter intervals between neoadjuvant chemoradiation therapy and surgery were associated with lower rates of pathologic complete response, whereas intervals beyond 60 days were associated with increased rates of positive surgical margins and a 25% increase in mortality.

between 2004 and 2006 and who underwent preoperative radiation therapy (most with chemotherapy), followed by radical surgical resection (excluding transanal excision). Surgery was done within 6 months of diagnosis and within 4 months of radiation therapy. The median followup for these patients was 5.6 years.

Pathologic Complete Response Optimized at 60 Days “Increasing the radiation-surgery interval was associated with an increase in the rate of pathologic complete response up to 60 days (P = .0003), but the rate did not appear to increase thereafter,” Dr. Salo reported.

A longer radiation-surgery interval beyond 60 days was associated with an increase in the rate of positive surgical margins. Positive margin rates were 4.1% for an interval up to 30 days; 5.4% for an interval between 30 and 44 days; 4.8% for an interval between 45 and 59 days; 6.7% for an interval between 60 and 74 days; and 7.7% for an interval more than 75 days (P = .0067). An interval beyond 60 days was also associated with shorter overall survival. When stratified by intervals of up to 60 days vs more than 60 days, the longer interval was associated with a 25% increased mortality risk, which was highly significant (P < .0001), he reported. Dr. Salo proposed two explanations for the relationship between longer radiation-surgery interval and worse overall survival. It is possible, he said, that an increasing interval directly affects cancer outcomes, possibly through tumor regrowth, as suggested by the increase in positive margins shown in his study.

Other Prognostic Factors Patients with longer intervals in the database may also have been affected by other factors, such as comorcontinued on page 19

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%). 86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer. Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or diseaserelated symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION • Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information on the next page. Please see additional Selected Safety Information on the next page and the Brief Summary of Prescribing Information on the adjacent pages.

For patients For patientswith withunresectable unresectableorormetastatic metastaticmelanoma melanomaand anddisease diseaseprogression progressionfollowing followingipilimumab ipilimumaband, and, if BRAF V600 if BRAF V600mutation mutationpositive, positive,a aBRAF BRAFinhibitor inhibitor

KEYTRUDA: KEYTRUDA: DURABILITY DURABILITY OF OF RESPONSE RESPONSE 24% 24%overall overallresponse responserate rate(complete (completeresponse+partial response+partialresponse) response) with withsingle-agent single-agentKEYTRUDA KEYTRUDA(95% (95%CI, CI,15–34) 15–34) Data Datafor for2 2mg/kg mg/kgevery every33weeks weeks(n=89) (n=89)

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

• •Similar Similaroverall overallresponse responserate rateresults resultswere wereobserved observed in in the the10-mg/kg 10-mg/kgarm. arm. • •Patients Patientscontinued continuedtreatment treatmentwith with KEYTRUDA KEYTRUDA until until unacceptable unacceptable toxicity toxicity or or disease disease progression progression that that was wassymptomatic, symptomatic,was wasrapidly rapidlyprogressive, progressive, required required urgent urgent inter intervention, vention, occurred occurred with with aa decline decline in in performance performancestatus, status,ororwas wasconfirmed confirmedat at44to to66 weeks weeks with withrepeat repeatimaging. imaging.

Study design: AA multicenter, open-label, Study design: multicenter, open-label,randomized, randomized,dose-comparative dose-comparativestudy studycohort cohortofofthe theongoing ongoingKEYNOTE-001 KEYNOTE-001Phase Phase1b1btrial trialininpatients patientswith with unresectable or or metastatic melanoma and progression unresectable metastatic melanoma and progressionofofdisease. disease.Key Keyeligibility eligibilitycriteria criteriaincluded includedprior priortreatment treatmentwith withipilimumab ipilimumab(2(2orormore moredoses doses at at 3 mg/kg or or higher) and a BRAF oror MEK inhibitor, if BRAF 3 mg/kg higher) and a BRAF MEK inhibitor, if BRAFV600 V600mutation–positive; mutation–positive;and anddisease diseaseprogression progressionwithin within2424weeks weeksfollowing followingthe thelast lastdose dose of of ipilimumab. Patients were randomized to toreceive ipilimumab. Patients were randomized receive2 mg/kg 2 mg/kg(n=89) (n=89)oror1010mg/kg mg/kg(n=84) (n=84)ofofKEYTRUDA KEYTRUDAevery every3 3weeks weeksuntil untilunacceptable unacceptabletoxicity toxicityoror disease progression. The major efficacy disease progression. The major efficacyoutcome outcomemeasures measureswere wereconfirmed confirmedoverall overallresponse responserate, rate,asasassessed assessedbybyblinded blindedindependent independentcentral central review using Response Evaluation Criteria in in Solid review using Response Evaluation Criteria SolidTumors Tumors(RECIST (RECIST1.1), 1.1),and andduration durationofofresponse. response.Tumor Tumorresponse responsewas wasassessed assessedevery every1212weeks. weeks.

SELECTED SELECTEDSAFETY SAFETYINFORMATION INFORMATION • Pneumonitis • Pneumonitisoccurred occurredin in1212(2.9%) (2.9%)ofof411 411patients, patients,including including Grade 2 or 3 cases in in 8 (1.9%) and 1 (0.2%) Grade 2 or 3 cases 8 (1.9%) and 1 (0.2%)patients, patients,respectively, respectively, receiving KEYTRUDA. Monitor patients forfor signs and receiving KEYTRUDA. Monitor patients signs andsymptoms symptomsofof pneumonitis. Evaluate pneumonitis. Evaluatesuspected suspectedpneumonitis pneumonitiswith withradiographic radiographic imaging. imaging.Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater pneumonitis. TRUDA pneumonitis.Withhold WithholdKEY KEY TRUDAforforGrade Grade2;2;permanently permanently discontinue KEYTRUDA forfor Grade 3 or 4 pneumonitis. discontinue KEYTRUDA Grade 3 or 4 pneumonitis. • Colitis • Colitis(including (includingmicroscopic microscopiccolitis) colitis)occurred occurredinin4 4(1%) (1%)ofof411 411 patients, including patients, includingGrade Grade2 2oror3 3cases casesinin1 1(0.2%) (0.2%)and and2 2(0.5%) (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients, respectively, receiving KEYTRUDA. Monitorpatients patientsforfor signs and symptoms signs and symptomsofofcolitis. colitis.Administer Administercorticosteroids corticosteroidsfor for Grade 2 or greater colitis. Withhold Grade 2 or greater colitis. WithholdKEYTRUDA KEYTRUDAforforGrade Grade2 2oror3;3; permanently discontinue KEYTRUDA forfor Grade 4 colitis. permanently discontinue KEYTRUDA Grade 4 colitis. • Hepatitis (including autoimmune hepatitis) occurred • Hepatitis (including autoimmune hepatitis) occurredinin2 (0.5%) 2 (0.5%)ofof 411411 patients, including a Grade 4 case in in 1 (0.2%) patient, receiving patients, including a Grade 4 case 1 (0.2%) patient, receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforchanges changesininliver liverfunction. function. Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greaterhepatitis hepatitis and, based onon severity ofof liver enzyme elevations, and, based severity liver enzyme elevations,withhold withholdoror discontinue KEYTRUDA. discontinue KEYTRUDA. • Hypophysitis occurred in in 2 (0.5%) ofof 411411 patients, including • Hypophysitis occurred 2 (0.5%) patients, includinga aGrade Grade2 2 case in in 1 and a Grade 4 case case 1 and a Grade 4 casein in1 (0.2% 1 (0.2%each) each)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforsigns signsand andsymptoms symptomsofof hypophysitis. Administer hypophysitis. Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater hypophysitis. hypophysitis.Withhold WithholdKEYTRUDA KEYTRUDAforforGrade Grade2;2;withhold withholdoror discontinue forfor Grade 3; 3; and permanently discontinue discontinue Grade and permanently discontinueKEYTRUDA KEYTRUDA forfor Grade 4 hypophysitis. Grade 4 hypophysitis.

• Nephritis • Nephritisoccurred occurredinin3 3(0.7%) (0.7%)patients, patients,consisting consistingofofone onecase caseofof Grade Grade2 2autoimmune autoimmunenephritis nephritis(0.2%) (0.2%)and andtwo twocases casesofofinterstitial interstitial nephritis nephritiswith withrenal renalfailure failure(0.5%), (0.5%),one oneGrade Grade33and andone oneGrade Grade4.4. Monitor Monitorpatients patientsfor forchanges changesininrenal renalfunction. function. Administer Administer corticosteroids corticosteroidsfor forGrade Grade2 2ororgreater greater nephritis. nephritis. Withhold Withhold KEYTRUDA KEYTRUDAfor forGrade Grade2;2;permanently permanentlydiscontinue discontinueKEYTRUDA KEYTRUDAfor for Grade Grade3 3oror4 4nephritis. nephritis. • Hyperthyroidism • Hyperthyroidismoccurred occurredinin5 5(1.2%) (1.2%)ofof411 411patients, patients,including including Grade Grade2 2oror3 3cases casesinin2 2(0.5%) (0.5%)and and1 1(0.2%) (0.2%)patients, patients,respectively, respectively, receiving receivingKEYTRUDA. KEYTRUDA.Hypothyroidism Hypothyroidismoccurred occurredinin34 34(8.3%) (8.3%)ofof411 411 patients, patients,including includinga aGrade Grade3 3case caseinin11(0.2%) (0.2%)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Thyroid Thyroiddisorders disorderscan canoccur occuratatany anytime timeduring during treatment. treatment.Monitor Monitorpatients patientsfor forchanges changesininthyroid thyroidfunction function(at (atthe the start startofoftreatment, treatment,periodically periodicallyduring duringtreatment, treatment,and andas asindicated indicated based basedononclinical clinicalevaluation) evaluation)and andfor forclinical clinicalsigns signsand andsymptoms symptomsofof thyroid thyroiddisorders. disorders.Administer Administercorticosteroids corticosteroidsfor forGrade Grade33ororgreater greater hyperthyroidism. hyperthyroidism.Withhold WithholdKEYTRUDA KEYTRUDAfor forGrade Grade3;3;permanently permanently discontinue TRUDA for discontinueKEY KEYTRUDA forGrade Grade4 4hyperthyroidism. hyperthyroidism.Isolated Isolated hypothyroidism hypothyroidismmay maybebemanaged managed with with replacement replacement therapy therapy without withouttreatment treatmentinterruption interruptionand andwithout withoutcorticosteroids. corticosteroids. • Other • Otherclinically clinicallyimportant importantimmune-mediated immune-mediatedadverse adverse reactions reactions can canoccur. occur.The Thefollowing followingclinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsoccurred occurredininless lessthan than1% 1%ofofpatients patientstreated treated with withKEYTRUDA: KEYTRUDA:exfoliative exfoliativedermatitis, dermatitis,uveitis, uveitis,arthritis, arthritis,myositis, myositis, pancreatitis, pancreatitis,hemolytic hemolyticanemia, anemia,partial partialseizures seizuresarising arisingininaapatient patient with withinflammatory inflammatoryfoci fociininbrain brainparenchyma, parenchyma,adrenal adrenalinsufficiency, insufficiency, myasthenic myasthenicsyndrome, syndrome,optic opticneuritis, neuritis,and andrhabdomyolysis. rhabdomyolysis.

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

••Among progression of of disease disease 2.8, 2.8, 2.9, 2.9, and and 8.2 8.2 months months Among the the 21 21 patients patients with with an an objective response, 3 (14%) had progression after after initial initial response. response. •• The durations ranging ranging from from 1.4+ 1.4+ to to 8.5+ 8.5+ months, months,which which The remaining remaining 18 18 patients patients (86%) (86%) had ongoing responses with durations included included 88 patients patients with with ongoing ongoing responses of 6 months or longer. •• One first tumor tumor assessment assessment concurrent concurrentwith withaa Oneadditional additional patient patient developed developed 2 new asymptomatic lesions at the first 75% 75% decrease decrease in in overall overall tumor tumor burden. —KEYTRUDA was durable durable for for 5+ 5+ months. months. —KEYTRUDA was was continued continued and and this reduction in tumor burden was

SELECTED SELECTED SAFETY SAFETY INFORMATION INFORMATION (CONTINUED) common adverse adverse reactions reactions (reported (reported inin at at least least ••For For suspected suspected immune-mediated immune-mediated adverse reactions, ensure • The most common patients) were were fatigue fatigue (47%), (47%), cough cough (30%), (30%), nausea nausea adequate 20% of patients) adequate evaluation evaluation to to confirm confirm etiology or exclude other pruritus (30%), (30%), rash rash (29%), (29%), decreased decreasedappetite appetite(26%), (26%), causes. (30%), pruritus causes.Based Basedon on the the severity severity of of the the adverse reaction, withhold (21%), arthralgia arthralgia (20%), (20%),and anddiarrhea diarrhea(20%). (20%). KEYTRUDA constipation (21%), KEYTRUDA and and administer administer corticosteroids. corticosteroids. Upon improvement of ofthe theadverse adversereaction reaction to to Grade Grade 11 or or less, initiate corticosteroid • It is not known known whether whether KEYTRUDA KEYTRUDA isis excreted excreted ininhuman humanmilk. milk. taper taper and and continue continue to to taper taper over over at least 1 month. Restart drugsare areexcreted excretedin inhuman humanmilk, milk,instruct instructwomen women Because many drugs KEYTRUDA KEYTRUDA ifif the the adverse adverse reaction reaction remains at Grade 1 or less. nursing during during treatment treatmentwith withKEYTRUDA. KEYTRUDA. to discontinue nursing Permanently Permanently discontinue discontinue KEYTRUDA KEYTRUDA for any severe or Grade 3 effectiveness of KEYTRUDA have notbeen been • Safety and effectiveness of KEYTRUDA have not immune-mediated immune-mediated adverse adverse reaction reaction that recurs and for any lifeestablished in pediatric pediatric patients. patients. threatening immune-mediated adverse reaction. threatening immune-mediated adverse ••Based Based on on its its mechanism mechanism of of action, action, KEYTRUDA may cause the Brief Brief Summary Summary of of the the Please see the fetal fetal harm harm when when administered administered to to aa pregnant woman. If used Information on on the the adjacent adjacent pages. pages. Prescribing Information during during pregnancy, pregnancy, or or ifif the the patient patient becomes pregnant during treatment, treatment,apprise apprise the the patient patient of of the the potential hazard to a fetus. Merck Oncology Oncology Advise Advisefemales females of of reproductive reproductive potential potential to use highly effective 2014 Merck Merck Sharp Sharp && Dohme DohmeCorp., Corp., Copyright © 2014 contraception contraception during during treatment treatment and and for 4 months after the last a subsidiary of of Merck Merck & & Co., Co., Inc. Inc. dose doseof ofKEYTRUDA. KEYTRUDA. All rights reserved. reserved. ONCO-1116177-0000 ONCO-1116177-000011/14 11/14 keytruda.com keytruda.com

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use INDICATIONS AND USAGE KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis: Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks–9.9 months). The median duration was 4.9 months (range 1 week–14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1–34) followed by a corticosteroid taper. Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2–3 pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) pneumonitis. Immune-Mediated Colitis: Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3– 9.8). The median duration was 2.6 months (range 0.6 weeks–3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4–41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis. Immune-Mediated Hepatitis: Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Immune-Mediated Hypophysitis: Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe (Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hypophysitis. Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3–4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-threatening (Grade 4) nephritis. Immune-Mediated Hyperthyroidism and Hypothyroidism: Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5–2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with highdose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks–19 months). All but two of the patients with hypothyroidism were

treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Other Immune-Mediated Adverse Reactions: Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency. Across clinical studies with KEYTRUDA in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Embryofetal Toxicity: Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail above. • Immune-mediated pneumonitis. • Immune-mediated colitis. • Immune-mediated hepatitis. • Immune-mediated hypophysitis. • Renal failure and immune-mediated nephritis. • Immune-mediated hyperthyroidism and hypothyroidism. • Immune-mediated adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS and PRECAUTIONS section reflect exposure to KEYTRUDA in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received KEYTRUDA at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18–94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease. KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis. Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18–88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year. KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Risk Summary: Based on its mechanism of action, KEYTRUDA may cause fetal harm when In appropriate patients with advanced melanoma administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway KEYTRUDA 2 mg/kg every 3 weeks N=89

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data: Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects General Disorders and Administration Site Conditions on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve Fatigue 47 7 pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 Peripheral edema 17 1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus Chills 14 0 and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA Pyrexia 11 0 during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, Gastrointestinal Disorders there were no malformations related to the blockade of PD-1 signaling in the offspring of Nausea 30 0 these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Constipation 21 0 Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab Diarrhea 20 0 has the potential to be transmitted from the mother to the developing fetus. Based on its Vomiting 16 0 mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing Abdominal pain 12 0 immune-mediated disorders or of altering the normal immune response. Respiratory, Thoracic And Mediastinal Disorders Nursing Mothers: It is not known whether KEYTRUDA is excreted in human milk. No studies Cough 30 1 have been conducted to assess the impact of KEYTRUDA on milk production or its presence in Dyspnea 18 2 breast milk. Because many drugs are excreted in human milk, instruct women to discontinue Skin And Subcutaneous Tissue Disorders nursing during treatment with KEYTRUDA. Pruritus 30 0 Pediatric Use: Safety and effectiveness of KEYTRUDA have not been established in Rash 29 0 pediatric patients. Vitiligo 11 0 Geriatric Use: Of the 411 patients treated with KEYTRUDA, 39% were 65 years and over. Metabolism and Nutrition Disorders No overall differences in safety or efficacy were reported between elderly patients and Decreased appetite 26 0 younger patients. Musculoskeletal and Connective Tissue Disorders Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is Arthralgia 20 0 needed for patients with renal impairment. Pain in extremity 18 1 KEYTRUDA is indicated of patients with pharmacokinetic unresectable Hepatic Impairment: Based on a population analysis, noor dosemetastatic adjustment is Myalgia 14 for the 1 treatment needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN Back pain 12 1 melanoma and disease progression following ipilimumab and, if BRAF V600 mutation and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has Nervous System Disorders not been studied in patients withunder moderate (TB greater than 1.5 to 3 times ULN and anybased AST) positive, a BRAF inhibitor. This indication is approved accelerated approval Headache 16 0 or severe (TB greater than 3 times ULN and any AST) hepatic impairment. on tumor response rate11and durability of response. An improvement in survival or diseaseDizziness 0 Females and Males of Reproductive Potential: Based on its mechanism of action, KEYTRUDA Blood and Lymphatic System Disorders related symptoms has not yet been established. Continued approval this may may cause fetal harm when administered to a pregnant for woman. Adviseindication females of Anemia 14 5 reproductive potential to use highly effective contraception during treatment with KEYTRUDA of clinical benefit in the confirmatory trials. Psychiatric Disordersbe contingent upon verification and description and for at least 4 months following the last dose of pembrolizumab. Insomnia 14 0 OVERDOSAGE Infections and Infestations There is no information on overdosage with KEYTRUDA. Upper respiratory tract infection 11 1 *There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4. PATIENT COUNSELING INFORMATION

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

Other clinically important adverse reactions observed in up to 10% of patients treated with KEYTRUDA were: Infections and infestations: sepsis Table 2: Laboratory Abnormalities Increased from Baseline in ≥20% of Patients with Unresectable or Metastatic Melanoma KEYTRUDA 2 mg/kg every 3 weeks N=89 Laboratory Test

All Grades (%)

Grades 3–4 (%)

Chemistry Hyperglycemia 40 2* Hyponatremia 35 9 Hypoalbuminemia 34 0 Hypertriglyceridemia 25 0 Increased Aspartate Aminotransferase 24 2* • Immune-mediated adverse24reactions Hypocalcemia 1 Hematology occurred with KEYTRUDA, including Anemia 55 8*

SELECTED SAFETY INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including: — Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath. —Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain. —Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding. —Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes. —Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. —Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism. • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests. • Advise women that KEYTRUDA may cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA.

pneumonitis, colitis, hepatitis, hypophysitis, • Advise nursing mothers not to breastfeed while taking KEYTRUDA. For more detailed information, please read the Prescribing Information. nephritis, hyperthyroidism, and hypothyroidism. uspi-mk3475-iv-1409r000 Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. Based on the severity of the adverse reaction, Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) Revised: 09/2014 assay results, a subset analysis was performed in the patients with a concentration KEYTRUDA should be withheld or ofdiscontinued pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. corticosteroids For moreCopyright information analysis, none of and the 97 patients who were treated with administered. 2 mg/kg every 3 weeks tested All rights reserved. positive for treatment-emergent anti-pembrolizumab antibodies. regarding immune-mediated adverse reactions, please 11/14 read ONCO-1116177-0000 The detection of antibody formation is highly dependent on the sensitivity and specificity of the additional Selected Safety Information on the next page. the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) *Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each).

positivity in an assay may be influenced by several factors including assay methodology, sample handling,Please timing of sample concomitant medications, and underlying see collection, additional Selected Safety Information on the disease. For these reasons, comparison of incidence of antibodies to KEYTRUDA with the next page and the Brief Summary of Prescribing Information incidences of antibodies to other products may be misleading.

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | MARCH 25, 2015

PAGE 19

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Rectal Surgery continued from page 18

bidities, poor access to care, and older age, which can adversely affect cancer outcomes. Multivariate Cox modeling showed a number of factors associated with overall survival, including age (P < .0001), gender (P = .0034), insurance status (P = .0029), Charlson comorbidity score (P < .0001), tumor grade (P = .0004), clinical nodal status (P = .0006), pathologic tumor grade (P < .0001), pathologic nodal status (P < .0001), surgical margins (P < .0001),

length of hospital stay (P < .0001), and radiation-surgery interval (P < .0001). On the other hand, the type of resection did not seem to affect long-term survival. “Surgical margins were a highly powerful prognostic indicator, as was postoperative length of stay,” Dr. Salo noted. “Radiation dose, radiation boost, and elapsed radiation therapy time did not make a difference, but the interval between radiation therapy and surgery was important, even in the multivariate analysis, and was an

important prognosticator for overall survival.” The study found the delay between radiation therapy and surgery was longer for patients who were older; had more comorbidities; and were Hispanic, black, or uninsured. Longer intervals related to comorbidities or poor access to care could be related to worse survival but would not explain an increase in positive surgical margins with longer intervals, he suggested. He hypothesized that the interval between radiation therapy and surgery

might directly be detrimental to overall survival, perhaps through regrowth of tumor. n

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

Reference 1. Huntington CR, Boselli D, Hill JS, Salo JC: Optimal timing of surgical resection after radiation therapy in locally advanced rectal adenocarcinoma: An analysis of the National Cancer Database. 2015 Gastrointestinal Cancers Symposium. Abstract 510. Presented January 17, 2015.

EXPERT POINT OF VIEW

ancy Kemeny, MD, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, discussed the study at the session and noted several limitations: The data could be outdated (chemotherapy and surgery could be better now), some patient- and treatmentrelated specifics were lacking or not reported, and the pathologic complete response rate of 6.8% is lower than most current reports (12%–28%). However, she said that this large retrospective study “has given support to the concept” that a longer interval (more than 60 days) from the end of chemoradiation therapy to surgery is necessary to increase the chance of complete response, but waiting more than 60 days decreases overall survival.” Discussing what is already known about rectal cancer treatment and outcomes, she pointed out that the attainment of a complete response is predictive of outcomes “and may allow for more tailored treatment.”

For example, she indicated that many such patients are now avoiding surgery at Memorial Sloan Kettering, and results for this nonoperative management approach were reported at the Symposium.1 (These results

and found that poor responders (by maximum standardized uptake values on PET/CT) were less likely to achieve a complete response (7% vs 38%) and less likely to demonstrate tumor regression (16% vs 45%).2

This study has given support to the concept that a longer interval from the end of chemoradiation therapy to surgery is necessary to increase the chance of complete response, but waiting more than 60 days decreases overall survival. —Nancy Kemeny, MD

were also reported in the February 10 issue of The ASCO Post. Visit A SCOPost.com to view them.) Elaborating on the importance of achieving a complete response, she cited a study that assessed patients 6 weeks after neoadjuvant treatment

She added that large, bulky tumors need more time to achieve a complete response, but longer intervals may not be necessary for all tumors. “High” rectal tumors may need less time; however, “low” rectal tumors may need longer intervals when sphincter

preservation is sought, she said. Dr. Kemeny indicated that although it may take time to develop a complete response, in the absence of a tumor response, these longer intervals actually may be harmful. A longer wait time could facilitate local tumor growth and metastasis, enhance fibrosis, and delay the resumption of postoperative chemotherapy. n

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

References 1. Smith JJ, Chow OS, Eaton A, et al: Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy. 2015 Gastrointestinal Cancers Symposium. Abstract 509. Presented January 17, 2015. 2. Perez RO, Habr-Gama A, São Julião GP, et al: Optimal timing for assessment of tumor response to neoadjuvant chemoradiation in patients with rectal cancer: Do all patients benefit from waiting longer than 6 weeks? Int J Radiat Oncol Biol Phys 84:1159-1165, 2012.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Leah Christl, PhD, and Albert Deisseroth, MD, PhD, on Biosimilar Products see page 42

Sandra Sanchez-Reilly, MD, AGSF, FAAHPM, on Avoiding Burnout see page 54

Joseph Mikhael, MD, MEd, on ‘the Big 5’ in Relapsed Myeloma see page 59

Patricia Ganz, MD, on New Breast Cancer Survivors’ Mobile App see page 78

David Hui, MD, MSc, on Physical Signs of Impending Death see page 93

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | MARCH 25, 2015

PAGE 20

Journal Spotlight Breast Cancer

Hypofractionated Whole-Breast Irradiation After Breast-Conserving Surgery Used in Up to One-Third of Eligible Patients By Matthew Stenger

n a study reported in JAMA, Justin E. Bekelman, MD, of the University of Pennsylvania Perelman School of Medicine, and colleagues found that approximately two-thirds of patients with early-stage breast cancer for whom hypofractionated whole-breast irradiation (for 3–5 weeks) was endorsed received conventional wholebreast irradiation (for 5–7 weeks) after breast-conserving surgery.1 Healthcare expenditures were significantly lower for patients receiving hypofractionated whole-breast irradiation.

node involvement, and the hypofractionation-permitted cohort included patients younger than 50 years of age or those with prior chemotherapy or axillary lymph node involvement. Hypofractionated whole-breast irradiation was defined as 11 to 24 fractions (3–5 weeks of whole-breast irradiation), and conventional whole-breast irradiation was defined as 25 to 40 fractions (5–7 weeks of whole-breast irradiation). Uptake of and costs associated with hypofractionated whole-breast irradiation were assessed for 2008 through 2013,

Hypofractionated whole-breast irradiation after breast-conserving surgery increased among women with early-stage breast cancer in 14 U.S. commercial health-care plans between 2008 and 2013. —Justin E. Bekelman, MD, and colleagues

In 2011, the American Society for Radiation Oncology (ASTRO) practice guidelines endorsed hypofractionated whole-breast irradiation as being of equal effectiveness for in-breast tumor control and comparable with regard to long-term adverse effects compared with conventional whole-breast irradiation in patients with early-stage breast cancer who are at least 50 years old, have pathologic stage T1 or T2N0 disease, have no prior chemotherapy, and have radiation dose heterogeneity higher or lower than 7% of prescription dose.2 The guidelines also permitted hypofractionated wholebreast irradiation for other patients with early-stage breast cancer, including those younger than age 50.

Study Details In this retrospective observational cohort study, administrative claims data from 14 commercial health-care plans covering 7.4% of U.S. adult women in 2013 were used to classify patients with incident early-stage breast cancer treated with lumpectomy and whole-breast irradiation from 2008 and 2013 into a hypofractionation-endorsed cohort (n = 8,924) and a hypofractionation-permitted cohort (n = 6,719). The hypofractionation-endorsed cohort included patients 50 years of age and older without prior chemotherapy or axillary lymph

covering the years before and after the release of the ASTRO guidelines. Use of hypofractionated vs conventional whole-breast irradiation was analyzed using multivariable logistic regression, with adjustment for patient, clinical, demographic, and contextual variables, including year of treatment, age, comorbid disease, history of chemotherapy before and after lumpectomy, axillary lymph node involvement, practice setting, use of intensity-modulated radiotherapy, density of radiation oncologists by hospital service area, population density of county of residence, median household income, and level of educational attainment. In the hypofractionation-endorsed cohort, the mean age was 62.7 years, and 66.0% of patients were younger than age 65. In the hypofractionation-permitted cohort, the mean age was 52.7 years, 47.0% were younger than age 50, 20.4% had axillary lymph node involvement,

10.6% received chemotherapy prior to surgery, and 59.6% received chemotherapy prior to whole-breast irradiation.

Increasing Use Use of hypofractionated whole-breast irradiation increased from 10.6% (95% confidence interval [CI] = 8.8%–12.5%) in 2008 to 34.5% (95% CI = 32.2%– 36.8%) in 2013 in the hypofractionationendorsed cohort (adjusted odds ratio [OR] per year = 1.4, P < .001) and from 8.1% (95% CI = 6.0%–10.2%) in 2008 to 21.2% (95% CI = 18.9%–23.6%) in 2013 (adjusted OR per year = 1.3, P < .001) in the hypofractionation-permitted cohort. In adjusted analyses, younger women were less likely to receive hypofractionated whole-breast irradiation in the hypofractionation-endorsed cohort, with the modality being used in 15.4% of those aged 50 to 54 years, 23.5% of those aged 70 to 74 years (P < .001), and 29.4% of those older than age 75 (P < .001). Age was not significantly associated with use of hypofractionated whole-breast irradiation in the hypofractionation-permitted cohort. In the hypofractionation-endorsed cohort, use of hypofractionated wholebreast irradiation was more likely in the hospital outpatient setting vs freestanding facilities (21.6% vs 17.5%, adjusted OR = 1.4, P < .001). Use of intensity-modulated radiotherapy vs no intensity-modulated radiotherapy was associated with a significantly greater likelihood of use of hypofractionated whole-breast irradiation in both the hypofractionation-endorsed cohort (27.1% vs 19.5%, adjusted OR = 1.5, P < .001) and the hypofractionation-permitted cohort (18.2% vs 12.2%, adjusted OR = 1.6, P < .001).

ventional whole-breast irradiation in the hypofractionation-endorsed cohort (difference = $2,894, P < .001) and $64,273 for hypofractionated whole-breast irradiation and $72,860 for conventional whole-breast irradiation in the hypofractionation-permitted cohort (difference = $8,587, P < .001). Estimated savings with hypofractionated whole-breast irradiation were 9.1% in the hypofractionationendorsed cohort and 11.8% in the hypofractionation-permitted cohort. There were no differences in mean total patient out-of-pocket expenses between hypofractionated and conventional wholebreast irradiation in either cohort. Adjusted mean radiotherapy-related expenditures within the 3.5-month radiation period were significantly lower for hypofractionated whole-breast irradiation than for conventional wholebreast irradiation in both the hypofractionation-endorsed cohort ($12,622 vs $16,961, difference = $4,338, P < .001) and the hypofractionation-permitted cohort ($14,974 vs $19,762, difference = $4,785, P < .001). Patient out-of-pocket radiotherapy-related expenses were lower with hypofractionated whole-breast irradiation in both cohorts ($617 vs $746, P < .001; $519 vs $619, P = .04). The investigators concluded: “Hypofractionated whole-breast irradiation after breast-conserving surgery increased among women with early-stage breast cancer in 14 U.S. commercial health-care plans between 2008 and 2013. However, only 34.5% of patients with hypofractionation-endorsed and 21.2% with hypofractionation-permitted early-stage breast cancer received hypofractionated whole-breast irradiation in 2013.” n

Disclosure: For full disclosures of the study authors, visit jama.jamanetwork.com.

Costs Adjusted mean total health-care expenditures (adjusted for inflation to 2013) in the 1 year after diagnosis were $28,747 for hypofractionated wholebreast irradiation and $31,641 for con-

Hypofractionated Whole-Breast Irradiation After Breast-Conserving Surgery ■■ In 2013, 34.5% of “hypofractionation-endorsed” and 21.2% of “hypofractionation-permitted” patients received hypofractionated wholebreast irradiation (ie, 3–5 weeks of radiotherapy as opposed to 5–7 weeks). ■■ Hypofractionated whole-breast irradiation was associated with cost savings.

References 1. Bekelman JE, Sylwestrzak G, Barron J, et al: Uptake and costs of hypofractionated vs conventional whole breast irradiation after breast conserving surgery in the United States, 2008-2013. JAMA 312:2542-2550, 2014. 2. Smith BD, Bentzen SM, Correa CR, et al: Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol 81:59-68, 2011. See commentary by Lori J. Pierce, MD, on page 23.

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ASCOPost.com | MARCH 25, 2015

PAGE 23

Perspective Breast Cancer

Increasing the Use of Hypofractionated Radiation in Early-Stage Breast Cancer: The Way Forward By Lori J. Pierce, MD

ekelman and colleagues are to be congratulated on the publication of an important paper—reviewed in this issue of The ASCO Post—alerting us all to the underutilization of hypofractionated whole-breast irradiation in the treatment of early-stage breast cancer.1 As background, recent randomized radiation trials have proven what preclinical radiation biology studies and biologic models previously predicted. Specifically, these trials demonstrated that delivering fewer large daily radiation doses (hypofractionation) to a moderate total dose over approximately 4 weeks resulted in clinical outcomes comparable to those with conventional fractionation, which uses smaller daily fractions to higher total doses over 5 to 6 weeks.2-4 Preclinical laboratory studies in conjunction with linear-quadratic modeling suggested that short-course hypofractionation would result in high rates of tumor control while minimizing normal-tissue toxicity.5,6 This was indeed demonstrated in four recent randomized trials. These results were unexpected, since early studies using hypofractionation to high total doses resulted in increased rates of late normal-tissue toxicity and morbidity. This, in turn, led to the abandonment of using large daily doses and the adoption of smaller fractions as standard practice in most radiation centers. However, an important difference between the earlier hypofractionation schedules and the more recent hypofractionation trials was the reduction in the total dose in the recent trials, which, as predicted by biologic models, resulted in low rates of normal-tissue toxicity.

ASTRO Task Force In 2009, the American Society for Radiation Oncology (ASTRO) convened a task force to review the data from the randomized hypofractionation trials and generate an evidencebased guideline for treatment recommendations for early-stage breast Dr. Pierce is Professor of Radiation Oncology at the University of Michigan School of Medicine in Ann Arbor and Director of the Michigan Radiation Oncology Quality Consortium.

cancer.7 There was clear consensus among task force members that the data demonstrated no significant difference in the rates of tumor control in the breast, cosmesis, or complications between hypofractionated radiation and conventional fractionation in women 50 years and older with pathologic T1,2 N0 cancers who did not receive systemic chemotherapy and in whom dose homogeneity was within 7% of the prescribed dose. These patients represented the majority of the patients entered in the randomized trials. A consensus was not reached for other patient subgroups underrepresented in the trials. This guideline was published in 2011.

A Closer Look at the Bekelman Study Bekelman et al now report the rates of usage of hypofractionated radiotherapy using claims data from

of the clinical and pathologic factors (such as tumor size, nodal status, and dose homogeneity) important in the selection of patients in some of the randomized trials and important in the development of the ASTRO guideline. As the authors noted, misclassification would have biased the estimates of the use of hypofractionated radiotherapy downward.

