TAP Vol 6 Issue 9 by Harborside Press LLC

NCCN Guidelines Updates 12–15 | HER2-Positive Breast Cancer

96–97

| Pembrolizumab in Melanoma

123–124

VOLUME 6, ISSUE 9

MAY 25, 2015

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

ASCO Annual Meeting

Docetaxel Combined With Hormone Therapy Extends Survival in Advanced Prostate Cancer

Illumination and Innovation: Transforming Data Into Learning

By Alice Goodman By Peter Paul Yu, MD, FACP, FASCO

esults from the STAMPEDE trial showed that the addition of docetaxel to standard hormone therapy improved overall survival by a median of 10 months over hormone therapy alone in men with newly diagnosed, advanced, hormone therapy–naive prostate cancer.1 The study also showed that zoledronic acid added no benefit over standard hormone therapy or standard hormone therapy plus docetaxel. “Docetaxel improved survival in patients with newly diagnosed metastatic prostate cancer starting hormones, and it should be routinely used in these patients as part of upfront treatment. In nonmetastatic disease, docetaxel should be offered to men about to start hormones for the first time, because it prolongs failure-free survival. There is some uncertainty regarding its effect on overall survival in men with nonmetastatic disease, and longer follow-up is needed. It’s clear that zoledronic acid does not benefit patients with advanced prostate cancer and should not be offered as upfront treatment,”

said lead author Nicholas David James, MD, PhD, of the University of Warwick in Coventry, United Kingdom, at a press briefing held in advance of the ASCO Annual Meeting, where the new data will be presented (abstract 5001, being Nicholas David James, presented May 31, 2015). MD, PhD STAMPEDE is the largest randomized clinical trial conducted to date of treatment for prostate cancer. Since 2005, more than 6,500 men have been enrolled, and the standard of care arm continues to enroll patients. The innovative, multiarm, adaptive design discards ineffective treatments and includes newer effective treatments based on trial results. The study continues to assess newer treatments.

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ASCO Annual Meeting

Novel Agent Elotuzumab Added to Lenalidomide/Dexamethasone Extends Progression-Free Survival in Multiple Myeloma By Caroline Helwick

he ASCO Annual Meeting is our Society’s premier event and without a doubt one that is highly anticipated by the oncology world. The success of the meeting stems from the desire to share with each other our data and the knowledge we have gleaned from those data over the course of the past year. The diversity of research interests of ASCO members has led to a record-breaking number of nearly 6,000 abstracts this year. Alongside the original research of the Scientific Program is the Educational Program, which provides attendees with a synthesis of emerging data and knowledge. Data and knowledge on one hand and learning on the other are two sides of the same coin. The theme for ASCO 2015 is Illumination

at a press briefing in advance of the meeting by Sagar Lonial, MD, Professor and Executive Vice Chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta. “Elotuzumab, a monoclonal antibody with a novel immunotherapeutic mechanism of action, showed improved progression-free survival, with minimal added toxicity, in combination with lenalidomide/dexamethasone vs lenalidomide/ dexamethasone alone,” Dr. Lonial reported. “We are We are very excited about the fact very excited about the fact that there was such a big difference in that there was such a big difference in progressionprogression-free survival between the free survival between the arms, and we attribute this to a novel arms, and we attribute this to a novel first-in-class anfirst-in-class antibody. tibody.” He added, “it was —Sagar Lonial, MD particularly striking that the

he monoclonal antibody elotuzumab, given with lenalidomide (Revlimid) and dexamethasone, extended progression-free survival by a median of 5 months, compared with lenalidomide/dexamethasone alone, in the eagerly awaited phase III ELOQUENT-2 trial, which will be presented at the 2015 ASCO Annual Meeting (abstract 8508, being presented June 2, 2015).1 The results were reported

Dr. Yu is President of ASCO for 2014–2015 and Director of Cancer Research at Palo Alto Medical Foundation in California.

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO Annual Meeting �� 1, 3–5 NCCN Annual Conference �� 12–15 International Liver Congress 2015 ��16–20 AACR Annual Meeting �� 21–24, 30–32 SGO Annual Meeting �� 37, 40, 42 Larry Norton, MD, on Breast Cancer ��33 Direct From ASCO �� 79–82 Integrative Oncology ��89 Cancer Pain �� 145 In Memoriam �� 178, 180–181 Profile: ASCO President, 2015–2016, Julie M. Vose, MD, MBA, FASCO �� 193–194

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The ASCO Post | MAY 25, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

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Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

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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

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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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Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January 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 | MAY 25, 2015

PAGE 3

ASCO Annual Meeting Dermatologic Oncology

Simple Means of Preventing Nonmelanoma Skin Cancer Reported By Caroline Helwick

wo daily doses of nicotinamide, a form of vitamin B3, significantly reduced the occurrence of nonmelanoma skin cancers by 23% in individuals considered at high risk for these lesions in an Australian study. Results of the phase III ONTRAC trial, which will be presented at the 2015 ASCO Annual Meeting,1 were revealed at a press briefing ahead of the conference. “This is the first clear evidence that we can reduce skin cancers using a simple vitamin, together with sensible sun protection,” said senior author Diona Damian, MBBS, PhD, Professor of Dermatology at the Dermatology University of Sydney, Australia. The study’s first author was Andrew James Martin, MD, of the NHMRC Clinical Trials Centre at the University of Sydney.

skin cancer are basal cell carcinoma and squamous cell carcinoma. In ONTRAC, nicotinamide was equally effective in preventing both these common cancers. Nicotinamide is believed to work by reducing “photocarcinogenesis.” Ultraviolet radiation in sunlight causes skin cancer

This is the first clear evidence that we can reduce skin cancers using a simple vitamin, together with sensible sun protection. —Diona Damian, MBBS, PhD

through two key pathways: by damaging DNA and by suppressing the immunity that normally eradicates abnormal cells. Nicotinamide both enhances the repair of DNA in damaged skin cells and protects the skin’s immune system against ultraviolet light, presumably by replenishing cellular energy after sunlight, she explained.

ONTRAC Details Andrew James Martin, MD

“It’s safe, obscenely inexpensive—less than $10 a month—and it is ready to go straight to the clinic,” Dr. Damian commented in the press briefing. She suggested nicotinamide be offered to individuals who have already had skin cancer.

Major Advance Peter Paul Yu, MD, FACP, FASCO, President of ASCO and Director of Cancer Research at the Palo Alto Medical Foundation in California, commented at the press briefing, “This is a very exciting prevention trial. We all clamor for preventing, rather than treating, disease, and this is a major advance for us.” The incidence of skin cancer is increasing worldwide, despite intensive sun protection campaigns. In the United States, 5 million people are treated for nonmelanoma skin cancer each year. The most common types of nonmelanoma

with no adjustment, the study found. “Nicotinamide reduced the incidence of new nonmelanoma skin cancers by 23%,” Dr. Damian reported. “And [the effect] seemed to start as early as the first 3-month visit. When patients stopped after 12 months, benefit was no longer seen.”

The phase III Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) trial involved 386 Australian adults (mean age, 66 years; 63% male) who had been treated for two or more nonmelanoma skin cancers in the past 5 years (mean number, 8), thus rendering them a high-risk population. They were randomly assigned to oral nicotinamide (500 mg twice daily) or placebo for 12 months. The primary endpoint was the number of new nonmelanoma skin cancers at 12 months. Secondary endpoints included the number of squamous cell carcinomas, basal cell carcinomas, and actinic keratoses. Dermatologists examined the patients’ skin every 3 months. The average number of skin cancers per year of the study was significantly lower for the nicotinamide group (1.77) than the placebo group (2.42). The estimated relative rate reduction was 0.23 (P = .02), adjusted for treatment center and patient skin cancer history, and 0.27 (P = .02)

Nicotinamide in Nonmelanoma Skin Cancers ■■ The phase III ONTRAC trial found that a form of vitamin B could significantly reduce risk of nonmelanoma skin cancers in high-risk individuals. ■■ Nicotinamide, 500 mg twice daily, reduced skin cancers by 23% over placebo. ■■ The average number of skin cancers per year of the study was significantly lower for the nicotinamide group (1.77) than the placebo group (2.42).

This observation was based on two skin examinations performed during the 6 months post-treatment. “All the skin cancer numbers returned to normal; the nicotinamide and placebo numbers were not different. The benefit wears off fairly quickly when you stop taking it. This rebound is similar to what we see with retinoids, which are often prescribed for patients with very large

numbers of skin cancers,” she indicated. The magnitude of benefit in preventing lesions was comparable for basal cell carcinomas and squamous cell carcinomas. Actinic keratosis counts were also reduced in the nicotinamide arm, by 11% at 3 months (P = .01), 14% at 6 months (P < .001), 20% at 9 months (P < .0001), and 13% at 12 months (P < .005). There were no clinically relevant differences in adverse events between the arms, and treatment discontinuation rates were similar: 10% for nicotinamide and 9% for placebo. Dr. Damian emphasized that nicotinamide should not be confused with nicotinic acid (niacin), another form of vitamin B that produces flushing and other side effects. The authors plan to study nicotinamide in immunosuppressed persons, whose skin cancer rates are up to 50 times higher than immunocompetent persons. n

Disclosure: Drs. Damian, Martin, and Yu reported no potential conflicts of interest. For full author disclosures, visit asco.abstracts. org.

Reference 1. Martin AJ, et al: 2015 ASCO Annual Meeting. Abstract 9000. To be presented May 30, 2015.

EXPERT POINT OF VIEW

saac Brownell, MD, PhD, Investigator with the Dermatology Branch of the National Cancer Institute, commented on the findings of the Australian ONTRAC trial for The ASCO Post.

It is important to note that nicotinamide can’t replace sun avoidance and sun protection measures in skin cancer prevention strategies, nor does it prevent sunburn. —Isaac Brownell, MD, PhD

“This is an interesting finding, and it expands on prior work showing reductions in [ultraviolet]-induced DNA damage and prevention of [ultraviolet]induced immunosuppression in the skin by nicotinamide. A prior study also found a reduction in actinic keratoses, a potential precursor to [squamous cell carcinoma], in subjects who took oral nicotinamide,” Dr. Brownell noted. “But it is important to note,” he added, “that nicotinamide can’t replace sun avoidance and sun protection measures in skin cancer prevention strategies, nor does it prevent sunburn.” Study senior author Diona Damian, MBBS, PhD, Professor of Dermatology at the Dermatology University of Sydney, Australia, also addressed this point in the press briefing. “We still need sunscreens … and dermatologists,” she said. n Disclosure: Drs. Damian and Brownell reported no potential conflicts of interest.

The ASCO Post | MAY 25, 2015

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ASCO Annual Meeting Genitourinary Oncology

STAMPEDE Trial continued from page 1

The presentation at the 2015 ASCO Annual Meeting will focus on the first overall survival results in 2,962 hormonenaive men randomized between October 2005 and March 2013 in a 2:1:1:1 ratio to one of four of STAMPEDE’s nine different treatment arms: standard of care, standard of care with docetaxel for six cycles, standard of care with zoledronic acid for 2 years, and standard of care with both docetaxel and zoledronic acid. In this comparison, standard of care was at least 3 years of androgen-deprivation therapy, with local radiation for suitable patients. About 60% had metastatic disease at enrollment, and 40% had highrisk, locally advanced, nonmetastatic prostate cancer, defined as node-negative, stage T3-4, prostate-specific antigen level ≥ 40 ng/mL, or Gleason score of 8–10. Overall survival was a median of 10 months longer in the docetaxel arm vs standard of care: 77 months vs 67 months,

respectively, reflecting a 24% relative improvement in survival. The magnitude of improved overall survival was even greater when docetaxel was added to hormone therapy in the subset of patients with metastatic disease: 65 months vs 43 months, respectively, a difference of 22 months. In the overall analysis, failure-free survival was improved by 38% with docetaxel. In an analysis of metastatic vs nonmetastatic disease, metastatic patients had a clinical and statistically significant 37% improvement in survival, but the study was not powered to detect a significant survival benefit in the nonmetastatic group. The addition of docetaxel to hormone therapy does lead to increased toxicity. The STAMPEDE data come on the heels of two other trials in this setting, which reported conflicting findings. CHAARTED, a 790-patient U.S. trial, found that docetaxel achieved a significant survival advantage, whereas GETUG-15, a 385-patient French trial, did not [see box].

CHAARTED and GETUG-15 Studies

t the 2014 ASCO Annual Meeting, the phase III E3805 (CHAARTED) trial presented at the Plenary Session showed that the addition of docetaxel to standard hormone therapy extended survival by more than 1 year in men with newly diagnosed, hormone-sensitive prostate cancer.1 The survival benefit of docetaxel was mainly driven by men with extensive metastatic disease. Lead author Christopher J. Sweeney, MBBS, of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, said: “The data from STAMPEDE and CHAARTED identify a strategy that prolongs survival in newly diagnosed metastatic prostate cancer. The benefit is substantial and warrants this being adopted as a new Christopher J. Sweeney, MBBS standard treatment for men who have high-extent disease and are able to tolerate chemotherapy.” The study randomized 790 men to androgen-deprivation therapy alone vs androgen deprivation plus six cycles of docetaxel. Median overall survival was significantly superior in the docetaxel-containing arm: 57.6 months vs 44 months (P = .0003), for a 39% reduction in the risk of death. In men with extensive disease, median overall survival was 49.2 months for the combination vs 32.2 months for androgen deprivation alone (P < .0006), for a 40% reduction in the risk of death. At the 2015 Genitourinary Cancers Symposium, lead author Gwenaelle Gravis, MD, reported an updated overall survival analysis of GETUG-15.2 The updated analysis, with a follow-up of 82.9 months, Gwenaelle Gravis, MD showed a median overall survival of 60.9 months for androgen-deprivation therapy plus docetaxel vs 46.5 months for androgendeprivation therapy alone, which was not statistically significant. n Disclosure: Dr. Gravis is on the board of and receives travel support from SanofiAventis. Dr. Sweeney is a compensated consultant for Astellas, AstraZeneca, Bayer, BIND Therapeutics, Genentech, Janssen, and Sanofi.

References 1. Sweeney C, et al: 2014 ASCO Annual Meeting. Abstract LBA2. 2. Gravis G, et al: 2015 ASCO Annual Meeting. Abstract 140.

STAMPEDE is larger than either of these studies, with broader enrollment criteria, and the authors believe that these new results should help clarify the role of docetaxel in newly diagnosed, high-risk cancer.

Additional Commentary “Considering these results along with the recently reported CHAARTED trial provides further evidence for adding docetaxel to androgen-deprivation therapy as part of the initial therapy for men with metastatic disease,” commented Howard I. Scher, MD, Chief, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York. Dr. Scher noted that at this point, however, it is premature to establish androgen-deprivation therapy and docetaxel as a standard of care for all newly diagnosed patients. “One consideration is that the benefit was not without cost, as there was a higher frequency of grade 3–5 adverse events

in the chemotherapy group. As such, it is important to know the outcome for each of the cohorts evaluated, in terms of both safety and efficacy, so that the potential risk/reward can be estimated and discussed with patients who are considering this approach,” stated Dr. Scher. “Another consideration is the proportion of men in the androgen deprivation– alone arm who received docetaxel at the time of disease progression. It is necessary to assess whether giving the combination ‘upfront’ is superior to giving hormones first and chemotherapy later,” he said. n

Disclosure: Dr. James has received honoraria from Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, and Astellas. Dr. Scher has had an advisory role for and received research grants from Sanofi-Aventis.

Reference 1. James ND, et al: 2015 ASCO Annual Meeting. Abstract 5001. To be presented May 31, 2015.

EXPERT POINT OF VIEW

“T

hese latest results of STAMPEDE lend further support to the early use of chemotherapy in men with advanced prostate cancer. They confirm the CHAARTED trial results reported last year by Christopher J. Sweeney, MBBS, which were practice-changing. Men with newly diagnosed metastatic hormone-sensitive advanced prostate cancer should be offered docetaxel in addition to hormone therapy upfront; in nonmetastatic patients, further follow-up is needed before early chemotherapy is routinely offered, since failure-free survival but not overall survival is improved,” stated Daniel Petrylak, MD, Professor of Medicine, Director, Genitourinary Oncology Research Program, and Co-Director, Signal Transduction Program at Yale Comprehensive Cancer Center in New Haven. Daniel Petrylak, MD The practice of offering chemotherapy along with hormone therapy to high-risk hormone-sensitive patients is becoming more widely adopted in clinical practice, and these results should help further that process. The results of the STAMPEDE trial provide level 1 evidence that the addition of docetaxel to standard androgen-deprivation therapy prolongs life relative to androgen-deprivation therapy alone in a population of men with newly diagnosed prostate cancer, which includes those with high-risk, localized, regionally metastatic, and more distant metastatic disease. STAMPEDE also shows that the addition of zoledronic acid to effective antitumor therapy, does not prolong life. Incorporating a continuously accruing control arm enabled three “experimental” arms to be evaluated at the same time, avoiding the need to wait for a single trial to fully accrue, mature, and report before starting the process of designing a new trial. The evaluation of several other “experimental” arms, some incorporating the recently approved life-prolonging agents, is ongoing. “The missing piece is the role of chemotherapy earlier in the course of disease. The TAX 3503 study evaluated whether docetaxel plus hormones vs hormones alone would delay metastasis and delay the need to restart hormones for nonmetastatic patients in the salvage setting following a rise in prostate-specific antigen level after radical prostatectomy,” Dr. Petrylak said. The PUNCH trial is now completing accrual, and that study is looking at docetaxel plus radical prostatectomy vs radical prostatectomy alone in high-risk localized prostate cancer. Long-term follow-up of both these trials is awaited. n

Disclosure: Dr. Petrylak has received honoraria from Sanofi-Aventis, Johnson & Johnson, Bayer, and Astellas.

ASCOPost.com | MAY 25, 2015

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ASCO Annual Meeting Hematology

Elotuzumab in Myeloma continued from page 1

difference between the elotuzumab and control groups seems to get bigger over time, which speaks to the power of this immune-based approach.” “A unique attribute of elotuzumab is that it appears to have a dual mechanism of action, targeting the tumor cell and enhancing the activation of natural killer cells,” Dr. Lonial said. “Natural killer cells make the targeting of myeloma cells with elotuzumab more effective; it’s a double whammy on the tumor.” Elotuzumab received breakthrough status from the U.S. Food and Drug Administration last year, in combination with lenalidomide and dexamethasone, for treating relapsed multiple myeloma.

ELOQUENT-2 Details ELOQUENT-2 is the largest study of a monoclonal antibody in multiple myeloma and the first phase III trial showing a benefit using a targeted immunebased approach in treating this disease. The study included 646 relapsed patients, who had received a median of

two prior therapies, including bortezomib (Velcade, 70%), thalidomide (Thalomid, 48%), and lenalidomide (6%). Subjects were randomly assigned to receive lenalidomide/dexamethasone (control group) or the same regimen plus elotuzumab. Elotuzumab was given at 10 mg/kg in weekly cycles 1 and 2 and then biweekly. Lenalidomide was given at 25 mg on days 1 to 21; dexamethasone was given weekly (40 mg on weeks when elotuzumab was given, 28 mg orally plus 8 mg intravenously). After a median follow-up of 24 months, elotuzumab significantly reduced the risk of disease progression and death by 30%. Median progression-free survival was 19.4 months with elotuzumab plus lenalidomide/dexamethasone, compared with 14.9 months with lenalidomide/ dexamethasone (P = .0004). Progressionfree survival was 68% in the elotuzumab arm vs 57% in the control arm at 1 year and 41% and 27%, respectively, at 2 years. “What was striking about this progression-free survival curve, compared with many others you will see, is that the two curves don’t appear to come back together at longer follow-up. The idea of

Elotuzumab in Multiple Myeloma ■■ Elotuzumab added to lenalidomide/dexamethasone reduced the risk of disease progression or death by 30%. ■■ Median progression-free survival was 19.4 months with elotuzumab plus lenalidomide/dexamethasone, compared with 14.9 months for lenalidomide/dexamethasone (P = .0004).

maintenance of benefit over time speaks to the power of an immune-based approach in cancer,” Dr. Lonial said. The progression-free survival benefit with the three drugs was consistent across key subgroups, including patients with high-risk cytogenetic profiles, he added. The triplet also increased the objective response rate, a second primary endpoint, from 66% to 79% (P = .0002).

Toxicity The three-drug combination was well tolerated. Grade 3-4 adverse events occurring in at least 15% of patients, for the elotuzumab arm vs the control arm, included neutropenia (25% vs 33%) and anemia (15% vs 16%). “The improvement in clinical pa-

rameters occurred without a significant increase in adverse events or toxicity,” he commented. “In fact, there was no reduction in quality of life for the group getting three drugs.” As of the data cutoff (November 2014), 35% of the elotuzumab group and 21% of the control group remained on therapy. There were 210 deaths, including 94 in the elotuzumab arm and 116 in the control arm. n

Disclosure: The study was funded by BristolMyers Squibb and AbbVie. Dr. Lonial reported having a consulting or advisory role with BristolMyers Squibb, Onyx, Celgene, Millennium, Janssen, and Novartis Healthcare A/S.

Reference 1. Lonial S, et al: 2015 ASCO Annual Meeting. Abstract 8508. To be presented June 2, 2015.

EXPERT POINT OF VIEW

“A

nother exciting multiple myeloma treatment will be presented at the 2015 ASCO Annual Meeting,” Philip L. McCarthy, MD, Professor of Oncology and Director of the Blood and Marrow Transplant Center at Roswell Park Cancer Institute, Buffalo, New York, commented in an interview with The ASCO Post. “ELOQUENT-2 is the first phase III trial to examine a monoclonal antibody, elotuzumab, for the treatment of relapsed and refractory multiple myeloma.” Preclinical studies had suggested that bortezomib (Velcade) or lenalidomide (Revlimid) plus elotuzumab would be superior to either drug alone.1 However in the clinic, the combination of bortezomib and elotuzumab did not appear to generate responses comparable to those with lenalidomide, elotuzumab, and dexamethasone,2,3 Dr. McCarthy pointed out. Previous preclinical work had demonstrated that lenalidomide influences the immune synapse between lymphoma cells and T cells.4,5 “This may, in part, explain the efficacy of lenalidomide when combined with antibodies for the treatment of multiple myeloma. Lenalidomide potentiates the monoclonal antibody antitumor activity,

as was demonstrated with rituximab [Rituxan] in a preclinical lymphoma model,” he explained. How will the clinician approach the use of elotuzumab for clinical use when it

refractory multiple myeloma,” he suggested. In ASPIRE, the progression-free survival was significantly improved with the carfilzomib regimen: 26.3 months vs 17.6 months without carfilzomib, which

Future studies will determine how monoclonal antibodies such as elotuzumab will advance the longterm control of multiple myeloma. —Philip L. McCarthy, MD

becomes readily available? For one thing, Dr. McCarthy said, since elotuzumab has limited efficacy as a single agent,6 it must be partnered with lenalidomide and dexamethasone. The other question will be how this regimen compares with other novel high-efficacy regimens, he said.

Comparison With ASPIRE Data “It will be critically important to contrast the published results, when available, to the ASPIRE trial,7 which examined carfilzomib [Kyprolis], lenalidomide, and dexamethasone vs lenalidomide/dexamethasone for relapsed and

is “somewhat different” than the median progression-free survival of 19.4 vs 14.9 months in this study, he pointed out. But, he noted, the ASPIRE trial patient population appeared to contain a lower percentage of high-risk cytogenetic patients (31.5%) compared with ELOQUENT-2 (41%). The proportion of patients with refractory disease may also differ. During the press briefing, Dr. Lonial acknowledged that the patient populations were very different, including more refractory patients and more with high-risk genetics in ELOQUENT-2.

Dr. McCarthy said that the combination of elotuzumab with lenalidomide and dexamethasone may overcome lenalidomide resistance, “but this will depend on the reporting of results and subset analyses. With the ongoing development of anti-CD38 antibodies, … we will have multiple options for relapsed and refractory multiple myeloma and eventually for upfront therapy. Future studies will determine how monoclonal antibodies will advance the long-term control of multiple myeloma,” he said. n

Disclosure: Dr. McCarthy serves on advisory boards and is a consultant for Bristol-Myers Squibb, Celgene, Millenium Takeda, Sanofi, Janssen, and Karyopharm.

References 1. Tai YT, et al: Blood 112:1329-1337, 2008. 2. Jakubowiak AJ, et al: J Clin Oncol 30:1960-1965, 2012. 3. Lonial S, et al: J Clin Oncol 30:19531959, 2012. 4. Ramsay AG, et al: Blood 114:47134720, 2009. 5. Hernandez-Ilizaliturri FJ, et al: Clin Cancer Res 11:5984-5992, 2005. 6. Zonder JA, et al: Blood 120:552559, 2012. 7. Stewart AK, et al: N Engl J Med 372:142-152, 2015.

For appropriate patients with previously treated metastatic melanoma

NOW

THERE’S

The Only PD-1* Immune Checkpoint Inhibitor That Has Demonstrated Efficacy in a Phase 3 Study1 *Programmed death receptor-1

Indication OPDIVO® (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following YERVOY® (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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Select Important Safety Information OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

Common Adverse Reactions The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%).

OPDIVO – A PD-1 Immune Checkpoint Inhibitor That Delivered a Response Rate of 32% (95% CI*: 23-41)

RESPONSE RATE

32%

(38 of 120) confirmed Objective Response Rate (ORR) (95% CI: 23-41). 3% (4 of 120) achieved a complete response 28% (34 of 120) achieved a partial response

DURABILITY OF RESPONSE

87 %

(33 of 38) of patients treated with OPDIVO with confirmed response were still in response at the time of analysis. Duration of response (2.6+, 10.0+ months), which included 13 patients with ongoing responses of 6 months or longer.

Responses to OPDIVO were demonstrated in both patients with and without BRAF mutation *Confidence Interval

Grade 3/4 adverse reactions occurred in 42% of patients receiving OPDIVO1 OPDIVO was discontinued for adverse reactions in 9% of patients1

Study design: OPDIVO was studied in a randomized, Phase 3 trial evaluating OPDIVO 3 mg/kg (n=268), administered intravenously every two weeks, or chemotherapy (n=102) (investigator’s choice of either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks) in patients with advanced melanoma who had been previously treated and progressed with YERVOY® (ipilimumab) and, if BRAF mutation positive, a BRAF inhibitor. The primary objective of this analysis of the CHECKMATE 037 trial was objective response rate (ORR).1,2 The efficacy of OPDIVO was evaluated based on a single-arm, non-comparative planned interim analysis of the first 120 patients who received OPDIVO with a minimum of 6 months follow-up in the Phase 3 CHECKMATE 037 trial. The ORR achieved with OPDIVO was 32% (95% CI: 23-41).1,2 *Based on blinded independent central review using Response Evaluation Criteria in Solid Tumors 1.1.1 ALT=alanine aminotransferase; AUC=area under curve.

Please visit www.OPDIVO.com/HCP for more information Please see additional Important Safety Information on the following page and the brief summary of Full Prescribing Information on the following pages.

Responding to Your Needs in 24 Hours or Less

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction ́ In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormonereplacement therapy.

Embryofetal Toxicity Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation ́ It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment. Serious Adverse Reactions Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

Common Adverse Reactions The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). Please see brief summary of Full Prescribing Information on the following pages.

References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Bristol-Myers Squibb. A study to compare BMS-936558 to the physician’s choice of either dacarbazine or carboplatin and paclitaxel in advanced melanoma patients that have progressed following anti-CTLA-4 therapy (CheckMate 037). Identifier: NCT01721746. http://clinicaltrials.gov/show/NCT01721746. Updated February 12, 2015. Accessed March 4, 2015.

Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Expect More. Do More.

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) 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 [see Clinical Studies (14.1) in full Prescribing Information]. This indication is approved under accelerated approval based on tumor response rate and durability of response. 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 Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days to 3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as complete resolution of symptoms with completion of corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immunemediated colitis from initiation of OPDIVO was 2.5 months (range: 1 to 6 months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days to 2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT

(16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving OPDIVO (nivolumab): two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. In two patients, OPDIVO was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4 to 15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO and, in one patient, Grade 3 immunemediated hepatitis recurred resulting in permanent discontinuation of OPDIVO. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVOtreated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction (defined as ≥ Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and 6 months after OPDIVO initiation, respectively. OPDIVO was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days to 11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while continuing to receive levothyroxine. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. The median time to onset in OPDIVO-treated patients was 1.6 months (range: 0 to 3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immunemediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients in Trials 1 and 3 (n=385): adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO, administer highdose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion

of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO (nivolumab) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] 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. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma. Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions]. Unresectable or Metastatic Melanoma The safety of OPDIVO was evaluated in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1) in full Prescribing Information]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) with a median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year. In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumabrelated Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%). OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Table 1 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients. The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 1:

Selected Adverse Reactions Occurring in ≥10% of OPDIVO (nivolumab)-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1) OPDIVO (n=268) All Grades

Adverse Reaction

Grades 3-4

Chemotherapy (n=102) All Grades

Grades 3-4

Percentage (%) of Patients Skin and Subcutaneous Tissue Disorders Rasha Pruritus Respiratory, Thoracic, and Mediastinal Disorders Cough Infections and Infestations Upper respiratory tract infectionb General Disorders and Administration Site Conditions Peripheral edema a

21 19

0.4 0

7 3.9

0 0

2.0

Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, and dermatitis acneiform. b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in Trial 1 were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis. Table 2:

Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1) Percentage of Patients with Worsening Laboratory Test from Baselinea OPDIVO

Test Increased AST Increased alkaline phosphatase Hyponatremia Increased ALT Hyperkalemia a

Chemotherapy

All Grades

Grades 3-4

All Grades

Grades 3-4

28 22

2.4 2.4

12 13

1.0 1.1

25 16 15

5 1.6 2.0

18 5 6

1.1 0 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range 252 to 256 patients) and chemotherapy group (range 94 to 96 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses.