The MROQC Initiative The utilization of hypofractionated whole-breast irradiation in earlystage breast cancer patients treated with breast conservation was also recently reported by Jagsi et al using data prospectively collected in the state of Michigan from radiation oncology practices participating in the Michigan Radiation Oncology Quality Consortium (MROQC).8 This is a quality initiative funded by Blue Cross Blue Shield of Michigan.

Continued education regarding the effectiveness of the shorter 4-week course, which offers greater patient convenience and health-care savings, will hopefully result in the increased use of this fractionation schedule. —Lori J. Pierce, MD

14 commercial health-care plans in the United States in patients treated with breast-conserving surgery and radiotherapy from 2008 to 2013.1 They show usage in 34.5% of the hypofractionation-“endorsed” cohort and 21.2% in those women for whom a consensus by the ASTRO task force was not reached (ie, the hypofractionation-“permitted” cohort). These rates of hypofractionated whole-breast irradiation were low despite equivalent results demonstrated in the clinical trials and the reduction in the adjusted mean total health-care expenditures associated with the shorter course. The methodology in their study was rigorous, but the data were retrospective and based on claims thus subject to misclassification bias. The authors were unable to ascertain many

Of MROQC participants registered between October 2011 and December 2013 with T1-2 N0 cancers, 31% were identified as having received hypofractionated whole-breast irradiation. When patients were further selected using factors consistent with the ASTRO-endorsed cohort (ie, age 50 years and older, no receipt of chemotherapy, and breast separation < 25 cm [a metric used to assess dose homogeneity]), the rate of hypofractionation use was increased to 43%. Although this rate was higher than that in the unselected cohort, these results demonstrated a lower rate of hypofractionated radiotherapy utilization than expected in patients who were excellent candidates for this fractionation schedule. The reasons behind the low utilization rate of hypofractionated whole-

breast irradiation are unclear. The financial differential for radiation oncology practices has been suggested as a contributing factor. Providers could also have been hesitant to use large fractions because of persistent concerns over placing patients at risk for the long-term toxicities observed in the hypofractionation studies of the past. Even in the ASTRO evidencebased guideline (published before the publication of the 10-year results of the START trials), task force members had “lingering uncertainty regarding late effects of hypofractionated whole-breast irradiation on cardiac function.”7 Thus, the relative “newness” of the hypofractionation schedules in the randomized trials may have tempered enthusiasm. Perhaps the low uptake was due in part to patient decisions not to choose the more-recent fractionation schemes with 10-year follow-up, when 20+ years of outcomes data were available for conventional whole-breast fractionated therapy.

Increasing Awareness At present, we don’t understand the reason(s) leading to the under utilization of the short-course hypofractionated regimens: this must be carefully studied. However, if the increased trajectory for use observed among the hypofractionation-endorsed group in the last year of the Bekelman et al study is sustained, it suggests that large-fraction radiotherapy is being integrated into routine American practice. Continued education regarding the effectiveness of the shorter 4-week course, which offers greater patient convenience and health-care savings, will hopefully result in the increased use of this fractionation schedule. ASTRO’s Choosing Wisely campaign encourages discussion of whole-breast hypofractionation in women 50 years and older diagnosed with early-stage disease.9 An update of the ASTRO guidelines is also anticipated in the coming months, and this will increase awareness of the clinical utility and practicality of the shorter course. Finally, prospective analyses from clinical trials and observational studies such as MROQC, continued on page 24

The ASCO Post | MARCH 25, 2015

PAGE 24

Perspective

Lori J. Pierce, MD continued from page 23

as well as retrospective analyses from studies such as that by Bekelman et al, will also help to educate healthcare providers and the patients we serve. n Disclosure: Dr. Pierce reported no potential conflicts of interest.

References 1. Bekelman JE, Sylwestrzak G, Barron J, et al: Uptake and costs of hypofractionated vs conventional whole breast irradiation after breast conserving surgery

in the United States, 2008-2013. JAMA 312:2542-2550, 2014. 2. Whelan TJ, Pignol JP, Levine MN, et al: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362:513-520, 2010. 3. Owen JR, Ashton A, Bliss JM, et al: Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumor excision: Long-term results of a randomised trial. Lancet Oncol 7:467-471, 2006. 4. Haviland JS, Owen JR, Dewar JA, et al: The UK Standardisation of Breast Radiotherapy (START) trials of radio-

therapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14:1086-1094, 2013. 5. Fowler JF: The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 62:679-694, 1989. 6. Whelan TJ, Kim DH, Sussman J: Clinical experience using hypofractionated radiation schedules in breast cancer. Semin Radiat Oncol 18:257-264, 2008. 7. Smith BD, Bentzen SM, Correa CR, et al: Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based

guideline. Int J Radiat Oncol Biol Phys 81:59-68, 2011. 8. Jagsi R, Griffith KA, Heimburger D, et al: Choosing wisely? Patterns and correlates of the use of hypofractionated whole-breast radiation therapy in the state of Michigan. Int J Radiat Oncol Biol Phys 90:1010-1016, 2014. 9. American Society for Radiation Oncology: Five things physicians and patients should question. Available at: http://www.choosing wisely.org/doctor-patient-lists/american-society-forradiation-oncology. Accessed January 29, 2015.

Journal Spotlight

New Analysis Reports Increased Risk of Thyroid Cancer After Breast Cancer Diagnosis

reast cancer survivors are at increased risk of developing thyroid cancer, especially within 5 years of their breast cancer diagnosis, according to a new analysis of a large national database. The study results were presented at the Endocrine Society’s 97th Annual Meeting.1 “Recognition of this association between breast and thyroid cancer should prompt vigilant screening for thyroid cancer among breast cancer survivors,” said lead investigator Jennifer Hong Kuo, MD, Assistant Professor of Surgery at Columbia University. Until now, Dr. Kuo said, the relation-

ship between breast and thyroid cancer has been controversial, largely based on single-institution studies that have suggested a possible increase in thyroid cancer incidence after breast cancer.

Study Details The researchers used the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) 9 database to identify the number of individuals with a diagnosis of breast and/or thyroid cancer between 1973 and 2011. They found 704,402 patients with only breast cancer, 49,663 patients with only

Images in Oncology

thyroid cancer, and 1,526 patients who developed thyroid cancer after breast cancer. Compared with patients with breast cancer alone, women who had breast cancer followed by thyroid cancer were younger on average when diagnosed with their breast cancer. They also were more likely to have had invasive ductal carcinoma and to have received radiation therapy as part of their breast cancer treatment. There was no difference in risk based on whether the breast cancer was hormone receptor–positive or had spread to lymph nodes. Compared with patients who had only thyroid cancer, breast cancer survivors who developed thyroid cancer were more likely to have a more aggressive type of thyroid cancer, but the cancers were smaller in size and fewer patients required additional radioactive iodine treatment. Because thyroid cancer tends to occur at younger ages than breast cancer does, breast cancer survivors who then developed thyroid cancer were older on average than those with only thyroid cancer: 62 vs 45 years, respectively, Dr. Kuo reported.

Next Steps in Screening

Apoptotic HeLa Cell—Scanning electron micrograph of an apoptotic HeLa cell. Source: National Institutes of Health. Send your high-resolution image and caption to editor@ASCOPost.com. Please include your name and a caption for the photo.

The study findings showed that breast cancer survivors developed thyroid cancer at a median of 5 years. Therefore, Dr. Kuo recommended that every year for the first 5 years after a breast cancer diagnosis, patients should undergo a dedicated thyroid exam—especially survivors who received radiation therapy. Radiation therapy to the head, neck, or chest is a known risk factor for thyroid cancer, according to the Endo-

Thyroid Cancer Risk

omen who had breast cancer followed by thyroid cancer were younger on average when diagnosed with their breast cancer than those with breast cancer alone. They also were more likely to have had invasive ductal carcinoma and to have received radiation therapy as part of their breast cancer treatment. Researchers plan to study whether tamoxifen treatment, typically given for 5 years after a breast cancer diagnosis, may play a role in increasing the risk of thyroid cancer. n crine Society’s Hormone Health Network. Dr. Kuo said she plans to study whether tamoxifen treatment, typically given for 5 years after a breast cancer diagnosis, may play a role in increasing the risk of thyroid cancer. n

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

Reference 1. Kuo JH, Chabot J, Terry MB, et al: Increased incidence of thyroid cancer among breast cancer survivors: An analysis of the SEER 9-database. Poster THR-049. Presented at the Endocrine Society’s 97th Annual Meeting, March 5–8, 2015, San Diego, California.

DID YOU KNOW? SINCE THE APPROVAL OF DOCETAXEL IN 1999, NO SECOND-LINE REGIMEN HAS EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF METASTATIC 1-3 NSCLC PATIENTS

NSCLC=non-small cell lung cancer.

NEW FDA APPROVAL CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECONDLINE TREATMENT OF METASTATIC NSCLC4 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

•

Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

•

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

•

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

•

Clinical Deterioration in Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

•

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

10.5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

15% INCREASE IN MEDIAN OS

MONTHS

0.8

OS PROBABILITY

MAJOR OUTCOME MEASURE

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 4

527

415

329

231

156

103

501

386

306

197

129

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progressionfree survival; ORR=objective response rate. *ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.5 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.4

VISIT www.CYRAMZAHCP.com Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Use in Specific Populations •

Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

•

Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

•

Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Most Common Adverse Reactions •

•

The most commonly reported adverse reactions (all grades; Grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colonystimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

•

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

•

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions •

No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page. RB-L HCP ISI 17DEC2014 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/ fda-docetaxel/print. Accessed August 26, 2014. 4. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 5. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

CONTRAINDICATIONS None.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZAtreated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA plus docetaxel (N=627) All Grades Grade 3-4 (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 Neutropenia 55 49 Thrombocytopenia 13 3 Gastrointestinal Disorders Stomatitis/Mucosal 37 7 inflammation Eye Disorders Lacrimation increased 13 <1 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 Peripheral edema 16 0 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 Vascular Disorders Hypertension 11 6 Adverse Reactions (MedDRA) System Organ Class

Placebo plus docetaxel (N=618) All Grades Grade 3-4 (Frequency %) (Frequency %) 10 46 5

10 40 <1

50 9

11 <1

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent antiramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST)

CYRAMZA® (ramucirumab) injection

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

ASCOPost.com | MARCH 25, 2015

PAGE 29

Journal Spotlight Breast Cancer

Adjuvant Ovarian Suppression May Benefit Women With Premenopausal Breast Cancer Who Received Prior Chemotherapy By Matthew Stenger

n a phase III trial (SOFT) reported in The New England Journal of Medicine, Prudence A. Francis, MD, of Peter MacCallum Cancer Centre, Melbourne, Australia, Meredith M. Regan, ScD, of IBCSG Statistical Centre at Dana-Farber Cancer Institute, Boston, and colleagues found that the addition of ovarian suppression to tamoxifen did not improve disease-free survival among all women with premenopausal hormone receptor–positive breast cancer but appeared to have a beneficial effect in those who had received adjuvant

years, 46.7% of the patients had not received prior chemotherapy and 53.3% had received prior chemotherapy and remained premenopausal, and 34.9% of patients had node-positive disease. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve diseasefree survival vs tamoxifen alone. The study was originally designed to compare disease-free survival between the three treatment groups with three pairwise comparisons. However, enrolled patients were older and had low-

Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population.

Additional information can be found at www.CYRAMZAhcp.com.

—Prudence A. Francis, MD, Meredith M. Regan, ScD, and colleagues

chemotherapy and remained premenopausal.1 Treatment with exemestane plus ovarian suppression vs tamoxifen alone was associated with even greater benefit in this higher-risk group.

Study Details

RB-L HCP BS 17Dec2014

In the study, 3,066 premenopausal women with breast cancer were randomized to receive 5 years of tamoxifen (n = 1,021), tamoxifen plus ovarian suppression (n = 1,024), or exemestane plus ovarian suppression (n = 1,021) between December 2003 and January 2011. Randomization was stratified by receipt or nonreceipt of adjuvant chemotherapy. Ovarian suppression was achieved by triptorelin (Trelstar depot in the U.S.) treatment, bilateral oophorectomy, or bilateral ovarian irradiation. Patients had a median age of 43

er-risk characteristics than anticipated, and the rate of disease-free survival was higher than expected. A protocol amendment to the statistical analysis plan was adopted in 2011; it designated the test of superiority of tamoxifen/ ovarian suppression over tamoxifen alone as the primary analysis and the comparison of exemestane/ovarian suppression vs tamoxifen alone as a secondary analysis.

Outcomes in Total Population After a median follow-up of 67 months, 14.7% of patients had recurrent disease or a second invasive cancer or had died. The rate of diseasefree survival at 5 years was 86.6% in the tamoxifen/ovarian suppression group vs 84.7% in the tamoxifen group (hazard ratio [HR] = 0.83, P = .10). continued on page 30

The ASCO Post | MARCH 25, 2015

PAGE 30

Perspective

SOFT Trial Results Inconclusive: Further Study Needed By Edith A. Perez, MD

he results of the SOFT trial— presented at the 2014 San Antonio Breast Cancer Symposium, reported recently by Francis et al in The New England Journal of Medicine,1 and reviewed in this issue of The ASCO Post—were not as conclusive as we had

mone receptor–positive breast cancer who were randomized to receive one of three antiestrogen approaches. The results demonstrated that most of these patients had a very good outcome in response to the physician’s decisions (in consultation with the patient) of

The challenge here is that the decision for chemotherapy was left to physician discretion, so the study does not provide guidelines on how to exactly assign need for chemotherapy. —Edith A. Perez, MD

hoped. In essence, the study enrolled women with resected early-stage horDr. Perez is Deputy Director at Large, Mayo Clinic Cancer Center; Group Vice Chair, Alliance for Clinical Trials in Oncology; and Director, Mayo Clinic Breast Cancer Translational Genomics Program.

Adjuvant Ovarian Suppression continued from page 29

On multivariate analysis adjusting for prognostic factors, the HR was 0.78, P = .03. The 5-year rate of disease-free survival with exemestane/ovarian suppression was 89.0% (HR = 0.68, 95% confidence interval [CI] = 0.53–0.86, vs tamoxifen). The 5-year rate of freedom from breast cancer was 88.4% with tamoxifen/ovarian suppression vs 86.4% with tamoxifen (HR = 0.81, P = 0.09; adjusted HR = 0.75, P = 0.02) and 90.9% with exemestane/ovarian suppression (HR = 0.64, 95% CI = 0.49–0.83). The 5-year rate of freedom from distant tumor recurrence was 91.3% with tamoxifen/ovarian suppression vs 90.7% with tamoxifen (HR = 0.88, 95% CI = 0.66–1.18) and 93.0% with exemestane/ovarian suppression (HR = 0.71, 95% CI = 0.52–0.96, vs tamoxifen). Overall survival at 5 years was 96.7% with tamoxifen/ovarian suppression vs 95.1% with tamoxifen (HR = 0.74, P = 0.13) and 95.3% with exemestane/ ovarian suppression (HR = 0.97, 95% CI = 0.68–1.40, vs tamoxifen).

surgery, chemotherapy, radiation therapy, plus one of the three hormonal approaches tested. This is good news, although it does not imply that all women may not have had side effects of these treatments nor did not develop tumor recurrence or will not develop tumor recurrence

Patients Who Had No Prior Chemotherapy Among patients who did not receive chemotherapy (median age, 46), more than 95% remained free from breast cancer at 5 years in all treatment groups. The 5-year rates for the tamoxifen/ovarian suppression, tamoxifen, and exemestane/ovarian suppression groups were 93.4%, 93.3%, and 95.2% for diseasefree survival; 95.1%, 95.8%, and 97.1% for freedom from breast cancer; 98.7%, 98.6%, and 99.3% for freedom from distant tumor recurrence; and 99.2%, 99.8%, and 98.8% for overall survival. The treatment groups weren’t statistically compared (ie, no statistical test and P value) within the subgroup of patients who didn’t receive prior chemotherapy.

Patients Who Had Prior Chemotherapy Among patients who had received prior chemotherapy and remained premenopausal (median age, 40), 5-year disease-free survival rates in the tamoxifen/ovarian suppression, tamoxifen, and exemestane/ovarian suppression groups were 80.7% (HR = 0.82, 95% CI

in the years to come. However, at least at the reported follow-up, survival was greater than 95%, and about 85% of patients were alive without tumor recurrence.

Deciding Who Needs Chemotherapy In terms of the main hypothesis of the trial, the results demonstrated that we cannot recommend ovarian function suppression as standard therapy for all patients with hormone receptor–positive breast cancer diagnosed in the premenopausal stage. This statement is based on the lack of statistical difference between tamoxifen and tamoxifen with ovarian function suppression. However, the important caveat to this overall “negative result” of this study is that for the subset of patients whose physicians thought they should receive chemotherapy, ovarian function suppression appeared to add to tamoxifen (or exemestane). The challenge here is that the decision for chemotherapy was left to physician discretion, so the study does not

provide guidelines on how to “exactly” assign need for chemotherapy. Therefore, we need to await further understanding of molecular profiling added to clinicopathologic characteristics to eventually make more informed and accurate decisions than those we can make today regarding who “needs” chemotherapy to optimize diseasefree and overall survival. Thus, we are still left with a situation where we need to continue discussing options with each patient, sharing the results of this trial (efficacy as well as toxicities observed), while awaiting further study followup related to long-term breast-related events to determine whether there are clinically relevant negative effects of ovarian function suppression. n

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

Reference 1. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.

Adjuvant Ovarian Suppression in Premenopausal Breast Cancer ■■ The addition of ovarian suppression to tamoxifen did not appear to improve outcomes among all patients. ■■ Improvements in outcomes were observed with the addition of ovarian suppression to tamoxifen (and further improvement with ovarian suppression plus exemestane) compared with tamoxifen alone in higherrisk patients who had received prior chemotherapy and remained premenopausal.

= 0.64–1.07, vs tamoxifen), 77.1%, and 83.8% (HR = 0.70, 95% CI = 0.53–0.92, vs tamoxifen). Five-year rates of freedom from breast cancer were 82.5% (HR = 0.78, 95% CI = 0.60–1.02), 78.0%, and 85.7% (HR = 0.65, 95% CI = 0.49– 0.87). Five-year rates of freedom from distant tumor recurrence were 84.8% (HR = 0.87, 95% CI = 0.64–1.17), 83.6%, and 87.8% (HR = 0.72, 95% CI = 0.52–0.98). Five-year overall survival rates were 94.5% (HR = 0.64, 95% CI = 0.42–0.96), 90.9%, and 92.3% (HR = 0.87, 95% CI = 0.59–1.27). The investigators concluded: “Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. How-

ever, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression.” n

Disclosure: This study was supported by the International Breast Cancer Study Group, Ipsen, the National Cancer Institute, and Pfizer. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. December 11, 2014 (early release online).

when it’s time for

first-line Cll treAtment

indication GAZYVA® (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). Boxed WArninGs: HePAtitis B VirUs reACtiVAtiOn AnD PrOGressiVe MUltifOCAl leUKOenCePHAlOPAtHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal leukoencephalopathy (PMl) including fatal PMl, can occur in patients • receiving GAZYVA

For the first-line treatment of CLL in combination with chlorambucil1 ®

stArt with GAZYVA

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) include obinutuzumab (GAZYVA®) + chlorambucil as a preferred first-line regimen for CLL patients with comorbidities, without del(17p) 2,a,b a

NCCN treatment suggestions for patients with del(17p) are not segmented by age or comorbidities. Obinutuzumab (GAZYVA) + chlorambucil is included as a suggested treatment for this patient population. Suggested treatment regimens are listed in alphabetical order. Obinutuzumab (GAZYVA) + chlorambucil is listed first as a suggested treatment regimen for this patient population. Treatment regimens are listed in order of preference. Note: All recommendations are category 2A unless otherwise indicated.

iMPOrtAnt sAfetY infOrMAtiOn Hepatitis B Virus reactivation

• Hepatitis B virus (HBV) reactivation, in some cases

•

resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive) HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death

• Screen all patients for HBV infection by measuring HBsAg

• •

and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation

neArLY A 1-YeAr imProVement in meDiAn Pfs (23.0 months Vs 11.1 months; hr=0.16; 95% Ci, 0.11-0.24; P<0.0001)1 siGnifiCAntlY sUPeriOr Pfs: GAZYVA in combination with Clb more than doubled median Pfs vs Clb monotherapy1 1.0 Hr=0.16; 95% CI, 0.11-0.24; P<0.0001

0.9 0.8

84% risk reduction

0.7

Pfs

0.6 0.5 0.4 0.3

11.1

0.2 GAZYVA + chlorambucil (n=238) Chlorambucil (n=118)

0.1

23.0

0.0

GAZYVA + chlorambucil Chlorambucil

0 n at risk

time (months)

238

208

201

146

111

118

PFS, progression-free survival; Clb, chlorambucil; HR, hazard ratio; CI, confidence interval. Cll-11 trial Design1: GAZYVA, in combination with chlorambucil, was evaluated in a Phase III, open-label, multicenter, 3-arm, randomized, parallel-group comparative study in patients with previously untreated CD20+ chronic lymphocytic leukemia and coexisting medical conditions and/or reduced renal function. Patients with creatinine clearance <30 mL/min or inadequate liver function were excluded. The primary endpoint was progression-free survival. Overall response rate and complete response rate were secondary endpoints.

enhanced response rates1 • GAZYVA + Clb more than doubled response rates vs Clb monotherapy (75.9% vs 32.1%, respectively) • More than 1 in 4 patients receiving GAZYVA + Clb achieved a complete response (27.8% vs 0.9%, respectively) the most common Grade 3-4 adverse reactions were infusion reactions, neutropenia, and thrombocytopenia1 • The most common adverse reactions were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) Progressive Multifocal leukoencephalopathy (PMl)

wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new • Premedicate patients with acetaminophen, antihistamine, onset or changes to preexisting neurologic manifestations. and a glucocorticoid. Institute medical management Evaluation of PML includes, but is not limited to, for infusion reactions as needed. Closely monitor patients consultation with a neurologist, brain MRI, and lumbar during the entire infusion. Infusion reactions within 24 puncture. Discontinue GAZYVA therapy and consider hours of receiving GAZYVA have occurred discontinuation or reduction of any concomitant • For patients with any Grade 4 infusion reactions, including chemotherapy or immunosuppressive therapy in patients but not limited to anaphylaxis, acute life-threatening who develop PML respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently infusion reactions discontinue GAZYVA therapy • GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mgs infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (eg, bronchospasm, larynx and throat irritation,

• JC virus infection resulting in PML, which can be fatal, was

Please see the following pages for additional important safety information and brief summary of full Prescribing information, including Boxed WArninGs.

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) infusion reactions (cont’d)

• For patients with Grade 1, 2, or 3 infusion reactions: •

Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to and during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication

thrombocytopenia (cont’d)

Fatal hemorrhagic events during Cycle 1 have also been reported. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (ie, platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle

immunization

• The safety and efficacy of immunization with live or

attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery

tumor lysis syndrome (tls)

• Acute renal failure, hyperkalemia, hypocalcemia,

hyperuricemia, and/or hyperphosphatemia from TLS can occur within 12-24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (>25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12-24 hours prior to the infusion of GAZYVA. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated

Pregnancy: Category C

• Women of childbearing potential should use effective

contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Geriatric Use

• Two hundred and forty previously untreated CLL patients

received GAZYVA in combination with chlorambucil. Of the 109 patients ≥75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) experienced an adverse event leading to death. Similar rates were observed in the comparator arm

infections

• Serious bacterial, fungal, and new or reactivated viral

infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection

neutropenia

• GAZYVA, in combination with chlorambucil, caused Grade

• •

3 or 4 neutropenia in 34% of patients. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days) Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered

thrombocytopenia

• GAZYVA, in combination with chlorambucil, caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Visit GAZYVA.com for more information

Additional important safety information

• The most common adverse reactions (≥10%) were: infusion •

reactions (69%), neutropenia (40%), thrombocytopenia (15%), anemia (12%), pyrexia (10%), cough (10%), and musculoskeletal disorders (17%) Grade 3/4 adverse reactions were: infusion reactions (21%), neutropenia (34%), thrombocytopenia (11%), anemia (4%), leukopenia (5%), and pyrexia (<1%)

You are encouraged to report side effects to Genentech and the fDA. You may contact Genentech by calling 1-888-835-2555. You may contact the fDA by visiting www.fda.gov/medwatch, or calling 1-800-fDA-1088. references: 1. GAZYVA full Prescribing information. south san francisco, CA: Genentech UsA, inc.; June 2014. 2. referenced with permission from the nCCn Clinical Practice Guidelines in oncology (nCCn Guidelines®) for non-hodgkin’s Lymphomas V.1.2014. © national Comprehensive Cancer network, inc. 2014. All rights reserved. Accessed march 31, 2014. to view the most recent and complete version of the guideline, go online to www. nccn.org. nAtionAL ComPrehensiVe CAnCer networK®, nCCn®, nCCn GUiDeLines®, and all other nCCn Content are trademarks owned by the national Comprehensive Cancer network, inc.

Please see the following pages for brief summary of full Prescribing information, including Boxed WArninGs.

ASCOPost.com | MARCH 25, 2015

PAGE 31

Journal Spotlight

Physician-Controlled Decisions in Cancer Care Linked to Lower Quality Rating

atients who described physiciancontrolled decisions about their cancer care vs shared decision-making were less likely to report receiving excellent quality of care, according to a study published by JAMA Oncology.1 The Institute of Medicine has called

for shared decision-making and accommodation of patient preferences to improve the overall quality of health care. Although metrics of quality are controversial, patients’ reports about the quality of their care are increasingly important health -care performance measures. GAZYVA® (obinutuzumab)

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)]. Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

Nancy L. Keating, MD, MPH, of Harvard Medical School, and colleagues surveyed patients in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study who were diagnosed with lung and/or colorectal cancer. The authors analyzed

responses from 5,315 patients who reported decision roles for 10,817 treatment decisions. They then assessed the association between patients’ roles in their decisions and their reported quality of care and physician communication.

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

continued on page 32

Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Injury, poisoning, and procedural complications Infusion 69 21 0 0 reactions

Anemia

Leukopenia

Infections and infestations Urinary tract 6 2 infection

Musculoskeletal and connective tissue disorder Back pain 5 <1 2 0

Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Adverse Reactions (MedDRAa) System Organ Class

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Injury, poisoning and procedural complications Infusion 66 20 38 4 reactions Blood and lymphatic system disordersb Neutropenia 38 33 32

Thrombocytopenia 14

Leukopenia

General disorders and administration site conditions Pyrexia 9 <1 7 <1

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Thrombocytopenia 15

Respiratory, thoracic, and mediastinal disorders Cough 10 0 7 <1

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

Blood and lymphatic system disordersb Neutropenia 41 35 18

General disorders and administration site conditions Pyrexia 10 <1 7 0

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

Constipation

Infections and infestations Nasopharyngitis 6 <1 Urinary tract infection

MedDRA coded adverse reactions as reported by investigators.

Adverse events reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

The ASCO Post | MARCH 25, 2015

PAGE 32

Journal Spotlight Physician-Controlled Decisions continued from page 31

A total of 58% of patients preferred shared roles in decision-making about their cancer, 36% preferred patientcontrolled decisions, and 6% preferred physician-controlled decisions. Of the treatment decisions made by patients, 42% were regarding surgery, 36% regard-

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) GAZYVA + Chlorambucil n = 241

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

Lymphopenia

Leukopenia

Chemistry Hypocalcemia

Hyperkalemia

Hyponatremia

AST (SGOT increased)

Creatinine increased

ALT (SGPT increased)

Hypoalbuminemia

Alkaline phosphatase 18 increased

Hypokalemia

Table 6 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Investigations

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

Lymphopenia

Leukopenia

Thrombocytopenia 48

Anemia

Chemistry Hypocalcemia

Hyperkalemia

Hyponatremia

AST 27 (SGOT increased)

ALT 28 (SGPT increased)

Hypoalbuminemia 23

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused. Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)]. Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

Nancy L. Keating, MD, MPH

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1. Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%). Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity. 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be 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 obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

ing chemotherapy, and 22% regarding radiation therapy. The patients in the study reported their actual decision-making process was patient-controlled in 39% of decisions, shared in 44% of decisions, and controlled by physicians in 17% of decisions. Patients reported their care by the physician performing the treatment as excellent in 67.8% of cases. While a pa-

8.5 Geriatric Use Of 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by: Genentech, Inc.

Code Revision Date: December 2014

A Member of the Roche Group South San Francisco, CA 94080-4990

GAZYVA is a registered trademark of Genentech, Inc.

U.S. License No: 1048

tient’s preferred role in decision-making was not associated with quality ratings, patient reports that treatment decisions were controlled by physicians (vs shared) were associated with lower odds of excellent patient-reported quality. Overall, 55.8% of patients gave their physicians the highest possible rating of communication. However, patients who preferred physician-controlled to shared decisions were less likely to give top ratings to their physicians, as were patients who reported actually experiencing physician-controlled vs shared decisions, the results show. “Given the increasing emphasis on patient experiences and ratings in health care, these results highlight the benefits of promoting shared decision making among all patients with cancer, even those who express preferences for less active roles,” the study concludes.

Shared Decision-Making In a related commentary,2 Sarah T. Hawley, PhD, MPH, and Reshma Jagsi, MD, DPhil, both of the University of Michigan, wrote, “We find it unsurprising that even patients who preferred a physician-controlled decision rated the physician communication outcomes highest when the actual decision-making process was more shared, as the individual items that constitute the communication measure described elements most likely to be absent when the actual decision is not shared.” They continued, “More compelling is the association found between shared decision-making and patient appraisal of excellent quality of care. It is intriguing that this association remained, even when controlling for preferred role. Dr. Kehl and colleagues conclude from this finding that it is important to promote shared decision-making, even among patients who may seek less active roles. Yet these results are in some contrast to prior work that has suggested that it is the match between patients’ preferred and actual involvement that contributes to greater satisfaction with care. These conflicting results underscore the need for further work to better quantify and link measures of shared decision making to patient appraisal of care,” they concluded. n Disclaimer: This work of the CanCORS Consortium was supported by grants from the National Cancer Institute and the Department of Veterans Affairs.

References 1. Kehl KL, Landrum MB, Arora NK, et al: JAMA Oncol. February 12, 2015 (early release online). 2. Hawley ST, Jagsi R: JAMA Oncol. February 12, 2015 (early release online).

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Expert’s Corner Health-Care Policy

Ongoing Controversies in Allocating Our Health-Care Resources A Conversation With Richard ‘Buz’ Cooper, MD By Ronald Piana

Richard ‘Buz’ Cooper, MD

isparities of care that result in poorer outcomes among certain populations have long been an issue addressed by the cancer community and its major organizations such as ASCO. While ethnicity and race play key roles in this ongoing debate over equitable allocation of our precious health-care resources, another persistent issue frames the larger story of the haves and have-nots in cancer care outcomes: poverty and the politics of health-care distribution. To bring clarity to the issue of how we apportion health-care services and the doctors who deliver them, The ASCO Post visited with Richard “Buz” Cooper, MD, Director of the Center for the Future of the Healthcare Workforce and a Senior Fellow in the Leonard Davis Institute of Health Economics at the University of Pennsylvania. At the Upper East Side apartment he shares with his wife, Barrie R. Cassileth, MS, PhD, the Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, Dr. Cooper shared his experiences in hematology and oncology, as well as his current work in public health.

Early Career With the Manhattan skyline stretching out from the 32nd-floor apartment, Dr. Cooper, a tall man with a professorial bearing, explained that his early career as a hematologist was influenced by his work at the National Cancer Institute (NCI) in 1963, when Drs. Emil Frei and Emil J. Freireich first began using combination chemotherapy to treat childhood acute leukemia. “It was an extraordinary experience to see these children with a heretofore fatal disease respond to this first-time-ever treatment. It was truly a remarkable time in oncology, and I wanted to be part of it,” said Dr. Cooper.

After his stint at the NCI came to a close, Dr. Cooper finished his hematology fellowship at Boston City Hospital. In 1971, he went to the University of Pennsylvania to start a hematology/ oncology program. “Interest was building to expand the nation’s cancer centers, so we gathered our resources and developed a cancer center attached to the university, which broke the mold of the freestanding centers that the NCI preferred,” said Dr. Cooper. He added, “Dr. Peter Nowell, who discovered the Philadelphia chromosome, assumed the director’s mantle for the first years; then I took over, and we developed the center into a nationally recognized multidisciplinary cancer institute.” The next chapter in Dr. Cooper’s career took him back to his hometown of Milwaukee, where he became Dean of the Medical College of Wisconsin. “It

and I soon found a glaring error in the surplus projection: Their conclusion was based on outdated census data, which assumed that the U.S. population was not going to increase. So, I called the Census Bureau and had them send me the current data,” said Dr. Cooper. Dr. Cooper applied the Census Bureau’s updated projection of population growth with the existing projections of physician growth based on the numbers coming out of medical schools, currently working, and those retiring. “The administration’s projection of a surplus of doctors by 2000 was wrong. Instead, we were on track for a dangerous shortage of doctors,” said Dr. Cooper. “My findings caused an outrage. But there were nuances that the administration was missing. For instance, at one point, lung cancer was virtually untreatable so of course you didn’t need

All of these academic conclusions about overutilization of physician services being the main driver of our socalled fiscal crisis in health-care point at specialties, such as oncology, as the main cause. However, it is just the opposite; our specialists drive innovation and excellent, cost-effective care in our system. —Richard “Buz” Cooper, MD

was a small school that struggled financially. Much like the Penn cancer center, which we really made out of whole cloth, the Medical College, in a sense, had to be built from the ground up. It was a 9-year project of love, and when I left the College it was on the cusp of being a powerhouse,” said Dr. Cooper.

Physician Supply and Demand The next period of Dr. Cooper’s career was transformative and, in part, informs his current work in public health. During the Clinton administration’s health-reform initiative, a startling observation emerged: We were heading for a surplus of 100,000 doctors by 2000. According to Dr. Cooper, this projection would reduce the recruiting of students into medical school and drastically cut residency programs, causing long-term reductions in America’s physician force. “This doctor surplus dogma was held by many experts. A friend of mine at the [American Medical Association] asked if I could address this issue. I did,

lung cancer specialists. But advances in detection and treatment fostered a need for more oncologists to treat that and other diseases. We needed more doctors, not fewer.” In 2009, Dr. Cooper was called to testify at a Senate hearing on the need for innovative models in health care, which was, in part, a subtle call for a reduction in physician services. During the hearing, Dr. Cooper made his opinion clear: “My analysis of our need to expand physician supply and encourage innovation in physician practices stands against a set of beliefs that more physicians and more health care may not be good for the nation…. In fact, the preponderance of data do not support these conclusions.” To this day, Dr. Cooper laments that after all his work on the issue of physician supply and demand, there was still a core of influential policymakers who favored a reduction in the number of physicians. “I have an upcoming debate at the National Resident Matching Program, but the fact that I’m arguing whether or not we need

to expand physician supply is sad. There is an entrenched body of opinion in certain sectors of health care that refuses to recognize, for instance, that we are facing a workforce shortage crisis in oncology,” he said.