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 OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 272 patients randomized to OPDIVO in Trial 1, 35% of patients were 65 years or older and 15% were 75 years or older.

Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO. PATIENT COUNSELING 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 OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations]. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A1

Revised: March 2015 1506US15BR00210-03-01

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National Comprehensive Cancer Network Annual Conference Guidelines

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): 2015 Updates By Caroline Helwick

“F

or 2 decades, the NCCN Guidelines® have been recognized as the standard of cancer care in the United States, combining evidence, experience, and choice, so that multidisciplinary cancer treatment teams— including patients—are empowered to make informed decisions about cancer care,” said Robert W. Carlson, MD, Chief Executive Officer of NCCN. In 1996, the National Comprehensive Cancer Network® (NCCN®) published its first set of NCCN Guidelines®, covering eight tumor types. Today, NCCN Guidelines are published for tumor types, prevention and screening topics, supportive care considerations, and age-related recommendations. Some of the key updates were presented at NCCN’s 2015 Annual Conference and are briefly summarized here. For a more complete description of all updates, visit www.nccn.org.

New Guidelines for Smoking Cessation

Solove Research Institute. The new NCCN Guidelines for Smoking Cessation will help oncologists effectively manage these patients. The inaugural guidelines focus primarily on the 2014 Surgeon General’s Report on Smoking and Health, the adverse outcomes associated with smoking in cancer patients, and the common barriers to smoking cessation. They guide oncologists in assessment, recommend evidence-based pharmacotherapy and behavioral therapy, stress the importance of close follow-up and adequate documentation in the medical records, and present a variety of resources (quit lines, online support, and mobile apps). The key points of the Guidelines for Smoking Cessation follow: • Brief initial assessment can be accomplished in minutes by any member of the treatment team. • The management algorithm is specific to current vs former smokers/recent quitters. • Patients at high risk for relapse may need pharmacotherapy and behavioral therapy. • Patients are assessed for willingness to quit and for level of nicotine dependence. • Personalized quit plans are established. • Close follow-up is critical.

Melanoma Updates “We wanted to come up with guidelines that would be clear, relevant, and something that could literally be done in the clinic in just a few minutes.” —Peter G. Shields, MD

Even after a cancer diagnosis, for any stage and prognosis, patients with cancer can reap the health benefits of smoking cessation. However, only 50% of oncologists advise their patients to quit smoking, and most of them do not provide steps on how to do it, according to Peter G. Shields, MD, Professor of Medicine at The Ohio State University and Deputy Director of The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and

“The updated Guidelines elevate PD-1 agents to the front-line setting, because we are convinced that response rates are higher and toxicity is lower than we see with ipilimumab.” —John A. Thompson, MD

Immunotherapies along with the targeted BRAF and MEK inhibitors have dramatically improved outcomes in advanced melanoma. The availability of these novel approaches has necessitated changes to the NCCN Guidelines for Melanoma, which now feature algorithms that aid treatment selection and include antiprogrammed death protein receptor-1 (PD-1) agents among the preferred options, said John A. Thompson, MD, Co-Director of the Melanoma Clinic at the Seattle Cancer Care Alliance and Professor of Medical Oncology at the University of Washington School of Medicine. The key updates in melanoma follow: • The systemic therapy section was significantly revised by converting the “preferred regimens” and “other active regimens” into algorithms for the treatment of patients with BRAF-mutated vs BRAF–wild-type breast cancer. • The systemic options for advanced or metastatic melanoma now include the following: ipilimumab (Yervoy, category 1 [see box below]), dabrafenib (Tafinlar) plus trametinib (Mekinist, category 1), nivolumab ( Opdivo, category 1), pembrolizumab (Keytruda), high-dose interleukin 2 (in select patients), and enrollment on a clinical trial; vemurafenib (Zelboraf) and dabrafenib are also options as single agents for BRAF-mutant patients expected to deteriorate in < 12 weeks. • A new “Principles of Immunotherapy and Targeted Therapy” section discusses the effectiveness of these novel treatments, with recommendations for managing their related toxicities. • For newly diagnosed patients, the incorporation of mitotic rate in staging has been revised. Stage IA is defined as ≤ 1 mm thick, no ulceration, and a mitotic rate ≤ 1 per mm2; stage IB is ≤ 1 mm thick with ulceration or a mitotic rate ≥ 1 per mm2 or 1.01–2.0 mm thick without ulceration and/or a mitotic rate ≤ 1 per mm2. Sentinel lymph node biopsy is generally not recommended for lesions < 0.75 thick.

NCCN Category 1 Level of Evidence Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Breast Cancer Updates

“We still need lymph node staging information, at least for making decisions about adjuvant treatment, but we are not treating cancer by removing lymph nodes.” —Amy Cyr, MD

Three breast cancer experts updated attendees on the latest advances in early-stage breast cancer, HER2-positive breast cancer, hormone-sensitive breast cancer, and triple-negative breast cancer. The key updates in breast cancer follow: • NCCN now accepts the definition of a negative margin as “no ink on the tumor.” • The use of shorter-course hypofractionated irradiation is generally preferred over standard (longer) courses of whole-breast irradiation. Some patients are also eligible for shortcourse accelerated partial-breast irradiation, with caveats regarding short follow-up of clinical trial patients and some concerns regarding cosmesis. • The 21-gene recurrence score can be considered in select node-positive patients to guide the addition of combination chemotherapy to standard hormone therapy. • Axillary surgery is no longer recommended for clinically node-negative patients meeting the criteria of ACOSOG Z0011: T1/2 tumors, one or two positive sentinel nodes only, no neoadjuvant therapy, breast-conserving therapy, and whole-breast irradiation planned. For other sentinel node–positive patients, axillary radiation may replace level I/II axillary dissection for regional control of disease. • For hormone receptor–negative

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National Comprehensive Cancer Network Annual Conference HER2-positive tumors ≤ 0.5 cm, adjuvant chemotherapy with trastuzumab (Herceptin) can be considered for node-negative patients. • For postmenopausal patients with metastatic estrogen receptor (ER)– positive disease, the CDK4/6 inhibitor palbociclib (Ibrance) plus letrozole is a new therapeutic option; it is a recommended first-line treatment in HER2-negative patients. • For premenopausal ER-negative patients, the Guidelines recognize that ovarian suppression with gonadotropin-releasing hormone agonists given during adjuvant chemotherapy may preserve ovarian function and diminish the likelihood of amenorrhea.

Multiple Myeloma Updates

ow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, Boston. The key updates in multiple myeloma follow: • Panobinostat (Farydak)/bortezomib (Velcade)/dexamethasone is a category 1 option for relapsed myeloma in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. • Carfilzomib/lenalidomide (Revlimid)/dexamethasone is a category 1 option for relapsed myeloma. • Carfilzomib/lenalidomide/dexamethasone is a category 2A primary therapy option for transplant candidates. • Lenalidomide plus low-dose dexamethasone (recommended last year as primary therapy for nontransplant patients) should be given continuously until disease progression.

Chronic Myelogenous Leukemia Updates

“Immunotherapies and other novel approaches will soon be coming to a clinic near you.” —Kenneth C. Anderson, MD

The 2015 NCCN Guidelines provide new recommendations for the use of carfilzomib (Kyprolis) and pomalidomide (Pomalyst), which when given in combination with other traditional agents can yield response rates of approximately 90%, according to Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School and Director of the LebDisclosure Information

“Early molecular response is a harbinger of good things to come…. The milestone of major molecular response is a safe harbor, and very few bad things happen once you go south of that.” —Jerald P. Radich, MD

Dr. Cyr reported no conflicts of interest. Dr. Shields on scientific advisory boards, promotional advisory boards, and speakers bureaus for various law firms involved in chemical exposure cases and as a consultant or expert witness for the National Cancer Institute. Dr. Thompson has received or participated in clinical research support/data safety monitoring board for Bristol-Myers Squibb Company, Genentech, GlaxoSmithKline, Merck & Co, Novartis Pharmaceuticals Corportation, Agensys, Altor Biosciences, and Seattle Genetics, and has served on scientific advisory boards and as a consultant or expert witness for Amgen Inc, Bristol-Myers Squibb, and Celldex. Dr. Anderson has served on scientific advisory boards and as a consultant or expert witness for Bristol-Myers, Celgene Corporation, Millennium Pharmaceuticals, Gilead Sciences, and sanofi-aventis U.S. Dr. Anderson also reported potential conflicts of interents with Acetylon and Oncopep. Dr. Radich has received or participated in clinical research support/data safety monitoring board for Novartis, and has served on scientific/promotional advisory boards, speakers bureaus, or as an expert witness or consultant for Novartis, Pfizer, Inc, ARIAD Pharmaceuticals, and Incyte. Dr. Grothey has received or participated

The success story of the various generations of tyrosine kinase inhibitors in chronic myelogenous leukemia (CML) is well known, with many patients achieving long-term benefits from treatment. However, not every patient with CML tolerates this therapy, responds to initial treatment, or avoids disease progression or drug resistance. Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center and Professor of Medicine at the University of Washington School of Medicine, Seattle, emphasized the critical role of monitoring response at 3 months, explored issues pertaining to patient adherence to therapy, discussed timing for mutational analysis, and highlighted the need to prevent evolution from chronic-phase disease into accelerated-phase/blast crisis. The key updates in CML follow: • The Guidelines emphasize the importance of assessing response at various “milestones,” rather than upon “failure,” with consideration of treatment switching. These assessments should be at 3, 6, 12, and 18 months. • Nilotinib (Tasigna) and dasatinib (Sprycel) were added as treatment options for de novo acceleratedphase disease. • Ponatinib (Iclusig) was added as a treatment option for patients with a T315I mutation or disease not responding to two prior tyrosine kinase inhibitors, in the primary treatment setting and after hematopoietic stem cell transplantation. A page has been devoted to management of ponatinib-associated toxicities, which can include vascular occlusion, heart failure, and hepatotoxicity, as well as a variety of other hematologic and nonhematologic events, for which specific interventions are given.

Colorectal Cancer Updates

“Long-term survival for patients with metastatic colorectal cancer is not based on choice of firstline therapy but on the incremental benefits that accrue over time using available agents.” —Axel Grothey, MD

Multiple effective agents can, and should, be incorporated into the continuum of treatment for colorectal cancer, and treatment targeting the vascular endothelial growth factor (VEGF) should be extended. NCCN now emphasizes the importance of identifying patients with any mutation in the RAS pathway, and for RAS–wild-type patients, chemotherapy plus bevacizumab (Avastin) or antibodies targeting the epidermal growth factor receptor (EGFR) are viable first-line options, according to Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, who emphasized individualization of treatment. The key updates in colorectal cancer follow: • The NCCN panel strengthened its recommendations for testing for all RAS and BRAF mutations in patients with metastatic disease. continued on page 14

in clinical research support/data safety monitoring board for Bayer Healthcare, Eisai, Eli Lilly and Company, Genentech, ImClone Sytems Incorporated, and Pfizer, and has served on scientific advisory boards and as a consultant or expert witness for Bayer, Bristol-Myers Squibb, and Genentech. Dr. Armstrong has received or participated in clinical research support/data safety monitoring board for Active Biotech AB, Bristol-Myers Squibb, Dendreon Corporation, ImClone, Johnson & Johnson, Novartis, Kanglaite, Medivation, Pfizer, and sanofi-aventis U.S., and has served on scientific advisory boards, promotional advisory boards, and speakers bureaus and a consultant or expert witness for Johnson & Johnson, Astellas, and Dendreon. Dr. Tempero has received or participated in clinical research support/data safety monitoring board for Celgene; and has served on scientific advisory boards, promotional advisory boards, and speakers bureaus and as a consultant or expert witness for Celgene, Genentech, Myriad Genetic Laboratories, Inc, and Targovox. For more information visit http://www.nccn.org/disclosures/default.asp.

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National Comprehensive Cancer Network Annual Conference NCCN Guidelines continued from page 13

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—Margaret Tempero, MD

Peter G. Shields, MD, Chair, NCCN Guidelines Panel for Smoking Cessation John A. Thompson, MD, Vice-Chair, NCCN Guidelines Panel for Melanoma Amy Cyr, MD, NCCN Guidelines Panel for Breast Cancer Kenneth C. Anderson, MD, Chair, NCCN Guidelines Panel for Multiple Myeloma Jerald P. Radich, MD, Vice-Chair, NCCN Guidelines Panel for Chronic Myelogenous Leukemia Axel Grothey, MD, Member, NCCN Guidelines Panel for Colon and Rectal Cancers Andrew J. Armstrong, MD, ScM, Vice-Chair, NCCN Guidelines Panel for Prostate Cancer Margaret Tempero, MD, Chair, NCCN Guidelines Panel for Pancreatic Adenocarcinoma

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More on Guidelines

Pancreatic cancer remains a vexing treatment challenge, as the cure rate remains just 7%. Two effective regimens— gemcitabine/nab-paclitaxel (Abraxane) and FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin)—have improved outcomes and are being used earlier in the disease, but meaningful differences in outcomes may not be realized without novel strategies. Targeting of the immune system is an active area of research. The key updates in pancreatic cancer follow: • For imaging as part of the initial assessment, MRI was removed, and a pancreatic protocol CT is now recommended. If imaging shows no mass in the pancreas and no metastatic disease, endoscopic ultrasonography is the preferred next step. • Adjuvant therapy should be initiated within 12 weeks (not within 4–12 weeks). • The Guidelines state there is no clear benefit for the addition of conventional chemoradiation after gemcitabine monotherapy. • For patients with a good performance status, treatment options are separated into “preferred” and “other.” The preferred options are a clinical trial, FOLFIRINOX (category 1), or gemcitabine plus nab-paclitaxel (category 1). n NCCN Panel Members

“If you are thinking about giving patients with locally advanced disease gemcitabine monotherapy, and they do well on it, you cannot justify following this with radiation.” ROUND: 3 Last Saved: 11-21-2014 6:50 PM

Most men with metastatic prostate cancer progress through local disease, rising prostate-specific antigen (PSA) levels, and local therapy and then to nonmetastatic castration-resistant disease

DATE

—Andrew J. Armstrong, MD, ScM

Pancreatic Cancer Updates

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

“We are now facing multiple lines of effective systemic therapies, but the appropriate sequence of these agents is not well known.”

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Prostate Cancer

castration-resistant prostate cancer, recommendations for patients with and without visceral metastases were stratified based on prior therapy with enzalutamide/abiraterone vs docetaxel. • Several new points were made in the imaging section: (1) as compared to plain radiography, CT or MRI may be more useful for assessing fracture risk; (2) with bone scans, newer technology using 18F-NaF (18F sodium fluoride) as the tracer for a PET scan can be used as a diagnostic study; (3) PET and hybrid imaging may be more sensitive than conventional 99-technetium bone scans; (4) multiparametric MRI can be used for staging and characterizing disease, to risk-stratify men for active surveillance, and to detect large and poorly differentiated tumors and extracapsular extension. S&H • For brachytherapy, low-dose-rate brachytherapy as monotherapy is indicated for patients with low-risk cancers and selected patients with lowvolume intermediate-risk cancers. 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

• For patients with resectable synchronous liver and or lung metastases, after colectomy, FOLFOX (folinic acid, fluorouracil [5-FU], oxaliplatin) plus cetuximab was added as a treatment option. • For patients with unresectable metastases, systemic therapy with FOLFOXIRI (FOLFOX and irinotecan) with or without bevacizumab is now a category 2A option (not 2B). • For rectal cancer, FOLFOX and CapeOx (capecitabine and oxaliplatin) are noted as “preferred” adjuvant treatments. • For rectal cancer, treatment options prior to resection are FOLFOX or CapeOx (preferred) or 5-FU/leucovorin or capecitabine, followed by chemoradiation (capecitabine/radiotherapy preferred) or infusional 5-FU/ radiotherapy (preferred) or bolus 5-FU/leucovorin and radiotherapy.

before the onset of metastases. About 3% to 5% of men, however, will present at diagnosis with metastatic disease. Patients with prostate cancer typically move through first, second, and third lines of therapies, often sequencing through secondary hormonal strategies such as the antiandrogens (eg, enzalutamide [Xtandi], androgen synthesis inhibitors (eg, abiraterone [Zytiga]), immunotherapy (eg, sipuleucel-T [Provenge]), and maybe even an alpha emitter (radium-223 [Xofigo]). As their disease transitions to treatment-refractory metastatic castration-resistant prostate cancer, they often face fourth-line options. Most of the updates in the 2015 NCCN Guidelines centered on the context in which to use the host of new systemic agents, as described by Andrew J. Armstrong, MD, ScM, Associate Professor of Medicine and Co-Director of the Clinical Research Program at Duke Cancer Institute, Durham, North Carolina. The key updates in prostate cancer follow: • For men with clinically localized disease, a tumor-based molecular assay could be considered for stratifying risk. • The algorithm for systemic therapy for advanced disease was divided into M0 or low-volume M1 disease, vs high-volume M1 disease; highvolume disease is differentiated from low-volume disease by visceral metastases and/or four or more bone metastases, with at least one metastasis beyond the pelvic vertebral column. • For high-volume disease in castration-sensitive men, continuous androgen deprivation therapy and docetaxel without prednisone for six cycles is an option. • For castration-resistant prostate cancer without visceral metastases, the following category 1 options were added: enzalutamide; abiraterone with prednisone; docetaxel with prednisone; radium-223 for men with symptomatic bone metastases. • For first-line therapy in castrationresistant prostate cancer with visceral metastasis, enzalutamide was added as a category 1 option. • For second-line therapy in advanced

ej 1

See pages 46 and 54 in this issue of The ASCO Post 29452a for a report “ASCO 11.25.14 133 Endorses American Cancer Society Prostate Cancer Survivorship Guidelines,” with further commentary from Matthew J. Resnick, MD.

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National Comprehensive Cancer Network Annual Conference

NCCN Presents Rodger Winn Award to Daniel G. Coit, MD

t the 20th Annual Conference of the National Comprehensive Cancer Network (NCCN) held in March 2015 in Hollywood, Florida, NCCN presented Daniel G. Coit, MD, with the Rodger Winn Award. The award, named for NCCN’s “founding father” of the Guidelines Program and the first

decision-making pathway from diagnosis through palliation,” said Joan McClure, MS, Senior Vice President of Clinical Information and Publications for NCCN, in a recently published tribute.1 “NCCN gives the Rodger Winn

Award to a panel member who embodies Rodger’s enthusiasm, love of life, and dedication to the NCCN Guidelines program. He was a role model and B:8.75” trailblazer,” Ms. T:7.75” McClure said. S:6.875” Dr. Winn died on April 4, 2007,

of complications from esophageal cancer. n Reference 1. McClure J: NCCN: Touched by cancer. J Natl Compr Canc Netw 13:380, 2015.

Daniel G. Coit, MD

Editor-in-Chief of the group’s journal, JNCCN, is presented annually to a member of a guidelines panel. Dr. Coit is Chair of the NCCN Guidelines Panel on Melanoma. He is also a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. Dr. Coit’s primary area of clinical and research interest is melanoma. He introduced lymph node mapping and sentinel lymph node biopsy for melanoma and other selected skin cancers in 1991.

Rodger Winn Award “Rodger [Winn] was a medical oncologist who had the idea that cancer

STRENGTHEN HER DEFENSE

Rodger Winn, MD

guidelines could be constructed as process maps that allowed a user to “follow the finger” across the clinical

NCCN gives the Rodger Winn Award to a panel member who embodies Rodger’s enthusiasm, love of life, and dedication to the NCCN Guidelines program. He was a role model and trailblazer. —Joan McClure, MS

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.

Cancer Rates Significantly Increased Among Patients With Hepatitis C

esults presented at The International Liver CongressTM 2015 show that cancer rates in patients with the hepatitis C virus (HCV) were significantly increased compared to the non-HCV cohort. The researchers suggest an extrahepatic manifesta-

tion of HCV may be an increased risk of cancer.

Study Details Researchers aimed to describe the rates of all cancers in the cohort of HCV patients compared to the non-

HCV population. Known cancer types associated with hepatitis C include non-Hodgkin lymphoma as well as renal, prostate, and liver cancers. S:6.875” A retrospective study at Kaiser Permanente Southern California was conducted. The study authors recorded all

cancer diagnoses in patients over 18 years of age with or without HCV from 2008 to 2012. Within the time frame of the study, 145,210 patient years were included in the HCV cohort, and 13,948,826 patient years were included in the non-HCV cohort.

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

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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

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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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The International Liver Congress 2015 Study Results

per 100,000) when liver cancer was excluded. When all cancers are considered, the rate is 2.5 times higher in the HCV cohort; when liver cancers are excluded, the rate is still almost 2 times higher. Lisa Nyberg, MD, MPH, of Kaiser S:6.875” Permanente Southern California, explained, “The results suggest that cancer rates are increased in the cohort of hepa-

In the HCV cohort, there were 2,213 cancer diagnoses (1,524 per 100,000) during the 5-year period, and 1,654 cancer diagnoses when liver cancer was excluded (1,139 per 100,000). In the nonHCV cohort, there were 84,419 cancer diagnoses (605 per 100,000) during the same 5-year period, and 83,795 (601

titis C patients vs the non–hepatitis C patients, both including and excluding liver cancers. These findings certainly point to the suggestion that hepatitis C may be associated with an increased risk of cancer. However, the findings must be interpreted with caution, as the study also showed that confounding factors such as alcohol abuse, tobacco, obesity,

and diabetes modified the results.” Laurent Castera, MD, PhD, ViceSecretary, European Association for the Study of the Liver, commented, “These data add to the evidence bank linking hepatitis C with an increased risk of cancer and highlight that there is still a long way to go in order to fully understand this complex and devastating disease.” 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

100

HR=0.68 95% CI: 0.56-0.84 P=0.0002

90 80

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70 60 OS (%)

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• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

median line

40.8 MONTHS

40 30

• 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

10 371 350

20 318 289

30 268 230

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226 179

104 91

28 23

1 0

0 0

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

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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

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• 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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The International Liver Congress 2015 Genomic Analyses Point to the Potential of Personalized Care for Liver Cancer Patients

new study presented at The International Liver Congress™ 2015 in Vienna, Austria, showed that by using genomic analyses to understand how and when carcinogenic mutations oc-

cur in patients with hepatocellular carcinoma, it is possible to identify specific molecular profiles. It is hoped that these molecular profiles will help identify which patients would benefit 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.

from specific anticancer treatments. Using exome sequencing, a technique for sequencing all the protein-coding genes in a genome, the study identified relationships between environmental expoIn 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.

sures, such as tobacco smoke, alcohol use, and mutational patterns in hepatocellular carcinoma. It also determined the landscape of driver genes and pathways altered in different clinical stages and etiologic 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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The International Liver Congress 2015 backgrounds. Out of eight mutational signatures identified in the study, two new mutational signatures for hepatocellular carcinoma were found.

Differentiating Mutational Processes Jessica Zucman-Rossi, MD, PhD, Director of the INSERM/University ParTable 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.

is Descartes Functional Genomics of Solid Tumors Laboratory, explained, “Mutational signatures help with understanding the biological history of a cancer and can enable differentiation between ongoing mutational processes and historical ones. This helps identify potential new targets for anticancer therapies.” In the study, most patients had at least 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

one damaging alteration which could potentially be treated with either a U.S. Food and Drug Administration–approved drug (28% of patients) or an investigational drug (86% of patients) that has been studied in phase I to phase III clinical trials. “Hepatocarcinogenesis is a multistep process in which precancerous lesions can ultimately transform into liver canpatients 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)

cer. Genomic analyses, such as exome sequencing, allow us to better understand the mutational processes involved in the development of cancers. This detailed knowledge then helps us to unravel the mutagenic processes and to optimize personalized patient care,” said Markus Peck, MD, Secretary General, European Association for the Study of the Liver. n

The ASCO Post | MAY 25, 2015

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AACR Annual Meeting Thoracic Cancer

Pembrolizumab Safe and Effective in Patients With NSCLC, Especially in Those With Tumors Showing High Levels of PD-L1 Expression By Alice Goodman

dd lung cancer to the growing list of cancers that may derive benefit from immunotherapy. The KEYNOTE-001 trial found that

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

pembrolizumab (Keytruda) achieved durable responses in a proportion of patients with non–small cell lung cancer (NSCLC) and high levels of

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

expression of the protein PD-L1 (programmed death ligand 1) in tumor tissue correlated with overall response rate and progression-free survival.

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.

These results suggest that PD-L1 is a potential, albeit imperfect, biomarker for response to anti–PD-1 therapy with pembrolizumab. “With these data, we can confidently say that in previously treated patients with NSCLC and PD-L1 expression in at least 50% of tumor cells, pembrolizumab is associated with superior outcomes compared to what can be expected with cytotoxic chemotherapy,” stated Edward B. Garon, MD, of David Geffen School of Medicine at the University of California, Los Angeles. No significant differences were observed in efficacy and side-effect profile between patients receiving various dose levels of pembrolizumab, which has been shown by other investigators, Dr. Garon noted. Dr. Garon reported the KEYNOTE-001 results at the 2015 Annual Meeting of the American Association for Cancer Research,1 and the study was published in The New England Journal of Medicine to coincide with his presentation.2

Study Details 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

KEYNOTE-001 was a phase Ib study that assigned 495 treatmentnaive and previously treated NSCLC patients receiving pembrolizumab at a dose of either 2 mg every 3 weeks or 10 mg/kg every 2 weeks to either a training group (n = 182) or a validation

Pembrolizumab in Non–Small Cell Lung Cancer ■■ Pembrolizumab demonstrated efficacy in previously treated and treatment-naive patients with advanced NSCLC in a randomized phase Ib study. ■■ Safety and efficacy were similar at different dose levels and schedules. ■■ PD-L1 expression identified those likely to have the best response and outcomes. However, at this time, PD-L1 remains an imperfect assay. ■■ There are high PD-L1 expressors who progress on pembrolizumab and low PD-L1 expressors who derive some benefit from this immunotherapy. ■■ The best use of a PD-L1 assay appears to be to prioritize treatment decisions.

ASCOPost.com | MAY 25, 2015

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AACR Annual Meeting group (n = 313). PD-L1 expression was assessed in tumor samples. Among all patients, the overall response rate was 19.4%, with no clear difference based on prior treatment, dose of pembrolizumab, or histology. As has been reported previously with immunotherapy, smokers had an improved response compared with never

ritus, and decreased appetite, and these effects were similar at all dose levels.

PD-L1 Expression In the training set, a cutoff point of at least 50% of cells that stained positive for PD-L1 was deemed highly positive. In the validation set, three proportion scores were used to categorize PD-L1 ex-

We can confidently say that in previously treated patients with NSCLC and PD-L1 expression in at least 50% of tumor cells, pembrolizumab is associated with superior outcomes compared to what can be expected with cytotoxic chemotherapy. —Edward B. Garon, MD

smokers. Median duration of response among responders was 12.5 months. Median duration of progression-free survival among all patients was 3.7 months, and median duration of overall survival was 12 months. Pembrolizumab was generally well tolerated. The most common treatmentrelated adverse events were fatigue, pru-

pression: proportion score < 1% = low; proportion score = 1% to 49% = intermediate; proportion score ≥ 50% = high. The validation set included 313 patients (223 previously treated, 90 treatmentnaive to systemic therapy for NSCLC). PD-L1 staining correlated with response, with no difference in previously treated or treatment-naive patients. In

those with a proportion score ≥ 50% (the highest expression of PD-L1), the overall response rate was 42.5%; median progression-free survival was 6.3 months, and median overall survival had not yet been reached. The overall response rate was significantly better in high expressors than in those with a proportion score of between 1% and 49% and those with a proportion score < 1% (P < .001). Progression-free survival in pooled data from the training and validation set showed a correlation with high PD-L1 expression. Median progression-free survival according to PD-L1 expression was 6.3 months for the highest group vs 3.3 months for the intermediate group and 2.3 months for the lowest PD-L1–expressing group. At a median follow-up of 10.9 months, median overall survival was not reached in those with the highest proportion score (≥ 50%) in both previously treated and treatment-naive patients. In the previously treated patients, median overall survival was 7.3 months for those with a proportion score of 1% to 49% and 8.6 months for the lowest PD-L1–expressing group; in the treatment-naive patients, median overall survival was 16.2 months for the intermediate group and 10.4 months for the lowest PD-L1–expressing group. “The PD-L1 level also [correlated

with] overall survival,” Dr. Garon told The ASCO Post. “There is no real distinction in my mind between the quality of the data for progression-free and overall survival,” he said. Dr. Garon pointed out that the efficacy of pembrolizumab in patients with low expression of PD-L1 was also “compelling.”