Health-Care Disparities Dr. Cooper further commented that along with the erroneous statistics used to project a surplus of physicians, the government-driven agenda was claiming that addressing waste and inefficiency would ameliorate the need for more doctors and services. “The fundamental underpinning of this grand assumption is derived from The Dartmouth Atlas of Health Care, which contends that regional variations in cost are driven by variations in how physicians practice,” he said. Although Dr. Cooper agrees that there is substantial waste and inefficiency in the health-care system, he contends that it is economic disparity in care, and not physician practice patterns, that drive overutilization of health-care services. He stressed that poorer people, for a number of socioeconomic reasons, are less healthy than economically stable or affluent people and therefore cost more to treat. “For example,” he said, “Mississippi, which is the poorest state in the country, has very high per capita Medicare spending, simply because the population presents with serious health issues that are costly to treat.” Dr. Cooper emphasized his point: “Health-care costs on the affluent Upper East Side of New York are about 80% of the national average. But walk a few blocks up to Harlem, for instance, and the per capita costs are about three times the national average. The same health-care providers are serving patients from both areas, but the patients from Harlem simply cost more to care for because of the negative health consequences of living in poverty. And if you merge the data from the two economically divergent areas, you get a very distorted view of costs relative to physician services in Manhattan.” In Dr. Cooper’s opinion, projects like The Dartmouth Atlas and other cost-effectiveness initiatives that ostensibly seek to decrease waste and inefficiency in our health-care system have an unintended consequence—they erode physician autonomy and move the locus of control continued on page 34

The ASCO Post | MARCH 25, 2015

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Expert’s Corner Richard ‘Buz’ Cooper, MD continued from page 33

from the medical professional to the regulators and health-care administrators. “All of these academic conclusions about overutilization of physician services being the main driver of our socalled fiscal crisis in health-care point at specialties, such as oncology, as the main cause. However, it is just the opposite; specialists drive innovation and excellent, cost-effective care.” He continued, “In fact, when all of the states across the country are critically examined, more total spending and more specialists are associated with better-quality health outcomes—just

the opposite of The Dartmouth Atlas message, but just what you would expect if you analyze how the delivery of health-care services truly affects populations of vastly different socioeconomic structures. Furthermore, more spending at the high end improves outcomes because the care consists of a broader spectrum of beneficial services.”

Poverty and Health-Care Costs “There is a small group of researchers who generally get lumped into the “social justice world” of medicine. They’re a good bunch of professionals who have collected abundant evidence showing that poverty is strongly associated with poor

health status, greater per capita spending, more hospital readmissions, and poorer outcomes. It is the single strongest factor in geographic variations in health care and the single greatest contributor to excess spending,” said Dr. Cooper. He stressed that in order to fully understand how different populations access health care and utilize services, we must develop a risk-assessment methodology that captures all of the social and demographic variables. “A new report by the [Institute of Medicine] has recommended such an approach. It will be difficult to implement over time, given the complexity of these variables, but at least it points us in the right di-

rection and blows the whistle on those policymakers who slice and dice the data to arrive at politically expedient conclusions,” said Dr. Cooper. Dr. Cooper is a firm believer that more doctors—especially oncologists and other specialists—are ultimately needed to deliver high-quality cost-effective medical care as our aging population grows. He also is firm about another subject: Poverty is a huge driver of health-care costs. To that end, Dr. Cooper is working on the last chapter of a soon-to-be-published book titled Cancer Through the Lens of Poverty. n Disclosure: Dr. Cooper reported no potential conflicts of interest.

NCI-ASCO Teams in Cancer Care Project: Call for Participants The National Cancer Institute (NCI) and American Society of Clinical Oncology (ASCO) are collaborating to illustrate models of team-based care at a workshop and in JOP content. Teamwork involves delineating roles and responsibilities for multidisciplinary care across many settings. At a time of increasing expectations and pressure to demonstrate value in oncology care, this project will explore how oncology care can provide an effective model. Goal: Illustrate in presentations and manuscripts effective approaches to delivering coordinated, patient-centered cancer care and apply the evidence for effective cancer care teams Who: Approximately 10 writing groups will be formed with the following participants: n Clinicians (physicians, nurse practitioners, physician assistants, and nurses) n Patient advocates n Researchers studying team effectiveness in health care (not only oncology) in the United States or Canada

What: Groups including clinicians, patient advocates, and team researchers will develop a presentation and manuscript applying principles of team-based care to a case within the cancer care continuum (prevention, screening, diagnosis, active treatment of curable and incurable disease, survivorship, end of life). Important Dates: n Applications due: June 15, 2015 n Selection of teams: July 17, 2015 n In-person meeting at ASCO offices, Alexandria, VA: August 28, 2015 n Presentations at NCI-ASCO Workshop: February 25, 2016

Apply as individuals or teams at www.ASCO.org/Teams Questions: teams@asco.org

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | MARCH 25, 2015

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Announcements

UPMC Whitfield Cancer Centre Receives Joint Commission International Accreditation

or the third time since 2008, the University of Pittsburgh Medical Center (UPMC) Whitfield Cancer Centre, operated by UPMC in Waterford, Ireland, has successfully achieved

accreditation from the Joint Commission International ( JCI). This recognition is based on an extensive review of the center’s patient safety, quality standards, and processes.

The JCI accreditation process focuses on determining whether a health care facility has the right systems and processes in place to support highquality and safe patient care and has

Erbitux® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WArNiNG: SEriOuS iNFuSiON rEACtiONS and CArDiOPuLMONArY ArrESt infusion reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European union (Eu)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-Fu) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing information.] iNDiCAtiONS AND uSAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFr-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.] Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONtrAiNDiCAtiONS None WArNiNGS AND PrECAutiONS infusion reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] use of Erbitux in Combination With radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

the culture and capacity to continuously improve care. JCI’s surveyors examine crucial issues such as patient and family education, access to care, continued on page 36

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor receptor (EGFr) Expression and response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADvErSE rEACtiONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). table 1:

incidence of Selected Adverse reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus radiation radiation therapy Alone (n=208) (n=212) body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc Alkaline Phosphatase, highc 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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Announcements UPMC Whitfield Cancer Centre continued from page 35

and medication management. The process requires hospitals to demonstrate a track record of standards compliance and relies on candid interviews with patients, nurses, and physicians about care practices. “The success of this third accredita-

tion survey reflects the ongoing efforts of the whole Cancer Centre team and their dedication to continuing to provide a quality service to all cancer patients,” said Catriona McDonald, Director of Operations and Radiotherapy Services Manager. “Demonstrating compliance with JCI standards serves as validation of an

organization’s commitment to an internationally recognized, time-tested, and comprehensive level of quality,” said Cheryl Brill, UPMC’s Vice President of International Clinical Operations and Quality. UPMC Whitfield Cancer Centre offers the most advanced radiation therapy, including intensity-modulated

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux (cetuximab) provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). table 2:

incidence of Selected Adverse reactions (≥10%) in Patients with recurrent Locoregional Disease or Metastatic SCCHN Eu-Approved Cetuximab Platinum-based plus Platinum-based therapy with therapy with 5-Fu 5-Fu Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona infections and infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). table 3:

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radiation therapy and image-guided radiation therapy, to residents of the southeast region of Ireland. One of only four ambulatory care centers to be JCI-accredited in Ireland, the center is committed to delivering the highest standard of radiation therapy and supportive care for patients with all types of cancer. n

table 3: (Continued)

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). table 4:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFr-expressing, Metastatic Colorectal Cancer treated with Erbitux Monotherapya Erbitux plus bSC bSC alone (n=118) (n=124) Grades Grades Grades body System Grades b 3 and 4 1–4 3 and 4 Preferred Term 1–4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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Geriatrics for the Oncologist Hyman Muss, MD continued from page 1

grow at an explosively high rate. This has led me to conclude that the most important advance in geriatric oncology over the course of my career has been the recognition that older cancer patients need to be managed differently than their younger counterparts. To that end, we all need to

learn to do routine geriatric assessments, and as oncologists, learn to practice like mini-geriatricians, factoring all the other health-related baggage common in older patients into our treatment plans. Now that we’ve gained more knowledge in this area, it’s important that a proper assessment be done so older patients do not get low-balled in treatment

decisions. The danger using age in recommending a treatment plan is to deny state-of-the-art treatment to those who deserve it and may benefit from it.

GUEST EDITOR

Functional, Not Chronologic Age Besides a chronologic measure, how do we determine who is a geriatric cancer patient? Stuart M. Lichtman, MD

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DruG iNtErACtiONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. uSE iN SPECiFiC POPuLAtiONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OvErDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLiNiCAL tOxiCOLOGY Carcinogenesis, Mutagenesis, impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PAtiENt COuNSELiNG iNFOrMAtiON Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

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r. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org). When we see an older patient, the primary question we should be asking is not what the patient’s age is, but what is the patient’s life expectancy and how might treatment affect function and quality of life. There are some very good online tools to help in this assessment process. One, ePrognosis (eprognosis. ucsf.edu), is a tool for estimating the life expectancy of elders. It is easy to use, accurate, and a great help for busy clinicians. I show how ePrognosis works in all my lectures at ASCO meetings. There are several tools that can be used depending upon the status of the patient. The tools require that a few extra questions be asked of the older patient, and then the calculators allow you to get a fairly good picture of your patient’s 5and 10-year life expectancy—which is essential in determining an appropriate treatment program. Our guesses on life expectancy, even by the most seasoned clinician, are notoriously bad. There is also an emerging group of predictive models for chemotherapyrelated toxicity in which you can input clinical and geriatric information and get an idea of the risk of your patient having grade 3 and higher chemotherapy toxicity. Martine Extermann, MD, PhD, has developed a wonderful model called the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH). It is specifically designed to score laboratory test values and geriatric assessment parameters besides age, such as functional and nutritional status, comorbidity, cognition, psychological state, and social support, to predict the risk of severe toxicity from checontinued on page 38

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Geriatrics for the Oncologist Geriatric Oncology

Hyman Muss, MD continued from page 37

motherapy in older patients. A similar model, the Cancer and Aging Research Group (CARG) model, has been developed by Arti Hurria, MD.

More Data Needed on Chemoprevention Is chemoprevention a management tool in geriatric oncology? Chemoprevention in the elderly cancer patient has little clinical application. And there aren’t enough trials in this area to understand what, if any, cancer chemoprevention strategies may benefit the geriatric population. In elderly patients with a life expectancy of 5 years or more, screening for breast and colorectal cancers may have benefit, but we need more information. In terms of chemoprevention, what can we really prevent? For instance, most of the chemoprevention studies with tamoxifen do not show a significant survival benefit, so I think there is no reason to put an older cancer patient on tamoxifen or an aromatase inhibitor, especially considering the side effects. In short, there are no large data sets to prove the benefit of chemoprevention strategies in the elderly, and I certainly wouldn’t go in that direction with my patients. Just like in younger patients, keeping fit and eating a healthy diet is the best advice we can give to prevent cancer and other diseases that increase with aging.

An Educational Opportunity Since community doctors deliver the majority of cancer care, is there a knowledge gap in the busy community setting about managing the more complex needs Geriatrics for the Oncologist is guest edited by Stuart Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Visit SIOG.org for more on geriatric oncology.

of their geriatric patients? I don’t think either academic or community doctors are up to speed with the special assessment and care of geriatric cancer patients. For instance, we looked within our own institution at the University of North Carolina Lineberger Comprehensive Cancer Center at data we collected about patient falls; we found that almost none of the patients who had a history of falls were referred for physical or occupational therapy evalution, even though these interventions in older patients with falls lower morbidity and mortality. This shows that most doctors think that because most cancer patients are older, we intuitively know how to care for them, but at least in this instance, we didn’t deliver the kind of specialized care needed in this more challenging population. There are many educational opportunities for doctors to learn more about their older patients. For instance, ASCO

Not One-Size-Fits-All Treatment Decisions One common misconception about older patients that needs changing is that they should always be spared the rigors of aggressive therapy. This attitude is being proved false, but it may be difficult to convince oncologists, because there are so few clinical trials that include the elderly. What’s your opinion on this? I think the word on the issue of undertreating elderly cancer patients is finally getting out, and both community and academic clinicians are becoming more aware that otherwise healthy older cancer patients deserve state-of-the-art therapies. That said, treating elderly patients, as I’ve mentioned, depends largely on doing thorough and accurate assessments. For instance, the small potential benefit of chemotherapy is usually unwarranted in an 80-year-old patient with a few positive nodes who has hormone receptor–positive cancer. However, a

Just like in younger patients, keeping fit and eating a healthy diet is the best advice we can give to prevent cancer and other diseases that increase with aging. —Hyman Muss, MD

has a terrific series of slides on general geriatric care at ASCO University; there are other equally good websites, and I have a series of slides on geriatric oncology on our Lineberger Comprehensive Cancer Center website that can be downloaded. I am always available to colleagues who want to get hold of this valuable information. But the truth is that clinicians simply don’t have the time for extra educational activity. With all the new demands of electronic medical records, meaningful use, other data collection, and paperwork, who wants to go home after a long day in the clinic and begin studying slides on how to do a geriatric assessment? We need to figure out how to get this information into all training programs and make it part of lifelong learning.

75-year-old woman with triple-negative breast cancer who is in otherwise good shape should be treated with the same state-of-the-art therapies as her younger counterpart. Treatment decisions in the elderly are not one-size-fits-all; it is all about patient-by-patient assessment.

Don’t Overlook Early Dementia Dementia in the elderly patient with cancer is a big challenge. Are we doing a good job meeting that challenge? No. A clinician must do a cognitive function test in the office to identify patients with dementia. I’ve learned that very few doctors do these tests routinely, quite frankly because it is a time-consuming practice, even though a screen can be done in a few minutes. For example, a well-dressed older person who

For more information, visit http://www.siog.org/

is articulate when answering yes-or-no questions frequently may not know what she had for breakfast. Early dementia is frequently overlooked. So, you have to probe, and that takes time, but it’s part of geriatric best practices and worth it.

Defining Value and Quality Any thoughts on how the movement in oncology to value over quantity might affect geriatric oncology, especially in an environment that is growing increasingly sensitive over health-care costs? The terms “value” and “quality” are variable across the whole spectrum of cancer care. If I can define what value is for my patient, and then we’ll determine whether the cost is worth it for one quality-adjusted year of life. Do you think a 75-year-old retired person who has led a productive life has less value as a human being than a 15-yearold who is incarcerated for drugs? The examples are endless, so definitions of value and cost can be fuzzy and unfair. Quality is another tough one. Is it that I follow national treatment guidelines or have free parking?

Closing Thoughts Would you like to share any final thoughts? I am very pleased that so many great cancer organizations are now paying attention to the issues of elderly patients. ASCO, in particular, has been a leader in this field, providing valuable venues for training and education for the oncology community and the younger doctors entering oncology. This is the way forward, which will finally integrate geriatric oncology into our daily practice. n Disclosure: Dr. Muss reported no potential conflicts of interest.

Who will crack the cancer code? Itâ&#x20AC;&#x2122;s the question that millions of people are asking. Pushing us to explore every idea, continually refining our approach, and collaborating with innovators across the globe to explore cancer genomes as never before. Leading us to identify cancer mutations and mechanisms, like PD-1 interactions and EGFR, discoveries that help all of us develop more targeted therapies. Together, we can find solutions to the toughest problems, because the more answers we find, the more lives we save.

Videos, whitepapers and more at DiscoverCareBelieve.org/code.

ÂŠ 2015 Dana-Farber Cancer Institute

The ASCO Post | MARCH 25, 2015

PAGE 40

In the Clinic Hematology

Lenalidomide in Combination With Dexamethasone in Newly Diagnosed Multiple Myeloma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n February 18, 2015, the indication for lenalidomide (Revlimid) in combination with dexamethasone was expanded to include patients with newly diagnosed multiple myeloma.1 Lenalidomide in combination with dexamethasone was previously approved for use in patients with multiple myeloma who had received at least one prior treatment.

Supporting Trial The expanded indication is based on findings in an open-label phase III trial in which 1,623 newly diagnosed patients who were not candidates for stem cell transplant were randomized to receive dexamethasone 40 mg/d (20 mg/d for age > 75 years) on days 1, 8, 15, and 22 of 28-day cycles plus lenalidomide 25 mg/d on days 1 to 21 of 28-day cycles either continuously until progressive disease (continuous group, n = 535) or for up to 18 cycles (18-cycle group, n = 541) or melphalan, prednisone, and thalidomide (MPT, n = 547).1,2 All patients received prophylactic anticoagulation, usually with aspirin. The primary endpoint was progression-free survival. Overall, patients had a median age of 73 years (35% > 75 years); 59% had International Staging System stage I/II and 41% had stage III disease; 9% had severe renal impairment and 23% had moderate renal impairment; and Eastern Cooperative Oncology Group performance status was 0 in 29%, 1 in 49%, and 2 in 21%. Median progression-free survival was significantly longer in the continuous lenalidomide group vs the MPT group (25.5 vs 21.2 months, hazard ratio [HR] = 0.72, P < .0001) as well as vs the 18-cycle lenalidomide group (20.7 months, HR = 0.70, 95% confidence interval [CI] = 0.60–0.82). No difference was observed between the 18-cycle lenalidomide group and the MPT group (HR = 1.03, 95% CI = 0.89–1.20). Overall response rates were 75.1% vs 62.3% and 73.4%. Me-

dian overall survival was 58.9 months with continuous lenalidomide vs 48.5 months with MPT (HR = 0.75, 95% CI = 0.62–0.90) and 56.7 months in the 18-cycle lenalidomide group (HR = 0.91, 95% CI = 0.75–1.09; HR = 0.83, 95% CI = 0.69–0.99, vs MPT).

How It Works Lenalidomide is a thalidomide analog with immunomodulatory, antiangiogenic, and antineoplastic properties. It inhibits cell proliferation; induces apoptosis of certain hematopoietic tumor cells, including mantle cell lymphoma, multiple myeloma, and del (5q) myelodysplastic syndromes in vitro; and delays tumor growth in hematopoietic tumor models, including multiple myeloma. The immunomodulatory properties of the agent include activation of T cells and natural killer (NK) cells, increased numbers of NK T cells, and inhibition of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin 6) by monocytes. The

mide-containing therapy. Starting doses should be 10 mg once daily for moderate renal impairment, 15 mg every 48 hours for severe renal impairment, and 5 mg once daily following dialysis in patients requiring dialysis. Treatment should be interrupted in patients developing grade 3 or 4 thrombocytopenia or neutropenia, and complete blood cell counts should be followed weekly; upon recovery, treatment should be resumed at a lower dose. Treatment should be interrupted for other grade 3 or 4 adverse events and resumed at a lower dose upon resolution to grade ≤ 2.

Safety Profile In the phase III trial in newly diagnosed myeloma, the most common adverse events of any grade in the continuous lenalidomide group included diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), and back pain (32%), and the most common grade 3 or 4 events were neutropenia

Expanded Indication for Lenalidomide in Combination With Dexamethasone ■■ Lenalidomide (Revlimid) in combination with dexamethasone is now indicated in the treatment of patients with newly diagnosed multiple myeloma. ■■ In multiple myeloma, the recommended starting dose of lenalidomide is 25 mg/d on days 1 to 21 of repeated 28-day cycles in combination with dexamethasone.

combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis in multiple myeloma cells.

How It Is Given In multiple myeloma, the recommended starting dose of lenalidomide is 25 mg/d on days 1 to 21 of repeated 28-day cycles in combination with dexamethasone, with treatment continued until disease progression or unacceptable toxicity. In patients who are eligible for autologous stem cell transplantation, hematopoietic stem cell mobilization should occur within 4 cycles of lenalido-

OF NOTE Lenalidomide carries boxed warnings for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.

(28%), anemia (18%), and pneumonia (11%). Infections were observed in 75% of patients in the continuous lenalidomide group vs 56% of patients in the MPT group. In the continuous lenalidomide group, the most common adverse events leading to dose interruption were infections (29%), the most common adverse events leading to dose reduction were hematologic events (11%), and the most common adverse events leading to treatment discontinuation were infections (3.4%). In both lenalidomide groups, the frequency of adverse events was generally highest in the first 6 months of treatment, except with regard to cataracts; the frequency of cataracts increased from 0.7% during the first 6 months of treatment to 9.6% by the second year of treatment with continuous lenalidomide. Lenalidomide carries boxed warn-

OF NOTE Lenalidomide is a thalidomide analog with immunomodulatory, antiangiogenic, and antineoplastic properties. The combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis in multiple myeloma cells.

ings for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism. To avoid embryofetal exposure, lenalidomide is available only through a restricted distribution program, the Revlimid REMSTM program, formerly known as the “RevAssist®” program (information available at www.celgeneriskmanagement.com or 1-888-423-5436). Patients with del (5q) myelodysplastic syndromes should have complete blood cell counts monitored weekly for the first 8 weeks and monthly thereafter. A significantly increased risk of deep vein thrombosis and pulmonary embolism and a risk of myocardial infarction and stroke have been observed in patients with multiple myeloma; antithrombotic prophylaxis is recommended. Lenalidomide also carries warnings/ precautions for serious and fatal cardiac adverse events (observed in patients with chronic lymphocytic leukemia), second primary malignancies, hepatic failure including fatalities, allergic reactions including fatalities, tumor lysis syndrome including fatalities, tumor flare reactions (observed in chronic lymphocytic leukemia and lymphoma), and impaired stem cell mobilization. Lenalidomide is contraindicated during pregnancy and in patients with demonstrated hypersensitivity to the agent. n References 1. Revlimid (lenalidomide) capsules prescribing information, Celgene Corporation, February 2015. Available at http://www.revlimid.com/wp-content/ uploads/2013/11/PI.pdf. Accessed March 3, 2015. 2. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: Lenalidomide and dexamethasone in transplantineligible patients with myeloma. N Engl J Med 371:906-917, 2014.

ASCOPost.com | MARCH 25, 2015

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Announcements

New Lurie Cancer Center Program Combines Oncology With Genomics to Provide More Personalized Cancer Care

he Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in collaboration with the Northwestern Medicine Developmental Therapeutics Institute and Northwestern Memorial Hospital, has launched a new research program, Northwestern Onco-SET (Sequence, Evaluate, Treat). The program’s goal is to provide a more personalized, precision medicine option for cancer patients by combining oncology with genomics. This program will initially focus on patients with any type of cancer that is not responsive to traditional therapies.

Center’s Molecular Tumor Board, which brings together a group of experts to review every tumor’s genomic profile. The board comprises a wide spectrum of cancer specialists, including pathologists;

medical, surgical, and radiation oncologists; cancer geneticists; genome biologists; molecular scientists; bioethicists; and bioinformaticists. By offering cancer patients care

within Onco-SET, the program is also expanding the Lurie Cancer Center’s preclinical research by collecting and analyzing detailed data from each patient’s tumor genomic profiles. n

Molecularly Defined Targets “Northwestern Onco-SET will help establish Chicago as a national and international leader in precision medicine for cancer,” said Leonidas Platanias, MD, PhD, Director of the Lurie Cancer Center. “This is the first time cancer treatment in Chicago will be offered in a

Leonidas Platanias, MD, PhD

comprehensive, multidisciplinary program. Onco-SET will use molecularly defined genomic targets as a basis for determining treatment options, including novel, early-phase clinical trials.” Onco-SET personalizes cancer care for patients by sequencing the individual genetic profile of their tumors and evaluating the results to provide the treatments or clinical trials that will benefit them most. Some of these approaches include site-agnostic, pathway-driven treatments, which use therapies developed to target the specific genetic abnormalities of one type of cancer and apply them to treating a different kind of cancer if it shares the same genetic abnormalities. “As part of our work with Onco-SET, we are also planning to initiate a pilot program of site-agnostic, pathway-driven tumor clinics,” added Dr. Platanias.

Wide Spectrum of Specialists To evaluate and discuss the best treatment options for each patient, Onco-SET created the Lurie Cancer

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The ASCO Post | MARCH 25, 2015

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Inside the Black Box

Development and Approval of Biosimilar Products By Leah Christl, PhD, and Albert Deisseroth, MD, PhD

INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, Leah Christl, PhD, and Albert Deisseroth, MD, PhD, answer questions about biosimilar products. Dr. Christl is the Associate Director for Therapeutic Biologics and the team leader for the Office of New Drugs’ Therapeutic Biologics and Biosimilars Team in the Center for Drug Evaluation and Research. Dr. Deisseroth is a team leader in the Division of Hematologic Products.

he Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of health reform (the Affordable Care Act) and was signed into law on March 23, 2010. The BPCI Act created an abbreviated licensure pathway for biologic products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. The ASCO Post spoke with Drs. Christl and Deisseroth about biosimilars and the BPCI Act.

Understanding Biosimilars First, can you tell us what a biosimilar product is? Dr. Christl: To understand biosimilar products, it is important first to understand how biologic products are defined and regulated. Many of today’s important medications are biologic products, generally derived from a living organism. This material can come from many sources, including humans, animals, microorganisms, or yeast. Biologic products are licensed under the Public Health Service Act (PHS Act), unlike drugs that are approved under the Food, Drug, and Cosmetic Act (FD&C Act). In addition to creating an abbreviated pathway for licensure of biosimilar biologic products, the BPCI Act revised the definition of “biologic product” to include proteins, except for chemically synthesized polypeptides. The term “biologic product” is defined under the PHS Act as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or

derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product … applicable to the prevention, treatment, or cure of a disease or condition of human beings.…” Historically, some proteins, such as human growth hormone, have been approved as drugs under the FD&C Act, whereas other proteins, such as blood factors, have been licensed as biologics under the PHS Act.

What is the abbreviated license pathway for biologic products? Dr. Christl: A biologic product that is demonstrated to be “biosimilar” to the reference product may rely for licensure on, among other things, publicly available information regarding FDA’s previous determination that the reference product is safe, pure, and potent. This licensure pathway under section 351(k) of the PHS Act permits a biosimilar biologic product to be licensed based on less than a full complement of product-specific preclinical and clinical data. Can you clarify the differences between “stand-alone” and biosimilar product development? Dr. Christl: As previously noted, the reference product is the single biologic product licensed under the PHS Act against which a biosimilar is evaluated. The reference product is licensed by FDA under section 351(a) of the PHS Act based on a full complement of product-specific preclinical and clinical data. The reference product can be con-

There is no single study that will demonstrate biosimilarity. That is why FDA recommends a stepwise approach to data generation and evaluation of residual uncertainty at each step. —Leah Christl, PhD

A biosimilar is a biologic product that is highly similar to an FDAlicensed reference product, notwithstanding minor differences in clinically inactive components, and has no clinically meaningful differences in terms of safety, purity, and potency (ie, safety and effectiveness) from the reference product. The term “reference product” here refers to the single biologic product licensed under the PHS Act against which a biosimilar is evaluated. A biosimilar product can only be licensed if it has the same mechanism(s) of action, route of administration, dosage form, and strength as the reference biologic product and only for the indications and condition(s) of use that have been approved for the reference biologic product.

sidered a “stand-alone” application. The goal of “stand-alone” development is to independently demonstrate that the product is safe and effective for the intended conditions of use, and drug development starts with preclinical research and progresses through phase I, II, and III trials. The goal of biosimilar development is to demonstrate biosimilarity between the proposed product and a reference product and not to independently establish the safety and effectiveness of the proposed product. What is required to demonstrate biosimilarity? Dr. Christl: The PHS Act requires that a 351(k) application include information demonstrating biosimilarity based upon data derived from (1)

FDA Clinical Reviewers

Leah Christl, PhD

Albert Deisseroth, MD, PhD

analytic studies demonstrating that the biologic product is “highly similar” to the reference product, notwithstanding minor differences in clinically inactive components; (2) animal studies (including the assessment of toxicity); and (3) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product. FDA may determine, in its discretion, that an element described above is unnecessary in a 351(k) application. FDA has articulated in guidance to industry that it will use a totality of the evidence approach to review applications for biosimilar products, consistent with a longstanding Agency approach to evaluation of scientific evidence. What is analytic similarity? Dr. Christl: Analytic similarity studies generate data to characterize the reference product variability and product quality characteristics, characterize

ASCOPost.com | MARCH 25, 2015

PAGE 43

Inside the Black Box the proposed biosimilar product quality characteristics and variability, and identify and evaluate the potential impact of observed differences between the proposed biosimilar product and the reference product. The sponsor must demonstrate that the products are highly similar. The potential effect of differences on safety, purity, and potency should be addressed and supported by appropriate data. Analytic similarity data are the foundation of a biosimilar development program and provide the necessary extensive structural and functional characterization of the molecule (critical quality attributes and clinically active components and the impact of manufacturing changes that occur during product development) and an understanding of the relationship between quality attributes and the clinical safety and efficacy profile. This aids in determining the residual uncertainty about biosimilarity and in predicting expected clinical similarity.

Role of Clinical Studies What clinical studies are expected? Dr. Christl: As a scientific matter, FDA expects an adequate clinical pharmacokinetic and pharmacodynamic (if relevant, eg, the endpoint reflects the biologic effect(s) of the product) comparison between the proposed biosimilar product and the reference product. Also, as a scientific matter, at least one clinical study that includes a comparison of the immunogenicity of the proposed and reference product generally will be expected. A comparative clinical study will be necessary to support demonstration of biosimilarity if there are residual uncertainties about whether there are clinically meaningful differences between the proposed and reference products based on structural and functional characterization, animal testing, human pharmacokinetic and pharmacodynamic data, and clinical immunogenicity assessment. Can you tell us more about the clinical studies that may be necessary? Dr. Christl: If analytic differences have been observed, then any clinical study should be designed to best evaluate their potential impact. A comparative clinical pharmacokinetic study is generally expected, and pharmacodynamic data are desirable on a case-by-case basis. The goal is to demonstrate similarity by assessing whether there are clinically meaningful differences in pharmacokinetics

(and pharmacodynamics) between the proposed biosimilar and the reference product. The assumption is that similar exposure (and pharmacodynamic response) will provide similar efficacy and safety (ie, an exposure-response relationship exists). Depending on the product, the study may be conducted in healthy volunteers or patients. A comparative clinical study for a biosimilar development program should be designed to investigate whether there are clinically meaningful differences between the proposed product and the reference product. Important determinants of the study design can include the complexity of the product; limitations of analytic testing; the extent of knowledge about critical quality attributes; the degree of understanding of the mechanism of action of the reference product; the extent of knowledge about how differences in analytic, animal, and clinical pharmacokinetics or pharmacodynamics predict differences in clinical outcome; and the sensitivity of the study design (eg, population, dose, endpoint[s]). An adequate scientific justification must be provided for the choice of study design, study population, study endpoint(s), estimated effect size for the reference product, and study margin(s). The potential exists for a biosimilar product to be approved for one or more conditions of use for which the U.S.-licensed reference product is licensed based on extrapolation of clinical data intended to demonstrate biosimilarity in one condition of use. Sufficient scientific justification for extrapolation is necessary. You mentioned a “totality-of-theevidence” approach. Can you elaborate further? Dr. Christl: There is no single study that will demonstrate biosimilarity. That is why FDA recommends a stepwise approach to data generation and evaluation of residual uncertainty at each step. If analytic differences are observed, their potential impact(s) should be evaluated before proceeding to the next step in development. For example, the results of analytic studies would provide information on the animal studies that would be warranted as the next step in evaluating residual uncertainty, and the results of the analytic and animal studies would provide information needed for the design of clinical pharmacokinetic and pharmacodynamics studies and the clinical immunogenicity assessment. All of these data together would be

used to determine the residual uncertainty about the biosimilarity of the two products and the type of additional clinical data that would be needed.

GUEST EDITOR

First Biosimilar Marketing Application FDA held a meeting of the Oncology Drug Advisory Committee (ODAC) on January 7, 2015, which was the first biosimilar marketing application discussed at a public advisory committee meeting. Could you summarize what kind of molecule was under review and its history? Dr. Deisseroth: Sandoz submitted a 351(k) biologics license application requesting licensure of a granulocyte colony-stimulating factor (G-CSF) product, referred to during development as EP2006, as a biosimilar to U.S.-licensed filgrastim (Neupogen). Filgrastim is an analog of G-CSF, a hematopoietic growth factor that induces proliferation and differentiation of neutrophil-committed progenitor cells into neutrophils. Filgrastim also induces the release of neutrophils as well as CD34-positive hematopoietic progenitor cells from the marrow into the peripheral blood. Filgrastim is made up of 175 amino acids without glycosylation, so, from a molecular perspective, this product may be one of the easier ones to replicate in terms of manufacturing. In its application, Sandoz requested that EP2006 be designated as a biosimilar to filgrastim for all of its five currently approved indications; they include decreasing the incidence of infections in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs; reducing the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation; reducing the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia; mobilizing hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leuekmia. Since 2009, Sandoz has marketed Zarzio, a European Union (EU)–approved biosimilar product to EU-approved filgrastim. Marketing experience with biosimilar filgrastim outside of the United States includes in excess of 7.5 million days of patient exposure.

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.

What did Sandoz present at the advisory committee meeting, and what was the reaction of FDA to this presentation? Dr. Deisseroth: The foundation of biosimilar applications and a key hurdle to surmount is whether the biosimilar product is “highly similar” to the reference product from an analytic perspective. FDA agreed with the conclusions of Sandoz that EP2006 is “highly s imilar” to U.S.-licensed filgrastim based on its extensive studies of the physicochemical and functional properties of the two products. FDA also agreed with Sandoz’s conclusion that its nonclinical studies supported a demonstration of biosimilarity of its product, EP2006, to U.S.-licensed filgrastim. Sandoz then summarized its extensive clinical pharmacokinetic and pharmacodynamic studies in normal human subjects comparing biosimilar filgrastim with both U.S.-licensed filgrastim and EU-approved filgrastim at a wide range of doses. It is important to note that it was necessary for Sandoz to build a scientific bridge between biosimilar filgrastim, EU-approved filgrastim, and U.S.-licensed filgrastim to justify the relevance of the data generated using EU-approved filgrastim as part of the basis demonstrating biosimilarity to U.S.-licensed filgrastim. Sandoz also summarized immunogenicity and safety evaluations, which had been carried out in normal human subjects and in patients with breast cancer. FDA agreed with Sandoz that these studies did not show any clinically meaningful differences between the products, which is the second criterion for demonstrating biosimilarity of two products. Finally, Sandoz presented safety, efficacy, and immunogenicity data from a continued on page 44

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The ASCO Post | MARCH 25, 2015

Inside the Black Box Biosimilar Products

fda.gov/Drugs/GuidanceCompliancontinued from page 43 ceRegulatoryInformation/Guidances/ comparative clinical study that random- ucm290967.htm) should be used. FDA ized patients with breast cancer receiv- scientists are available to meet with ing chemotherapy between biosimilar companies at each step of development filgrastim and U.S.-licensed filgrastim to and when an application is submitsupport its conclusion that there were ted to evaluate the applicant’s integrano clinically meaningful differences tion of various types of information between biosimilar filgrastim and U.S.- to determine whether the applicant’s licensed filgrastim. FDA commented that although it agreed with Sandoz’s conclusions, a sponsor generally will not need to conduct a comparative clinical study to evaluate efficacy and safety to support demonstration of biosimilarity unless there are residual uncertainties from the analytic, animal, and/or clinical pharmacokinetic and pharmacodynamic studies that need to be evaluated further. The final issue addressed by the advisory committee was whether biosimilar filgrastim should be licensed for all of the five indications for which filgrastim is currently approved. FDA recommended that biosimilar filgrastim be licensed for all five of the filgrastim indications due to the common mechanism of action for all of these indications and the totality of the evidence presented by Sandoz. The advisory committee voted unanimously that biosimilar filgrastim should receive licensure as a biosimilar to U.S.-licensed filgrastim for all of the indications for which filgrastim is currently approved.