Blurry Biomarker “These are very exciting results in advanced NSCLC,” stated Suzanne Topalian, MD, of Sidney Kimmel

Suzanne Topalian, MD

Comprehensive Cancer Center at Johns Hopkins University in Baltimore. “This is a difficult-to-treat patient population. Second- and third-line agents are not expected to prolong survival, so results are especially impressive in this setting.” Dr. Topalian was less enthusiastic about continued on page 22

EXPERT POINT OF VIEW

D-L1 is an imperfect biomarker, according to formal discussant of this paper, D. Ross Camidge, MD, PhD, of the University of Colorado Comprehensive Cancer Center, Denver. “The importance of a good predictive assay in this field [of immunotherapy] is so great that it is impossible to ascribe any true differences in efficacy between drugs separate from the degree of enrichment their associated assays produce,” he stated. Three different companies are developing companion PD-L1 assays for their respective anti–PD-1 compounds. In the case of pembrolizumab, the Merck assay identifies about 23% of lung cancers with a high performance status (PS) score in whom PD-1 inhibition is associated with an overall response rate of 42%. But you cannot say the drug works any better than one with a lower response rate, unless it is being compared in the same enriched population, Dr. Camidge emphasized. “It is impressive that this assay appears to identify a group with prolonged progression-free survival that is approximately the same size as the

responder group. But, as mentioned, it is not a perfect assay. In all of the groups including the high PD-L1 group, approximately 30% to 40% of

selves: either PD-L1 expression itself is a good prognostic factor, or, alternatively, the biomarker may be predicting for ongoing benefit after the therapy is

Even an imperfect enrichment assay can dramatically alter the ‘bang for the buck’ a drug offers in different settings… (and be used) to prioritize the selection of therapy with the greatest chance of success at each point in the treatment continuum. —D. Ross Camidge, MD, PhD

patients are still rapid progressers on therapy,” he explained. Looking at overall survival, the biomarker-positive group has impressive survival, he continued. “But as the overall survival tail seems to exceed the size of the groups that are either responding or having prolonged progression-free survival, two hypotheses present them-

finished, including potentially modifying outcomes from subsequent lines of therapy,” he continued. Even though the biomarker is imperfect, it can be useful, according to Dr. Camidge. “When we don’t know in whom a drug works, this does not mean either that we shouldn’t give it to anyone until we do or that we

should give it to everybody. Even an imperfect enrichment assay can dramatically alter the ‘bang for the buck’ a drug offers in different settings, addressing the increasingly common hurdle of health economics that exists in health systems around the world.” In addition, Dr. Camidge concurred with Dr. Topalian that an imperfect enrichment biomarker could be used most pragmatically to prioritize the selection of therapy with the greatest chance of success at each point in the treatment continuum. For example, in the group with a PS ≥ 50%, pembrolizumab holds the potential to be a better first- and secondline therapy than chemotherapy. In the group that has a PS of between 1% and 49%, first-line therapy would probably be chemotherapy, but pembrolizumab might be prioritized over second-line chemotherapy. In the biomarker-negative group, pembrolizumab might be deprioritized to a salvage therapy. “All of this would have to be proven prospectively,” he emphasized. n Disclosure: Dr. Camdige reported no potential conflicts of interest.

The ASCO Post | MAY 25, 2015

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AACR Annual Meeting Genomics

Many Miles to Go: Targeted Treatment Based on Whole-Genome Sequencing By Alice Goodman

he ability to do genomic analysis of patients’ tumors holds great promise to revolutionize cancer treatment, and genomics has already made some great strides. However, the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial is a cautionary tale about the hurdles involved in taking genomic profiling data to the clinical setting. The IMPaCT trial sought to perform genomic profiling of patients with pancreatic cancer and to identify actionable genetic targets for treatment. After 93 patients were screened, 76 were eligible for profiling, and the researchers were able to identify only 22 candidate cases for a variety of reasons. And, none of these 22 patients has gone on to receive targeted therapy on the trial. Disappointed by the results, lead

author Lorraine A. Chantrill, MD, of The Kinghorn Cancer Centre, Garvan Institute of Medical Research, and The Macarthur Cancer Therapy Centre at Campbelltown Hospital, Sydney, New South Wales, Australia, said: “We are on a learning curve. The technology is ahead of what our health-care systems can deliver. It will take time for this to become a reality. At the moment, our health-care systems are not set up for this.” Dr. Chantrill presented the IMPaCT trial results at the 2015 Annual Meeting of the American Association of Cancer Research,1 and the study was published simultaneously in Clinical Cancer Research.2

A Closer Look Among the reasons for the failure to get patients on therapy targeted to their

We are on a learning curve. The technology is ahead of what our health-care systems can deliver. It will take time for this to become a reality. —Lorraine A. Chantrill, MD

identified mutations were the difficulty in obtaining adequate tumor tissue for biopsy, the lag time in getting tumor tissue to the lab and back, the very short life span of pancreatic cancer patients, patients’ desire not to be randomized if they had an identifiable genetic abnormality, patients’ urgent desire to get

onto treatment as quickly as possible, and the teamwork needed among the various specialties involved. The study screened for three molecular targets: HER2 amplification, KRAS wild-type, and mutations in DNA damage repair pathways (BRCA1, BRCA2, continued on page 23

EXPERT POINT OF VIEW

laine Mardis, PhD, Co-director of The Genome Institute at Washington University School of Medicine, St. Louis, commented on the IMPaCT trial and the constraints of the U.S. health-care system.

when their genome is studied to determine a targeted therapy they might respond to vs the standard of care,” Dr. Mardis wrote in an e-mail. Her second point refers to reimbursement. “While historically insur-

The correct clinical trial has not yet been performed to demonstrate the clinical utility of genomic sequencing to determine treatment with targeted therapies. —Elaine Mardis, PhD

“The correct clinical trial has not yet been performed to demonstrate the clinical utility of genomic sequencing to determine treatment with targeted therapies. In other words, do patients have better outcomes (so defined)

Pembrolizumab in NSCLC continued from page 21

the potential for PD-L1 as a biomarker for preselecting patients for therapy. “This is more clear-cut with tyrosine kinase inhibitors, where biology tells us that if a patient does not have a specific mutation, the therapy will not work. This biomarker is a lot more blurry than a BRAF mutation in melanoma, for example. Patients with lower PD-L1 staining still had a response.”

ance payors have covered the cost of most single-gene sequencing assays or other ‘companion diagnostics,’ the current Centers for Medicare and Medicaid Services (CMS) determination is that code-stacking the cost of multiple

“In this study, highly PD-L1–positive patients were more likely to respond to pembrolizumab, but there is still a group of patients who are markernegative who do respond. PD-L1 might be used to stratify patients who are more likely to respond and to prioritize the use of pembrolizumab. For example, if a patient with NSCLC has a proportion score ≥ 50%, pembrolizumab could be a good first choice, but another patient

single-gene assays is not reimbursable. As such, panels of genes or exomes are not being reimbursed by insurance companies [so someone else has to pay]. Hence, the number of patients who can afford these assays from their own pockets is limited,” she wrote. In the IMPaCT study, the research was supported by government and foundation funding. Dr. Mardis commented that several large cancer centers, including Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center, have raised funds to study clinical utility and reimbursement of genomic sequencing by generating genomic data for patients and using those data to enroll patients onto clinical trials. “Earliest reports from these efforts are that while many patients can be identified with a mutation in a known driver gene, sometimes the impact of the mutation on the protein function is unknown [variants of unknown sig-

with low PD-L1 expression might be a better candidate for first-line chemotherapy,” she continued. Combinations and sequencing of immunotherapies are the next important areas of study. PD-L1 expression could be used to prioritize combinations and sequencing, she added. n Disclosure: The study was funded by Merck. Dr. Garon’s institution received funds to conduct the trial.

nificance], the variant is known but the drug is not approved in that disease site [off-label indication], or there is not a clinical trial available for that gene/ drug combination and/or disease site,” Dr. Mardis continued. The drug clinical trials design and U.S. Food and Drug Administration (FDA) approval conundrum is another factor that limits this approach. “While FDA has its new breakthrough status to get drugs to patients more quickly, pharmaceutical companies have been slow to open trials that accept most or all cancer patients regardless of disease site for a given gene/drug combination [‘basket’ or ‘bucket’ trials]. So, drugs that might otherwise reach breakthrough status quickly in multiple tissue sites are slow to become available via the basket/bucket trial design,” she stated. n Disclosure: Dr. Mardis reported no potential conflicts of interest.

References 1. Garon EB, Rizvi N, Hui R, et al: Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer. 2015 AACR Annual Meeting. Abstract CT104. Presented April 19, 2015. 2. Garon EB, Rizvi N, Hui R, et al: Pembrolizumab for the treatment of nonsmall-cell lung cancer. N Engl J Med. April 19, 2015 (early release online).

ASCOPost.com | MAY 25, 2015

PAGE 23

AACR Annual Meeting Whole-Genome Sequencing

Lessons Learned

continued from page 22

In the course of the trial, several amendments were necessary, Dr. Chantrill explained. The first was to allow patients to have one cycle of treatment while waiting for results (at the time, gemcitabine was standard). The second was to do away with randomization. “Patients didn’t want to be random-

“The take-home message from this trial is that it is the simple things at the grass-roots level that determine whether this effort pans out: Can I get adequate tissue? Can I get the tissue to a lab in a timely fashion? Can I work with other specialists as a team to expedite this process? It’s not the bells and continued on page 24

Now enrolling for alectinib

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

PALB2, ATM). Tumor biopsies and archived tumor samples were collected from 93 patients with newly diagnosed or recurrent pancreatic cancer, and 76 were screened. Of the 76, 17 were unsuitable for tissue processing for a variety of reasons, including ineligibility, objection to randomization, and death due to pancreatic cancer. Only 22 of those screened turned out to be candidate cases. Of these 22 patients with actionable targets identified, 6 died before results were obtained (1 suicide, 5 pancreatic cancer deaths), 1 had intercurrent prostate cancer making him ineligible, 3 could not be offered treatment due to worsening performance status, 1 withdrew consent, 1 declined consent, 2 were found to have cholangiocarcinoma on pathology and were ineligible, 1 had unacceptable liver abnormalities, 4 received chemotherapy before results were returned, and 3 resected patients are alive without disease recurrence and considered potential long-term survivors. “Results have to be given in a meaningful time frame, considering the swift progression of pancreatic cancer and the desire patients have to start treatment immediately. We amended our study to allow patients to have one cycle of chemotherapy while waiting for results, and 75% of patients got results in less than 28 days,” she said.

ized if they had a target identified,” Dr. Chantrill explained. The second amendment also allowed for the addition of BLEED:8.625" nab-paclitaxel (Abraxane) to gemcita bine for one cycle ofTRIM:7.875" chemotherapy. “At the moment, itSAFETY:7" is still a randomized trial,” she said. Once the second amendment is passed, the IMPaCT investigators will enroll 10 more patients to start.

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

Genomic Profiling in Advanced Pancreatic Cancer ■■ There are many hurdles involved in applying data from whole-genome sequencing for treatment selection in clinical trials of advanced pancreatic cancer. ■■ These obstacles include getting an adequate tissue sample, providing results in an acceptable time frame for people suffering from a cancer with a median survival of 6 to 8 months, as well as patients’ desire for urgent treatment and nonrandomization if a genetic target is identified. ■■ Health-care systems will have to adapt to the needs of molecular profiling clinical trials if they are to go forward.

• 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.

The ASCO Post | MAY 25, 2015

PAGE 24

AACR Annual Meeting Hematology

Adoptive T-Cell Therapy Successfully Treats Devastating Complication of Stem Cell Transplantation By Alice Goodman

new “off-the-shelf” treatment promises to induce remission in rituximab (Rituxan)-refractory Epstein-Barr virus (EBV)-associated lymphoproliferative dis-

at Memorial Sloan Kettering, presented the study results at the AACR meeting. EBV reactivation often occurs in patients who undergo allogeneic bone mar-

These T cells are usable off the shelf and can be given to patients within 24 hours. —Richard J. O’Reilly, MD

order, a potentially fatal complication of hematopoietic stem cell transplantation. Historically, this complication has been difficult to treat because the most effective treatment known to induce remission was to administer donor-derived EBV-immune T cells, which took 60 days or more to generate.

row transplant. Some of these patients— ranging from 1% to 7%, depending on the type of transplant—will develop EBV- associated lymphoproliferative disorder. “This is an extremely aggressive complication, and without therapy, patients die within 31 days,” Dr. O’Reilly said.

Study Background “We wanted to develop an approach that can be delivered more rapidly,” said Richard J. O’Reilly, MD, Chair of the Department of Pediatrics at Memorial Sloan Kettering Cancer Center, New York. The novel approach that he and his colleagues studied is called EBV-specific cytotoxic T-lymphocyte therapy. As senior author of their investigation, Dr. O’Reilly spoke about the strategy at a press conference during the 2015 Annual Meeting of the American Association for Cancer Research (AACR).1 Susan E. Prockop, MD, also a pediatric oncologist

Susan E. Prockop, MD

EBV-associated lymphoproliferative disorder in hematopoietic stem cell transplant recipients is most often diffuse large B-cell lymphoma; it is monomorphic or polyclonal, CD20-positive,

EBV-Specific Cytotoxic T-Lymphocyte Therapy ■■ A new technique for banking donor and third-party T cells can be used to treat Epstein-Barr virus–associated lymphoproliferative disorder. ■■ This new type of therapy can be used “off the shelf” within a time frame that can save patients’ lives.

Whole-Genome Sequencing continued from page 23

whistles of sophisticated technology that move this forward,” she stated.