Final Comments What are your final comments about biosimilar development? Dr. Christl: There is no “one-sizefits-all” development plan for a biosimilar. The principles discussed herein and as outlined in FDA guidances (www.

Did You Know? Sales of herbal products reached $6 billion in 2013. See page 76 for more on increasing problems in herbal supplements.

product is biosimilar to the reference product. Additional information can be found at www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. Note: On March 6, 2015, subse-

quent to this interview, FDA licensed the product discussed in this article as Zarxio (filgrastim-sndz), a biosimilar to U.S.-licensed filgrastim. More information about the approval of this biosimilar can be found at www.ascopost.com/ ViewNews.aspx?nid=23634. n Disclosure: Drs. Christl and Deisseroth reported no potential conflicts of interest.

BLEED TRIM:

LIVE: 1

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Announcements

FDA Names Geoffrey Kim, MD, Director of the Division of Oncology Products

D: 15.4” 15.15”

14.15”

he U.S. Food and Drug Administration (FDA) recently announced the appointment of Geoffrey Kim, MD, as Director of the Division of Oncology Products 1 (DOP1) in the Office of Hematology Oncology Products. Dr. Kim assumed this posi-

tion effective March 22, 2015. Dr. Kim previously served as the Acting Deputy Director in Division of Oncology Products 1. He was involved with numerous cross-center working groups, developing policies pertaining to in-vitro companion diagnostics,

combination products, and dose finding optimization strategies for oncology products. Dr. Kim is also the gynecologic malignancies scientific liaison for Office of Hematology Oncology Products, and he is active with outreach to the ovarian

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cancer community through the Society for Gynecologic Oncologists, Gynecologic Oncology Group, and the Ovarian Cancer National Alliance. Dr. Kim began working at the FDA in 2010 as a Medical Officer in Division of Oncology Products 1. He received his bachelor’s degree at UCLA, his medical degree at the New York Medical College, and completed his residency in internal medicine at the Montefiore Medical Center. He performed laboratory research at these institutions with a particular focus on cell adhesion molecules and cellular signaling. Dr. Kim completed his medical oncology fellowship at the National Cancer Institute (NCI) where he was active in both laboratory and clinical research in the NCI molecular signaling section and the ovarian cancer clinic. Amna Ibrahim, MD, served as Acting Division Director of Division of Oncology Products 1 during the transition period. Dr. Ibrahim will assume her previous role as the Deputy Division Director of Division of Oncology Products 1. n

Contact

The ASCO Post BLEED: 10.825”

LIVE: 9.575”

TRIM: 10.575”

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

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The ASCO Post | MARCH 25, 2015

PAGE 46

In the Clinic Hematology

Panobinostat in Combination With Bortezomib-Dexamethasone in Previously Treated Multiple Myeloma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n February 23, 2015, panobinostat (Farydak) was granted accelerated approval for use in combination with bortezomib (Velcade) and dexamethasone in the treatment of patients with multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.1,2 As a condition of accelerated approval, the sponsor is required to conduct a trial to verify and describe the clinical benefit of panobinostat in patients with multiple myeloma.

Supporting Study Approval was based on outcomes in a double-blind phase III trial in which 758 patients with relapsed multiple myeloma received oral panobinostat or placebo in combination with bortezomib and dexamethasone.2,3 Data supporting efficacy in the current indication were from a prespecified subgroup analysis of progression-free survival involving 193 patients (94 in the panobinostat group and 99 in the control group) who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of two prior therapies. In this subgroup, the median age was 60 years (range, 28– 79 years), and 76% had received at least two previous lines of treatment. In the subgroup analysis, median progression-free survival was 10.6 months (95% confidence interval [CI] = 7.6–13.8 months) in the panobinostat group vs 5.8 months (95% CI = 4.4–7.1 months) in the control group (hazard ratio = 0.52, 95% CI = 0.36–0.76). Objective response rates were 58.5% vs 41.4%, including complete response in 8.5% vs 2.0% and near-complete response in 13.8% vs 7.1%.

How It Works Panobinostat is a histone deacetylase (HDAC) inhibitor. These enzymes catalyze the removal of acetyl groups from lysine residues of histones and some nonhistone proteins. Inhibition of HDAC enzymatic activity results in increased acetylation of histone proteins, an epigenetic alteration that results in relaxing

of chromatin and leads to transcriptional activation. In in vitro studies, panobinostat resulted in accumulation of acetylated histones and other proteins and induced cell-cycle arrest or apoptosis of some transformed cells. Panobinostat treatment resulted in increased levels of acetylated histones in mouse xenografts and exhibited greater cytotoxicity in tumor cells vs normal cells.

How It Is Given The recommended starting dose of panobinostat is 20 mg once every other day for three doses per week in weeks 1 and 2 of each 21-day cycle for up to 8 cycles. In patients with clinical benefit who do not have unresolved severe or medically significant toxicity, continuation of treatment for an additional 8 cycles should be considered (total duration of 16 cycles over 48 weeks). The recommended dose of bortezomib is 1.3 mg/m2, and the recommended dose of dexamethasone is 20 mg. In cycles 1 through 8, the 21-day cycle consists of panobinostat on days 1, 3, and 5; bortezomib on days 1 and 4; and dexamethasone on days 1, 2, 4, and 5 of weeks 1 and 2, with no treatment during week 3. In cycles 9 through 16, the 21-day cycle consists of panobinostat on days 1, 3, and 5; bortezomib on day 1; and dexamethasone on days 1 and 2 of weeks 1 and 2, with no treatment during week 3. Dose reduction of panobinostat for toxicity should occur in 5-mg increments; if a reduction to less than 10 mg three times per week is required, panobinostat should be discontinued. Panobinostat labeling provides specific instructions for dose modification for panobinostat and bortezomib for thrombocytopenia, neutropenia, and diarrhea and for panobinostat for anemia and nausea/vomiting. The starting dose of panobinostat should be reduced to 15 mg in patients with mild hepatic impairment and to 10 mg in those with moderate hepatic impairment; panobinostat should be

avoided in patients with severe hepatic impairment. The starting dose of panobinostat should be reduced to 10 mg when it is coadministered with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, and lopinavir-ritonavir).

Safety Profile In the total population of the phase III trial, the most common adverse events of any grade occurring at an incidence of at least 5% higher in the panobinostat vs control groups were diarrhea (68% vs 42%), fatigue (60% vs 42%), and nausea (36% vs 21%), and the most common grade 3 or 4 adverse events were diarrhea (25% vs 8%), fatigue (25% vs 12%), vomiting (7% vs 1%), and nausea (6% vs 1%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (67% vs 31%), lymphopenia (53% vs 40%), neutropenia (34% vs 11%), leukopenia (23% vs 8%), hypophosphatemia (20% vs 12%), anemia (18% vs 19%), hypokalemia (18% vs 7%), and hyponatremia (13% vs 7%). Serious adverse events occurred in 60% vs 42%, with the most frequent in the panobinostat group being pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Adverse events led to discontinuation of panobinostat in 36% of patients, with the most common causes being diarrhea, fatigue, and pneumonia. Electrocardiographic changes, including new T-wave changes and STsegment depression, occurred in 64% vs 42% of patients, with arrhythmia occurring in 12% vs 5%. The incidence of death not due to progressive disease was 7% vs 3.2%. Panobinostat carries boxed warnings for severe diarrhea and severe and fatal cardiac ischemic events, severe arrhythmia, and electrocardiographic changes. It also carries warnings/precautions for hemorrhage, including fatal and serious gastrointestinal and pulmonary hemorrhage, hepatotoxicity, and embryo-fetal toxicity. Monitoring should include complete

Panobinostat in Previously Treated Multiple Myeloma ■■ Panobinostat (Farydak) was granted accelerated approval for use in combination with bortezomib (Velcade) and dexamethasone in the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. ■■ The recommended starting dose of panobinostat is 20 mg once every other day for three doses per week in weeks 1 and 2 of each 21-day cycle for up to 8 cycles.

OF NOTE Panobinostat carries boxed warnings for severe diarrhea and severe and fatal cardiac ischemic events, severe arrhythmia, and electrocardiographic changes.

blood cell count; electrocardiography; measurement of serum electrolytes, including potassium and magnesium; and liver function tests prior to and during therapy. Prior to treatment, the platelet count should be ≥ 100 × 109/L, and the neutrophil count should be ≥ 1.5 × 109/L. Patients should receive transfusion for low platelet counts as needed. Complete blood cell count should be monitored weekly or more often as clinically indicated. QT correction formula Fridericia (QTcF) should be < 450 msec prior to initiation of treatment; treatment should be interrupted for QTcF increases to ≥ 480 msec, with electrolyte abnormalities being corrected. Treatment should be permanently discontinued if QT prolongation does not resolve. In the phase III trial, electrocardiography was performed at baseline and prior to initiation of each cycle for the first 8 cycles. Abnormal electrolyte values should be corrected before treatment. In the phase III trial, electrolyte monitoring was performed prior to the start of each cycle, at day 11 of cycles 1 through 8, and at the start of each cycle for cycles 9 through 16. The panobinostat dose should be adjusted if abnormal liver function tests are observed. Women should be advised of potential hazard to the fetus and to avoid pregnancy while taking panobinostat. n References 1. U.S. Food and Drug Administration: Approved drugs. Panobinostat. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm435339. htm. Accessed March 4, 2015. 2. Farydak (panobinostat) capsules prescribing information, Novartis Pharmaceuticals, February 2015. Available at http:// www.accessdata.fda.gov/drugsatfda_docs/ label/2015/205353s000lbl.pdf. Accessed March 4, 2015. 3. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Lancet Oncol 15:1195-1206, 2014.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

All Grades (%)

Grades 3–4 (%)

SELECTED SAFETY INFORMATION

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | MARCH 25, 2015

PAGE 47

Direct From ASCO

2015 Pre–Annual Meeting Seminars Feature Important Topics for Modern Cancer Care Providers

SCO will once again be offering a series of Pre–Annual Meeting Seminars ahead of its 2015 Annual Meeting in Chicago. First offered in 2012, the Pre–Annual Meeting Seminars are a series of in-depth educational opportunities dedicated to topics of interest in the oncology community.

planning committees select faculty and finalize the programs. The 2015 program will feature two new seminar topics: “Faculty Development for Medical Educators: Advancing My Career and Teaching Repertoire” and “The Economics of Cancer Care.” In addition, three of the popular topics fea-

With the new Pre–Annual Meeting Seminars, [ASCO] now begins its own journey as a national leader in medical education professional development. —Jill Gilbert, MD

The seminars are conveniently scheduled ahead of the Annual Meeting in Chicago for attendees looking to maximize their learning and networking opportunities. All seminars are held onsite at McCormick Place in Chicago from 12:30 PM on Thursday, May 28, until 11:00 AM on Friday, May 29. Each year, ASCO members and volunteers propose topics for the Pre– Annual Meeting Seminars, which are then reviewed and discussed by ASCO leadership. Once the topics are selected,

tured at the 2014 Pre–Annual Meeting Seminars are returning in 2015: “New Drugs in Oncology,” “Genetics and Genomics for the Practicing Clinician,” and “Hematology for the Oncologist,” which is cosponsored by the American Society of Hematology (ASH).

Faculty Development for Medical Educators The first new seminar added to the 2015 Pre–Annual Meeting Seminars is “Faculty Development for Medical Edu-

cators: Advancing My Career and Teaching Repertoire.” This seminar will feature an interactive workshop discussing personal career development, the challenges and opportunities for medical educators, development of strong educational portfolios, and how to maximize the use of technology for teaching. “Traditionally, the focus of professional development within oncology has centered on the development of the clinical or laboratory-based investigator,” said seminar Co-Chair Jill Gilbert, MD, Associate Professor of Medicine and Director of the Hematology/Oncology Fellowship Program at the Vanderbilt University School of Medicine. “However, ASCO recognizes that we are entering a new era of medical education—a renaissance of sorts—and that landmark changes in the health-care landscape demand that established providers and trainees are prepared to take on the challenges of delivering high-quality, compassionate care, with attention to fiscal responsibility and patient involvement.” In this changing environment, it is anticipated that medical educators will serve as the catalyst for such change both on an institutional and a national professional organization level. “ASCO recognizes the current gap in development opportunities for the

medical educator, and with the Pre– Annual Meeting Seminars, now begins its own journey as a national leader in medical education professional development,” Dr. Gilbert said. “As session Co-Chair, I strongly encourage medical educators at all stages of their careers to take advantage of this first-of-its-kind, exciting opportunity.”

The Economics of Cancer Care The second new 2015 seminar will discuss the dramatically shifting landscape of financing and organization in cancer care. ASCO recognizes that many stakeholders, including cancer care providers, are likely affected by the rapid pace of change occurring in reimbursement models, treatment pathways, and how best to provide quality care. “The Economics of Cancer Care” will provide participants sufficient background knowledge to make betterinformed decisions in their relations with patients and payers. This seminar will cover current and innovative strategies for rewarding research and development in cancer therapeutics and diagnostics, trends in trial costs, drug pricing, financial burdens placed on patients, the basics of reimbursement and coverage decision-making, lessons from innovative reimbursecontinued on page 49

ASCO Supports FDA’s Proposed Regulation of Laboratory Developed Tests

FDA Takes Steps to Simplify Compassionate Use Process, Invites Comment

n comments submitted to the U.S. Food and Drug Administration (FDA), ASCO expressed its support for the agency’s draft guidance, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs).” ASCO also strongly recommends that the agency proceed with regulatory authority in a way that helps ensure ongoing innovation in the field of molecular testing, as well as timely patient access to validated molecular diagnostics that help improve use of precision medicine. Increasingly, multiplex genomic and proteomic tests are being used to guide therapy selection for people with cancer.

“ASCO believes that the tests used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients,” ASCO President Peter Paul Yu, MD, FACP, FASCO, wrote. “Our patients depend on highquality tests as much as they depend on carefully studied, safe, and effective drugs to achieve the best possible outcomes.” Read the FDA’s draft guidance on LDT regulation at www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM416685.pdf. n

he U.S. Food and Drug Administration (FDA) introduced a more streamlined form for requesting permission for patient access to investigational drugs outside of clinical trials. The new form is available for comment in a draft guidance for industry entitled “Individual Patient Expanded Access Applications: Form FDA 3926.” This draft guidance introduces and describes draft Form FDA 3926: Individual Patient Expanded AccessInvestigational New Drug Application (IND). When finalized, the form will be available for physicians to use for expanded access requests for indi-

vidual patient INDs. In a post on the FDA Voice Blog, Peter Lurie, MD, MPH, Associate FDA Commissioner for Public Health Strategy and Analysis, wrote that the agency developed the new form in response to concerns from physicians and patients that the current form was too difficult. It required 26 types of information and seven attachments, taking physicians about 100 hours to fill out. The new form requires only eight elements of information and a single attachment, and should take physicians about 45 minutes to complete. n

The ASCO Post | MARCH 25, 2015

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Direct From ASCO

Beating the Odds in The Big Casino

ore than 35 ASCO members contributed personal essays to a recently published collection of stories about humanism in medicine, including ASCO Past Presidents Paul A. Bunn, Jr, MD, FASCO, and Emil J. Freireich, MD, FASCO, and current President-Elect Julie M. Vose, MD, MBA, FASCO. The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories is a collaboration between Stanley H. Winokur, MD, Medical Director of Axess Oncology and ASCO member, and Vincent Coppola, a journalist and author who was diagnosed with cancer in 2012. In the interview that follows, Dr. Winokur discusses the book’s contributors, themes, and his own essays. “Young doctors, especially, are going to be inspired by the stories in the book,”

he said. “The authors are their mentors, their heroes, being completely real.”

Young doctors, especially, are going to be inspired by the stories in the book. The authors are their mentors, their heroes, being completely real.

Humanizing Physicians The author list is impressive. Were you surprised by the response when you asked for contributors? The doctors who answered the call are some of the busiest doctors in the world. And without fail, they all responded that they were grateful for the opportunity. I believe there are hundreds more doctors who would have contributed. It’s therapeutic to share these stories. I’m looking at creating a website where people can continue to submit their stories as a vehicle to share the gifts we’ve been given. What guidance did you give to the authors for their contributions?

—Stanley H. Winokur, MD

I personally talked with every author I invited, and I said, “You’re a rock star in the world of medicine. Everyone knows who you are as a scientist and a clinician. I’d like you to write about who you are as a human being.” Patients talk about how grateful they are to their doctors. This book is about our gratitude for our patients, and the precious

gifts they’ve given us—gifts of courage, strength, hope, humor, determination, and joy. So the question I asked the authors was, “What have you gotten from your patients?”

Humor and Hope You contributed two stories to the continued on page 50

Helping Patients Understand Palliative Care

he booklet Palliative Care: Improving Quality of Life for Patients and Families is one of the latest additions to the ASCO Answers collection of patient education materials developed by ASCO for people with cancer and their caregivers. These materials provide oncologist-approved information in a conversational tone, to give patients and their caregivers the tools and resources

they need to become active participants in their cancer care. In the Palliative Care booklet, patients and their families learn about this specialized area of medicine and how it differs from hospice care. It explains that palliative care is more than receiving a drug to ease physical symptoms, but rather, involves supporting a patient’s physical, social,

spiritual, and emotional health, from diagnosis into recovery. Additionally, patients and caregivers can find a list of questions to ask the health-care team, a list of national organizations that can provide additional information and support, and a dictionary of terms related to palliative care that they might hear during diagnosis, treatment, and recovery.

Talking about palliative care soon after a cancer diagnosis helps patients better understand their prognosis and goals of treatment, clarifies their expectations, and helps them maintain the best quality of life. By using this booklet, patients and their families are better able to talk with members of their health-care team about their concerns, continued on page 49

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

ASCOPost.com | MARCH 25, 2015

PAGE 49

Direct From ASCO Pre–Annual Meeting Seminars continued from page 47

ment, coverage and treatment models, options for reimbursement reform, and quality in the outpatient setting.

New Drugs in Oncology Returning in 2015 is the seminar “New Drugs in Oncology.” This seminar’s focus will be the theoretical and

George Sledge, MD, FASCO

practical aspects of both recently approved drugs and those on their way to approval, including information on mechanisms of action, administration, toxicity, side effect management, and use in the clinic. The seminar will be co-chaired by George Sledge, MD, FASCO, Professor of Medicine at the Stanford University Medical Center, and Anthony Tolcher, MD, Director of Clinical Research at South Texas Accelerated Research Therapeutics.

Genetics and Genomics for the Practicing Clinician Another of the returning seminars is “Genetics and Genomics for the Practicing Clinician.” Oncology is benefiting from revolutionary advances in DNA-sequencing technology and genomic analysis, and, as a result, the field is changing very rapidly, according to seminar Co-Chair, Michael F. Berger, PhD, Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center.

Tumor genomic profiling is now routinely performed in academic and— increasingly—community settings. “This practice can provide important diagnostic and prognostic information and enable the selection of therapies tailored to a patient’s molecular profile,” Dr. Berger said. “However, it can also reveal unexpected inherited susceptibilities to cancer and other diseases, with major consequences for patients and their families.” Practicing oncologists and other cancer providers must work to understand the variety of tests available, when they should be administered, and what to consider when interpreting the results. This Pre–Annual Meeting Seminar will cover both tumor and inherited genetic variation, as well as explain the variety of tests available to the clinician and when they should be administered. “We’ve put together a really exciting program covering both tumor and germline analysis, focusing on case studies illustrative of scenarios frequently encountered by clinicians,” Dr. Berger said.

practice, such as the etiology and treatment of disorders of red cells or platelets, myeloproliferative syndromes,

Gary I. Cohen, MD

clotting disorders, and more. “As oncologists in general practice, we have worked diligently with our ASH colleagues to provide current updates on both the common and complex hematologic problems encountered in a typical oncology consultative

Volume 7, Issue 3

May 2011

Journal of oncology Practice

Anyone interested in attending the Pre–Annual Meeting Seminars can register at the ASCO Annual Meeting Registration Site. Registration includes a boxed lunch on Thursday and a continental breakfast on Friday. If registered on or before April 22, 2015, registration is $100 for ASCO members and $200 for nonmembers. These live activities have been approved for AMA PRA Category 1 Credit™. n © 2015. American Society of Clinical Oncology. All rights reserved.

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

The Authoritative Resource for Oncology Practices

Hematology for the Oncologist In 2014, ASCO teamed up with ASH to offer a seminar titled, “Hematology for the Oncologist,” and this popular seminar has been brought back for the 2015 Pre–Annual Meeting Seminars. “Medical oncologists are constantly being asked to consult on benign hematology issues, whether or not they have done additional formal training in hematology,” said seminar Co-Chair Gary I. Cohen, MD, Director of the Sandra and Malcolm Berman Cancer Institute at the Greater Baltimore Medical Center and Associate Professor of Oncology at Johns Hopkins School of Medicine. For that reason, this cosponsored seminar will focus on hematologic issues that medical oncologists commonly encounter in a consultative

practice,” Dr. Cohen said. “I encourage attendance by all oncologists to get a better understanding of these critical clinical care issues that we all face in everyday practice.”

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer by Chau Dang, et al Duration of Androgen Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Oncology Group Randomized Clinical Trial 9910 by Thomas M. Pisansky, et al Relationship Between Male Pattern Baldness and the Risk of

Palliative Care Booklet continued from page 48

and work with them to manage the challenges that come with cancer. The new Palliative Care booklet can be purchased in packs of 125 from the ASCO University Bookstore at cancer.net/estore. ASCO members receive a 20% discount, and all patient education materials ship for free. It is also available to download at cancer.net/palliativecare. For more information on quality-oflife issues, your patients can also turn

to Cancer.Net’s symptom management resources. At cancer.net/sideeffects, patients can find articles on more than 45 side effects of cancer and cancer treatments. These articles explain symptoms that should be reported to their health-care team and how each side effect can be managed. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Helping Patients Understand Palliative Care.” ASCO Connection, January 2015: 35. All rights reserved.

Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial by Cindy Ke Zhou, et al Reproducible and Sustained Efficacy of Targeted Therapy With Vemurafenib in Patients With BRAF V600E-Mutated ErdheimChester Disease by Julien Haroche, et al Risk of Marrow Neoplasms After Adjuvant Breast Cancer Therapy: The National Comprehensive Cancer Network Experience by Antonio C. Wolff, et al

The ASCO Post | MARCH 25, 2015

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Direct From ASCO The Big Casino continued from page 48

book. The first, “How to Tell Patients They Have Cancer,” demonstrates a sense of gallows humor. Is that an essential trait when working in oncology? Yes, absolutely. That story happened when I was in medical school, about 40 years ago, and it shows the intense fear that doctors had of being real. We talked about “neoplasms” and “lesions” because we didn’t know how to tell patients that they had cancer. We didn’t want to use that word. It was our armor, to avoid telling patients they might die. There was a dark humor in the way we discussed it. That dark humor exists today in other ways. As doctors, we very rarely share those kinds of stories with the public because we don’t want to be seen as minimizing someone’s suffering or to be perceived as insincere. The humor is really about our own fear. If readers take away only one message from the book, what do you hope they understand? Hope is a precious gift. We should never say to our patients, “There’s nothing else I can do for you.” There might not be any more drugs or therapies we can give them, but we can give them our compassion and our gratitude. We can stand next to them

ASCO’s Patient Resources for Colorectal Cancer Awareness Month

tock your practice with Cancer. Net resources. Cancer.Net has a comprehensive guide to colorectal cancer at www.cancer.net/colorectal and a shorter, one-page colorectal cancer fact sheet. You will also find specialized resources for survivorship, palliative care, and managing the cost of cancer care. Copies can be purchased from the ASCO University Bookstore at cancer.net/ eStore. Shipping is free, and ASCO members save 20%. n

and hold their hands. There is always something we can do. Dr. Winokur’s hope is that every oncologist and patient will have the opportunity to read The Big Casino. The book is being sold at cost, and no editor or contributor is profiting from its sales. Print and ebook edi-

tions are available on Amazon.com; visit thebigcasino.org for a full list of contributors and information about discounted bulk orders for your training program, cancer center, or practice. n Originally printed in ASCO Connection. © American Society of Clinical Oncology.

“Beating the Odds in The Big Casino.” ASCO Connection, January 2015: 32-34. All rights reserved. See page 86 to read an excerpt from The Big Casino, or visit http://bit.ly/1wk9nsm for past essays published in The ASCO Post.

NOW APPROVED

LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Visit LENVIMAinfo.com Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction. Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

ASCOPost.com | MARCH 25, 2015

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Announcements Health-Care Policy

New Oncology Care Model: Encouraging Better Coordination for Cancer Care

n February 12, 2015, the U.S. Department of Health and Human Services (HHS) announced its new Oncology Care Model, a multipayer payment and care delivery model intended to support better coordination for cancer care. The initiative will

include 24-hour access to practitioners for beneficiaries undergoing cancer treatment and is based on coordinated, person-centered care, aimed at rewarding value of care, rather than volume. “Based on feedback from the medical, consumer, and business communi-

ties, we are launching this new model of care to support clinicians’ work with their patients,” said Patrick Conway, MD, Centers for Medicare & Medicaid Services (CMS) Chief Medical Officer and Deputy Administrator for Innovation and Quality. “We aim to provide

Events of renal impairment were reported in 14% of LENVIMA-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed. LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%). Please see Brief Summary of Prescribing Information on the following pages. LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0185

Medicare beneficiaries struggling with cancer with high-quality care around the clock and to reward doctors for the value, not volume, of care they provide.” As part of the Department’s approach to improving health delivery, the Oncolcontinued on page 52

The ASCO Post | MARCH 25, 2015

PAGE 52

Announcements Oncology Care Model

that a new way of paying for and delivering oncology care is needed. This model will invest in physician-led practices, allowing the practices to innovate and deliver higher-quality care to their patients.

continued from page 51

ogy Care Model is one of many innovative payment and care delivery models developed by the CMS Innovation Center and advanced by the Affordable Care Act. The model was created in response to feedback from the oncology community, patient advocates, and the private sector

A Closer Look at the Model Patrick Conway, MD

The model focuses on three key areas: (1) linking payment to quality of

care, (2) improving and innovating in care delivery, and (3) sharing information more broadly to providers, consumers, and others to support better decisions while maintaining privacy. The Oncology Care Model encourages participating practices to improve care and lower costs through episode-based, performance-based payments that finan-

T:14.625” S:14.375”

resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information. resolved to Grade 0 to 1Discontinue or baseline.LENVIMA Either resume at a reduced LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information. severity and persistence of hepatotoxicity. for hepatic failure. dose or discontinue LENVIMA depending on the 1 INDICATIONS AND USAGE severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. 1 forINDICATIONS USAGE 5.5 Proteinuria LENVIMA is indicated the treatment ofAND patients with locally recurrent or metastatic, progressive, radioactive 5.5 Proteinuria LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo iodine-refractory differentiated thyroid cancer (DTC). 1, 3proteinuria reported in 34% ofpatients LENVIMA-treated patients and 3% of patients in the placebo group. The incidenceInofStudy Grade proteinuriawas in LENVIMA-treated was 11% compared to none in the 2 DOSAGE AND ADMINISTRATION group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose placebo group. Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria 2.1 Recommended Dose The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once proteinuria before of,protein. and periodically treatment. If urine than or equalMonitor to 2+ isfor detected, obtain a 24initiation hour urine Withholdthroughout LENVIMA for ≥2 grams of dipstick proteinuria recommended daily dose of disease LENVIMA is 24 mg (two 10 mg capsules and one 4occurs. mg capsule) orallygreater taken once daily with or withoutThe food. Continue LENVIMA until progression or until unacceptable toxicity than oratequal to 2+dose is detected, obtain a 24ishour urine protein. Withhold LENVIMA hoursgreater and resume a reduced when proteinuria <2 gm/24 hours. Discontinue LENVIMAfor ≥2 grams of daily with or without food. Continue LENVIMA until disease progression or until unacceptable toxicity proteinuria/24 occurs. proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that nephrotic Takedose LENVIMA the time sameoftime each day. If a dose is missed and cannot be taken within 12 hours,for skip that syndrome. for nephrotic syndrome. dose and take the next at the at usual administration. 5.6 Renal Failure and Impairment dose and take the next dose at the usual time of administration. 5.6 Renal Failure and Impairment Severe Renal or Hepatic Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% Severe Renal or Hepatic Impairment In Study 1, events of renal impairment reported 14% oforLENVIMA-treated patients The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment of patients in the placebo group. The incidence of Grade 3 were or greater renalinfailure impairment was 3% in compared to 2% recommended of LENVIMA is by 14 the mg Cockroft-Gault taken orally once daily inorpatients severe renal impairment of patients theinplacebo group. The incidence of risk Grade 3 orfor greater renal failure or impairment was 3% in (creatinine clearanceThe [CLcr] less than 30dose mL/min calculated equation) severe with hepatic LENVIMA-treated patients and in 1% the placebo group. The primary factor severe renal impairment in (creatinine LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in impairment (Child-Pugh C). clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. impairment (Child-Pugh C). LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. 2.2 Dose Modifications Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or 2.2 Dose Modifications Withhold LENVIMA forordevelopment Grade 3 depending or 4 renal failure/impairment resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose discontinue of LENVIMA on the severity anduntil persistence Hypertension Hypertension of renal impairment.baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to of renal impairment. • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment. 5.7 Gastrointestinal Perforation and Fistula Formation blood pressure prior to persists and during treatment. 5.7 Gastrointestinal Perforation and Fistula Formation • Withhold LENVIMAcontrol for Grade 3 hypertension that despite optimal antihypertensive therapy; resume In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and • (see Withhold for Grade 3ishypertension antihypertensive therapy; resume In Study 1, events at a reduced dose Table 1)LENVIMA when hypertension controlled atthat lesspersists than ordespite equal tooptimal Grade 2. placebo group.of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and at afor reduced dose (seehypertension. Table 1) when hypertension is controlled at less than or equal to Grade 2. 0.8% of patients in the 0.8% of patients in the placebo group. • Discontinue LENVIMA life-threatening Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction•or hemorrhage Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. Cardiac dysfunction or hemorrhage 5.8 QT Interval Prolongation • Discontinue for a Grade 4 event. 5.8 QT Interval Prolongation • Discontinue for a Grade 4 event. In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in • Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline. In Study 1, QT/QTc reported 9% ofwas LENVIMA-treated patients and 2% of patients in Withhold LENVIMA for 1)development of Grade 3 event until improved to Grade incidence of QTinterval intervalprolongation prolongationwas of Grade 3 oringreater 2% in LENVIMA-treated • Either resume at•a reduced dose (see Table or discontinue LENVIMA depending on the severity and0 or 1 or baseline.the placebo group. The thenoplacebo The incidence QT interval prolongation ofinGrade 3 orwith greater was 2%long in LENVIMA-treated • Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and patients compared to reportsgroup. in the placebo group.ofMonitor electrocardiograms patients congenital persistence of the adverse event. patients compared to no reports in the placebo group. Monitor electrocardiograms in patients QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT with congenital lon Arterial thrombotic eventpersistence of the adverse event. QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT Arterial thrombotic event interval, including Class Ia and III antiarrhythmics. • Discontinue LENVIMA following an arterial thrombotic event. interval, including Class Ia and III antiarrhythmics. • Discontinue LENVIMA following an arterial thrombotic event. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Renal failure and impairment or hepatotoxicity Monitor andprolongation. correct electrolyte abnormalities patients. for the development of Renal failure and impairment or hepatotoxicity Grade 3 or greater QT interval Resume LENVIMA atina all reduced doseWithhold when QTLENVIMA prolongation • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0Grade or 1 or3 baseline. Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 • or baseline. resolves to Grade 0 or 1 or baseline. to Gradedose 0 to(see 1 or Table baseline. 5.9 Hypocalcemia • Either resume at a reduced 1) or discontinue LENVIMA depending on the severity and 5.9 Hypocalcemia • Either resumeorathepatotoxicity. a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity In andStudy 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in persistence of renal impairment Studycases 1, 9%hypocalcemia of LENVIMA-treated patients experienced 3 or greater hypocalcemia persistence of failure. renal impairment or hepatotoxicity. the placebo group. In In most responded to replacement andGrade dose interruption/dose reduction.compared to 2% in • Discontinue LENVIMA for hepatic the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction. • Discontinue LENVIMA for hepatic failure. Proteinuria Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Proteinuria Monitor blood calcium levels at least monthly and replace calcium as necessary during Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and LENVIMA treatment. • Withhold LENVIMA for ≥2 grams of proteinuria/24 hours. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and • Withhold LENVIMA ≥2 proteinuria grams of proteinuria/24 hours. persistence of hypocalcemia. • Resume at a reduced dose (see Table 1) for when is <2 gm/24 hours. persistence of hypocalcemia. • Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours. • Discontinue LENVIMA for nephrotic syndrome. 5.10 Reversible Posterior Leukoencephalopathy Syndrome • Discontinue 5.10 Reversible Posterior Leukoencephalopathy Syndrome Gastrointestinal perforation or fistulaLENVIMA formationfor nephrotic syndrome. Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible Gastrointestinal perforation or fistula formation Across clinical studies(RPLS). in which 1108 patients received LENVIMA, thereWithhold were 3 reported • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. posterior leukoencephalopathy syndrome Confirm the diagnosis of RPLS with MRI. for RPLSevents until of reversible leukoencephalopathy (RPLS). Confirm the diagnosis of RPLS MRI.and Withhold for RPLS unti QT prolongation • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. fully resolved. Uponposterior resolution, resume at a reducedsyndrome dose or discontinue LENVIMA depending on thewith severity QT prolongation fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. persistence of neurologic symptoms. • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. persistence of neurologic symptoms. • Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline. Hemorrhagic Events Resume LENVIMAsyndrome at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 5.11 or baseline. 5.11 Hemorrhagic Events Reversible posterior•leukoencephalopathy (RPLS) In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. Reversible posterior leukoencephalopathy syndrome (RPLS) In Study 1, hemorrhagic eventswas occurred 35% of LENVIMA-treated patients and in 18% • Withhold for RPLS until fully resolved. However, the incidence of Grade 3-5 hemorrhage similarinbetween arms at 2% and 3%, respectively. The of the placebo group. Withhold for RPLSdose until or fully resolved. LENVIMA depending on the severity and However, the incidence Grade 3-5 hemorrhage similar at 2% and 3%, respectively. The • Upon resolution,•resume at a reduced discontinue most frequently reported hemorrhagic eventofwas epistaxis (11% Gradewas 1 and 1% between Grade 2). arms Discontinuation due to • Upon resolution, frequently reported hemorrhagicpatients. event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to persistence of neurologic symptoms. resume at a reduced dose or discontinue LENVIMA depending on the severity andhemorrhagic eventsmost occurred in 1% of LENVIMA-treated persistence of neurologic symptoms. hemorrhagic events occurred in 1% of LENVIMA-treated patients. Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported Manage other adverse reactions according to theininstructions in Table the absence of clinical clinical in which 1108 patients received LENVIMA, 3 or greater hemorrhage was reported experience, there are no recommendations on resumption of dosing patients with Grade1.4 Based clinicalon adverse in 2% of patients. InAcross Study 1, therestudies was 1 case of fatal intracranial hemorrhage amongGrade 16 patients who received experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse in 2% of patients.atInbaseline. Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received reactions that resolve. lenvatinib and had CNS metastases reactions that resolve. lenvatinib and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at Withhold LENVIMA the development of Grade hemorrhage resolvedDiscontinue to Grade 0 to 1. Either resume a Table 1 Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 a reduced dose or discontinue LENVIMAfor depending on the severity and 3persistence of until hemorrhage. Table 1Reactions Recommended Dose Modifications for Persistent and Intolerable Grade 2LENVIMA or Gradein3patientsa who a reduced dose or Grade discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue Adverse or Grade 4 Laboratory Abnormalities experience 4 hemorrhage. a Adverse Reactions or Grade 4 Laboratory Abnormalities LENVIMA in patients who experience Grade 4 hemorrhage. 5.12 Impairment of Thyroid Stimulating Hormone Suppression Adverse Reaction Modification Adjusted Doseb 5.12 Impairment of Thyroid Stimulating Hormone Suppression b LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid Adverse Reaction Modification Adjusted Dose impairs exogenous In patients Study 1, with 88%aofnormal all patients a baseline thyroid stimulating hormoneLENVIMA (TSH) level less than or equalthyroid to 0.5 suppression. mU/L. In those TSH athad baseline, Interrupt until resolved to 20 mg (two 10 mg capsules) orally stimulating (TSH) level less or equal to 0.5ofmU/L. In those patients withasa normal TSH at baseline, First occurrence Interrupt until resolved to 20 mg (two 10 mg capsules) orally elevation of TSH level above 0.5hormone mU/L was observed postthan baseline in 57% LENVIMA-treated patients once daily First occurrenceGrade 0-1 or baseline of TSH level placebo. above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as Grade 0-1 or baseline once daily compared with 14%elevation of patients receiving compared with 14% of patients receiving placebo. 14 mg (one 10 mg capsule Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. Interrupt until resolved to 14 mg (one 10 mg capsule Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. plustoone 4 mg capsule) Second occurrencec Interrupt until resolved c 5.13 Embryofetal Toxicity Grade 0-1 or baseline plus one 4 mg capsule) Second occurrence orally once daily 5.13 Embryofetal Toxicity Grade 0-1 or baseline Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm orally once daily on its mechanism actionreproduction and data from animal reproduction studies, LENVIMA can cause fetal harm Interrupt until resolved to 10 mg (one 10 mg capsule) orally when administered Based to a pregnant woman. In of animal studies, oral administration of lenvatinib Third occurrencec Interrupt until resolved to once daily 10 mg (one 10 mg capsule) orally when administered to recommended a pregnant woman. animal reproduction studies, oralfetotoxicity, administration of lenvatinib c Grade 0-1 or baseline during organogenesis at doses below the humanIndose resulted in embryotoxicity, Third occurrence Grade 0-1 or baseline once daily and teratogenicity induring organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of a and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk2to a fetus. Advise females of Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction reproductive potential to use effective contraception during treatment with LENVIMA and for at least weeks a Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks of LENVIMA following completion of therapy. of LENVIMA b following completion of therapy. Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) b 6 ADVERSE REACTIONS Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification 6 reactions ADVERSE c The following adverse are REACTIONS discussed elsewhere in the label. Please see the Warnings and Precautions Refers to the same or a different adverse reaction that requires dose modification The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions 4 CONTRAINDICATIONS sections in the full prescribing information. 4 CONTRAINDICATIONS sections in the full prescribing information. None. • Hypertension None. • Hypertension • Cardiac Dysfunction 5 WARNINGS AND PRECAUTIONS • Cardiac Dysfunction • Arterial Thromboembolic Events 5.1 Hypertension5 WARNINGS AND PRECAUTIONS • Arterial Thromboembolic Events 5.1 Hypertension • Hepatotoxicity In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo • Hepatotoxicity Proteinuria In Study 1 hypertension was reported in 73% of was LENVIMA-treated patients and 16% of patients in the•placebo group. The median time to onset of new or worsening hypertension 16 days for LENVIMA-treated patients. • Impairment Proteinuria •patients. Renal Failure and group. The median time to onset of new or to worsening hypertension was 16 daysofforGrade LENVIMA-treated The incidence of Grade 3 hypertension was 44% as compared 4% for placebo, and the incidence 4 •Perforation Renal Failure and Impairment Gastrointestinal and Fistula Formation Thethan incidence Grade 3 hypertension wasand 44% as in compared to 4% for placebo, and the incidence of•Grade 4 hypertension was less 1% in of LENVIMA-treated patients none the placebo group. • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group. • QT Interval Prolongation Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks • Hypocalcemia Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks • Hypocalcemia for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA Reversible Posterior Leukoencephalopathy Syndrome for thedespite first 2 months, and then at leasttherapy; monthlyresume thereafter treatment withhypertension LENVIMA. Withhold • LENVIMA • Reversible Posterior Leukoencephalopathy Syndrome for Grade 3 hypertension optimal antihypertensive at aduring reduced dose when • Hemorrhagic Events 3 hypertension optimal antihypertensive therapy; resume at a reduced dose when hypertension • Hemorrhagic is controlled at less for thanGrade or equal to Grade 2. despite Discontinue LENVIMA for life-threatening hypertension. • Impairment of Thyroid StimulatingEvents Hormone Suppression is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension. • Impairment of Thyroid Stimulating Hormone Suppression 5.2 Cardiac Dysfunction 6.1 Clinical Trials Experience 5.2 Cardiac Dysfunction 6.1 Clinical Trials Experience In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the In in Study 1, cardiac dysfunction, defined(2% as decreased or right function, cardiac failure, orBecause pulmonary Because trialscompared are conducted under widely varying observed in the edema, was reported 7% of LENVIMA-treated patients Grade 3 orleft greater) andventricular 2% (no Grade 3 or greater) trials of a drug cannotclinical be directly to rates in the clinical trialsconditions, of anotheradverse drug andreaction may notrates reflect edema,group. was reported in 7% LENVIMA-treated patients (2%patients Grade 3 (14 or greater) and 2% (no Grade 3clinical or greater) trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflec of patients in the placebo The majority ofof these cases in LENVIMA-treated of 17 cases) were the rates observed inclinical practice. of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were the rates observed in practice. based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMASafety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across based1on decreased ejection infraction asfraction assessed echocardiography. Six of 261 (2%) LENVIMAtreated patients in Study hadfindings greaterofthan 20% reduction ejection asby measured by echocardiography Safety data obtained in 1108 patientsrisks withofadvanced solid tumors who received as a single agent acros multiple clinical studies was used to further characterize serious adverse drug reactions. TheLENVIMA median age treated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo. clinicalThe studies further risks of serious drug reactions. The median age was 60 years (rangemultiple 21-89 years). dose was rangeused wasto0.2 mg tocharacterize 32 mg. The median durationadverse of exposure in the compared to no patients who received placebo. was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development entire population was 5.5 months. Monitor patients for clinicaltosymptoms or 1signs of cardiac decompensation. Withhold LENVIMA for development entire population was 5.5 months. of Grade 3 cardiac dysfunction until improved Grade 0 or or baseline. Either resume at a reduced dose or safety of Grade 3 cardiac improvedoftocardiac Gradedysfunction. 0 or 1 or baseline. EitherLENVIMA resume atfor a reducedThe dose or data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinediscontinue LENVIMA depending on thedysfunction severity anduntil persistence Discontinue The safety described below are derived from Study 1 which randomized (2:1)The patients with radioactive iodine refractoryfor differentiated thyroiddata cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). median discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA Grade 4 cardiac dysfunction. refractory differentiated thyroidand cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA 3.9 months for placebo. Grade 4 cardiac dysfunction. treatment duration was 16.1 months for LENVIMA and643.9years, months forwere placebo. 5.3 Arterial Thromboembolic Events Among 261 patients who received LENVIMA in Study 1, median age was 52% women, 80% were 5.3 Arterial Thromboembolic Events Among 261 who received LENVIMA in Studyas1,having median age wasor64 years, 52% were women, 80% were In Study 1, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients White, 18% were Asian, and 2%patients were Black; 4% identified themselves Hispanic Latino ethnicity. Study 1, arterial thromboembolic events events were reported of LENVIMA-treated patients and 2% of patients White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. in the placebo group.InThe incidence of arterial thromboembolic of Gradein35% or greater was 3% in LENVIMAInLENVIMAStudy 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in In Study 1, the most common adverse reactions observed in LENVIMA-treated patients treated patients and 1% in the placebo group. equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, (greater than or treated patients and 1% in the placebo group. to 30%) were,nausea, in order stomatitis, of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial decreased appetite,equal weight decreased, headache, vomiting, proteinuria, palmar-plantar Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial decreased appetite, weight pain, decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an erythrodysesthesia (PPE) syndrome, abdominal and dysphonia. The most common serious adverse thromboembolic has not 6been established and LENVIMA has not been studied in patients who have had an(at least 2%) erythrodysesthesia syndrome, abdominal pain,dehydration and dysphonia. arterial thromboembolic event withinevent the previous months. reactions were pneumonia(PPE) (4%), hypertension (3%), and (3%).The most common serious adverse arterial thromboembolic event within the previous 6 months. reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). 5.4 Hepatotoxicity Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving 5.4 Hepatotoxicity Adverse reactions led to doseand reductions in 68% of placebo patients for receiving 5%most of patients receiving placebo; 18% of patients discontinued LENVIMA 5% discontinued adverseLENVIMA reactions.and The In Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% placebo;(at18% of10%) patients discontinued 5% discontinued placebo for (13%), adverse reactions. The most In Study 1, 4% of aminotransferase LENVIMA-treated (AST) patients alanine aminotransferase (ALT)common and 5%adverse reactions least resulting in dose LENVIMA reductionsand of LENVIMA were hypertension experienced an increase in aspartate thatexperienced was Grade an 3 orincrease greater.inNo patients in the common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 proteinuria (11%), decreased (10%),(1%) and diarrhea (10%); the most common adverse reactions (at least placebo group experienced Grade 3fatal or greater in ALTinor3AST. Across 1108resulting in discontinuation of LENVIMA wereappetite hypertension and asthenia (1%). patients received LENVIMA, hepatic failure (including events)increases was reported patients andclinical acute studies in which1%) 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient. Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAhepatitis was reported in 1 patient. 2 presents theplacebo percentage of double-blind patients in Study adverse reactions at a higher rate in LENVIMA Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly treated patients thanTable patients receiving in the phase1 experiencing of the DTC study. Monitor liver function before for initiation of LENVIMA, weeksliver for the first 2 months, treated patients than patients receiving placebo in the double-blind phase of the DTC study. thereafter during treatment. Withhold LENVIMA the development of then Gradeevery 3 or 2greater impairment until and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until

ASCOPost.com | MARCH 25, 2015

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Announcements

cially incentivize high-quality, coordinated care. Participating practices will also receive monthly care management payments for each Medicare fee-for-service beneficiary during an episode to support oncology practice transformation, including the provision of comprehensive, coordinated patient care. “With the Oncology Care Model,

CMS has the opportunity to achieve three goals in the care of this medically complex population who are facing a cancer diagnosis: better care, smarter spending, and healthier people,” added Dr. Conway. “As a practicing physician and son of a Medicare beneficiary who died of cancer, I know the importance of well-coordinated care focused on the patient’s needs.”

Application Details Physician group practices and solo practitioners who provide chemotherapy for cancer and are currently enrolled in Medicare may apply to participate. Other payers, including commercial insurers, state programs, and Medicaid managedcare plans, are also encouraged to apply. To be considered, interested payers

” T:14.625” ” S:14.375”

must submit a letter of intent through the Oncology Care Model inbox at OncologyCareModel@cms.hhs.gov by March 19, 2015. Interested practices must submit letters of intent by April 23, 2015. Practices and payers who submit a timely letter of intent will be sent an authenticated web link and password with which to submit an electronic application. Applications must be submitted by June 18, 2015. n Disclosure: Dr. Conway reported no potential conflicts of interest.

Table 2

ASCO Expresses Concern Over New Oncology Care Model

hile commending the Centers for Medicare & Medicaid Services (CMS) for seeking new approaches to physician payment, ASCO expressed concerns over the model’s limited scope. “We are disappointed [CMS has] chosen to pursue only one model—and one that continues to rely on a broken fee-for-service system,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO. In comments submitted to CMS on a draft version of its model, ASCO supported testing the Oncology Care Model as well as other payment reform models to determine new approaches to payment for oncology care. Moreover, ASCO urged the Center to test models that include more fundamental reform, which moves away from the fee-for-service system. “ASCO looks forward to working with both public and private payers to explore new payment strategies that better reflect modern oncology practice and support high-value, patient-centered care,” said Dr. Schilsky. ASCO has developed a comprehensive proposal that, it believes, better matches payments to the work performed by cancer care providers. In May 2014, ASCO released its Consolidated Payments for Oncology: Payment Reform to Support Patient-Centered Care for Cancer, outlining a new approach to physician payment for cancer care services under Medicare, and shared it with CMS and private insurance companies. The Society is also working on piloting its proposal in different U.S. oncology settings. n

T:10” S:9.5”

Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater The background risk of major birth defects and miscarriage for the indicated population is unknown; however, Table 2 Adverse Reactions Occurring Patients with a Between-Group Differencethe of Greater background riskpopulation of major birth defects and miscarriage theofindicated population is unknown; however, than or Equal to 5% All Grades or Greater than orinEqual to 2% Grades 3 and 4 background risk The in the U.S. general of major birth defects is 2-4%forand miscarriage is 15-20% of than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4clinically recognizedthe background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of pregnancies. clinically recognized pregnancies. LENVIMA 24 mg Placebo LENVIMA 24 mg N=131 PlaceboData N=261 Data N=261 N=131 Animal Data All Grades Grades 3-4 All Grades Grades 3-4 Animal Datastudy, daily oral administration of lenvatinib mesylate at doses greater than or In an embryofetal development All Grades Grades 3-4 All Grades Grades 3-4 Adverse Reaction (%) (%) (%) (%) In an embryofetal study, daily oral administration mesylate doses equal to 0.3 mg/kg [approximately 0.14development times the recommended human dose basedofonlenvatinib body surface area at (BSA)] to greater than or Adverse Reaction (%) (%) (%) (%) to 0.3 mg/kg [approximately 0.14 times the recommended dose based on body Vascular Disorders pregnant rats duringequal organogenesis resulted in dose-related decreases in mean fetalhuman body weight, delayed fetal surface area (BSA)] to Vascular Disorders pregnant rats during organogenesis resulted inedema dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal and tail abnormalities), visceral, and 73 44 16 4 Hypertensiona and dose-related increases in fetal external edema(approximately and tail abnormalities), visceral, and Hypertensiona 73 44 16 4 anomalies. ossifications, skeletal Greater than 80% postimplantation loss was observed at (parietal 1.0 mg/kg/day 0.5 Hypotension 9 2 2 0 skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 Hypotension 9 2 2 0 the recommended times human dose based on BSA). Gastrointestinal Disorders times the recommended human dose based on BSA). Gastrointestinal Disorders Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external Diarrhea 67 9 17 0 Daily oral administration of lenvatinib mesylate pregnant rabbits during organogenesis in fetal external (short subclavian artery), and skeletaltoanomalies at doses greater than or equalresulted to Diarrhea 67 9 17 0 tail), visceral (retroesophageal (short tail), (retroesophageal artery), andsurface skeletalarea). anomalies doses greater than or equal to Nausea 47 2 25 1 0.031mg/kg (approximately 0.03visceral times the human dose ofsubclavian 24 mg based on body At theat0.03 mg/kg Nausea 47 2 25 0.03 mg/kg (approximately 0.03 timesdeath, the human dose of 24 mgLenvatinib based on body surface area).inAt the 0.03 mg/kg 41 5 8 0 Stomatitisb dose, increased post-implantation loss, including 1 fetal was also observed. was abortifacient 41 5 8 0 resulting in dose, Stomatitisb increasedinpost-implantation loss, including 1 fetaltreated death, at was also observed. rabbits, late abortions approximately one-third of the rabbits a dose level of 0.5Lenvatinib mg/kg/daywas abortifacient in Vomiting 36 2 15 0 rabbits, in late clinical abortions in approximately Vomiting 36 2 15 0 (approximately 0.5 times theresulting recommended dose of 24 mg basedone-third on BSA).of the rabbits treated at a dose level of 0.5 mg/kg/day Abdominal painc 31 2 11 1 c (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). Abdominal pain 31 2 11 8.2 1Lactation Constipation 29 0.4 15 1 8.2 Lactation Constipation 29 0.4 15 Risk1Summary 25 1 2 0 Oral paind Risk LENVIMA Summary is present in human milk. However, lenvatinib and its metabolites are excreted 25 1 2 Oral paind It is 0not known whether Dry mouth 17 0.4 8 0 It is not known LENVIMA is present in human However, lenvatinib and its metabolites are excreted in rat0 milk at concentrations higher whether than in maternal plasma. Because of themilk. potential for serious adverse reactions Dry mouth 17 0.4 8 in rat milk at concentrations than in maternal plasma. Because of the with potential for serious adverse reactions Dyspepsia 13 0.4 4 0 in nursing infants from LENVIMA, advise womenhigher to discontinue breastfeeding during treatment LENVIMA. Dyspepsia 13 0.4 4 0 in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. General Disorders and Administration Site Conditions Data General Disorders and Administration Site Conditions Data Fatiguee 67 11 35 4 Animal Data Fatiguee 67 11 35 4 Animal Following administration ofData radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related Edema peripheral 21 0.4 8 0 Following administration of (based radiolabeled lenvatinib to lactating Edema peripheral 21 0.4 8 0 radioactivity was approximately 2 times higher on AUC) in milk compared toSprague maternalDawley plasma.rats, lenvatinib-related Musculoskeletal and Connective Tissue Disorders radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma. Musculoskeletal and Connective Tissue Disorders 8.3 Females and Males of Reproductive Potential Arthralgia/Myalgiaf 62 5 28 3 ng 8.3 Females and Males of Reproductive Potential Arthralgia/Myalgiaf 62 5 28 3 Contraception Metabolism and Nutrition Disorders Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman. Metabolism and Nutrition Disorders Weight decreased 51 13 15 1 Based on its potential mechanism of action, LENVIMA can cause fetaltreatment harm when to a pregnant woman. Advise females of reproductive to use effective contraception during withadministered LENVIMA and Weight decreased 51 13 15 1 Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and Decreased appetite 54 7 18 1 for at least 2 weeks following completion of therapy. Decreased appetite 54 7 18 1 for at least 2 weeks following completion of therapy. Dehydration 9 2 2 1 Infertility Dehydration 9 2 2 1 Infertility Nervous System Disorders Females Nervous System Disorders LENVIMA may resultFemales in reduced fertility in females of reproductive potential. Headache 38 3 11 1 LENVIMA may result in reduced fertility in females of reproductive potential. Headache 38 3 11 1 Males Dysgeusia 18 0 3 0 LENVIMA may resultMales in damage to male reproductive tissues leading to reduced fertility of unknown duration. Dysgeusia 18 0 3 0 Dizziness 15 0.4 9 0 LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration. 8.4 0Pediatric Use Dizziness 15 0.4 9 Renal and Urinary Disorders 8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established. Renal and Urinary Disorders Proteinuria 34 11 3 0 The safety and effectiveness of LENVIMA in pediatric patients have not been established. Juvenile Proteinuria 34 11 3 0 Animal Data Skin and Subcutaneous Tissue Disorders Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 Skin and Subcutaneous Tissue Disorders administration ofof lenvatinib juvenileretardation rats for 8 weeks starting postnatal day 21 Palmar-plantar erythrodysesthesia 32 3 1 0 (approximately equalDaily to aoral human pediatric age 2 years) mesylate resulted intogrowth (decreased bodyonweight Palmar-plantar erythrodysesthesia 32 3 1 0 (approximately to a human pediatric of 2length years) of resulted in growth retardation (decreased body weight g il gain, decreased food consumption, equal and decreases in the widthage and/or the femur and tibia) and secondary 21 0.4 3 0 Rash g gain, decreased food consumption, decreases in thegreater width and/or femur and tibia) and secondary 21 0.4 3 0 in physical development Rash d delays and reproductive organ and immaturity at doses than orlength equalof tothe 2 mg/kg Alopecia 12 0 5 0 delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg Alopecia 12 0 5 0 (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length Hyperkeratosis 7 0 2 0 (approximately 1.2 to 54times exposure by AUC at the recommended human dose). of the persisted following weeksthe of clinical recovery. In general, the toxicologic profile of lenvatinib was Decreased length Hyperkeratosis 7 0 2 0 femur and tibia Respiratory, Thoracic and Mediastinal Disorders of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at of lenvatinib was Respiratory, Thoracic and Mediastinal Disorders similar between juvenile and adult rats, though toxicities including broken teethtime-points at all doseinlevels and mortality at Dysphonia 31 1 5 0 the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment Dysphonia 31 1 5 0 the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats. Cough 24 0 18 0 o juvenile rats. Cough 24 0 18 8.5 0Geriatric Use Epistaxis 12 0 1 0 8.5 Geriatric Use Epistaxis 12 0 1 0 Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and Psychiatric Disorders Of 261 patients whotoreceived Study differences 1, 118 (45.2%) were greater than or equal Psychiatric Disorders 29 (11.1%) were greater than or equal 75 yearsLENVIMA of age. Noinoverall in safety or effectiveness wereto 65 years of age and Insomnia 12 0 3 0 29 (11.1%) were than or equal to 75 years of age. No overall differences in safety or effectiveness were Insomnia 12 0 3 0 observed between these subjects andgreater younger subjects. Infections and Infestations observed between these subjects and younger subjects. Infections and Infestations at 8.6 Renal Impairment Dental and oral infectionsh 10 1 1 0 Renal Impairment 10 1 1 0 adjustment8.6 Dental and oral infectionsh No dose is recommended in patients with mild or moderate renal impairment. In patients with severe Urinary tract infection 11 1 5 0 Norecommended dose adjustment in patients with mildwith or moderate In patients with severe renal0 impairment, the doseis isrecommended 14 mg taken once daily. Patients end stagerenal renalimpairment. disease were Urinary tract infection 11 1 5 Cardiac Disorders renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied. Cardiac Disorders not studied. Electrocardiogram QT prolonged 9 2 2 0 8.7 Hepatic Impairment Electrocardiogram QT prolonged 9 2 2 0 8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased No dose the adjustment is recommended withdaily. mild or moderate hepatic impairment. In patients with a severe hepatic impairment, recommended dose is 14 in mgpatients taken once Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure severe hepatic impairment, the recommended dose is 14 mg taken once daily. blood pressure b 10 OVERDOSAGE Includes aphthousb stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation OVERDOSAGE Includes aphthous stomatitis, stomatitis, glossitis, mouth abdominal ulceration, and c Includes abdominal discomfort, abdominal pain, abdominal pain lower, painmucosal upper, inflammation There is no specific 10 antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not c Includes abdominal discomfort, pain, abdominal pain lower, abdominal pain upper, There isAdverse no specific antidote for overdose withsingle LENVIMA. to the highasplasma abdominal tenderness, epigastric discomfort, and abdominal gastrointestinal pain expected to be dialyzable. reactions in patients receiving dosesDue of LENVIMA high asprotein 40 mgbinding, were lenvatinib is not abdominal tenderness, epigastric discomfort, and gastrointestinal pain d expected to be dialyzable. Adverse reactions patients receiving Includes oral pain, glossodynia, and oropharyngeal pain similar to the adverse events reported in the clinical studies at theinrecommended dose.single doses of LENVIMA as high as 40 mg were d Includes oral pain, glossodynia, and oropharyngeal pain e similar to the adverse events reported in the clinical studies at the recommended dose. Includes asthenia, fatigue, and malaise e 17 PATIENT COUNSELING INFORMATION Includespain, asthenia, fatigue, malaise arthralgia, and myalgia f Includes musculoskeletal back pain, painand in extremity, PATIENT COUNSELING f Advise the patient to17read the FDA-approved patientINFORMATION labeling (Patient Information). Includes pain, pain in rash extremity, arthralgia, and myalgia g Includes rash macular, rashmusculoskeletal maculo-papular,pain, rashback generalized, and Advise the patient to read the FDA-approved patient labeling (Patient Information). g Includes rash macular, rash maculo-papular, rash generalized, and rash h Hypertension: Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, h Hypertension: abscess, Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood and tooth infectionIncludes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth and tooth infection pressure is elevated.Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients A clinically importantofadverse reaction occurring moreembolism frequently(3%, in LENVIMA-treated patients Cardiac Dysfunction:pressure is elevated. receiving placebo, but with an incidence less than 5% was pulmonary including fatal reports vs than patients Dysfunction: receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reportspatients vs Advise thatCardiac LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider 2%, respectively). Advise patients that LENVIMA cause cardiac dysfunction to immediately their healthcare provider 2%, respectively). if they experience any clinical symptoms of cardiaccan dysfunction such as shortnessand of breath or swellingcontact of ankles. if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles. Table 3 Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events Arterial Thrombotic Events Table 3 Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 4 Events a Arterial Thrombotic Events and at a Higher Incidence in LENVIMA-Treated Patients Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms a and at a Higher Incidence in LENVIMA-Treated Patients Advise patients immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarctiontoorseek stroke. Laboratory Abnormality LENVIMA 24 mg Placebo consistent with myocardial infarction or stroke. Hepatotoxicity: Laboratory Abnormality LENVIMA 24 mg Placebo N=258b N=131b Hepatotoxicity: b b N=258 N=131Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new Grades 3-4 Grades 3-4 patients they will need to undergo lab tests to monitor for liver function and to report any new indicatingAdvise hepatic toxicitythat or failure. Grades 3-4 (%) Gradessymptoms 3-4 (%) symptoms indicating hepatic toxicity or failure. Failure/Impairment: (%) (%) Proteinuria and Renal and to Renal Failure/Impairment: Chemistry Advise patients thatProteinuria they will need undergo regular lab tests to monitor for kidney function and protein in Chemistry Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine. Creatinine increased 3 0 the urine.or fistula formation: Creatinine increased 3 0 Gastrointestinal perforation Alanine aminotransferase (ALT) increased 4 0 perforation formation: perforation or fistula and to seek immediate Alanine aminotransferase (ALT) increased 4 0 Advise patients thatGastrointestinal LENVIMA can increase the or riskfistula of gastrointestinal Aspartate aminotransferase (AST) increased 5 0 thatpain. LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate severepatients abdominal Aspartate aminotransferase (AST) increased 5 0 medical attention forAdvise Hypocalcemia 9 2 medical attention for severe abdominal pain. Hypocalcemia 9 2 Hemorrhagic Events:Hemorrhagic Events: Hypokalemia 6 1 Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for Hypokalemia 6 1 bleeding or symptoms ct Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for of severe bleeding. Lipase increased 4 1 Lipase increased 4 1 Embryofetal Toxicity:bleeding or symptoms of severe bleeding. Embryofetal Toxicity: ss Hematology Hematology Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of Platelet count decreased 2 0 Advise femalesAdvise of reproductive of thepotential potentialtorisk a fetus and to inform their healthcare provider of pregnancy. females ofpotential reproductive usetoeffective contraception during Platelet count decreased 2 0 a known or suspected a known suspected Advisecompletion females of of reproductive a treatment with LENVIMA andorfor at least 2pregnancy. weeks following therapy. potential to use effective contraception during With at least 1 grade increase from baseline a treatment with LENVIMA and for at least 2 weeks following completion of therapy. With at least 1 grade increasevalue from baseline b Lactation: Subject with at least 1 post baseline laboratory b Lactation: with at least 1 post baseline laboratory value e- In addition the followingSubject Advise nursing women to discontinue breastfeeding during treatment with LENVIMA. laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated Advise nursing women to discontinue breastfeeding during treatment with LENVIMA. In that addition following laboratory abnormalities Grades)placebo: occurredhypoalbuminemia, in greater than 5% of LENVIMA-treated patients and at a rate wasthe two-fold or higher than in patients who(all received patients and hypomagnesemia, at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypoglycemia, hyperbilirubinemia, hypercalcemia, e hypercholesterolemia, increased alkaline increased serumphosphatase, amylase, andhypomagnesemia, hyperkalemia. hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia. 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and No dose adjustment of LENVIMA recommended co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors andisCYP3A and P-gp when inducers. breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers. 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. 8.1 Pregnancy Risk Summary LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176 Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176 Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib when administered to recommended a pregnant woman. animal reproduction studies, oralfetotoxicity, administration during organogenesis at doses below the humanIndose resulted in embryotoxicity, and of lenvatinib A- teratogenicity in ratsduring organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and and rabbits. There are no available human data informing the drug-associated risk. Advise in rats rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women ofteratogenicity the potential risk to aand fetus. pregnant women of the potential risk to a fetus.

The ASCO Post | MARCH 25, 2015

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Education in Oncology Professional Development

Avoiding Burnout and Maintaining Well-Being While Caring for Seriously Ill Patients

A Conversation With Sandra Sanchez-Reilly, MD, AGSF, FAAHPM By Jo Cavallo

Sandra Sanchez-Reilly, MD, AGSF, FAAHPM

variety of studies, including one published this past year in the Journal of Clinical Oncology,1 have showed that clinicians who care for seriously ill patients are at high risk for diminished personal well-being, including high rates of burnout; moral distress, defined as the inability to act in a manner consistent with one’s personal and professional values; and compassion fatigue, in which physicians experience diminished emotional energy to care for patients. One key approach to mitigate the distress and grief oncologists and palliative care specialists often experience when caring for terminally ill patients is to engage in self-care, according to Sandra SanchezReilly, MD, AGSF, FAAHPM, Professor, Palliative Medicine Section Chief, and Director of Palliative Medicine at the University of Texas Health Science Center at San Antonio; and Interprofessional Fellowship Program Director at the South Texas Veterans Health Care System. She is also the lead author of the article “Caring for Oneself to Care for Others: Physicians and Their Self-Care,” which appeared in The Journal of Supportive Oncology.2 “Many times, our patients are critically or terminally ill and in very difficult situations, and we are right there with them,” said Dr. Sanchez-Reilly. “We are always in crisis mode, but to effectively care for our difficult patients, we need to take care of ourselves first.” The ASCO Post talked with Dr. Sanchez-Reilly about the factors that place oncologists at risk for diminished personal and professional well-being as well as the self-care tools and strategies oncologists can use to improve their overall well-being.

Self-Care Rounds and Retreats Please talk about how oncologists can promote and maintain well-being while

caring for patients with life-limiting cancer. Taking care of patients with advanced cancer is very difficult and all-consuming, often leading oncologists and palliative care specialists to experience distress and grief in response to their patients’ suffering. Unless recognized and dealt with, these emotions can compromise clinicians’ well-being and lead to burnout, moral distress, and compassion fatigue. So, the first thing is to recognize that we actually need to take care of ourselves, which we often don’t do well, and to understand that we are human beings, and it is natural to experience feelings of sadness, frustration, and anger when we lose a patient. Here at the University of Texas Health Science Center, we encourage physicians to use self-care strategies to maintain personal well-being throughout their professional lives. We also hold self-care rounds twice a month to give the medical staff an opportunity to talk about how their professional lives are affecting their personal lives. During these sessions, the staff may present case stories and explain how a specific patient situation is impacting

times, there are disagreements between oncologists and family members or the palliative care team members and oncologists, and these disagreements can be cumbersome to deal with. In addition to our twice-monthly sessions, once a year, we have a self-care retreat held somewhere outside the hospital to get away from our work environment and give participants a chance to focus on themselves. During the retreat, we discuss how to take care of ourselves so we have more energy and dedication to bring to the care of our patients.

The Wellness Wheel What are some self-care tools oncologists can employ to mitigate the stresses in their professional lives? Personal self-care refers to activities that are performed independently by individuals or a team to promote and maintain well-being throughout their professional lives. Some of those activities may include maintaining a healthy lifestyle through regular exercise, getting enough sleep, eating a healthy diet, and taking vacations; practicing mindfulness meditation; spending time with family

Many times, our patients are critically or terminally ill and in very difficult situations, and we are right there with them. But to effectively care for them, we need to take care of ourselves first. —Sandra Sanchez-Reilly, MD, AGSF, FAAHPM

them. For example, younger professionals tend to have a difficult time taking care of their younger patients with advanced cancer, because they identify with those patients. Or, a clinician may have lost a loved one to a particular cancer and finds that taking care of a patient with a similar diagnosis is difficult. Other issues, such as problems with time management, are discussed as well. Making patient decisions takes a lot of time, not only to see and treat the patient, but to document those decisions and meet the requirements from the different hospitals or health-care systems that may be involved in that patient’s care. There may also be issues surrounding coordinating care within the various medical teams in the hospital as well as dealing with family members. Some-

and friends; and pursuing spiritual development if that is personally significant. One instrument clinicians may find helpful is the Wellness Wheel (www.vanderbilt.edu/recreationandwellnesscenter/wellness/wellness-wheel). It includes seven areas of wellness to integrate into one’s life: physical, spiritual, social, emotional, intellectual, environmental, and occupational, depending on one’s specific needs.

Burnout, Moral Distress, and Compassion Fatigue What are some consequences of experiencing burnout, moral distress, and compassion fatigue? The symptoms and consequences are similar for all three. The one that has been most closely studied is burnout, which

Leora Horn, MD, MSc

GUEST EDITOR

ducation in Oncology focuses on faculty development, medical education curricula, fellowship training, and communication skills. The column is guest edited by Leora Horn, MD, MSc, Associate Professor of Medicine, Assistant Director of the Educator Development Program, and Clinical Director of the Thoracic Oncology Program at Vanderbilt University School of Medicine, Nashville. refers to a feeling of emotional exhaustion and may be associated with both high job turnover and poorer health. It is also linked to patient-related outcomes, such as medical errors by physicians and lower patient satisfaction, as well as unprofessional conduct and less altruistic values. Less is known about moral distress and compassion fatigue, both of which can lead to burnout, but physicians experiencing moral distress may have increased irritability, decreased job satisfaction, insomnia, headaches, high blood pressure, and depression. Compassion fatigue may manifest in symptoms similar to post-traumatic stress disorder, including hyperarousal and reliving events, such as clinical encounters with suffering patients or family members. Are all oncologists at risk for developing burnout, moral distress, and compassion fatigue? It is not only oncologists who are susceptible to these problems. Every health-care provider is at risk for developing these syndromes. In oncology, there is a more than 30% chance providers will experience these symptoms sometime during their professional continued on page 57

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IMPORTANT SAFETY INFORMATION There are no contraindications for LYNPARZA. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Coadministration of drugs which are potent inhibitors or inducers of CYP3A could increase or decrease exposure to LYNPARZA and should be avoided. Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. LYNPARZA is Pregnancy Category D. LYNPARZA is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), moderate renal impairment or severe renal impairment, since safety and efﬁcacy have not been established. Please see adjacent Brief Summary of the full Prescribing Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All Rights Reserved. 3076602 Last updated 01/15

ASCOPost.com | MARCH 25, 2015

PAGE 57

Education in Oncology Avoiding Burnout continued from page 54

lives. Physicians in emergency medicine have more than a 50% chance of experiencing burnout.

Finding Middle Ground To avoid these problems, would it be helpful for oncologists to maintain some

emotional distance from their patients? I would say no. Physicians need to feel empathy for their patients, and if they are emotionally distant from their patients, they won’t. Physicians have to find middle-ground territory, which is difficult, but that is where employing the elements in the Wellness Wheel can be helpful. It is important to main-

LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics. Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity. If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time. Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information]. Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction. The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg. If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg. Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza. Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

tain a balance in one’s physical, emotional, professional, social, and spiritual life to reduce the chances of stress and burnout.