Going Forward A possible approach in the future that could expedite targeted molecular analysis is the use of “liquid biopsies” using circulating tumor cells or cell-free DNA. This could overcome barriers in

obtaining adequate tissue samples, Dr. Chantrill said. Going forward, a multidisciplinary team dedicated to this effort is necessary to overcome all the many hurdles. The investigators have proposed a new organizational structure that includes interventional radiologists and molecular pathologists to procure specimens more quickly and turn them around more rapidly. “Establishing ‘biopsy teams’ is criti-

EXPERT POINT OF VIEW

“A

doptive T-cell therapy has been around for decades. This is only done at specialized centers and individually prepared for each patient. For the first time, Dr. O’Reilly has reported on an off-the-shelf reagent for a devastating complication of bone marrow transplant,” stated Suzanne Topalian, MD, Director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore. Dr. Topalian moderated the press conference where Dr. O’Reilly presented the data. Formal discussant of this trial, Antoni Ribas, MD, PhD, Professor of Medicine and Hematology/Oncology and Director of Tumor Immunology

This treatment can be delivered to multiple patients without inducing a ‘cytokine storm’ and with a very low incidence of graft-vs-host disease. —Antoni Ribas, MD, PhD

at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, commended this study as “an outstanding body of work.” He continued, “A 64% response rate shows the antitumor activity of third-party Epstein-Barr virus (EBV)-specific [cytotoxic T lymphocytes] for EBV-associated lymphoproliferative disorder. This treatment can be delivered to multiple patients without inducing a ‘cytokine storm’ and with a very low incidence of graft-vs-host disease. It is impressive that the cells expand in vivo after they are introduced, specifically in the patients who have a response…. The only limitation is that repeated dosing is needed [for third-party EBV-specific cytotoxic T lymphocytes].” n Disclosure: Drs. Topalian and Ribas reported no potential conflicts of interest.

and of donor origin. Patients can present with fever, exudative pharyngitis, abdominal pain, mental status changes, and disseminated intravascular coagulation. Common sites of involvement include Waldeyer’s ring, adenopathy above and below the diaphragm, intestine, liver/ spleen, central nervous system, and lung. At Memorial Sloan Kettering, the researchers developed a bank of virusspecific T cells from 330 donors. The T

cells were expanded in culture and stimulated to respond to multiple proteins from the EBV. “These T cells are usable off the shelf and can be given to patients within 24 hours,” Dr. O’Reilly said. To assess the usefulness of these banked cells, they evaluated the human leukocyte antigen (HLA) typing of 200 consecutive unrelated transplant and 100 cord blood trans-

cal, as is developing an efficient yet precise pipeline to generate high-quality genomic data, and will be especially challenging for multisite trials,” she said. “We need the health-care system to align with these barriers.” n

al: Precision medicine for advanced pancreas cancer: The individualized molecular pancreatic cancer therapy (IMPaCT) trial. 2015 AACR Annual Meeting. Abstract CT210. Presented April 20, 2015. 2. Chantrill LA, Nagrial AM, Watson C, et al: Precision medicine for advanced pancreas cancer: The individualized molecular pancreatic cancer therapy (IMPaCT) trial. Clin Cancer Res. April 20, 2015 (early release online).

Disclosure: Dr. Chantrill is on an advisory board for Specialised Therapeutics Australia.

References 1. Chantrill L, Simpson S, Jones A, et

continued on page 30

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the ﬁght with the ﬁrst approved PARP inhibitor1

* INDICATION 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION 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. 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.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

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. 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.

Use in Nursing Mothers 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.

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Abdominal pain/discomfort

Decreased appetite

Nausea

Vomiting

Diarrhea

Dyspepsia

Arthralgia/musculoskeletal pain

Myalgia

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information. References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

Decrease in absolute neutrophil count (neutropenia)

Decrease in platelets (thrombocytopenia)

Decrease in lymphocytes (lymphopenia)

Mean corpuscular volume elevation

Increase in creatininea

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

The ASCO Post | MAY 25, 2015

PAGE 30

AACR Annual Meeting Adoptive T-Cell Therapy continued from page 24

plant recipients and also fielded 175 requests from physicians for patients with EBV-associated malignancies, and were able to identify an EBVspecific cytotoxic T-lymphocyte line from the bank that was matched at two HLA alleles and appropriately HLA-

restricted for 98.6% of these patients. “The bank allows selection of partially HLA-matched EBV-specific [cytotoxic T lymphocytes] matched for two or more HLA alleles and that are HLArestricted by an HLA allele expressed by the patient’s tumor for more than 98% of patients who do not respond to initial management,” Dr. O’Reilly said.

Key Data At the AACR press conference, Dr. O’Reilly reported on 26 patients who developed EBV-associated lymphoproliferative disorder and received EBVspecific cytotoxic T lymphocytes from the original donor as well as two cohorts with a total of 31 patients who developed rituximab-refractory EBV-associated lym-

Trim: 7.625 x 10.5

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]

phoproliferative disorder and were treated with EBV-specific cytotoxic T lymphocytes from a third party. Patients received one course of three weekly infusions and were monitored for response. Those in complete remission at 3 weeks did not get any more treatment, whereas those in partial remission got additional doses. Response rates were as follows: for

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.

ASCOPost.com | MAY 25, 2015

PAGE 31

AACR Annual Meeting those treated with donor-derived EBVspecific cytotoxic T lymphocytes, 62% achieved a complete or partial response. In the third-party group (ie, rituximab-refractory patients), 64% achieved a complete or partial response. All responses were comparable whether donor or third-party EBVspecific cytotoxic T lymphocytes were used, and responses were durable.

“We see responses by the second or third course of T cells, whether donorderived or from a third party. You see complete resolution of disease,” he stated. Long-term disease-free survival was 50% at 12 months for the 12 patients who received third-party EBV-specific cytotoxic T lymphocytes and 71.8% at 12 months for the second cohort.

Trim: 7.625 x 10.5

LYNPARZA (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

T-Cell Pools Currently, patients are referred to Memorial Sloan Kettering to receive cell therapy. However, in the future, physicians will be able to send the HLA pathology of patients who develop EBV- associated lymphoproliferative disorder to Memorial Sloan Kettering, and get appropriately EBV-selected,

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

EBV-specific cytotoxic T lymphocytes back by return mail, he noted. “There is the potential to develop banks of T cells to treat other disorders. My quest is to identify peptide antigens that distinguish these disorders and develop pools of antigen-specific T cells to be used for these diseases.” he stated. The EBV-specific cytotoxic T-lymphocyte strategy has been assigned Breakthrough Therapy status by the U.S. Food and Drug Administration. n

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

Reference 1. Prockop S, et al: 2015 AACR Annual Meeting. Abstract 8841. Presented April 19, 2015.

Richard Pazdur, MD, Receives AACR Public Service Award

ichard Pazdur, MD, was awarded the American Association of Cancer Research’s (AACR) Distinguished Public Service Award at the 2015 AACR Annual Meeting. The Association chose Dr. Pazdur for this award based on his “extraordinary,

Richard Pazdur, MD

steadfast leadership in scientific and regulatory affairs” and his “unwavering commitment to ensuring the development of safe and effective treatments for cancer patients.” Also noted was Dr. Pazdur’s “important work has been and continues to be nothing short of spectacular, and it is saving lives every day from this most feared disease that affects so many.” As Director of the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration , Dr. Pazdur leads a staff of more than 150 oncologists, toxicologists, and other specialists dedicated to approving safe, effective drugs for cancer and bloodrelated conditions. He was recently recognized by Fortune magazine as one of the world’s 50 greatest leaders for his efforts to quicken the process of the approval of such drugs, speeding the process of getting cancer medications on the market and available to patients. n

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AACR Annual Meeting Genitourinary Cancer

Prostate Tumors With Genetic Abnormalities Respond to Olaparib By Alice Goodman

laparib (Lynparza) achieved encouraging response rates in men with metastatic prostate cancer, particularly those with mutations in genes involved in DNA repair (BRCA2 and ATM, most commonly).1 If validated, these results of the TOPARP-A trial will usher in the first drug targeted to somatic or germline mutations for prostate cancer. Olaparib is approved for the treatment of ovarian cancer and inherited BRCA mutations. This is the first trial to suggest this drug can benefit men with similar genomic abnormalities and prostate cancer. “TOPARP-A was initiated to show the anticancer effect of the PARP (poly ADP-ribose polymerase) inhibitor olaparib in men with metastatic castration-resistant prostate cancer and identify a molecularly distinct subgroup of patients that responds to the drug. These are potentially the first clinical data supporting molecular stratification of treatment for pros-

tate cancer, and we are testing this idea in the second stage of this trial, TOPARP‑B. For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP‑A,” said presenting author Joaquin Mateo, MD, Clinical Research Fellow at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, speaking at the Annual Meeting of the American Association for Cancer Research (AACR).

Study Details TOPARP was designed as a multistep trial with an adaptive design based on response rate and correlative biomarker studies. TOPARP-A enrolled 50 men with metastatic, castration-resistant prostate cancer, all of whom progressed after treatment with previous lines of therapy, including taxanes. No patient was previously exposed to platinum chemotherapy or a PARP inhibitor. These patients were

EXPERT POINT OF VIEW

“T

he PARP enzyme functions in aiding cells as they repair DNA. Olaparib hits the target. The question is how best to use it,” said William Nelson, MD, Director of the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore. Dr. Nelson moderated a press conference where these data were discussed.

Olaparib hits the target. The question is how best to use it. —William Nelson, MD

“This drug works on the concept of synthetic lethality, targeting lost genes by finding the synthetic lethal pair and targeting those functions. This is different from targeting oncogene addiction, for example, the androgen receptor,” Dr. Nelson explained. “The study suggests that olaparib will be active in men who have been treated with hormones, abiraterone [Zytiga], and enzalutamide [Xtandi] and are progressing. The findings raise the possibility that using a genome test to identify likely responders will achieve a higher response rate, which is being studied in TOPARP-B,” Dr. Nelson continued. “Prostate cancer has been treated with hormones for many years. With enzalutamide and abiraterone, we are still getting more mileage out of attacking the androgen receptor. With this study, we are looking at different targets off of the androgen receptor,” he said. n Disclosure: Dr. Nelson reported no potential conflicts of interest.

These are potentially the first clinical data supporting molecular stratification of treatment for prostate cancer. —Joaquin Mateo, MD

unselected for genetic abnormalities. Patients were biopsied and underwent repeat biopsy after treatment. Whole-exome sequencing was performed after the response rate was determined. Among 49 patients with evaluable data, 16 had a response to olaparib, for an overall response rate of 32.7%. Six patients had confirmed radiologic responses, according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and 11 patients had biochemical responses (ie, > 50% decline in prostate-specific antigen [PSA]). The majority of patients had responses for more than 6 months; four patients responded for more than a year; and five patients are still on therapy, Dr. Mateo said. Next-generation sequencing identified mutations in genes associated with DNA repair in biopsies from bone marrow and metastases, including BRCA2 and ATM genes, in tumor tissue from 16 of the 49 evaluable patients. Of these 16 mutation-positive patients, 14 (88%) responded to olaparib. Most of the mutations were somatic, developing in the tumor. BRCA2 was the most common gene, found in seven patients (three with germline and four with somatic mutations); all seven of these patients responded to olaparib. ATM was the second most common abnormal gene, found in five patients (three germline, two somatic mutations); four responded to olapa-

rib, and one had progressive disease. Losses in other genes that sensitize patients to olaparib were identified, including PALB2 and HDAC2. The specificity of the DNA gene repair panel was 94%. Dr. Mateo said this means that 94% of patients not responding to olaparib did not have mutations in these genes, and this will help clinicians select the right treatment, because they can be reasonably certain that olaparib will not benefit a patient who tests negative for these mutations. “There were no surprises regarding safety,” Dr. Mateo said. “The main toxicities with olaparib were anemia and fatigue, and some myelotoxicity was observed. Compared with tolerability in ovarian cancer, olaparib was better tolerated. We did not see major gastrointestinal toxicities.” “We worked with our U.S. colleagues on behalf of the Stand Up To Cancer-Prostate Cancer Foundation Dream Team to identify biomarkers of response to olaparib,” Dr. Mateo said. n

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

Reference 1. Mateo J, Sandhu S, Miranda S, et al: DNA repair defects and antitumor activity with PARP inhibitors: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. 2015 AACR Annual Meeting. Abstract CT322. Presented April 21, 2015.

Olaparib in Prostate Cancer With Genetic Mutations ■■ Prostate cancer has lagged behind breast, colorectal, and lung cancers regarding identification of abnormal mutations that can be targeted by drug treatment. ■■ For the first time, a study suggests that olaparib achieves preferential response in men with prostate cancer who have abnormalities in DNA repair genes, particularly BRCA2 and ATM. ■■ Further studies are needed to validate this finding and these genetic abnormalities as a biomarker for response to olaparib in prostate cancer.

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Expert’s Corner Breast Cancer

Managing Breast Cancer in 2015 A Conversation With Larry Norton, MD By Ronald Piana drug, learn how to use it in combination, and then compare the drug with other approaches. That said, we are currently ruminating over the best way to

use molecularly targeted therapies in clinical trials to answer those vital questions quicker and more accurately. This critical evaluation process is

important, because we’ve had times in medical oncology in which a dramatic response was seen as the endpoint, sti-

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Larry Norton, MD

ince 1990, we have seen an approximate 35% reduction in breast cancer mortality among women in the United States. Three protagonists can share this clinical success story: prevention, early detection, and better therapies. To shed light on the current state of breast cancer research and therapy, The ASCO Post spoke with internationally regarded breast cancer expert and ASCO past president Larry Norton, MD, Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center in New York.

Coming soon…

Reinvention of Clinical Trials Please tell the readers what has been the most significant advance in breast cancer treatment over the course of your career? This may surprise some, but I believe the most significant advance has been the development of clinical trial methodology. Innovative scientific ideas come along frequently, but they still have to be tested. Not everything logical is true, but everything that is true should be confirmed. And the major leap forward in that confirmation process was the emergence of the randomized controlled prospective trial. Over the past few decades, we’ve seen many good ideas sorted out by rigorous trials, which ultimately developed into active therapies. This is particularly relevant to this time in history, because we’re seeing a potential reinvention of clinical trials due to the advent of precision medicine: that is, defining a particular target, developing an intervention to hit that target, and then examining the results. Seeing responses in this setting is the most important step in the development of active therapeutics. However, it is a first step, and we then need to see how durable the response is, determine the optimal time in which to give the

continued on page 34

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Expert’s Corner Larry Norton, MD continued from page 33

fling further critique. For example, autologous bone marrow transplant with high-dose chemotherapy produced dramatic responses in breast tumor shrinkage. Investigators judged this a huge clinical win, which in effect created a consensus among the oncology community that further confirmatory randomized trials were not needed. It took us 10 years to discover that bone marrow transplant with high-dose chemotherapy was no better than standard chemotherapy, which was also less toxic. This episode offers an important cautionary lesson that shouldn’t be forgotten. Clearly, with the advent of molecularly targeted therapies, our opportunities are greater than ever, but we have to think very long about how we’re going to test these new therapies in trials that ensure their benefit before bringing them into the clinic.

Dissecting Resistance Pathways Chemoresistance has been a persistent problem in breast cancer. Are we making headway in this area? Drug resistance is a major problem throughout all medical disciplines where drugs are delivered. In cancer, it’s especially difficult because we’re treating a disease that comprises the host’s own cells. And evolution has taught these cells how to survive in a noxious environment of toxins. Drug resistance develops from a wide variety of cellular mechanisms, and one of the great powers of the modern molecular revolution is being able to dissect those resistance pathways and find ways to diagnose and prevent them. This is one of the most exciting areas we’re investigating in molecular therapeutics. We’re seeing a lot of the newer agents being developed as initial therapies. For instance, we have many effective hormone therapies for breast cancer; the next step is to combine a hormone therapy with a promising drug de novo, which might overcome potential mechanisms of resistance.

This approach is meritorious, but what might be more important in the long run is to treat a patient with a drug and if a resistance mechanism emerges, have another drug in place that will halt the resistance mechanism in its tracks. Both of these approaches tie into my leading argument about clinical trial methodology, which, if properly designed, can be used to find the mechanisms of drug resistance and then develop drugs specially engineered to “turn off ” those mechanisms. I think that’s the kind of clinical trial we’ll see more of in the future.

We’re currently doing a trial at Memorial Sloan Kettering in which we use cryoablation, radiotherapy, and other techniques, such as introducing DNA into the cancer cell to make it secrete its own immunostimulatory components, which are all methods to make the cancer cell a better target for the immune response. Then, if you combine that method with drugs that inhibit the checkpoint blockade for preventing cellular self-against-self attack, you’ve opened the door for promising immune therapies.

Immunotherapy

Targeting Both Growth and Migration

Immunotherapy is emerging as one of the most promising therapeutic opportunities in several cancers. Please discuss the future role of immunotherapy in breast cancer. Immunotherapy is part of the molecular revolution we’re talking about, because what made it possible is the discovery of particular mechanisms by which our cells can avoid attacking their host, in particular the CTLA-4 (cytotoxic T-lymphocyte antigen 4) mechanism, which has opened up this exciting area of molecularly targeted therapies. What truly makes this interesting is that this process exists at the interface of the

The metastatic process remains, to a certain extent, still a mystery. Are we getting closer to a full understanding of the process? And can you please bring our readers up to speed on your fascinating work on tumor self-seeding. Cancer is basically two things: growth and migration. Over the decades, we’ve gotten much better at treating the growth abnormalities with chemotherapy. We’re seeing targeted therapies such mTOR inhibiters and anti-CDK4/6 drugs, which are effective at perturbing the abnormal cell division of cancer, but we’ve lagged behind in attacking the other component

If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live. —Larry Norton, MD

cancer cell and a host’s white blood cell, which is an important topic for future development; it is not the cell itself but the cell’s relationship with other cells. Nobody ever died of breast cancer cells; you die of tumors, which are complex organs involving cancer cells, white blood cells, and host tissues such as fibroblasts. And those cells in the tumor environment have a functional relationship, and the communication among those cells is a valuable target—I think that is the core of immunotherapy in cancer.

of cancer—the ability of cancer cells to migrate. And evidence suggests that cell migration may be key to the malignant process, because when migratory cells return to their original primary site, they bring white blood cells and blood vessels, which are tools to reinvigorate the malignant process. To that end, there is tremendous interest in developing antimigratory drugs, which is a better term then antimetastatic. I think that moving forward this will be one of the most important

areas of research in modern medical science. If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live. In other words, if we can inhibit the circulating cancer cells from lodging and forming tumors, it doesn’t matter how many cancer cells are in the blood, because the patient will never get sick. We’re also making headway in a very novel technique, which is a trap that can actually capture circulating cancer cells. The immediate application is to capture the cells for study, hopefully to lead us to better molecular targets. However, it may have therapeutic value in being able to rid the body of cancer cells before they have the opportunity to root in an organ and form tumors.

Closing Thoughts Please share a closing thought or two about the state of breast cancer research and care from your perspective as Director of the MSKCC Evelyn H. Lauder Breast Center. We have never had a period like this in all the history of cancer research and treatment. Compared to just a few decades ago, our growing knowledge of cancer biology is nothing short of incredible, but we have challenges ahead. For one, funding for research is very tight, and it’s a problem that we all wrestle with, one that ASCO has taken a lead on. I also think that the business model used to develop early ideas needs to be reinvented. The brilliant MIT economist Andrew Lo has written extensively about this. He’s also organized a yearly meeting in Boston that is attempting to find better ways to finance drug trials. I have great confidence that if the oncology community partners with innovators such as Andrew Lo and others, we will generate the creative juices needed to reinvigorate the clinical trial process and bring these novel ideas to fruition. n Disclosure: Dr. Norton reported no potential conflicts of interest.

Visit The ASCO Post at the ASCO Annual Meeting May 29 - June 2, 2015 The ASCO Post BOOTH 6012

ASCOPost.com | MAY 25, 2015

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American College of Surgeons Annual Meeting Prevention

HPV-Related Anal Cancer on the Rise By Caroline Helwick

ore than 7,200 cases of anal cancer were diagnosed in 2014— approximately 2,600 in men and 4,600 in women—representing an increase of more than 4,000 from 8 years ago. In more than 90% of patients, infection with the human papillomavirus (HPV) is the cause, tagging anal cancer as a largely preventable malignancy. However, this fact is often ignored, reflective of the anemic acceptance of the merit of the HPV vaccine. “We have found that the number one

tact with an infected area of the body; although sexual contact is a primary means of transmission, intercourse is not necessary. An HPV infection can also spread from one part of the body to another, for example, originating in the genitals and then spreading to the anus. HPV infection is very common and usually clears on its own. When it persists, especially the high-risk HPV subtypes, cancer can develop at the site of infection. Individuals aged 15 to 24 are most at risk for the infection, but its clini-

Without prevention, novel screening, and treatment of premalignant lesions, I am afraid we will have at least 30 years of an increasing burden from HPV-related cancers. —Erich M. Sturgis, MD, MPH

A lot of papers describing the prevalence of disease [anal precancerous lesions/high-grade squamous intraepithelial lesions] in women have grossly underestimated the amount of disease that is there. It’s higher than most people think. —J. Michael Berry-Lawhorn, MD

reason parents do not vaccinate boys is that their pediatrician did not recommend it. We are making efforts to educate our pediatric and primary care colleagues that boys need this vaccination, too,” said Erich M. Sturgis, MD, MPH, of MD Anderson Cancer Center, Houston, one of several speakers at a session on HPV disease at the American College of Surgeons (ACS) Annual Meeting. “The HPV epidemic is happening. Without prevention, novel screening, and treatment of premalignant lesions, I am afraid we will have at least 30 years of an increasing burden from HPV-related cancers,” he said.

HPV Basics Most squamous cell anal cancers are associated with HPV-16, the subtype that also causes cancers of the cervix, vagina, vulva, penis, and oropharynx. HPV is transmitted via skin-to-skin con-

cal manifestation occurs many years later. Anal cancer accounts for 14% of HPV-related malignancies. Cervical cancer numbers are declining in the developed world due to screening programs, but anal cancer is increasing in both men and women (oropharyngeal cancer is increasing primarily among men) and across ethnic groups, according to Dr. Sturgis.

Anemic Vaccination Rates HPV vaccination in youth is recommended as a means of preventing both cervical and anal cancers and potentially HPV-related oropharyngeal cancer. “The problem is our vaccination rates. We are far behind other developed countries,” Dr. Sturgis noted. Although the goal is an 80% vaccination rate, in the United States, only 58% of girls receive one shot, and less than 38% complete the series. For boys, about

one-third receives the first shot, and only 14% are fully immunized, he said. A study presented at the American Public Health Association 2014 Annual Meeting confirmed these numbers and also found that state legislation supporting vaccination has no impact on uptake. In March 2007, the Advisory Committee on Immunization Practices (ACIP) recommended that females aged 9 to 26 receive the HPV vaccine; in 2009, males were included in the recommendation. Subsequently, about half the states have introduced legislation to encourage HPV vaccination. Darius Taylor, MPH, of the School of Public Health at the University of North Texas Health Science Center, Fort Worth, Texas, and colleagues hypothesized that the political climate, as measured by the status of HPV vaccine legislation, would encourage vaccine update. To study this, they examined the National Immunization Survey data (obtained through a telephone survey) from 2010 to 2012 to determine the prevalence of vaccine initiation, vaccine completion and intention patterns, and the influence of the primary care physician. Over half the respondents lived in states that produced legislation between 2006 and 2012. Among residents of states with no legislation, 45.3% of females and 9.4% of males were vaccinated. This was no higher than for states that endorsed HPV vaccination, with rates of 45.2% and 10.1%, respectively. “The effect of current health policy had little influence on HPV vaccine initiation,” Mr. Taylor reported. The primary care physician’s influence was also similar across the states: Physicians recommended vaccination for only 58% of female patients and 16% of boys. “For parents reporting a visit to a primary care physician within the past month, those with sons were 86% less likely to have HPV vaccines recommended than parents of daughters,” he said.

Risk Factors for Anal Cancer Although HPV-related infection is an equal-opportunity disease, risk for HPV-related anal cancer is greatly increased among certain groups. At the ACS meeting, J. Michael BerryLawhorn, MD, of the University of California, San Francisco, noted the incidence per 100,000 persons, according to risk group: HIV-infected individuals, 78 to 144; HIV-negative men having

sex with men, 35; HIV-positive women, 9.4 to 30; women in the general population, 1.5; and heterosexual men, 1. Anna Barbara Moscicki, MD, of the University of California, San Francisco, also speaking at the meeting, zeroed in on the “super risk factors” among women. HIV infection imparts a sevenfold risk (rising to 130-fold in the youngest age groups); other HPVassociated cancers, including cervical cancer and cervical intraepithelial neoplasia grade 3, impart a sixfold risk; and vulvar and vaginal cancers impart a 17- to 20-fold increased risk for anal cancer. The risk among the general population of women is relatively low, but Dr. Berry-Lawhorn noted that highresolution anoscopy identifies cases that might otherwise be missed. “A lot of papers describing the prevalence of disease in women have grossly underestimated the amount of disease that is there. It’s higher than most people think,” he maintained. One reason for this may be the rising acceptance of anal intercourse among females. According to Dr. Moscicki, “Anal sex is risky for infection because of the vulnerability and fragility of the tissue itself. Adolescents have been using anal sex for birth control. We have to do a better job of education and assuring they have appropriate birth control.” Dr. Berry-Lawhorn added, however, anal intercourse is not necessary for HPV transmission to the anal area. “Sex is a very moist experience, and HPV travels all over the place,” he said.

Progression From Premalignant to Malignant Disease The trick is finding the precursors— anal high-grade squamous intraepithelial lesions—before they progress to anal cancer. Dr. Berry-Lawhorn and colleagues recently demonstrated direct progression of high-grade squamous intraepithelial lesions to cancer by following 138 HIV-infected men who have sex with men diagnosed with anal canal or perianal squamous cancer between 1997 and 2011.1 All patients were followed with digital anorectal examination, high-resolution anoscopy, and high-resolution anoscopy-guided biopsy. Although treatment for high-grade squamous intraepithelial lesions and follow-up were recommendcontinued on page 36

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American College of Surgeons Annual Meeting HPV-Related Anal Cancers continued from page 35

ed, not all patients were treated, and some were lost to follow-up. Prevalent cancer was found in 66 men; the other 72 HIV-infected men who have sex with men developed anal cancer while under observation. In 27 of these 72 men, anal cancer developed at a previously biopsied site of a highgrade squamous intraepithelial lesion (45 were not analyzed due to inadequate documentation of its location). Progression to cancer occurred over approximately 5 years. High-grade squamous intraepithelial lesions are found in 50% of HIV-infected men who have sex with men, 25% of HIV-negative men who

have sex with men, and up to 40% of HIV-positive women (data are lacking in heterosexual men). Persons most likely to have high-grade squamous intraepithelial lesions are those who are HIV-infected (especially men who have sex with men), immunocompromised, older than age 35 with genital warts, symptomatic with extensive perianal lesions, and women with a history of vulvar high-grade squamous intraepithelial lesions, he indicated. Persons with abnormal anal cytology should be referred for high-resolution anoscopy. If found, high-grade squamous intraepithelial lesions can be excised or ablated, but Dr. Berry acknowledged, “there is no definitive proof that

ablation prevents anal cancer.” Proof could come from a study by the National Cancer Institute, which will screen approximately 17,000 HIVinfected persons to identify 5,000 high-grade squamous intraepithelial lesions, randomizing them to ablation or surveillance for 5 years. The goal is to reduce the number of incident cancers by 75%. (For more information, visit www.theanchorstudy.org.) As debate continues about whom and when to screen for anal cancer, there seems to be agreement that the best screening means is digital anorectal examination and anal cytology, with referral to high-resolution anoscopy. Unfortunately, according to Dr. Berry-Lawhorn, digital ano-

rectal examination is not performed often enough when patients present with anal pain and bleeding, and the number of clinicians experienced in high-resolution anoscopy remains “quite limited.” Thus, recognition and treatment of HPV-related anal cancer remain a work in progress. n

Disclosure: Drs. Sturgis and Berry-Lawhorn reported no potential conflicts of interest. Dr. Moscicki is a member of the advisory board for Merck.

Reference 1. Berry JM, Jay N, Cranston RD, et al: Progression of anal high-grade squamous intraepithelial lesions to invasive anal cancer among HIV-infected men who have sex with men. Int J Cancer 134:11471155, 2014.

Moffitt Cancer Center Hosts First HPV Summit By Caroline Helwick

n February 2015, the President’s Cancer Panel reported that human papillomavirus (HPV) vaccination uptake among boys and girls was falling drastically short of target rates,

Anna Giuliano, PhD

posing “a serious but correctable threat to progress against cancer.” In response, the National Cancer Institute (NCI) awarded short-term grants to 18 NCI-designated cancer centers for research and collaborations that would enhance HPV vaccination uptake.

On the heels of this funding, and to facilitate discussions of common approaches and goals between centers on a national level, Anna Giuliano, PhD, and Susan Vadaparampil, PhD, MPH, of the Moffitt Cancer Center, Tampa, Florida, spearheaded a conference of experts and stakeholders: “Increasing HPV Vaccination in the United States: A Collaboration of NCI-Funded Cancer Centers.” The conference was attended in January 2015 by representatives from cancer centers and others interested in driving the national conversation on HPV vaccine uptake.

Many Voices Heard Having so many educated and forward-looking voices in one room had incredible value, said Dr. Vadaparampil, a senior member in the Health Outcomes and Behavior Program at Moffitt. “We heard not only

We all agreed that where we need to start is in supporting provider recommendations. That is the target for increasing vaccine acceptance. —Susan Vadaparampil, PhD, MPH

from representatives of all the NCIdesignated cancer centers but from leadership at the American Cancer Society, NCI, and Centers for Disease Control and Prevention. We learned there are many ways we can bolster vaccination rates, but we all agreed that where we need to start is in supporting provider recommendations. That is the target for increasing vaccine acceptance,” she said. Discussions focused on shared

Attendees to the conference on “Increasing HPV Vaccination in the United States: A Collaboration of NCI-Funded Cancer Centers,” held at Moffitt Cancer Center in Tampa, Florida.

measures, common deliverables, challenges in vaccination communication, and strategies to identify and engage key stakeholders. Among the overarching themes were the need to discuss the importance of HPV vaccination as a cancer prevention method (rather than focusing on sexual transmission of the virus itself), the need for a gender-neutral approach to vaccination, and the need to account for diversity in target populations, Dr. Vadaparampil said. As a result of meeting together, a number of working groups were formed; participants will be sharing study instruments online to ensure consistency of data in crafting a national HPV vaccination overview. A follow-up meeting will be hosted by MD Anderson Cancer Center in September 2015 to review the first year of grant funding, revisit issues that were raised, address new concerns, and highlight successes among teams around the nation working toward HPV vaccination to prevent cancer. n

Disclosure: Drs. Giuliano and Vadaparampil reported no potential conflicts of interest.