Strategies for Self-Care Needed Current evidence shows that medical students, residents, and fellows receive inadequate self-care training. What can on-

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days. Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

43 22 64 43 31 25

8 1 3 4 1 0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory ﬁndings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily. Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush. Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo. Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

cology professionals do to initiate personal and professional self-care? The Accreditation Council for Graduate Medical Education (ACGME) has incorporated some areas of self-reflection into its hematology and medical oncology fellowship program requirements, but the program does continued on page 58

The ASCO Post | MARCH 25, 2015

PAGE 58

Education in Oncology Avoiding Burnout continued from page 57

not specify strategies to accomplish individual or team-based professional self-care. Some examples of strategies for improving individual professional self-care include regularly appraising all aspects of work life; developing a

network of peers and mentors; seeking organizational engagement opportunities; improving communication and management skills; increasing selfawareness in setting limits; prioritizing personal relationships with family members and close friends; and pursuing reflective writing. Strategies for improving team mem-

LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold. Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information]. Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy. Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

bers’ well-being include enhancing their skills to empathize with others; formalizing structures, policies, and procedures to guide team meetings; and sharing personal and professional sources of meaning and incorporating them into daily life. n Disclosure: Dr. Sanchez-Reilly reported no potential conflicts of interest.

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence. Nursing Mothers It is not known whether olaparib 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 olaparib, 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 Lynparza has not been established in pediatric patients. Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference. Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza. Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information]. OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically. 17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges. • MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information]. • Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information]. • Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information]. • Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information]. • Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

References 1. Shanafelt TD, Gradishar WJ, Kosty M, et al: Burnout and career satisfaction among US oncologists. J Clin Oncol 32:678-686, 2014. 2. Sanchez-Reilly S, Morrison LJ, Carey E, et al: Caring for oneself to care for others: Physicians and their self-care. J Support Oncol 11:75-81, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Hyman Muss, MD, on Caring for Older Patients with Cancer see page 1

Jeff M. Michalski, MD, on High-Dose Radiotherapy in Localized Prostate Cancer see page 5

Sandy Srinivas, MD, on Antiangiogenesis in Advanced Bladder Cancer see page 6

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MARCH 25, 2015

PAGE 59

Expert’s Corner Hematology

Five Questions Can Guide the Treatment of Relapsed Myeloma By Caroline Helwick more aggressive relapse requires a more aggressive treatment regimen, often using several agents in combination.

2. Should this patient be retreated with a previously used drug?

Joseph Mikhael, MD, MEd

oseph Mikhael, MD, MEd, myeloma expert at the Mayo Clinic in Arizona, Scottsdale, and Associate Dean of the Mayo School of Graduate Medical Education, considers five questions when selecting treatment for patients with multiple myeloma who relapse. “With prolonged survival, which approaches 10 years in standard-risk patients, most patients will undergo many lines of therapy, and this will require a long-term approach that balances disease control with the elimination of clones,” Dr. Mikhael said in an interview with The ASCO Post. “With many options available to the clinician, there is no simple or ideal sequence of treatments that has been established for treating relapsed disease. Balancing efficacy, toxicity, and cost will become ever more challenging with our increased options,” he noted. It is possible to do this, he maintained, by asking five critical questions that form a practical algorithm. These questions will help clinicians differentiate this highly heterogeneous patient population. “We surely cannot treat all patients the same way,” he commented.

1. Does this patient really need to be treated now? With slow, indolent relapse, certain patients—especially those with low-risk features—may be monitored closely (usually monthly), without intervention. “Identifying the ‘indolent’ vs the ‘aggressive’ relapse is crucial,” he emphasized. With indolent relapse, it is reasonable to introduce a sequential approach using one or two agents at a time, usually a proteasome inhibitor or an immunomodulatory drug plus dexamethasone, eventually using all the active agents. This “control” approach is more likely to be useful in standard-risk patients. A

Retreatment with the same drugs that were used upfront is often necessary, and this may or may not be effective. Several factors can be predictive of efficacy in the relapsed setting: depth of the initial response (the deeper the response, the more likely that re-exposure will produce a response); duration of first response (at least 6 months predicts for a future response); and good tolerability of the agent. Bortezomib was approved for retreatment in 2014, he noted.

3. Have the ‘Big 5’ been used? Five “novel” agents remain the center of myeloma therapy—thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst), bortezomib (Velcade), and carfilzomib (Kyprolis). Although carfilzomib and pomalidomide are newer-generation agents, the others remain a critical part of treatment and have not been replaced, Dr. Mikhael indicated. For the immunomodulatory drug class, thalidomide is best used late in the disease course, in patients who cannot tolerate myelosuppression, and in combination (especially with bortezomib/dexamethasone or with cyclophosphamide/bortezomib/dexamethasone). Lenalidomide has shown a survival advantage in large phase III trials and is successfully combined with bortezomib and carfilzomib. Pomalidomide is highly active in combination with dexamethasone and has been effectively combined with bortezomib and carfilzomib.

For the proteasome inhibitors, bortezomib can be effectively used alone or in combination with immunomodulatory drugs (including pomalidomide) and cyclophosphamide. Carfilzomib can be widely used, even in bortezomib-refractory patients, alone and in combination with essentially all other myeloma agents. Dr. Mikhael commented on the role of the two newest agents, carfilzomib and pomalidomide. “With very similar indications for relapsed myeloma, deciding between these two agents is

drugs are effective when combined, and therefore this doublet should be considered in aggressive relapse. The addition of the second agent when patients do not respond or progress on the other can also be considered. Elaborating on combinations of agents, Dr. Mikhael added that even when patients become resistant to a certain agent, they may become sensitive to it again, due to clonal evolution or because of something that occurs when the drug is combined with another. He noted that about 30% of patients who are resistant to

A patient’s risk status may influence the selection of relapsed therapy. Standard-risk patients may only require single-agent approaches, and high-risk patients require more intense combination regimens to effectively control their disease. —Joseph Mikhael, MD, MEd

a common clinical problem,” he noted. “It should be reassuring to clinicians that each myeloma patient is likely ultimately to see both agents, and the optimal sequence is not yet known.” Several factors can help clinicians choose between these agents (both of which are effective in high-risk disease). Factors favoring carfilzomib include the presence of renal insufficiency and preexisting neuropathy, whereas pomalidomide is favored when convenience of administration is important and in patients with poorly controlled heart failure or hypertension. “Class ‘switching’ is not necessarily supported by evidence,” he pointed out. This means that bortezomib-refractory patients may respond to carfilzomib, and lenalidomide-refractory patients may respond to pomalidomide. Evidence is emerging that these two

Fig. 1: Factors in Selecting Therapy for Relapsed Myeloma. Courtesy of Joseph Mikael, MD, MEd.

bortezomib and dexamethasone respond to the combination of bortezomib/ lenalidmide/dexamethasone (VRD).

4. Have the ‘add-on’ agents been used? Although the five key agents discussed here are considered the backbone of myeloma treatment, several others have activity that can enhance their efficacy: corticosteroids (dexamethasone weekly [20–40 mg], alternate-day prednisone (25–100 mg), alkylating agents (cyclophosphamide, melphalan), and liposomal doxorubicin. These agents can also be considered without a novel agent on board (ie, cyclophosphamide/prednisone).

5. Has an individualized, risk-stratified approach been considered? “A patient’s risk status may indeed influence the selection of relapsed therapy. Standard-risk patients may only require single-agent approaches. Intermediaterisk patients will likely benefit from bortezomib-containing regimens. And high-risk patients require more intense combination regimens to effectively control their disease,” he indicated. Elaborating on individual risk, Dr. Mikhael noted that relapse occurs sooner and more aggressively in high-risk patients and that close monitoring and rapid initiation of treatment in these patients continued on page 62

Cancer cell

Amgen is researching ways to help T cells target cancer.

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Activated dendritic cells can teach T cells to help find and fight cancer cells with a matching antigen profile.1

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The ASCO Post | MARCH 25, 2015

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Expert’s Corner Relapsed Myeloma continued from page 59

are critical. Risk factors may change since the time of first diagnosis, so patients should be reevaluated upon relapse. In addition to risk tier, several other patient factors should be considered because they may also influence the choice of treatment, especially age, performance status, renal insufficiency, bone marrow reserve (previous myelosuppression), preexisting neuropathy, and other comorbidities, such as cardiac disease and diabetes (see Fig. 1 on page 59).

Other Approaches Autologous stem cell transplantation remains the standard of care for

frontline therapy in eligible patients, although some may defer transplantation until relapse. However, a second autologous stem cell transplantation is also feasible as salvage later in the disease course assuming three criteria are met: (1) the patient responded to the first autologous stem cell transplantation, (2) the patient tolerated the first autologous stem cell transplantation, and (3) the patient did not progress for at least 2 years after autologous stem cell transplantation. When these conditions are met, patients can expect a progression-free survival that is 50% to 70% that achieved with the first autologous stem cell transplantation, he said. Alternative approaches include al-

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FDA Launches Drug Shortages Mobile App SIGNOFF

DATE

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—Valerie Jensen, RPh CD

The app identifies current drug shortages, resolved shortages, and discontinuations of drug products. Drugs in short supply can delay or deny needed care for patients. Drug shortages may also lead health care professionals to rely on alternative drug products, which may be less effective or associated with higher risks than the drug in shortage. “The FDA understands that healthcare professionals and pharmacists need real-time information about drug shortages to make treatment decisions,” said Valerie Jensen, RPh, Associate Director CW AE/AS ED PROD

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of the Drug Shortage Staff in the FDA’s Center for Drug Evaluation and Research. “The new mobile app is an innovative tool that will offer easier and faster access to important drug shortage information.” App users can search or browse by a

The FDA understands that health-care professionals and pharmacists need realtime information about drug shortages to make treatment decisions.

DATE: 11-21-2014 6:50 PM CW: L Gibbons INK Spec: 4C

Photo by Steve Gualdoni, PA-C, UP Health System - Marquette Hematology Oncology, Marquette, Michigan.

Disclosure: Dr. Mikhael has received institutional research funding from Onyx, Celgene, Sanofi, and AbbVie.

S&H

oday, the U.S. Food and Drug Administration (FDA) launched the agency’s first mobile application (app) specifically designed to speed public access to valuable information about drug shortages.

Fishing huts and gas pump on a lower harbor dock in Marquette, Michigan.

clophosphamide, etoposide]) may produce responses in about 50% of patients, although they tend to be shortlived. “This approach is likely best used as a bridge to a more definitive therapy or clinical trial,” he maintained. Dr. Mikhael hailed the emergence of new agents, especially those with new mechanisms of action. Monoclonal antibodies, histone deacetylase inhibitors, immune therapies, and agents directed toward new targets will expand the landscape of treatment and will likely further improve survival in myeloma, he predicted. n

Announcements JOB#: 40680 CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_Q40680_JA_D03.indd PG: CordobaR/MerinoR AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light) IMAGES: 40680_JA_1_fn.tif (CMYK; 300 ppi; 100%), 40680_glow_fn.psd (CMYK; 300 ppi; 100%), Perjeta_US_MBC_NEO_4C.eps (69.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: Macintosh HD:Users:cordobar:De...sk_prep:GNH_HER_Q40680_JA_D03.indd NOTES: None

Fishing Huts and Gas Pump, Marquette, Michigan

logeneic bone marrow transplant and high-dose chemotherapy. Allogeneic transplant remains controversial, based on the availability of novel agents and high treatment-related morbidity and mortality. “My approach is that only patients meeting four requirements will be candidates for allogeneic transplant,” he said. They must be “young,” have genotypically high-risk disease, and have phenotypically high-risk disease (ie, relapsing quickly), and the transplant should not be used as a “Hail Mary” after all other strategies have failed. High-dose chemotherapy (such as DT-PACE [dexamethasone, thalidomide, cisplatin, doxorubicin, cy-

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drug’s generic name or active ingredient, or browse by therapeutic category. The app can also be used to report a suspected drug shortage or supply issue to the FDA. The agency developed the drug shortages app to improve access to information about drug shortages, as part of the FDA’s efforts outlined in the “Strategic Plan for Preventing and Mitigating Drug Shortages”. The app is available for free download via iTunes (for Apple devices) and the Google Play store (for Android devices) by searching “FDA Drug Shortages.” n

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PAGE 63

Announcements

Seattle Children’s Names Jeff Sperring, MD, New Chief Executive Officer

eattle Children’s Hospital announced that the Board of Trustees has named Jeff Sperring, MD, Chief Executive Officer, effective early in May. Dr. Sperring, who currently serves as President and Chief Executive Officer of Riley Hospital for Children at Indiana University Health, will continue to implement Seattle Children’s 2012-2016 Strategic Plan, with the goal of carrying out the hospital’s mission to prevent, treat, and eliminate pediatric disease. Dr. Sperring has worked at Riley Hospital for Children since 2002. As Chief Executive Officer of the hospital, he provided pediatric strategic and policy over-

residency, he served as a United States Navy Medical Corps officer in Twentynine Palms, California, for 3 years.

Former CEO to Retire Dr. Sperring will replace current CEO Thomas N. Hansen, MD, who will re-

tire in May after 10 years of service. Dr. Hansen is credited with growing Seattle Children’s Research Institute, opening a major outpatient and ambulatory surB:8.75” gery center in Bellevue, and overseeing T:7.75” the completion of the Building Hope S:6.875” expansion at the hospital. After stepping

down as CEO, Dr. Hansen plans to remain an investigator at Seattle Children’s Research Institute. Dr. Sperring will oversee Seattle Children’s Hospital, Research Institute, Hospital, and Research Foundation and Guild Association. n

Jeff Sperring, MD

sight within the 18-hospital Indiana University Health system, and he developed the framework to transform Riley from a children’s hospital to a statewide children’s health system. He also managed the completion of the 750,000 square foot, $500 million Simon Family Tower, and implemented lean-based process improvement programs. Prior to taking the role of President and Chief Executive Officer, he served as Riley’s Chief Medical Officer, Associate Chief Medical Officer, and Director of Pediatric Hospital Medicine.

Passion and Dedication “We are thrilled that Dr. Sperring is assuming the role of CEO,”said Judy Holder, Chair, Board of Trustees. “He brings tremendous experience leading a highly ranked, complex healthcare organization, and he exudes a clear passion and dedication to our mission at Seattle Children’s.” “I am honored to have the opportunity to lead one of the best children’s hospitals in the country,” said Dr. Sperring. “Seattle Children’s already has a tremendous track record, and I look forward to carrying the torch to help bolster its ability to develop cures for pediatric disease and provide the highest level of care to every child in need,” Dr. Sperring said. Dr. Sperring obtained his Bachelor of Science in Biology from Emory University and his Doctor of Medicine from Vanderbilt University School of Medicine. He was a pediatric resident at the Naval Medical Center San Diego. After

STRENGTHEN HER DEFENSE

Treatment guidelines recommend PERJETA-based therapy as the preferred first-line option • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1 • ASCO® Clinical Oncology Practice Guidelines recommend pertuzumab + trastuzumab + docetaxel as first-line therapy for advanced HER2+ breast cancer 2 NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2 ; ASCO®=American Society of Clinical Oncology®.

Indication

PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eﬀective contraception. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

New Partnership Launches to Empower People Diagnosed With Lymphoma

he Leukemia & Lymphoma Society (LLS), together with the Lymphoma Research Foundation (LRF), CancerCare, the Association of Community Cancer Centers (ACCC), and Genentech announced the launch of a new partnership, the Alliance for Resource Collabora-

tion in Hematology (ARCH). ARCH was developed by these five leading organizations to connect people with lymphoma, their caregivers, and loved ones to educational resources and support. “Many people diagnosed with lymphoma, particularly in community can-

cer programs, are unaware of all the resources available to them,” said Louis J. DeGennaro, PhD, LLS’s President and Chief Executive Officer. S:6.875”“With this new initiative, our goal is to empower people with lymphoma to be active partners in their care, and ensure they don’t feel

isolated in their journey.” By visiting www.LymphomaResources .com, people can connect to the partner organizations to learn about the different types of lymphoma, explore treatment options, find information about specialists, and search financial support options. The

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

S&H

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6.1-month improvement in median PFS by independent review (primary endpoint)3 Placebo + Herceptin + docetaxel

100

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

HR=hazard ratio; CI=confidence interval. Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

Important Safety Information

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity CW

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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Announcements

ARCH website also helps in finding patient communities, peer support programs, and counseling services. The partner organizations provide these resources in a variety of formats, including in-person programs, online materials, and telephone support. It is estimated that only 15% of U.S. cancer patients are treated at the nation’s major academic cancer centers; the vast

With this new initiative, our goal is to empower people with lymphoma to be active partners in their care, and ensure they don’t feel isolated in their journey.S:6.875”

17.5”

5.5”

1.0”

—Louis J. DeGennaro, PhD

majority receive care at cancer programs in or near their home community, where resources may be more limited. By bringing together ACCC’s network of community cancer programs with the quality resources provided by LLS, LRF and CancerCare, ARCH aims to have an immediate impact on access to information for lymphoma patients where the need is greatest. n

Overall survival (OS) data PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis4 • In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)3 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel (HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

15.7-month improvement in median OS in the final analysis (secondary endpoint)4 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

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median line

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• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)4

20 10 0 0 P + H + D 402 PI + H + D 406

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At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).3 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).4

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCICTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

PER/100114/0010

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Most Common Adverse Reactions

• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. September 2013. 4. Data on file. Genentech, Inc. 5. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 6. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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Hypersensitivity Reactions/Anaphylaxis

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

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• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

S:9.875”

• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup5,6 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])3

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FDA Update

Dinutuximab Combination Approved for Pediatric High-Risk Neuroblastoma

he U.S. Food and Drug Administration (FDA) has approved dinutuximab (Unituxin), a monoclonal antibody targeting glycolipid GD2, as part of first-line therapy for pediatric patients with high-risk neuroblastoma. A chimeric monoclonal antibody that binds to

the surface of neuroblastoma cells, dinutuximab is being approved for use as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy for patients who have achieved at least a partial response to prior firstline multiagent, multimodality therapy. PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

“Dinutuximab marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “DinuIn patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

tuximab fulfills a critical need by providing a treatment option that prolongs survival in children with high-risk neuroblastoma.” The FDA granted dinutuximab priority review and orphan product designation. With this approval, the FDA also issued a rare pediatric disease priority In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 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. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

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FDA Update

review voucher to United Therapeutics, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review.

Clinical Trial The safety and efficacy of dinutuximab were evaluated in a clinical trial of 226 pediatric participants with high-risk neuroTable 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 PERJETA Placebo + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract 16.7 0.7 13.4 0.0 infection Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebotreated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

blastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Participants were randomly assigned to receive either an oral retinoid drug, isotretinoin, or dinutuximab in Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1 Edema 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0 peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0 Peripheral 12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0 Sensory Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0 Metabolism and nutrition disorders Decreased 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0 appetite Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0 The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCICTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

combination with interleukin-2 (Proleukin), granulocyte-macrophage colonystimulating factor, and isotretinoin. Three years after treatment assignpatients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3. Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal 23.6 0.0 20.0 0.0 17.1 1.3 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile 18.1 18.1 9.3 9.3 17.1 17.1 neutropenia Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 0.0 peripheral Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal 8.3 0.0 6.7 0.0 11.8 0.0 pain Metabolism and nutrition disorders Decreased 20.8 0.0 10.7 0.0 21.1 0.0 appetite Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 0.0 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

ment, 63% of participants receiving the dinutuximab combination were alive and free of tumor growth or recurrence, compared to 46% of participants treated with isotretinoin alone. In an updated analysis of survival, 73% of participants who received the dinutuximab combination were alive compared with 58% of those receiving isotretinoin alone. n

The ASCO Post | MARCH 25, 2015

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Announcements

Silvia C. Formenti, MD, Appointed Chair of Radiation Oncology at Weill Cornell and Radiation Oncologist-in-Chief at NewYork-Presbyterian/Weill Cornell

ilvia C. Formenti, MD, has been appointed Chair of the newly established Department of Radiation Oncology at Weill Cornell Medical College and Radiation Oncologist-in-

Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to

Chief at NewYork-Presbyterian/Weill Cornell Medical Center, effective April 15. Dr. Formenti, currently the Chair of Radiation Oncology at New York University Langone Medical Center, has

20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety

also been named the Associate Director of Radiation Oncology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College. A recognized leader in radiation on-

of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

Silvia C. Formenti, MD

cology and breast cancer research, Dr. Formenti’s work has transformed the paradigm in radiation biology, demonstrating the efficacy of combining radiotherapy with immunotherapy to control cancer cell growth in solid tumors. By recruiting patients’ immune systems to reject their individual tumor, the approach results in personalized immunotherapy, specific for each individual patient. She has translated preclinical work into clinical trials in metastatic breast cancer, lung cancer, and melanoma and has opened a new field of application for radiotherapy, whereby localized radiation can be used as an adjuvant to immunotherapy of solid tumors and lymphomas. In her new roles at Weill Cornell Medical College and NewYork-Presbyterian/Weill Cornell, Dr. Formenti will expand and enhance the existing radiation oncology program, building upon translational research to better investigate, target, and treat individual patients’ unique cancers. Faculty in the department will investigate precision medicine approaches to radiation oncology, focusing on combining radiotherapy with immunotherapy and other modifiers of the tumor microenvironment to design advanced treatments and therapies that are tailored to each patient’s individual tumor. “One of the biggest scientific breakthroughs of our generation is the revelation that not all cancers are the same, and, as such, neither should their treatments be the same,” said Laurie H. Glimcher, MD, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. “Dr. Formenti is at the forefront of this personalized approach to cancer. Her distinguished work in radiation oncology has left a lasting mark on cancer care.” Dr. Formenti received her medical degree from the University of Milan (Italy). She joined New York University Medical Center as Chair of the Department of Radiation Oncology in 1999. n

ASCOPost.com | MARCH 25, 2015

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Book Review

Medicine Turned Upside Down By Ronald Piana

ost books about health care center on fixing broken parts of the massive $3 trillion system, as seen with the passage of the Affordable Care Act, which is fixated, largely, on covering the uninsured and reducing costs. Health care, once the province of policy wonks, has now captured the national dialogue and continues to spur heated debates on both sides of the aisle and in the lay public, from plumbers to CEOs. Health care is more than the physician’s fee schedule, the amount of copays, or the cost of pharmaceuticals; it’s personal, because being sick and needing a doctor is a universally shared experience. Much of our health-care system is so mired in red tape and overworked doctors that getting medical care can become an unbearable chore. Often, you need to make a doctor’s appointment months in advance, and then when the appointment day finally ar-

life—one’s health—not buying a book. But the common thread is the power of information individualization. We are embarking on a time when each individual will have all their [sic] own data and the computing power to process it in the context of their [sic] own world.” That single paragraph drills into the book’s core message: New technology and the empowered patient are the future of American health care. However, there is so much more in this easy-toread value-added book. His short digressions into medical history, for one, add pleasure and context to the ideas with which he challenges the reader. In his previous book, The Creative Destruction of Medicine, Dr. Topol delved into how medicine would become digitized and how we had a new capability of digitizing human beings as well. However, that is a far cry from medicine becoming democratized. So

How can leading doctors today continue to ask whether patients should have direct access to their lab tests? —Eric Topol, MD

rives, you’ll probably wait for an hour or more before you hear, “The doctor will see you now.” Has the Affordable Care Act made this situation better or worse? Ask five people, and you’ll probably get as many opinions. However, doctor-author, Eric Topol, MD, sees more promise in creating a new way of thinking about health care than in wrangling over a system mired in politics. Dr. Topol’s first book, The Creative Destruction of Medicine, in which he described dozens of medical technologies that show great potential, won him legions of fans, who applauded his medical futurism. Now, still the futurist, Dr. Topol delivers another fine and forward-looking book, titled The Patient Will See You Now: The Future of Medicine Is in Your Hands.

Setting the Tone Dr. Topol sets the tone for the book in chapter 1. “Getting first-rate health care will always be quite different from ordering a book from Amazon. We’re talking about the most precious part of

now in his new book, Dr. Topol extends the model of digitized personalized health data to the concept of medical democratization, which he defines as making something, namely the individual’s health care, available to all people. “Until now,” he writes, “the flow of medical data has been to the doctor. If a patient was fortunate enough, their [sic] data, such as lab test, scans, might arrive in the mail…. Patients are now generating their own data on their own devices.”

A Tangible Way Forward Not one for empty philosophizing, Dr. Topol lays out a tangible way forward, giving the reader a comprehensive list and explanation of the personalized medical tools and technologies currently available and those coming down the pike. He offers hope for a new generation of the smart, digitally connected and democratized patient. Much of the first half of the book is geared toward empowering individual healthcare consumers in chapters such as My

Bookmark Title: The Patient Will See You Now: The Future of Medicine Is in Your Hands Author: Eric Topol, MD Publisher: Basic Books Publication date: January 2015 Price: $28.99; hardcover, 384 pages Lab Tests and Scans, where he makes the case for unlimited patient access to lab tests. Dr. Topol points out that roughly 10 billion lab tests are done each year in the United States, and they factor into about 80% of the medical decisions that doctors make. He then asks, “How can leading doctors today continue to ask whether patients should have direct access to their lab tests?” Their explanation is that patients will be confused by the results, which could induce undue anxiety, and only their doctors can really understand and put the information into context. Dr. Topol doesn’t buy that and cites numerous studies showing that the majority of patients, with a tiny bit of coaching, not only can read their lab results, but may feel better at having them made available online rather than waiting for a call or letter in the mail.

The Informed, Proactive Patient Naturally, Dr. Topol, a true believer in the power of technology gives the reader a dose of self-help advice and a roundup of future technologies in subchapters such as My Smartphone Lab. As you drill deeper into the well-written and neatly organized chapters, it is obvious that Dr. Topol’s worldview of healthcare reform centers on the informed, proactive patient. In other words, the best way to reign in our out-of-control spending and have better overall public health outcomes is to give patients the power to be the caregivers of their own health care, partnering with doctors in the process. In this new world of health care, we see home health-care centers in

which people monitor their own health metrics using personalized electronic health records and state-of-the-art technologies. This is a paradigm shift from what Dr. Topol views as “paternalistic medicine.”

Spiraling Health-Care Costs Dr. Topol also takes on our spiraling health-care costs in a chapter titled My Costs. His most important message here—although not breaking any new ground—is the opaque nature of our system separates patients from their doctors and the cost of care. In short, a senior can tell you to the penny how much a pound of top-round meat costs at the local supermarket but ask that same senior how much an MRI costs, and you’ll likely get a blank stare. He writes, “Only rarely will patients have any idea what they have been charged for or what their employer or insurer has actually paid…. There is an overall lack of incentive for those patients themselves to drive costs down.” Again, Dr. Topol’s answer to this nagging issue is technology-based transparency, making cost data widely available to each individual. However, getting patients to care about costs is a tough sell in America, and this chapter proves to be Dr. Topol’s weakest argument.

Medical Education Crisis Readers of The ASCO Post will probably most enjoy when Dr. Topol goes global, in chapters with enticing titles such as Predicting and Preempting Disease, Flattening the Earth, and Open Sesame, where he makes the point, “Both education and medicine are gocontinued on page 70

The ASCO Post | MARCH 25, 2015

PAGE 70

Book Review

Wrestling With the Challenges of Breast Cancer By Ronald Piana

ver the past decade or so, the oncology community has increased its understanding and recognition about issues and challenges faced by our growing survivorship community. A universal challenge among survivors is the sudden recognition of mortality that comes with a diagnosis of cancer. From that moment on, a cancer patient moves into survivorship and views life through a lens that looks at the possibility of recurrence. Many cancer patients describe survivorship as a subconscious anticipation, waiting for the next shoe to drop. Different disease sites also present with cancer-specific challenges. Breast cancer survivors wrestle with such issues as body image and sexual identity as they negotiate their way through life’s ups and downs, which are poignantly captured in the new book by Geralyn Lucas, Then Came Life: Living With Courage, Spirit, and Gratitude After Breast Cancer. Ms. Lucas was only 27 years old when she was diagnosed with aggressive breast cancer. “Because of my age and the type of cancer, the prognosis wasn’t great: They expected me to have a recurrence within 2 years, and my future recurrence would more than likely be, as they said, treatable, not curable,” writes Ms. Lucas.

Medicine Turned Upside Down continued from page 69

ing through economic crisis, and neither have sustainable archetypes.” To address this medical education crisis, Dr. Topol coined the term “MOOM,” for massive open online medicine. In a subchapter titled The Cancer MOOM, he writes, “Several cancer MOOMs are taking hold…. The American Society of Clinical Oncology is supporting such initiatives, and its CEO, Allen S. Lichter, MD, FASCO, said, ‘There’s a treasure trove of information inside case histories if we simply bring them together.’ They are, in a project called CancerLinQ.” Once again, Dr. Topol has delivered a highly informative, futuristic book that is not only a pleasure to read but offers real-life and actionable advice on how we can improve our health-care system by empowering patients to take control of their own bodies. Moreover, Dr. Topol has no ax to grind; he’s simply a doctor who wants the best for his patients. This is a must-read for all doctors and those thinking of joining the profession. n

An Important Reality Now at age 45, she seemingly has a lot to celebrate, first and foremost being a happily married, 16-year breast cancer survivor with a great career as

a television producer and two terrific kids. However, early on in the book, she poignantly summed up her private struggle: “For 16 years, I have been walking that tightrope with cancer on

one side and life on the other.” This metaphor speaks to an important reality that not just breast cancer patients but also all cancer patients share. Ms. Lucas voices the identity quandary

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ASCOPost.com | MARCH 25, 2015

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Book Review

that cancer patients face, separating themselves from the disease. And even after 16 years of survivorship, she still walked the tightrope. She further drove home this central issue of survivorship as she stared at herself in the mirror on the anniversary of her mastectomy. Ms. Lucas writes, “My huge faded-red mastectomy scar seems just as fresh and

tender now as it was at first. All these years later, I walk funny, holding one side of my body back protectively so no one can brush against me. My scar is a souvenir from that trauma. It is the badge I wear every day.”

A Sequel of Sorts Then Came Life is a sequel of sorts to her first memoir published in 2005,

Why I Wore Lipstick to My Mastectomy, which chronicles her experience as a 27-year-old, journalism school grad, having just landed her dream job as a reporter for the show 20/20, when she was diagnosed with breast cancer. But Ms. Lucas refused to capitulate to cancer and fall into the 24/7 gloom of victimhood. She penned Why I Wore

Bookmark Title: Then Came Life: Living With Courage, Spirit, and Gratitude After Breast Cancer Author: Geralyn Lucas Publisher: Gotham Books Publication date: October 2, 2014 Regrowth

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Cancer Stem Cells proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10 Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

www.bostonbiomedical.com

Price: $19.89; hardcover, 240 pages Lipstick to My Mastectomy, because in her words, “I really thought I was going to die. All the films, all the books, were just so gloomy and traumatic. I wanted to show women that they are so much more than their breasts, that there is life at the other side of the pain.” So, whereas her first memoir dealt with the shock of a breast cancer diagnosis, with all its rollercoaster, life-altering effects, Then Came Life has a slower, less volatile pace, dealing more with middle-aged angst, which is magnified by the looming shadow of recurrence that all survivors live with. Ms. Lucas mentions this on just about every page, but it never feels redundant; it simply reinforces the reality of survivorship.

Compelling Details Mixed With Diary Entries The fact that the arc of these two “cancer” memoirs spans 16 years is important to readers of The ASCO Post, speaking directly to the remarkable advances made in oncology. There are also some frank and well-informed talks with her oncologists, which offer insight into the territory of “difficult conversations” between doctor and patient. continued on page 72

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Book Review Challenges of Breast Cancer continued from page 71

Then there’s a sudden tragedy right after Ms. Lucas takes the reader through the emotional ups and downs of her 16th “cancerversary.” Her 39-year-old cousin, Hallie, is diagnosed with stage IV breast cancer. Ms. Lucas nails the shock of diagnosis with pithy, well-informed experience. And she is a good cousin, full of support, giving a detailed description, replete with her own diagnosis flashbacks, of the mind-numbing cancer-diagnosis experience. However, that’s where, at least for a while, the interesting content for the readers of The ASCO Post ends. This book, compelling as it is at times for Ms.

Lucas’ sheer energy, wit, and moxy, has a tendency to read too much like a personal diary, filling the pages with things only she and her tight circle of friends would appreciate.

Powerful Final Chapters Such grievances aside, the book closes its final chapters with Ms. Lucas serving as one of the caregivers for her cousin Hallie, who after a brave fight, succumbs to breast cancer. Ms. Lucas, to her credit, treats this section, the book’s most powerful and best written, with the care and decency that dying cancer patients deserve. She writes, “For several days we watch over Hallie in the hospital,

For 16 years, I have been walking that tightrope with cancer on one side and life on the other. —Geralyn Lucas

until we see the last pulsing vein in her neck…. The finality of it is stunning. My aunt Lydia crawls into bed with her daughter and hugs her baby for the last time…. She doesn’t want to let her go.”

No one wants to let go of a loved one, but sometimes we must, as Ms. Lucas ably described in her sometimes soapy, but otherwise sturdy read, especially for women in or near the breast cancer experience. n

Fred Hutchinson Health Economist Gary Lyman, MD, MPH, Editor of Recently Released Oncology Handbook

ncologist and health economist Gary Lyman, MD, MPH, Codirector of the Hutchinson Institute of Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, is the Editor of the second edition of the Oxford American Handbook of Oncology, published February 25, 2015, by Oxford University Press. The textbook is designed to be an essential reference for medical students,

Gary Lyman, MD, MPH

residents, and clinical oncologists seeking a current resource on state-of-the-art cancer care. The reference aims to help guide clinical decision-making, from treatment choices to best-practice guidelines. “This represents an updated and expanded edition of the handbook, which continues in the popular bulleted style that the Oxford handbooks have made popular across a range of medical disciplines,” said Dr. Lyman, a

member of the Public Health Sciences Division at Fred Hutchinson. The 864-page textbook covers cancer biology, genetics, prevention and screening, treatment complications, and supportive care. The handbook also provides background on molecular cancer biology, etiology, and epidemiology. More than 50 oncology professionals contributed to the reference guide. n

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The ASCO Post iPad App FREE from iTunes today!

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Esophageal Cancer Compiled by Liz Janetschek Primary Outcome Measures: Patient Reported Outcomes Measurement Information System (PROMIS) Scores (time frame: up to 30 day preoperatively for patients undergoing lung/esophageal

Study Type: Observational Study Title: A Study of Patientreported Outcomes in Patients With Lung or Esophageal Cancer Study Sponsor and Collaborators: University of Virginia; Alliance for Clinical Trials in Oncology; Patient Centered Outcome Research Institute Purpose: To determine if patient reported outcomes (using the PROMIS survey) will vary according to the presence of recurrent or metastatic lung or esophageal cancer. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No

0315, sgb2c@virginia.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02239328. continued on page 74

Now enrolling for alectinib

OBSERVATIONAL Study Type: Observational Study Title: Interrogation of Wnt, Notch and Hedgehog Activity in Chemo-naive Tumors Collected During the Staging Ultrasound of Patients Diagnosed With Esophageal Cancer Study Sponsor and Collaborators: University of Miami Purpose: To investigate the elucidation of signaling mechanisms, control of cellular processes and discovery of small molecules that selectively target Wnt, Shh, and Notch signaling pathways that are fundamental to cancer stem or progenitor cells (CSCs). Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Percentage of samples with identifiable Notch, Wnt and Hedghog pathways in the chemo naive esophageal tumor as well as in cancer stem cell populations (CSC) (time frame: 24 months) Principal Investigator: Anthony Capobianco, MD, University of Miami; 305-243-6308, tcapobianco@med .miami.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02221245.

BLEED:8.375” cancer surgery through a maximum of 5 TRIM:7.875” years after 1 survey is completed) SAFETY:7” Principal Investigator: Benjamin Kozower, MD, University of Virginia. Contact: Sandra Burks, RN, 434-243-

NCT 02075840 BO28984

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Randomize 1:1

he information contained in this Clinical Trials Resource Guide includes actively recruiting observational, interventional, phase I, phase II, and phase III clinical studies for patients with newly diagnosed or recurrent esophageal cancer. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

Patients (N=286) • Advanced, recurrent, or metastatic ALK-positive NSCLC

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

• Progression-free survival (PFS), investigator-assessed,

• Objective response rate, investigator-assessed,

by RECIST 1.1

using RECIST 1.1 • Time to CNS progression, IRC-assessed, using

RECIST 1.1 • PFS, IRC-assessed, using RECIST 1.1 • Duration of response • Overall survival • Safety: incidence of adverse events • AUC of alectinib • Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from

• ECOG performance status of 0-2 • No prior systemic therapy for advanced, recurrent, or

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com. 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

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Clinical Trials Resource Guide Esophageal Cancer Trials continued from page 73

Study Type: Observational Study Title: Prospective Collection of Health Information and Biospecimens in Esophageal Cancer Study Sponsor and Collaborators: Washington University School of Medicine Purpose: To create an esophageal cancer biospecimen repository that will collect, annotate, store, and distribute human esophageal cancer biospecimens. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Prospective Database (time frame: 5 years) Principal Investigator: Varun Puri, MD, Washington University School of Medicine. Contact: Jasmine A. Lewis, BSBA; 314-362-4611; lewisja@wudosis.wustl.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NTC01780961.

PHASE I Study Type: Phase I/interventional/ nonrandomized/single-group assignment Study Title: Epigenetically-Modified Autologous Tumor Cell Vaccines With ISCOMATRIX(TM) Adjuvant and Oral Celecoxib in Patients Undergoing Resection of Lung and Esophageal Cancers, Thymic Neoplasms, Thoracic Sarcomas, and Malignant Pleural Mesotheliomas Study Sponsor and Collaborators: National Cancer Institute Purpose: To assess the safety and effectiveness of tumor cell vaccines given with ISCOMATRIX and celecoxib in the treatment of lung and esophagus cancers. Ages Eligible: 18 to 75 years Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Tabulation of patient toxicities and their grades (time frame: 30 days after last vaccine up to 25 months) Principal Investigator: David S. Schrump, MD, National Cancer Institute; 301-496-2128, david_schrump@ nih.gov. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01258868. Study Type: Phase I/interventional Study Title: Phase I Dose Escalation of Neoadjuvant Proton Beam Radiotherapy With Concurrent Chemotherapy in Locally Advanced Esophageal Cancer

Study Sponsor and Collaborators: Abramson Cancer Center of the University of Pennsylvania Purpose: To investigate the safety and efficacy of treating patients with esophageal cancer with concurrent preoperative proton therapy, along with carboplatin and paclitaxel. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Number of adverse events (time frame: 3 years) Principal Investigator: John Plastaras, MD, Abramson Cancer Center of the University of Pennsylvania; 855216-0098, PennCancerTrials@emergingmed.com. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02213497. Study Type: Phase I/interventional Study Title: Allogeneic Tumor Cell Vaccine With Metronomic Oral Cyclophosphamide and Celecoxib as Adjuvant Therapy for Lung and Esophageal Cancers, Thymic Neoplasms, Thoracic Sarcomas, and Malignant Pleural Mesotheliomas Study Sponsor and Collaborators: National Cancer Institute Purpose: To evaluate the safety and effectiveness of tumor cell vaccines in combination with cyclophosphamide and celecoxib in patients with cancers involving the chest. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Tabulation of toxicity type and grade (time frame: 2 years) Principal Investigator: David S. Schrump, MD, National Cancer Institute; 301-496-2128, david_schrump@ nih.gov. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01143545.

PHASE II Study Type: Phase II/interventional/ single-group assignment Study Title: A Phase 2 Study of Paclitaxel With Cisplatin Versus Fluoropyrimidine With a Platinum Agent for Neoadjuvant Therapy in Operable Esophageal Cancer Based on CHFR Methylation Status in Diagnostic Biopsies Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center Purpose: To determine the rate of pathological complete response when the inclusion of paclitaxel in neoadju-

vant therapy is based on the presence or absence of CHFR methylation in diagnostic biopsy specimens. Ages Eligible: 18 to 75 years Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Prospective Database (time frame: 5 years) Principal Investigator: Ronan Kelly, MD, Johns Hopkins University; 443287-0005, rkelly25@jhmi@edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02239328. Study Type: Phase II/interventional/ randomized Study Title: Randomized Phase II Trial of PET Scan-Directed Combined Modality Therapy in Esophageal Cancer Study Sponsor and Collaborators: Cancer and Leukemia Group B; National Cancer Institute Purpose: To study PET scan imaging in assessing response in patients with esophageal cancer receiving combination chemotherapy. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: pCR rate of PET/CT non-responders within each induction treatment group Principal Investigator: Karyn A. Goodman, MD, Memorial Sloan Kettering Cancer Center. Contact: David H. Ilson, MD, PhD, 212-639-8895. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01333033. Study Type: Phase II/interventional/ single-group assignment Study Title: A Phase II, Multi-Center Study of Interventional Spray Cryotherapy for Early-Stage Esophageal Cancer (ICE-CANCER) Study Sponsor and Collaborators: University of Maryland Purpose: To evaluate the safety and efficacy of endoscopic spray cryotherapy using the CSA Medical, Inc. truFreeze System for patients with previously untreated early-stage cancer (T1a, N0, M0) that are ineligible or refuse conventional therapy, including surgery, chemotherapy, radiation therapy, and endoscopic resection. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Determining the response rate to therapy (time frame: 5 years) Principal Investigator: Bruce D. Greenwald, MD, University of Mary-

land; 410-328-8731, bgreenwa@medicine.umaryland.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01868139.

PHASE III Study Type: Phase III/interventional/randomized Study Title: A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of Her2-Overexpressing Esophageal Adenocarcinoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To study how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Disease-free survival (time frame: from the date of randomization to the date of first failure or last follow-up, assessed up to 8 years) Principal Investigator: Howard Safran, MD, NRG Oncology; 401-7932224, hsafran@lifespan.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01196390. Study Type: Phase III/interventional/ randomized Study Title: Phase III Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer Study Sponsor and Collaborators: MD Anderson Cancer Center Purpose: To study how safe and effective proton-beam therapy may be in comparison to intensity modulated radiation therapy in combination with chemotherapy in patients with esophageal cancer. Ages Eligible: 18 years and older Genders Eligible: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Progression-free survival (time frame: 6 weeks after radiation therapy) Principal Investigator: Steven H. Lin, MD, PhD, MD Anderson Cancer Center; 713-563-2300. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01512589. n Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov.

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Announcing an Additional Indication Please visit www.OPDIVO.com for more information. Website Call to Action

Website Call to Action

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Integrative Oncology Herbal Supplements: Increasing Problems By Jyothi Gubili, MS, K. Simon Yeung, PharmD, MBA, LAc, and Barrie R. Cassileth, MS, PhD

n Don Quixote, the 1605 Spanish literary masterpiece by Miguel Cervantes, “Balsam of Fierabras” is mentioned often as a therapeutic panacea. It calls for mixing rosemary, wine, oil, and salt. As the story goes, the knight relied heavily on this herbal preparation to relieve him of pain from the many beatings he was subjected to following his exploits.1 Since ancient times, herbs have been used as medicine in cultures around the world. Today, herbalists continue to prescribe herbal formulas to treat a range of ailments. The 1990s saw a major change in the way herbal medicines were consumed, as herbal remedies were marketed as supplements following the passage of the Dietary Supplement Health Education Act.

A Question of Quality

The major downside of the Dietary Supplement Health Education Act is that dietary supplements are not subjected to the same safety and effectiveness requirements as drugs are, by the U.S. Food and Drug Administration (FDA). With limited oversight, the quality of available products was found to vary substantially across manufacturers. Some contain too

the past 2 years. A 2013 study of 37 saw palmetto–containing supplements found that 6% contained species that cannot legally be sold as dietary supplements in the United States. The identity of an additional 9% of supplements remained inconclusive.2 A 2013 Canadian investigation of 44 herbal products sold by 12 companies revealed that the majority were of poor quality, including product substitution, contamination, and use of fillers.3 A recent case of questionable supplements was exposed by the New York Attorney General, which led to the issuance of cease-and-desist letters to four major retailers in the New York area, preventing them from selling those products.4 However, the validity of the DNA barcoding technique used in the investigations is being debated.5

Steps to Ensure Safety

The popular belief that herbs are safer than synthetic pharmaceuticals continues unabated. According to the most recent National Health Survey conducted in 2012, the most commonly used complementary approach was the use of natural products.6 Sales of herbal products reached $6 billion in 2013.7

The popular belief that herbs are safer than synthetic pharmaceuticals continues unabated. Sales of herbal products reached $6 billion in 2013. —Jyothi Gubili, MS, K. Simon Yeung, PharmD, MBA, LAc, and Barrie R. Cassileth, MS, PhD

much or too little of the labeled ingredient. Others are manufactured under poorly controlled conditions. Although companies are required to follow good manufacturing practices, lack of strict regulation has resulted in the proliferation of unscrupulous practices, including false health claims. Examples include reports on adulterated herbal products that have surfaced in

What steps can consumers take to purchase products with some certainty that what’s on the label is indeed inside the bottle? A good way to ensure the quality of supplements is to purchase products with labels indicating they have been tested by either the U.S. Pharmacopoeia (USP) Convention Dietary Supplement Verification Program or ConsumerLab. com. These are two major independent

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 Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 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, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. groups that routinely evaluate products submitted by manufacturers to ensure that they meet the minimum quality standards. A USP-verified product means it contains the listed ingredients at the strength indicated and that it has been screened for harmful contaminants. ConsumerLab. com is a company that collects several brands of a product and independently tests, reviews, compares, and rates them. The company’s process also involves ascertaining that the product contains the listed ingredients and is not contaminated or adulterated. In addition to labels on dietary supplement packaging, ConsumerLab.com provides detailed information about its findings in its paid-subscription offerings. However, neither USP nor ConsumerLab.com evaluates the efficacy of the products or product-prescription drug interactions.

Stricter Regulation Needed

In 2010, the FDA established a system for regulators to track complaints about dietary supplements and to prevent products in question from being sold. Given the estimated 65,000 products currently available,3 such checks and balances will barely impact the status quo. There is clearly an urgent need for stricter regulation of the dietary supplement industry. Had the rosemary used to concoct the Balsam of Fierabras been inauthentic, Don Quixote would not have been reinvigorated to continue his whimsical quests, depriving us of a great story. n Disclosure: Ms. Gubili, Dr. Yeung, and Dr. Cassileth reported no potential conflicts of interest.

References 1. López-Muñoz F, Alamo C, García-García P: Psychotropic drugs in the Cervantine texts. J R Soc Med 101:226-234, 2008. 2. Little DP, Jeanson ML: DNA barcode authentication of saw palmetto herbal dietary supplements. Sci Rep 3:3518, 2013. 3. Newmaster SG, Grguric M, Shanmughanandhan D, et al: DNA barcoding detects contamination and substitution in North American herbal products. BMC Med 11:222, 2013. 4. Press Release: A.G. Schneiderman asks major retailers to halt sales of certain herbal supplements as DNA tests fail to detect plant materials listed on majority of products tested. Press Release. Available at http://www.ag.ny. gov/press-release/ag-schneiderman-asksmajor-retailers-halt-sales-certain-herbal-supplements-dna-tests. Accessed February 18, 2015. 5. Sarma N: DNA testing of herbal supplements—Does it work or doesn’t it? Available at http://qualitymatters.usp.org/dna-testingherbal-supplements-does-it-work-or-doesntit. Accessed February 18, 2015. 6. National Center for Complementary and Integrative Health: What complementary and integrative approaches do Americans use? Key findings from the 2012 National Health Interview Survey. Available at https://nccih. nih.gov/research/statistics/NHIS/2012/ key-findings. Accessed February 18, 2015. 7. American Botanical Council: Herbal dietary supplement retail sales up 7.9% in 2013. Available at http://cms.herbalgram.org/ press/2014/2013_Herb_Market_Report.ht ml?ts=1411057336&signature=bd00edd664 48806455e36de3bc333928. Accessed February 18, 2015.

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MARCH 25, 2015

PAGE 77

Journal Spotlight Genomics/Genetics

Study Finds Websites That Market Personalized Cancer Care Services Overemphasize Benefits By Jo Cavallo

recent analysis of 55 Internet websites marketing a broad range of tests and services that promise the ability to personalize cancer treatment has found that the websites often overemphasize their purported benefits and downplay their limitations. In addition, the study results show that the majority of companies that market somatic tests online promote tests

Stacy W. Gray, MD, AM

that do not have evidence of clinical utility. The study by Stacy W. Gray, MD, AM, of Dana-Farber Cancer Institute, and colleagues, is published in the Journal of the National Cancer Institute.1

Study Methodology The researchers screened the top 30 websites on Google, Yahoo, and Bing, using 54 search items related to personalized or genomic cancer care, as well as websites identified through a literature review and an abstraction of exhibitor information from a national oncology conference. A Delphi Panel categorized Personalized Cancer Medicine as standard or nonstandard based on evidence of clinical utility. To capture websites that market cancer-related germline testing, genomic interpretative services, and providers who advertise personalized care, the researchers defined Personalized Cancer Medicine as products or services that could be used to tailor, personalize, or individualize care based on genomic or tumor-derived data. While the majority of websites were sponsored by commercial entities (56%), others were sponsored by academic institutions (20%), private institutions (15%), and individual physicians (2%). Thirty-one percent of the websites offered multiple Personalized Cancer Medicine services; 58% offered somatic analysis, and 20% offered germline analysis. In addition, 44% of the sites offered some form of personalized cancer care, and 15% offered interpretive services. About half of the commercial websites included the cost of testing, which ranged from $99 to $13,000.

Study Findings The researchersâ&#x20AC;&#x2122; analysis found that the vast majority (87%) of all websites included benefit information, and just

27% included limitation information. Websites included more information on the benefits of personalized cancer medicine than the limitations of per-

sonalized cancer medicine (P < .001). Compared with noncommercial websites, commercial websites were more continued on page 78

The ASCO Post | MARCH 25, 2015

PAGE 78

Survivorship

Mobile Patient-Centered App Tracks Breast Cancer Survivors’ Experiences

atricia Ganz, MD, Director of Cancer Prevention and Control Research at the Jonsson Cancer Center of UCLA, and collaborators Apple and Sage Bionetworks, recently announced the launch of “Share the Journey: Mind, Body and Wellness after Breast Cancer,” a patient-centered mobile application (app) that empowers women to be partners in the research process by tracking their symptoms and successes. Share the Journey was developed by

apps being launched in conjunction with Apple’s ResearchKit, an opensource tool that serves as a streamlined hub for iOS apps that can help speed scientific progress toward cures by amplifying the patient voice in shaping research directions and outcomes. Share the Journey shifts the center of care, healing, and intervention into the hands of women who have survived breast cancer. Women who have undergone surgery, radiation, or drug thera-

ing School of Public Health. “Access to more diverse patient-reported health data will help us learn more about

Stephen Friend, MD, PhD

The app has the potential to capture valuable information on the patient experience. Share the Journey can set us on a path toward understanding why some people recover, and some do not.

“We’re excited to use these new ResearchKit tools to expand participant recruitment and quickly gather even more data through the simple use of an app. The data it will provide takes us one step closer to developing more personalized care,” said Dr. Ganz, who also is a Professor at the UCLA Field-

long-term aftereffects of cancer treatments, and provide us with a better understanding of breast cancer patients’ experience.” Share the Journey is open to women between the ages of 18 and 80 who live in the United States, whether or not they have had breast cancer. Those who have not had breast cancer will contribute important data to the app that will help researchers understand which symptoms may be related to cancer treatment, and which may be part of the normal aging process. The developers also are creating a Spanish language version of the app, and planning to expand the study to other countries. “One reason to build these apps and run these studies is to see whether we can turn anecdotes into signals, and by generating signals, find windows for intervention,” said Stephen Friend, MD, PhD, President of Sage Bionetworks, and a Principal Investigator for Share the Journey. “We’re most interested in disease variations and the hourly, daily, or weekly ebb and flow of symptoms that are not being tracked and are completely missed by biannual visits to the doctor.” The platform is based on the concept

abstract, six websites offered chemotherapy sensitivity testing despite the fact that technology assessments from ASCO show insufficient evidence to recommend the tests. Currently, claims and other information posted on websites are not subject to regulation by the U.S. Food and Drug Administration (FDA) or the Federal Trade Commission, al-

though the FDA has said it intends to begin regulating genomic testing more broadly. “Given the lack of uniform regulation over Internet marketing, disproportionate claims of benefit, and promotion of nonstandard technologies, it is essential that clinicians and patients critically evaluate online products,” concluded the researchers. n

—Patricia Ganz, MD

UCLA’s Jonsson Comprehensive Cancer Center, Penn Medicine, Dana-Farber Cancer Institute, and Sage Bionetworks, and it is available for download now at the iTunes App Store. The app is an interactive research study that aims to understand why some breast cancer survivors recover faster than others, why their symptoms vary over time, and what can be done to improve symptoms.

App Collects and Tracks Symptoms Share the Journey marries science and technology by using surveys and sensor data on the iPhone to collect and track fatigue, mood and cognitive changes, sleep disturbances, and reductions in exercise. Share the Journey is one of five new

Marketing Personalized Care continued from page 77

likely to provide information on the benefits of personalized cancer medicine (100% vs 67%, P < .001). In addition, the analysis showed that the majority of companies that market somatic tests online promote tests that do not have evidence of clinical utility. According to the study

py to treat breast cancer often experience symptoms that affect their quality of life and impede recovery. The app’s creators say that collecting women’s experiences after breast cancer treatment will create a trove of data based on well-validated surveys and measurements, which will be continuously improved upon based on the participants’ feedback.

One Step Closer to More Personalized Care

that if individuals’ experiences were at the center of the research process, researchers working in virtual teams might be able to get efficient, inexpensive, and ubiquitous ways of gathering information using websites, tablets, or an app. This technology will allow Sage and other teams to include patients and other study participants as owners of their own data and equal partners. “We need to better understand some of the long-term negative treatment effects, such as fatigue, that can be associated with the disease control benefits of cancer therapies. What are the biological mechanisms that underpin those effects, and why some survivors are more vulnerable to those effects than others,” Dr. Ganz said. “With Share the Journey, women can tell us when something’s wrong, and the app has the potential to capture valuable information on the patient experience. Our current cancer care system lacks the ability to predict or treat these chronic and enduring symptoms, but Share the Journey can set us on a path toward understanding why some people recover, and some do not.”

Collaborators In addition to Dr. Ganz, Apple and Sage were advised in development of Share the Journey by Ann Partridge, MD, MPH, and Judy Garber, MD, MPH, of Dana-Farber Cancer Institute; Kathryn Schmitz, PhD, MPH, at the University of Pennsylvania Perelman School of Medicine; and Susan Love, MD, MBA, at UCLA and the Dr. Susan Love Research Foundation. n Disclaimer: Dr. Ganz reported no potential conflicts of interest. Dr. Friend is President of Sage Bionetworks, and a Principal Investigator for Share the Journey.

Disclosure: The study was supported by grants from the American Cancer Society and the National Institutes of Health. The study authors reported no conflicts of interest.

Reference 1. Gray SW, Cronin A, Bair E, et al: Marketing of personalized cancer care on the Web: An analysis of Internet websites. J Natl Cancer Inst 107(5):djv030, 2015.

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Through the Lens of Oncology History

A Century of Progress The text and photographs on this page represent the establishment of oncology as a viable medical specialty during the late 1800s and showcase the early medical advances and treatments in cancer. The images and captions are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History by Stanley B. Burns, MD, FACS. To view additional photos from this series, visit burnsarchive.com.

THE ANTISEPTIC ERA: 1876–1900 Dr. Halsted’s Breast Amputation Specimens, Johns Hopkins Hospital, 1894

n 1894, William Halsted, MD, illustrated his paper on the en bloc resection for breast cancer with photographs of the complete amputation (A, B). These images reflect the extent of surgical intervention necessary to give the patient a chance of survival. Many surgeons adopted his technique and saved thousands of lives. As the

new century dawned, Dr. Halsted’s success had a more important effect on the public’s mentality by the creation of hope for a cure rather than despair and expectation of an agonizing death. Patients slowly began to seek treatment for breast cancer while it was still in its early stages. By the 1920s, however, survival rates

had peaked and remained unchanged for the next 2 decades. In an attempt to improve cures, the super-radical mastectomy was developed by Drs. Jerome Urban, Mario Margottini, and Umberto Veronesi. This procedure required even more extensive removal of tissue but still did not provide a significant increase in breast cancer survival rates. A new stan-

dard of care was instituted, which required cancer surgeons to consult with oncologists preoperatively. Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Antiseptic Era 1876-1900 by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and the Burns Archive. n

“These images reflect the extent of surgical intervention necessary to give the patient a chance of survival. Many surgeons adopted his technique and saved thousands of lives.”

THERE’S A

NATURAL KILLER INSIDE EVERYONE WITH THE POTENTIAL TO TAKE ON

MULTIPLE MYELOMA

Despite recent advances, multiple myeloma remains a largely incurable disease, with fewer than half of patients surviving five years after diagnosis.1

Natural killer cells are part of the body’s first line of defense against cancer, but myeloma cells evade and suppress a patient’s natural immune response, making further medical advances challenging.2-11 We need a new approach. Bristol-Myers Squibb is deeply committed to furthering the science behind Immuno-Oncology. Leading the way in Immuno-Oncology research, Bristol-Myers Squibb is investigating the potential of the SLAMF7, KIR, and CD137 pathways to activate the body’s own natural killer cells to target myeloma cells. www.explorenaturalkillercells.com REFERENCES: 1. SEER Stat Fact Sheets: Myeloma, 2004-2010. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 17, 2014; 2. Godfrey J and Benson DM Jr. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 2012;53:1666-1676; 3. Cheng M, Chen Y, Xiao W et al. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 2013;10:230-252; 4. Bernal M, Garrido P, Jiménez P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma : implications for tumor evasion of T and NK cells. Human Immunol. 2009;70:854-857; 5. Jinushi M, Vanneman M, Munshi NC et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 2008;105:1285-1290; 6. Carbone E, Neri P, Mesuraca M et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105:251-258; 7. von Lilienfeld-Toal M, Frank S, Leyendecker C et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 2010;59:829-839; 8. Cook G, Campbell JDM, Carr CE et al. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66:981-988; 9. Yu J, Wei M, Becknell B et al. Pro- and anti-inflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24:575-590; 10. Nielsen H, Nielsen HJ, Tvede N et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99:340-346; 11. Tinhofer I, Marschitz I, Henn T et al. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95:610-618.

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2015

2015 Oncology Meetings March

April

Personalised Cancer Medicine and Big Data Analysis – 7th International Conference of Contemporary Oncology March 25-27 • Poznań, Poland For more information: www.termedia.pl/Konferencje?Invitat ion&e=372&p=2787

American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm

Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015 Northern New England Clinical Oncology Society March 27-28 • Portsmouth, New Hampshire For more information: http://nnecos.org/spring 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms. For more information, visit www.lymphcon.ch/imcl/index.php

Melanoma and Cutaneous Malignancies Meeting April 10-11 • New York, New York For more information: www.healio.com/meeting/ hemonctodaymelanoma/ home?promocode689-8045 Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919 2015 Business of Oncology Summit and 2015 Annual Meeting & Spring Session April 10-12 • Orlando, Florida For more information: www.flasco.org International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org HPV-Induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx OSMO Spring 2015 Oncology Conference April 11 • Portland, Oregon For more information: www.osmo.org/events/view/26

ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form VAHO Spring 2015 Membership Conference April 17-18 • Hot Springs, Virginia For more information: www.accc-cancer.org/ossn_network/ VA/VAHO-meetings.asp American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23-26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015

WCIO 2015 May 6-9 • New York, New York For more information: http://www.wcioevents.org Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu 54th Annual Conference of the Particle Therapy Co-Operative Group May 18-23 • San Diego, California For more information: http://ptcog54.org American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum Fourth Annual Cancer Pain Conference April 24-26 • Scottsdale, Arizona For more information: www.cancerpainconference.org

May

ASCO/C-KIN Joint Session at Cancer & the Kidney International Network’s First Annual Conference (C-KIN 2015) April 14-15 • Brussels, Belgium For more information: www.c-kin.org/conference2015/

International Society of Geriatric Oncology (SIOG): Cancer Care of the Older Adult Across the Cancer Continuum May 1 • New York, New York For more information: www.siog.org

ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile For more information: www.asco.org/international-programs/ multidisciplinary-cancer-managementcourses

The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

2015 ASCO State Affiliates’ Reception May 31 • Chicago, Illinois For more information: www.asco.org/about-asco/stateaffiliate-leadership-conference

June International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

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2015

2015 Oncology Meetings 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/index .html NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org/meetinginformation .html

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

APOS 12th Annual Conference and IPOS 17th World Congress of PsychoOncology July 28-August 1 • Washington, DC For more information: http://www.apos-society.org 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July 7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/ World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/international-programs/ multidisciplinary-cancer-managementcourses Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/ international-palliative-care-workshops 25th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org ILCA 2015 —The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org 16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/

2015 Breast Cancer Symposium September 25-27 • San Francisco, California For more information: http://breastcasym.org European Cancer Congress (ECC 2015) September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015

October 30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis and Immunology” October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/ tumorcourse Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: http://pallonc.org

November SITC 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.ncer.org/sitc-meetings/sitc2015

December 57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ Annual-Meeting/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

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Announcements

Harold Varmus, MD, Steps Down as NCI Director, Douglas Lowy, MD, Named Acting Director

arold Varmus, MD, who has led the National Cancer Institute (NCI) at the National Institutes of Health (NIH) for nearly 5 years, has announced that he will step down from his post, effective March 31, 2015.

Harold Varmus, MD

Douglas Lowy, MD

“It has been our great fortune to have Dr. Varmus at the helm of the NCI,” said NIH Director Francis S. Collins, MD, PhD. “His breadth and depth of expertise in biomedical research are unparalleled, and he’s been a tremendous colleague, invaluable to the agency.” Douglas Lowy, MD, who currently serves as the Deputy Director, will become Acting Director for NCI, beginning April 1, 2015. Dr. Lowy is a longtime NCI intramural researcher. He received the National Medal of Technology and Innovation from President Obama in 2014 for his research that led to the development of the human papillomavirus (HPV) vaccine.

Dr. Varmus to Join Weill Cornell Dr. Harold Varmus will join Weill Cornell Medical College’s faculty as the Lewis Thomas University Professor of Medicine, effective April 1. In conjunction with his appointment at Weill Cornell, Dr. Varmus will team up with the New York Genome Center as a Senior Associate Core Member to promote the use of cancer genomics throughout the New York region. In his new position at Weill Cornell, Dr. Varmus will continue to conduct research on fundamental aspects of cancer, in collaboration with investigators at the Sandra and Edward Meyer Cancer Center, led by Meyer Director Lewis C. Cantley. “This is a remarkable time in cancer research, Dr. Varmus said. “Technolog-

ical advances have enabled scientists to conduct comprehensive genomic studies that are revealing detailed portraits of cancer cells, sparking new opportunities to develop next-generation

therapies, diagnostics, and prevention strategies. I’m excited to join Weill Cornell Medical College and the New York Genome Center as we strive to reduce the burden of cancer and en-

hance human health in New York and around the world.” Dr. Varmus will also serve as a senior advisor to Laurie H. Glimcher, MD, the Stephen and Suzanne Weiss Dean of

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Announcements

Weill Cornell and provost for medical affairs for Cornell University, and will have an appointment in the Weill Cornell Graduate School of Medical Sciences.

Career Highlights Dr. Varmus has had a longstanding association with NIH, dating back to 1968–1970 when, as a young Public

Health Service Officer, he studied bacterial gene expression with Ira Pastan, MD, who is currently Chief of NCI’s Laboratory of Molecular Biology. In 1989, Dr. Varmus was Corecipient of the Nobel Prize in Physiology or Medicine for “discovery of the cellular origin of retroviral oncogenes.” From 1993–1999, he served as the Director

of NIH under President Bill Clinton. After leaving NIH and before returning to run NCI in 2010, Dr. Varmus served as President of Memorial Sloan Kettering Cancer Center. Before President Barack Obama appointed Dr. Varmus to lead NCI, he named him Co-Chair of the President’s Council of Advisors on Science and Technology. n

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014. Copyright © 2014 Clovis Oncology. DARO-101 8/14

ASCO Commends Dr. Varmus for Outstanding Leadership

ollowing news of Dr. Varmus’ planned departure from the National Cancer Institute (NCI), ASCO issued the following statement: ASCO is enormously grateful for the service and leadership of Harold Varmus, MD, as Director of the National Cancer Institute [NCI]. During Dr. Varmus’ tenure, the cancer community made important strides in modernizing cancer research for the molecular era. “Dr. Varmus established valuable initiatives that will help transform cancer research for the 21st century and improve cancer care on a global level,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, F ASCO. “He accomplished these tasks during a period when the NCI faced unprecedented financial instability.” After becoming NCI Director in June 2010, Dr. Varmus’ efforts included creating the Institute’s Center for Global Health; establishing an initiative for asking provocative questions on complex issues in cancer research; and developing the cancer component of the Precision Medicine Initiative, which was announced in January 2015. Dr. Varmus also led the transformation of the cooperative group program into the National Clinical Trials Network, which is now undertaking highly innovative clinical trials that aim to bring the benefits of precision medicine to patients. In addition, the Society was proud to have Dr. Varmus share his insights on decades of progress against cancer and the future of cancer research at ASCO’s 2011 Annual Meeting. “As NCI Director, Dr. Varmus drew on his deep knowledge of cancer biology and the nation’s biomedical research enterprise to focus the efforts of the cancer community on identifying and tackling the most vexing problems in cancer research and care,” said Dr. Schilsky. “ASCO is grateful for his service to the cancer community and the country.” n

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Reflections

The Center of Who We Are By Eric M. Genden, MD

The following essay by Eric M. Genden, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

Whether it’s a surgical procedure on the tongue, the upper jaw, or the skull base, the ability to speak, socialize, move the face—to self-express—is affected, which is a reason suicide and depression rank high among head and neck cancer patients. Unlike breast or abdominal surgery, you can’t put a shirt on and make these scars or this deformity disappear. There’s no way to hide it.

Advances in Care

here’s nothing more terrifying than having a cancer in the head and neck region—it’s the core and center of who we are—and to understand that it has to be removed or radiated or burned. No one marches for head and neck cancer. Unlike the pink-clad legions of breast cancer survivors, head and neck cancer patients often dwell in the shadows, dreading the workplace and avoiding the favorite restaurant or the friendly gin rummy game that was so much a part of their lives. My specialty, otolaryngology, is arguably different from every other type of surgery—particularly when it encompasses oncology—because there is no place you can do surgery on the human body that more affects the center of who we are. We express ourselves by speech and articulation, by the movement of our eyes and facial expressions. When we socialize with family and friends, we eat, we get a cup of coffee or something to drink; we break bread. Unfortunate as it is, much of how we do in life is based on our physical presentation. Head and neck cancer surgery almost always impacts all these things.

Eric M. Genden, MD, is Chairman of the Department of Otolaryngology and Professor of Otolaryngology-Head and Neck Surgery at Mount Sinai Hospital in New York.

During the past decade, minimally invasive surgical approaches and methods of reconstruction have become critically important in addressing these terrible challenges. Probably most significant has been the introduction of robotic surgery. In the past, if someone had a cancer in the back of the throat, to get back there and remove it safely we had to undertake a 15-hour surgery: cutting through the lip, the mandible (jaw), and the muscles of the floor of the mouth to open up and swing the jaw, much the way you’d open a book. The patient would be hospitalized for 15 days, with a 10% to 20% possibility of a permanent feeding tube or breathing tube. All this to resect a tumor no larger than a walnut.

were Mount Sinai (where I serve as Chairman of the Department of Otolaryngology) and the University of Pennsylvania (Penn Medicine). We can’t do robotic surgery in every case, but there just happens to be an epidemic of human papillomavirus (HPV)–induced cancers in people ranging in age from 35 to 70. In the next 5 years, these cancers will surpass cervical cancer in women in terms of prevalence.

Treating HPV-Induced Cancers For 100 years, patients who developed throat cancers have typically been smokers and drinkers, genetically predisposed to cancer and unable to repair the ravages of tobacco and alcohol. Such squamous cell carcinomas are aggressive and can afflict multiple areas, so the treatment needs to be equally aggressive—big surgeries with chemotherapy and radiation therapy. Most cancers in the head and neck are classified as squamous cell carcinoma, but they are more than one disease. Unfortunately, most oncologists are treating patients with HPV-induced cancer with the regimens designed for smokers and drinkers with aggressive squamous cell carcinoma. In many cases, the side effects of these treatments dramatically

No one marches for head and neck cancer. Unlike the pink-clad legions of breast cancer survivors, head and neck cancer patients often dwell in the shadows. —Eric M. Genden, MD

About 7 years ago, we introduced an approach in which a surgical robot (Intuitive’s daVinci™ system) is inserted through the mouth, and a laser is used to resect and remove the tumor. Instead of 14 hours, it’s a 2.5-hour surgery; the patient is hospitalized for 1 or 2 nights and is eating and drinking the next day. Most remarkably, it obviates the need for a potentially deforming facial incision. As a surgeon, when you don’t have to essentially decouple a patient’s jaw and face, you become a believer [in this technology] very, very quickly. The first two institutions in the world to adapt this technology—which was originally designed for cardiac, abdominal, and urologic applications—

impair a patient’s quality of life. HPV-induced squamous cell cancers are focal. The virus inoculates an area of the tonsil and creates a chronic infection that leads to a cancer, but, typically, the whole upper aerodigestive tract is not afflicted. These cancers are amenable to surgical removal with the robot. As a result, 20% of HPV-induced cancer patients will not require any radiation; 40% require radiotherapy— but in a reduced dose that significantly reduces acute toxicity and long-term chronic toxicity. How does this play out in terms of quality of life? I’ve seen a well-known chef with HPV-induced throat cancer who was scheduled to undergo high-

dose radiation and chemotherapy. He was 47 years old, a guy whose entire life revolved around his ability to taste the finest changes in food. Without question, chemotherapy and radiation would have destroyed his career. It’s no different from removing the vocal cords of a singer or amputating a surgeon’s hand. Since his procedure, he’s been cancer-free for 4 years and has opened two more successful restaurants. (See “It Sounds Crazy, but Cancer Has Made Me a Better Chef,” in the December 1, 2013, issue of The ASCO Post.)

Medicine Is Who I Am Ultimately, our patients become mirrors on which our own lives and careers are reflected. My father was a Navy fighter pilot who served three tours during the Vietnam War. Like the character in the movie The Great Santini, he was a perfectionist who insisted I follow in his footsteps. When I told him it just wasn’t in the cards, he said, “Well, if you have to go into medicine, for God’s sake, be a surgeon! On the flight deck, the only people we respect are the flight surgeons!” And so I did. I like to think I inherited my father’s passion and focus. Like flying Phantom jets, medicine is not a job but a way of life. It becomes who you are. Some people go to work and leave work and can put it all behind them; then there are others whose work, life, and family all intersect. There is no division. It’s not a thing you can face or misinterpret. It is the essence of who we are as doctors.

Coming Face to Face With the Unknowable As I’ve grown older, I find myself staring more deeply into the mirror. When I was a young surgeon, the challenge was to get patients to survive, to beat the cancer, and to get them reconstructed. My questions were, “Are you swallowing food? Are you able to eat without difficulty? Is there much pain?” Now I’m more focused on the deeper quality of life. Do they go out in public and feel good about themselves? Are they interacting with their family? Do they wake up every morning and say, “Boy, I’m glad I’m alive! Life is good for me and better than I had expected!”? Fulfillment comes with putting people back into society. With head and neck cancer, you can cure a lot of continued on page 88

Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

Indication » GRANIX 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. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » 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 treatment-emergent 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 Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

The ASCO Post | MARCH 25, 2015

PAGE 88

Reflections Eric M. Genden, MD continued from page 86

people, but that doesn’t mean you’re putting them back in the workforce. At Mount Sinai, we’ve been able to do that. We have a strong belief that quality of life and the ability to function are as important as removing the cancer. Finally, in the mirror, we come face

to face with the unknowable: things that seemingly defy the hard and fast dictates of science and medicine and carry us to some higher plane, where courage and determination, and yes, love are all that matter. Early in my career, an Indian woman with a horrible oral cancer came to see me. She’d had about six or seven opera-

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 nonmyeloid 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 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 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)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] 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 non-US-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.

tions. Now the tumor had come back in quite an extensive way. These were the days when we first started removing pieces of the jaw and the tongue and rebuilding them by transplanting tissue. We didn’t have a good way to do it. It would leave people so badly deformed they couldn’t eat or drink. She’d been to all the local places and

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 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-USapproved 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. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 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 Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an 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 (AUC) 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. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

had been turned away. I said, “Look, your tumor is too advanced. You need to have palliative care and pain control because there’s not much we can do.” She begged and begged me to help her. “Why don’t you come back next week, and we’ll align you with our oncologists,” I finally said. “They’ll give you palliative chemotherapy.” When she came back, she brought her 7-year-old daughter with her. At one point, the patient stepped away for a moment and the little girl essentially said to me, “You have to help her. You have to operate on her because if you don’t, nobody else will.” It was the first time, in fact, the only time, this has ever happened to me. I told her there was probably a 5% chance she’d actually beat this cancer, but we’d give it a try. We took out her jaw and half her tongue and rebuilt the jaw and tongue using the bone and skin from her lower leg. Now, it’s 15 years later, and I still get cards from her and her daughter. The little girl has graduated from college. And she still has her mom with her. I can see them in the mirror. n

The ASCO Post

@ASCOPost

ASCOPost.com | MARCH 25, 2015

PAGE 89

Patient’s Corner

Having Cancer So Early in Life Gave Me Purpose

Receiving a diagnosis of choroid plexus carcinoma when I was 24 forced me to follow my passion. The experience has changed my life. By Sheri Sobrato Brisson, MA, as told to Jo Cavallo

had every classic brain tumor symptom in the book—severe headaches, dizziness, morning nausea—which plagued me for 16 years, starting when I was 8. In college, if I allowed myself to sleep more than 4 hours a night, the morning headaches, which were centered on the top of my head, were so severe, I chose to sleep less to try to avoid the pain. This left me so exhausted during the day that it was difficult to concentrate on my schoolwork.

a vengeance, they would last 3 weeks. I was so young when the symptoms started that no one ever suspected I could have a brain tumor. Finally, when I was 24, I had a CT scan of my brain, which showed a malignancy in the fourth ventricle. The pathology report said the diagnosis was choroid plexus carcinoma. The cancer was so aggressive, my oncologist said I probably had only 6 months to live. Although the news was, of course,

Despite the lingering physical and emotional effects of having cancer at such a young age, I have to say, cancer has given me much more than it has taken away. —Sheri Sobrato Brisson, MA

Persistent Symptoms My parents continually tried to find the source of the problem, and over the ensuing years, I was diagnosed with various ailments, including migraine headaches, food allergies, histamine sensitivities, and even a sleep disorder. No matter how I adjusted my diet and lifestyle, the headaches persisted, although their patterns changed over the years, sometimes giving me a 6-month reprieve and then coming back with such

frightening, since I had had this cancer for most of my life, I didn’t believe it was now about to kill me. I was prescribed an aggressive course of treatment, which included surgery, then radiation therapy followed by combinations of chemotherapy, including vincristine, carboplatin, cisplatin, and cytarabine, the last delivered via a shunt inserted directly to my brain. Because the tumor was lodged on my brain stem, the surgeon could not remove it all with-

out jeopardizing my functioning, so I still have a remnant of the tumor left. Thankfully, the mass has remained stable for the past 28 years. I know how lucky I am to have staved off recurrent disease for nearly 3 decades. And although I have some hearing loss and peripheral neuropathy in my hands from the chemotherapy, there are currently no other late effects from my treatment.

Process of Self-Reflection Despite the lingering physical and emotional effects of having cancer at such a young age, I have to say, cancer has given me much more than it has taken away. Driven to succeed in everything I did, early in my career I worked on Wall Street and then was the number-two employee for a company that developed worksite child care. However, I was on a path that at the core was not who I am. So at 24, I was forced to go through a process of self-reflection not many people that age go through, and it gave me the opportunity to follow my passion of working with children and families coping with serious illness. The experience has changed my life. I went to graduate school for a degree in psychology and for over 15 years facilitated support groups for children with cancer and their families for such organizations as the American Cancer Society, the National Brain Tumor

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

Foundation, and Packard Children’s Hospital in California.

The Meaning of Cancer Working with other cancer survivors and listening to their stories about how their disease affects their lives has made me aware of how important it is for oncologists to ask their patients not just about the symptoms they are experiencing, but about what having the disease has meant to them. The information gleaned from these conversations will not only help oncologists gain an understanding of how best to support their patients emotionally, it may also impact the treatment plan they prescribe. Having cancer has made me a more authentic person and deepened my relationships with family members and friends. And although it initially stripped away my identity, it allowed me to concentrate on my core values, and that is how I rebuilt my life. I’m so grateful to have learned these lessons at such a young age. I know that this is the life I was meant to live. n Sheri Sobrato Brisson, MA, is the Founder and Manager of Resonance House Publishing and the coauthor with Rose Offner, MFA, of Digging Deep: A Journal for Young People Facing Health Challenges (Resonance House, 2014). She lives in Atherton, California, with her husband and two children.

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

For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

XGEVA VA® 120 mg Q4W (n = 2,862) VA

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001

†

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group. P value for superiority.

†

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab). Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. • RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity • XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page. REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:3082-3092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:2215-2222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_XGEVA_Tabloid_BS_V10_8pt_r13.indd 1

Body System GASTROINTESTINAL Nausea Diarrhea GENERAL Fatigue/ Asthenia IN VESTIGATIONS Hypocalcemiab Hypophosphatemiab NEUROLOGICAL Headache RESPIRATORY Dyspnea Cough

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

31 20

32 19

18 32

9 20

21 15

18 15

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes. • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva. Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. • Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy. USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation. Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated. Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake. Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a singleuse vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved. Printed in USA. 8/11/14 11:56 AM

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INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva. WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently. Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. 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 other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the

jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/ oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

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In the News End-of-Life Care

Recognizing Physical Signs Associated With Impending Death Can Assist Clinicians, Patients, and Caregivers With Complex Decisions By Charlotte Bath

n a recently published study of patients with advanced cancer whose status was systematically documented twice a day, from the time of admission to a palliative care unit until death or discharge, investigators identified eight physical signs associated with death within 3 days. Taken together with five physical signs reported earlier, “these objective bedside signs may assist clinicians, family members, and researchers in recognizing when the patient has entered the final days of life,” David Hui, MD, MSc, and colleagues reported in Cancer.1 That recognition, in turn, can inform physicians’ recommendations concerning continued treatment, as well as personal decisions by caregivers about maintaining a constant presence at the patient’s bedside and alerting others family members of the impending death. The eight identified signs, including seven neurologic conditions and one bleeding complication, had 95% or higher specificity and likelihood ratios

from 6.7 to 16.7 (with likelihood ratios > 5 suggesting good and > 10 suggesting excellent diagnostic value) for predicting death within 3 days.

Rehabilitation Medicine and Department of General Oncology at The University of Texas MD Anderson Cancer Center, Houston.

What is important about this study is that this is the first time we have systematically examined patients for these signs from the very first day they enter our unit. —David Hui, MD, MSc

Dr. Hui told The ASCO Post that he had been contacted by several reporters and that the study has been the subject of several editorials and perspectives. Moreover, he expects other articles to evolve over time as the study is discussed in the context of end-of-life care in general. Dr. Hui is Assistant Professor, Department of Palliative Care and

Investigating the Process of Dying The study reported in Cancer was a planned secondary analysis of the Investigating the Process of Dying study, a prospective, longitudinal, observational study that systematically documented an array of clinical signs every 12 hours among 357 consecutive patients with

advanced cancer admitted to acute palliative care units at two tertiary care cancer centers—MD Anderson and Barretos Cancer Hospital in Brazil. The average age of the patients was 58; 55% were female, 65% were of Hispanic origin, and 28% had a diagnosis of gastrointestinal disorder. Of the 357 patients, 203 (57%) died at the end of the admission, the investigators reported. The researchers compiled a list of 62 clinical signs, selecting 10 as target signs based on their prevalence in the literature. They had also previously identified five physical signs “that were highly diagnostic of impending death.” Based on their findings, which were published in The Oncologist2 (and subsequently reviewed in The ASCO Post3), these five signs are pulselessness of the radial artery, decreased urine output, Cheyne-Stokes breathing, respiration with mandibular movement, and death rattle. continued on page 94

Caregivers May Want to Know About a Patient’s Impending Death but May Be Afraid to Ask By Charlotte Bath

he likelihood of impending death of patients with advanced cancer “is one of those questions that many people want to know about, but they are too afraid to ask,” David Hui, MD, MSc, said in an interview with The ASCO Post. Dr. Hui is lead author of a study, published in Cancer, on clinical signs of impending death and Assistant Professor, Department of Palliative Care and Rehabilitation Medicine and Department of General Oncology at The University of Texas MD Anderson Cancer Center, Houston.

his prognosis?’ If they say, ‘I really do not want to hear anything about that,’ then we will be careful not to potentially traumatize them.” In many cases, Dr. Hui noted, family members already realize the patient is dying, but will say, “I just don’t know when it is going to happen and I need to plan ahead. I need to be able to decide whether I am going to stay tonight. If he might die over the next few days, I really want to spend the time here. I want to make sure that I get my family members in. When is a good time to get them?”

Foreseeing and Foretelling

Individualized Decisions

Physicians can use the clinical signs to estimate probability of death within 3 days, “foreseeing” what is likely to happen to the patient and “foretelling this to the family,” Dr. Hui stated. Although sometimes afraid to bring up the topic of death, “a majority of families do want to understand what is happening to the patient,” Dr. Hui said. “Of course, we will ask them, ‘Do you want to know more about

“Of course, each patient is unqiue. But when the probability of impending death is very high, then we can start to think about making decisions based on this diagnosis,” Dr. Hui stated. “For example, should we continue the daily blood work if the patient has only 3 days to live and the blood work is not going to contribute further to the patient care? This is a very individualized decision that the team needs

to make together with the family. The family will get a better sense of what to do and plan ahead,” Dr. Hui said. “[Impending death] is not just a simple diagnosis but one that is made with great care and often in consultation with other members of the team looking after the patient. If we all agree this is happening, then we will feel confident in talking to the family about this. We can say, ‘Based on our understanding, there is a very high chance that your loved one will die within the next 3 days.’ That can help families plan ahead during this very stressful time,” Dr. Hui added. “The more data we have, the more confident that we get. The diagnosis of impending death is one where we don’t want to make a mistake,” he stressed. “Having data to back up that confidence helps me a lot,” Dr. Hui said. “Before this study, I would say, ‘I think this is going to happen. There is a high chance, but I can’t give you a number.’ Now I know there is an 80% to 90% chance that the patient is go-

ing to die in the next 3 days … or even potentially in the next hour,” Dr. Hui clarified.

Caregivers Often Notice the Signs “When we explain the process of dying to families, we may tell them that the patient’s breathing might change or that it might be hard to recognize the pulse. And then the families say, ‘You know, I noticed that already,’” Dr. Hui said. “They are the ones who are by the bedside a lot of the time, and some of these signs are not difficult to detect.” Dr. Hui said that if the reliability of the signs to predict impending death is confirmed by further studies, they could prove more useful to family caregivers as well as clinicians. “Some of the signs may contribute to our better understanding of the very end of life and can help support decision-making. But we need to recognize that these signs are just one piece of the big puzzle when we do make decisions like that,” Dr. Hui concluded. n

The ASCO Post | MARCH 25, 2015

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In the News Signs of Impending Death continued from page 93

Powerful Predictors The secondary analysis looked at the remaining 52 physical signs. “The 10 signs that we looked at initially were the more commonly cited signs that people were already pretty sure about, and for this study, we were looking into the things that we are not as sure about. We found that 8 of these 52 signs were quite powerful in predicting death,” Dr. Hui said in an interview with The ASCO Post. The researchers explained: To determine the diagnostic utility of each sign, we computed the sensitivity, specificity, positive [likelihood ratio], and negative [likelihood ratio] for death within 3 days. Positive [likelihood ratios] indicate how many times the sign of interest appeared in patients who died within 3 days in comparison with patients who did not die within 3 days. Positive [likelihood ratios] > 5 and > 10 suggest good and excellent discriminatory test performance, respectively. The last 3 days was chosen as the cutoff for impending death because our previous study showed the emergence of many of the signs of impending death during this period, and knowing a patient is within the last 3 days of life could affect many medical decisions such as hospital discharge, discontinuation of prescription medications, artificial nutrition, and use of life- support measures.

The eight physical signs identified as highly diagnostic of impending death “occurred in 5% to 78% of the patients within the last 3 days of life, had a late onset, and had a high specificity (> 95%) and a high positive [likelihood ratio] for death within 3 days,” the authors noted. Listed from

high to low likelihood ratios, the 7 neurologic signs included nonreactive pupils (likelihood ratio = 16.7), inability to close eyelids (likelihood ratio = 13.6), grunting of vocal cords (likelihood ratio = 11.8), decreased response to verbal stimuli (likelihood ratio = 8.3), drooping of the nasolabial fold (likelihood ratio = 8.3), hyperextension of the neck (likelihood ratio = 7.3), and decreased response to visual stimuli (likelihood ratio = 6.7). In addition, upper gastrointestinal bleeding had a likelihood ratio of 10.3. On multivariate analysis, two physical signs (ie, decreased response to verbal stimuli and drooping of the nasolabial fold) were identified as independently significant, according to the study report. “However, the other physical signs with high positive [likelihood ratios], when present, could still be helpful in the diagnosis of impending death. This is particularly true because patients often do not present with all the physical signs at the same time.” It is important for clinicians to realize, Dr. Hui noted, that “if they don’t see the signs, it doesn’t mean that their patient won’t die in the next 3 days. These signs don’t always occur in patients. So the flip side is not always true.”

Systematic Examination From Day 1 Physicians have been aware of some of the signs of impending death, such as decreased level of consciousness, responsiveness, grunting of vocal chords, nonreactive pupils, Dr. Hui acknowledged, “but prior to this study, these signs had not really been examined systematically. What is important about this study is that this is the first time we have systematically examined patients for a large and comprehensive array of these signs in the

largest population to date from the very first day they enter our unit. Twice a day, we monitored these signs, and we continued that monitoring until they either died or were discharged.” Previous studies that have looked at signs of impending death “tended to start monitoring when people are already recognized as dying, and so there may be potential bias. That is why we started out from the very beginning to try to get an unselected and consecutive patient population to make sure that our findings are valid,” Dr. Hui added.

Signs Add Up to Higher Probability In addition to the reported results, further analysis of the data showed that a “higher number of signs tends to be associated with a higher probability of death,” Dr. Hui said. “Just to put things in context, let’s say that when patients come into a palliative care unit, there is maybe a 30% to 40% chance that they would die over the next 3 days.” If a patient, however, displays one of the eight signs, and that sign has a likelihood ratio of 10, “it would increase the probability to about 80% to 90% that they would die in the next 3 days. Then, if another sign is added, the probability of death would rise above 90%,” Dr. Hui added. Additional signs could raise the probability to 95% or 98%. “That is how we generally can use these signs,” Dr. Hui said. More signs can be confirmatory, but “even just one or two of these signs can be very informative.”

Next Generation of Studies Dr. Hui and his colleagues cautioned that the results concerning the reliability of the eight signs to predict death within 3 days among patients with advanced cancer should be considered preliminary.

“At this time, I would say that they provide good preliminary information, but, of course, I always want more confirmatory data,” Dr. Hui stated. “I do believe that this finding is at least applicable to the study population that we had, which was a unique population in the palliative care unit, as not too many hospitals have palliative care units.” Further studies “are actively in the planning phase right now,” Dr. Hui said. “We are not enrolling patients yet, but based on the findings from both studies, we are crafting the next generation of studies to further confirm our findings.” Whether the next round of studies will involve Dr. Hui’s study partners in Brazil or others “depends on funding opportunities,” he noted, “but we definitely want to expand into other populations, such as those in hospice care. A large proportion of people are under hospice care in the last days of life, and I think it is very important to see whether these signs hold outside of a hospital. Generally we believe they are universal in nature, but what distinguishes science from art is that we really want to get the numbers right by documenting things carefully.” n

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

References 1. Hui D, dos Santos R, Chisholm G, et al: Bedside clinical signs associated with impending death in patients with advanced cancer: Preliminary findings of a prospective, longitudinal cohort study. Cancer 121:960-967, 2015. 2. Hui D, dos Santos R, Chisholm G, et al: Clinical signs of impending death in cancer patients. Oncologist 19:681-687, 2014. 3. Piana R: Identifying impending death helps patients and caregivers. A conversation with David Hui, MD, MSc. ASCO Post, September 1, 2014.

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ASCOPost.com | MARCH 25, 2015

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In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Selenium Supplements After Diagnosis of Nonmetastatic Prostate Cancer May Raise Prostate Cancer Mortality Risk “Selenium supplementation of 140 or more μg/d after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality,” according to a prospective study following 4,459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-up Study from 1988 through 2010. “Caution is warranted regarding usage of such supplements among men with prostate cancer,” Stacey A. Kenfield, ScD, of the University of California, San Francisco, and coauthors advised in the Journal of the National Cancer Institute. The Health Professionals Follow-up Study is a prospective cohort study of 51,529 U.S. male health professionals between the age of 40 and 75 at the time of enrollment in 1986. Participants completed a baseline questionnaire that included extensive data, such as a medical history and lifestyle factors (diet and supplement use), and detailed information on the use and dose of supplements every 2 years. “Total selenium supplement intake was calculated as the sum from multivitamins and selenium supplements,” the investigators explained. The categories of total selenium supplement dosage follow: nonuser, 1 to 24 μg/d, 25 to 139 μg/d, and 140 or more μg/d. “We also calculated total duration of use to assess whether the association between selenium supplement use and prostate cancer mortality differed by duration,” the authors noted. The primary outcome in the current study was prostate cancer mortality. Secondary outcomes were biochemical recurrence, overall mortality, and cardiovascular mortality. After study participants reported a prostate cancer diagnosis, the investigators obtained medical records “to confirm the diagnosis and record the clinical T stage, Gleason score, treatments, prostate-specific antigen (PSA) values at diagnosis, PSA levels after treatment (to identify events of biochemical tumor recurrence), and metastasis. Participants also completed biennial follow-up questionnaires to update data on treatments, PSA levels, and clinical progression,” the researchers explained. “We documented 965 deaths, 226 (23.4%) from prostate cancer and 267 (27.7%) from cardiovascular disease, during a median follow-up of 8.9 years. In the

biochemical recurrence analysis, we documented 762 tumor recurrences during a median follow-up of 7.8 years. Crude rates per 1,000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140

or more μg/d,” the researchers reported. “In multivariable analyses, men who consumed 1 to 24 μg/d, 25 to 139 μg/d, and 140 or more μg/d of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73–1.91), 1.33 (95% CI

= 0.77–2.30), and 2.60-fold (95% CI = 1.44–4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, Ptrend = .001. There were no statistically significant associations between continued on page 96

ASCO in

Act io n Check out ASCO in Action on ASCO.org ASCO in Action covers the latest news on policy developments and ASCO’s advocacy positions on everything from Medicare reimbursement to federal funding for clinical cancer research to patient access to high-quality care. Find timely information on clinical affairs, government relations, and quality of care issues that affect cancer practice, research, and patient care. ASCO in Action also includes a variety of advocacy tools for ASCO members, including policy priorities, policy statements, and ASCO’s ACT (Alert Congress Now) Network. Check out ASCO in Action today!

ascoaction.asco.org Access all the latest policy and advocacy news in the Advocacy section of ASCO.org.

The ASCO Post | MARCH 25, 2015

PAGE 96

In the Literature Emerging Clinical Data continued from page 95

the use of selenium supplements and biochemical recurrence, cardiovascular disease mortality, and overall mortality. The authors noted that their study “is the first study to examine the relation of selenium supplements taken after diagnosis with risk of prostate cancer mortality.” Findings from previous studies of selenium supplementation by healthy men have included an inverse relationship between selenium levels and incidentadvanced prostate cancer, no association for incident prostate cancer but an increased risk for high-grade prostate cancer, and an increased risk of prostate cancer mortality when selenium supplements were taken prior to diagnosis. “These data underscore the potentially complex and variable role that lifestyle factors may play in the long etiologic course of some cancers, in particular that risk factors for incidence may be very different from those for mortality,” the investigators observed. “Associations between a given exposure and incident prostate cancer presumably reflect biologic effects of the exposure in the prostate gland, whereas associations with metastatic/fatal disease may reflect effects of the exposure in the prostate (if the tumor is still present) and/or effects on other organs or systems that influence the likelihood of metastatic disease developing and spreading. Additional studies with long-term follow-up of lifestyle factors before and after cancer diagnosis are warranted.” Kenfield SA, et al: J Natl Cancer Inst 107:360, 2014 (print January 2015).

BREAST CANCER Nearly Half of Women Taking Tamoxifen for Primary Prevention Discontinue Its Use Before 5 Years After 4.5 years of taking tamoxifen for primary prevention of breast cancer, 46% of women discontinued its use, according to research conducted within the Sister Study, a prospective cohort of women who had a sister diagnosed with breast cancer but did not have breast cancer themselves. Eligible women were between the ages of 35 and 74 at enrollment. Researchers examined characteristics associated with initiating and discontinuing tamoxifen for primary prevention of breast cancer. Tamoxifen has been approved by the U.S. Food and Drug Administration for primary prevention of breast cancer since 1998. “The U.S. Preventive Servic-

es Task Force (USPSTF) recently published a recommendation statement for risk reduction of primary breast cancer that encourages clinicians to offer to prescribe tamoxifen or raloxifene to reduce breast cancer risk,” Hazel B. Nichols, PhD, of the University of North Carolina Gillings School of Global Public Health, Chapel Hill, noted in the Journal of the National Cancer Institute. “National estimates indicate that less than 1% of eligible women use tamoxifen for prevention. It is unknown why so few women use tamoxifen for breast cancer prevention, although vasomotor symptoms, increased risk of adverse health effects, and difficulties in estimating or communicating risk-benefit profiles can be deterrents.” From 2003 to 2009, the Sister Study recruited 50,884 women in the United States and Puerto Rico. The current trial “identified 788 tamoxifen users and 3,131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer),” the investigators stated. Study participants self-reported tamoxifen use, ages when they started and stopped taking tamoxifen, and total duration of its use at enrollment. Women were categorized according to a risk-benefit index recommended by the USPSTF and the National Comprehensive Cancer Network (NCCN). “Briefly, the risk-benefit index classifies women according to the level of evidence (none, moderate, strong) for tamoxifen benefits (breast cancer and fracture prevention) to exceed the risk of serious side effects (endometrial cancer, stroke, pulmonary embolism, deep vein thrombosis, and cataract) using age, 5-year projected risk of invasive breast cancer, hysterectomy, and race,” the authors explained. “Overall, 74% of classified tamoxifen users had a favorable (defined as moderate to strong evidence for benefits to exceed risks) risk-benefit profile, and 20% had no evidence that the benefits exceeded risks; the risk-benefit index could not be calculated for 6%,” the researchers reported. “Absence of expected benefit was most pronounced for older women, African Americans, and those with an intact uterus,” the authors added. “Discontinuation of tamoxifen before the recommended 5 years (46%) was somewhat greater than the 24% to 36% nonadherence reported in prevention trials,” the authors acknowledged, but it “is closely aligned with a recent metaregression estimate of 47.2% 5-year

discontinuation of tamoxifen as adjuvant endocrine therapy.” The median duration of tamoxifen use among those who discontinued treatment was 3 years. “Raloxifene use after tamoxifen was associated with early discontinuation, potentially because of the availability of an alternative preventive therapy,” the researchers wrote. Women who reported a family history of breast cancer, BRCA1/2 testing, or positive mutation status appeared less likely to complete 5 years of tamoxifen. The authors concluded: “While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before 5 years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention.” Nichols HB, et al: J Natl Cancer Inst 107:354, 2014 (print January 2015).

CHRONIC PAIN Key Evidence Gaps and Research Priorities Should Be Addressed So Physicians Can Identify Patients Most Likely to Benefit From Opioids Key evidence gaps and research priorities must be addressed “so that physicians can recognize patients for whom opioids are most appropriate and use optimal regimens for these patients,” according to the National Institutes of Health (NIH) Pathways to Prevention Workshop final report on the role of opioids in the treatment of chronic pain. The workshop panel called for federal and nonfederal agencies to sponsor research “to identify which types of pain,

specific diseases, and patients are most likely to benefit and incur harm from opioids,” as well as the development of multidisciplinary pain interventions. “In the absence of definitive evidence, clinicians and health-care systems should follow current guidelines by professional societies about which patients and which types of pain should be treated with opioids and about how best to monitor patients and mitigate risk for harm,” the panel recommended. Among the clinical issues considered by the panel were the challenge of appropriate patient selection and how the type of pain could influence its management. “Data were presented on three distinct pain mechanisms: peripheral nociceptive (caused by tissue damage or inflammation), peripheral neuropathic (caused by damage or dysfunction of peripheral nerves), and centralized (characterized by a disturbance in the processing of pain by the brain and spinal cord). Persons with more peripheral nociceptive pain (such as acute pain due to injury, rheumatoid arthritis, or cancer pain) may respond better to opioid analgesics,” the panel stated. The lead author of the report was David B. Reuben, MD, of the David Geffen School of Medicine at the University of California, Los Angeles. The abridged report is published in Annals of Internal Medicine, and the full report at is available at the NIH website https://prevention.nih.gov/programsevents/pathways-to-prevention/ workshops/opioids-chronic-pain/ workshop-resources#finalreport. n Reuben DB, et al: Ann Intern Med. January 13, 2015 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | MARCH 25, 2015

PAGE 97

Perspective Issues in Oncology

Health-Care Fraud and Abuse continued from page 1

Abuse Control Project was started by the Department of Health and Human Services. This project allocates funds and resources to fight federal healthcare fraud and abuse, with much of the funding coming from financial recoveries obtained the prior year. The program reports annually to the public on the financial success of the recovery efforts.

of these cases, and $2.6 billion (71% of non-qui-tam-related recoveries) in recoveries. Health systems and related organizations accounted for 13 cases (25% of these cases), totaling $384 million in recoveries (10% of recoveries). Hospitals accounted for 10 cases (20% of the cases), totaling $347 million in recoveries (5% of recoveries).

Comprehensive Review

Dr. Lu is Assistant Professor, Department of Clinical Pharmacy and Outcome Sciences, University of South Carolina College of Pharmacy, Columbia. Dr. Chen and Dr. Quereshi are Assistant Professors, Health Services Policy and Management, Arnold School of Public Health, Columbia, South Carolina. Dr. Sartor is Medical Director, Tulane Cancer Center, New Orleans. Dr. Bennett is Frank P. and Josie M. Fletcher Professor of Pharmacy, University of South Carolina College of Pharmacy, Columbia.

These findings provide the first comprehensive look at the huge financial fines paid in the course of providing health care in the current era. In particular, financial recoveries from completed health-care fraud investigations returned an estimated $15 billion to $16 billion to the federal government between 2006 and 2011,

while qui tam relators (whistle-blowers) received an estimated $2 billion to $3 billion for their collaboration. Most importantly, the space of health-care fraud is dominated by pharmaceutical manufacturers—much more than they had previously. Pharmaceutical manufacturers now account for 30% continued on page 98

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We comprehensively reviewed major recently completed health-care fraud cases (2006–2011), attempting to overcome limitations of prior published reviews of health-care fraud. These limitations included a focus on cases initiated by qui tam relators or on specific sectors (pharmaceuticals and Medicaid, in particular).1-4 All cases were recovered under the federal False Claims Act, the primary legislation used to investigate health care fraud and abuse. Data sources included Lexis/ Nexis News (terms: “health care fraud,” “False Claims Act,” and “qui tam”), Taxpayers Against Fraud, and Department of Justice websites (2006–2011). Cases with recoveries over $5 million were included. Cases were evaluated as involving qui tam relators (whistle-blowers) or not, as relator cases historically account for 90% of all cases and 90% of all recoveries. 3 As illustrated in Table 1 (page 98), we found that between 2006 and 2011, 123 qui tam health-care fraud cases concluded, totaling $15.7 billion in recoveries (84% of the total recoveries). Pharmaceutical manufacturers accounted for 31% of these cases and $11.3 billion (72%) in recoveries. Health systems and related organizations accounted for 30 cases (24% of these cases), totaling $2.4 billion in recoveries (16% of recoveries). Hospitals accounted for 20 cases (16% of these cases), totaling $716 million in recoveries (5% of recoveries). Fifty-two cases not involving qui tam relators (whistle-blowers) also concluded during these years, totaling $3.7 billion in federal recoveries (16% of the total recoveries). Pharmaceutical manufacturers accounted for 31%

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PAGE 98

Perspective Health-Care Fraud and Abuse continued from page 97

of all federal health-care fraud cases and 70% of recoveries vs 4% of cases and 39% of recoveries previously (prior to 2006), 3 while cases not initiated by qui tam relators are increasingly important. Specific fraudulent activities involving the pharmaceutical industry in both time periods included overcharging Medicaid and off-label marketing. However, it should be noted that concealing findings on drug safety is a new fraudulent activity (accompanied by large fines and settlements) that has not been reported previously—as outlined in the $3 billion settlement with GlaxoSmithKline.4 Health-care provider systems and hospitals are emerging areas for False Claims Act investigation, now accounting for 25% of False Claims Act cases and 15% of recovered funds. Our findings suggest that accountability initiatives recently developed for banks and their executives5 should be extended to include all sectors of health care; executives of these corporations must be held personally liable if the corporate culture of the health-care industry is to be improved and fraud decreased. These findings have important implications for health care in general, and the

It is incumbent on oncologists to pay close attention to concerns such as off-label marketing and marketing of pharmaceuticals where safety considerations are not appropriately disseminated, and where kickbacks may be occurring. — Z. Kevin Lu, PhD, Brian Chen, JD, PhD, Zaina Qureshi, PhD, MPH, Oliver Sartor, MD, and Charles Bennett, MD, PhD, MPP (left to right)

discipline of oncology in particular. Oncology pharmaceuticals account for the majority of high-priced pharmaceuticals, and, hence, are the target of many of the federal investigations related to the False Claims Act. It is incumbent on oncologists to pay close attention to the medical necessity or safety of pharmaceuticals prescribed, and where kickbacks may be occurring. As oncologists, we can play an important role in the health-care system—particularly when oncology pharmaceuticals are involved. n Disclosure: This work was funded partly

2. Almashat S, Wolfe S: Pharmaceutical industry criminal and civil penalties. Available at www.citizen.org. Accessed February 9, 2015. 3. Kesselheim AS, Studdert DM: Whistleblower-initiated enforcement actions against health care fraud and abuse in the United States, 1996 to 2005. Ann Intern Med 149:342-349, 2008. 4. Department of Justice, Office of Public Affairs: GlaxoSmithKline to plead guilty and pay $3 billion to resolve fraud allegations and failure to report safety data. Available at www.justice.gov. Accessed February 9, 2015.

by the National Cancer Institute, the American Cancer Society, the South Carolina SmartState Program, and an unrestricted grant from Doris Levkoff Meddin to the South Carolina College of Pharmacy Center for Medication Safety and Efficacy. Drs. Lu, Chen, Qureshi, Sartor, and Bennett reported no potential conflicts of interest.

References 1. Institute of Medicine: Best care at lower cost. Washington, DC, National Academies Press, 2012. Available at www.iom. edu. Accessed February 9, 2015.

Table 1: Frequency of Enforcement Actions by Industry Type and Qui Tam Relator Status Qui Tam Relator Cases

Non–Qui Tam Relator Cases

Industry

Number of Cases (%)

Total Recoveries (millions of $) (%)

Mean Recoveries (millions of $)

Number of Cases (%)

Total Recoveries (millions of $) (%)

Mean Recoveries (millions of $)

Pharmaceutical manufacturer

38 (30.9%)

11,259 (71.6%)

296

16 (30.8%

2,636 (70.8%)

165

132

Health system

9 (7.3%)

1,385 (8.8%)

154

9 (17.3%)

304 (8.2%)

120

Other health-care related organization

21 (17.1%)

1,114 (7.1%)

4 (7.7%)

80 (2.1%)

Hospital

20 (16.3%)

716 (4.6%)

10 (19.2%)

200 (5.4%)

Medical equipment company

8 (6.5%)

294 (1.9%)

4 (7.7%)

347 (9.3%)

−50

Laboratory services provider

3 (2.4%)

363 (2.3%)

121

0 (0%)

121

Pharmacy or pharmacy chain

5 (4.1%)

152 (1.0%)

3 (5.8%)

81 (2.2%)

Home health-care provider

3 (2.4%)

186 (1.2%)

2 (3.8%)

18 (0.5%)

Physician practice or individual physician group

10 (8.1%)

149 (0.9%)

0 (0%)

Billing company

3 (2.4%)

71 (0.5%)

2 (3.8%)

33 (0.9%)

Long-term care facility

2 (1.6%)

22 (0.1%)

1 (1.9%)

20 (0.5%)

−9

Ambulance medical transportation company

1 (0.8%)

9 (0.1%)

1 (1.9%)

7 (0.2%)

Total

123 (100.0%)

15,720 (100.0%)

128

52 (100.0%)

3,725 (100.0%)

Difference in mean recoveries for qui tam relator vs non–qui tam relator recoveries (millions of dollars).

Mean Difference a

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