ASCOPost.com | MAY 25, 2015

PAGE 37

Society of Gynecologic Oncology Annual Meeting Targeted Therapy

PARP Inhibitors Have ‘Clear Benefit’ for Patients With Ovarian Cancer and BRCA Mutations, but When and at What Cost? By Charlotte Bath

“P

ARP inhibitors are promising targeted therapy in ovarian cancer” and have “clear benefit in BRCAmutation carriers,” but questions remain about when is the best time to use them and the cost-effectiveness of maintenance therapy, Elizabeth M. Swisher, MD, of the University of Washington in Seattle, said at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in Chicago. Using inhibitors of poly (ADP-ribose) polymerase (PARP) enzymes in combination with other targeted therapies, as well as chemotherapy, “definitely” has the potential, she added, “to make PARP inhibitors even more effective.” Dr. Swisher’s comments followed presentations on olaparib (Lynparza) monotherapy for patients with advanced relapsed ovarian cancer and the use of olaparib as maintenance therapy. Olaparib was approved by the U.S.

apy trials, including in the subgroup of patients who had received at least three prior lines of chemotherapy,” according to Ursula A. Matulonis, MD, of DanaFarber Cancer Center, Boston, who presented the results. Among patients with measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria, demographics and baseline characteristics were similar for the overall population of 273 patients and the 205 patients who had received at least three prior lines of chemotherapy. All patients received olaparib 400 mg in capsule formulation twice daily.

Response Declined With More Prior Therapies The overall response rate was 36% vs 31% for the more heavily treated patients, Dr. Matulonis reported. There was a gradual decline in overall re-

The response rate decreases with increasing number of prior therapies. So why would we want to wait until the fourth line to treat our mutation carriers. —Elizabeth M. Swisher, MD

Food and Drug Administration in 2014 for treatment of patients with advanced ovarian cancer and germline BRCA1/2 mutations who have received three or more prior lines of chemotherapy. In Europe, olaparib is approved “for maintenance therapy for platinum-sensitive relapse following chemotherapy in either germline or somatic BRCA mutations,” Dr. Swisher noted. “So the approval indications are quite different.”

Durable Responses in Relapsed Patients Pooled analysis of six phase I and II olaparib trials found that patients with relapsed ovarian cancer and germline BRCA1/2 mutations experienced durable responses of around 8 months and that the durable response rate was not reduced for patients who had received three or more lines of prior chemotherapy. The analysis “evaluated the efficacy and safety of olaparib in this patient population from completed monother-

sponse rate with increasing lines of chemotherapy, she added. “As Dr. Matulonis demonstrated, the response rate decreases with increasing number of prior therapies,” Dr. Swisher noted. “So why would we want to wait until the fourth line to treat our mutation carriers?” She said that many physicians probably have been faced with situations where they think patients might benefit from olaparib but “need to fail a couple more lines of chemotherapy first.” In addition, she said, “we all know that later in the disease course, gastrointestinal symptoms become more prominent, and an oral drug may not be tolerated. So we might lose the opportunity to treat these patients with these drugs.” In the pooled analysis, grade ≥ 3 adverse events occurred in 50% of the overall population and 54% of the subgroup. Serious adverse events occurred in 30% of all patients and 34% of the subgroups. All eight of the patients (3%) with an ad-

verse event leading to death had received at least three lines of chemotherapy, but none of those adverse events (sepsis, intestinal perforation, suture rupture, acute leukemia, cerebrovascular accident, chronic obstructive pulmonary disease, and pulmonary embolism) was considered causally related to use of olaparib. The most common adverse events of all grades were nausea (65%), fatigue (61%), and vomiting (39%).

Maintenance Therapy With PARP Inhibitors “Maintenance therapy for ovarian cancer has been very exciting,” Dr. Swisher stated. “Companies have invested heavily into maintenance therapy trials” with four PARP inhibitors, she added. In addition to olaparib, veliparib, rucaparib, and niraparib are in phase III maintenance trials for ovarian cancer. In these trials, “the patient either gets the PARP inhibitor or placebo, and then the time to subsequent progression is the primary outcome, as it was in study 19,” Dr. Swisher said. That study found that maintenance therapy with olaparib extended progression-free survival in patients with advanced ovarian cancer and BRCA mutations. Olaparib trials are “concentrating only on cases with BRCA mutations, whether germline or somatic, whereas the other three drugs have studies that are open both in the primary and relapsed setting for cases that are highgrade serous or endometrioid, and patients may have or not have BRCA mutations,” Dr. Swisher reported. “Predictors of response (and resistance) other than BRCA mutations are needed,” Dr. Swisher noted.

What Do Patients Really Want? “Patients really want extension of life and also time off treatment, especially when that treatment involves significant side effects,” Dr. Swisher said. Thus, maintenance therapy could be used to postpone the time until subsequent chemotherapy is needed. That is “a very important endpoint,” Dr. Swisher said. “I think we can all agree that delaying chemotherapy is an important clinical incentive.” However, there is some concern that using a PARP inhibitor as maintenance therapy might lead to chemoresistance, and some maintenance trials are look-

ing at second subsequent chemotherapy. “That time to second subsequent chemotherapy can reflect whether or not PARP inhibitor maintenance generates chemoresistance,” Dr. Swisher said. For example, if a patient who gets a PARP inhibitor then progresses and receives chemotherapy, but now that chemotherapy doesn’t work as well, the patient will need a different chemotherapy regimen sooner than if the patient didn’t get PARP inhibitor maintenance therapy, had a good response to subsequent chemotherapy, and was in remission again. In yet another scenario, starting a PARP inhibitor at the time of disease progression could actually end up further delaying the time to next chemotherapy and may be a more cost-effective approach.

‘Burning Questions’ Remain “So is it better to use a PARP inhibitor in maintenance or actually at the time of relapse? If we use it as maintenance, is it in the primary setting or the recurrent setting?” These two are among the “burning questions that we still need to answer about PARP inhibitor therapy in ovarian cancer,” Dr. Swisher said. Other questions center on assessing cost-effectiveness, determining a synergistic combination of PARP inhibitors with biologics or chemotherapy, developing tests to best define BRCAlike cancers that will respond to PARP inhibitors, and combining PARP inhibitors with other therapies that target DNA repair. This could “potentially extend PARP inhibitor therapy to cancers that are proficient in homologous recombination or cancers that have intact DNA repair,” Dr. Swisher said. “We know that ovarian cancers that are proficient in homologous recombination are not sensitive to PARP inhibitors,” Dr. Swisher explained. “Even BRCA-mutated ovarian cancers eventually develop resistance to PARP inhibitors, and much of that is through restoration of DNA repair and increase of homologous recombination. So new drugs that inhibit homologous recombination could be combined with PARP inhibitors.” In that scenario, an agent that inhibits homologous recombination could be used to render an ovarian cancer proficient in homologous recombination deficient in homologous recombination, which would allow a PARP continued on page 40

IN APPROACHING HR+ ADVANCED BREAST CANCER

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HAVE YOU LEFT YOUR PATIENTS VULNERABLE TO PI3K-mTOR SIGNALING? When overlooked, hyperactivation of the PI3K-mTOR pathway drives resistance to endocrine monotherapy and HR+ disease progression1,2 • PI3K-mTOR is the most common aberrantly activated pathway in breast cancer, with genetic defects occurring in >70% of cases2,3 • The PI3K-mTOR pathway is a major source of resistance and progression in HR+ advanced breast cancer1,2 • Novartis is committed to realizing the full therapeutic potential of targeting the PI3K-mTOR pathway for patients with HR+ advanced breast cancer

HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin. References: 1. Miller T. Endocrine resistance: what do we know? Am Soc Clin Oncol Educ Book. 2013:e37-e42. 2. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224-235. 3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-215.

The PI3K-mTOR pathway is an important component to consider in approaching HR+ advanced breast cancer. Find out more at TargetingPI3K-mTOR.com. Printed in USA

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The ASCO Post | MAY 25, 2015

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Society of Gynecologic Oncology Annual Meeting PARP Inhibitors in Ovarian Cancer continued from page 37

inhibitor to be synthetically lethal to that cancer. “There is definitely a lot of potential to make PARP inhibitors even more effective,” Dr. Swisher concluded.

Cost of Maintenance Therapy Cost issues associated with olaparib maintenance therapy were tackled in a separate presentation by Haller J. Smith, MD, and colleagues at the University of Alabama at Birmingham. They found that at an estimated cost of $7,000 per month for olaparib maintenance therapy is not cost-effective. [Editors note: The authors created the model for their study prior to olaparib

Haller J. Smith, MD

being approved by the FDA; therefore, the $7,000 cost they used in the original model was an estimate based on other targeted agents. The actual cost of olaparib is $13,440 per month.] The study compared the cost-effectiveness of olaparib maintenance therapy with observation in patients with platinum-sensitive recurrent ovarian

cancer who had received six cycles of paclitaxel and carboplatin. As explained in the study abstract, “Cost-effectiveness ratios and incremental cost-effectiveness ratios per progression-free lifeyear saved were calculated for patients with BRCA mutations and for patients with wild-type BRCA.” The researchers estimated that 5,549 patients were diagnosed with platinum-sensitive cancer in the United States and assumed a BRCA germline mutation rate of 20%. “Assuming a cost similar to that of other oral targeted agents, olaparib maintenance therapy would result in an increase in cost of $85.8 million compared with observation for patients with platinumsensitive recurrent ovarian cancer and a deleterious BRCA mutation. Mainte-

nance therapy with olaparib is not costeffective, with an incremental cost-effectiveness ratio of $135,672. To achieve an incremental cost-effectiveness ratio of less than $50,000, the cost of olaparib should be $2,500 or less per month,” the authors concluded. “For wild-type BRCA patients, maintenance therapy with olaparib is unlikely ever to be cost-effective.” n

Disclosure: Dr. Matulonis has received research funding from AstraZeneca, is on advisory boards for ImmunoGen and Genentech, and is a member of the speakers bureau for AstraZeneca. Drs. Swisher and Smith reported no potential conflicts of interest.

Dr. Ursula Matulonis offers further expert perspective on PARP inhibitors in ovarian cancer, see page 42

News Gynecologic Oncology

American College of Physicians Releases Best Practice Advice for Cervical Cancer Screening in Average-Risk Women By Jo Cavallo

n April 2015, the American College of Physicians (ACP) released its clinical advice guideline, Cervical Cancer Screening in Average-Risk Women: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians.1 The guideline aims to reduce the overuse of cervical cancer screening in asymptomatic, averagerisk women 21 years of age or older and is supported by the American Congress of Obstetricians and Gynecologists and endorsed by the American Society for Clinical Pathology. The guideline defines women at average risk as those with no history of a

evidence, including systematic reviews and recent guidelines, and is focused on primary screening rather than on management of abnormal screening test results.

Best Practice Advice Guideline The clinical guideline includes advice on when to start and stop screening, which screening tests to use, and at what screening interval. • Clinicians should not screen averagerisk women younger than age 21 for cervical cancer. • Clinicians should start screening average-risk women for cervical cancer at age 21 once every 3 years with cy-

The American College of Physicians’ advice for cervical cancer screening is designed to maximize the benefits and minimize the harms of testing. —David Fleming, MD, MACP

precancerous lesion (cervical intraepithelial neoplasia grade 2 or a more severe lesion) or cervical cancer; those who are not immunocompromised, including being HIV infected; and those without in utero exposure to the synthetic estrogen diethylstilbestrol. The Best Practice Advice guideline is based on a distillation of the best available

tology (cytologic tests without human papillomavirus [HPV] tests). • Clinicians should not screen average-risk women for cervical cancer with cytology more often than once every 3 years. • Clinicians may use a combination of cytology and HPV testing once every 5 years in average-risk women aged

30 years or older who prefer screening less often than every 3 years. • Clinicians should not perform HPV testing in average-risk women younger than age 30. • Clinicians should stop screening average-risk women older than age 65 for cervical cancer if they have had three consecutive negative cytology results or two consecutive negative cytology plus HPV test results within 10 years, with the most recent test performed within 5 years. • Clinicians should not screen averagerisk women of any age for cervical cancer if they have had a hysterectomy with removal of the cervix.

Harms of Screening According to the Best Practice Advice guideline, the harms of screening for cervical cancer can occur at any point along the sequence of care, including during the collection of cervical specimens, diagnostic evaluation, cervical treatments, and post-treatment surveillance. An abnormal screening test result can cause short-term anxiety, including concerns about sexually transmissible infections and their consequences, wrote the authors of the guideline.

Reducing Overuse of Screening To reduce overuse of cervical cancer screening, the ACP clinical guideline suggests that physicians and other healthcare providers know current guidelines

and understand the reasoning behind the recommendation of less testing. “The desire to find the right balance between benefits and harms should be familiar to all physicians steeped in a tradition of doing no harm,” said the authors. “One way to explain these new guidelines to women reluctant to be screened less frequently is to be frank about the expected balance of benefits and harms.” “ACP’s advice for cervical cancer screening is designed to maximize the benefits and minimize the harms of testing,” said David Fleming, MD, MACP, President of the ACP, in a statement. “Historically, physicians have low adherence to cervical cancer screening recommendations, beginning screening too early, performing screening too often, and continuing to screen women at low risk, either by age criteria or after hysterectomy with removal of the cervix.” As clinicians adhere more strongly to cervical cancer screening guidelines, concluded the article, it is anticipated that the harms and costs of cervical cancer screening will be minimized, and the benefits will be maximized. n

Disclosure: For full disclosures of the study authors, visit www.acponline.org/authors/icmje/ ConflictOfInterestForms.do?msNum=M14-2426.

Reference 1. Sawaya GF, Kulasingam S, Denberg T, et al: Cervical cancer screening in averagerisk women. Ann Intern Med. April 30, 2015 (early release online).

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The ASCO Post | MAY 25, 2015

PAGE 42

Perspective Targeted Therapy

PARP Inhibitors: The First Potential Treatment of Hereditary Ovarian Cancers By Ursula A. Matulonis, MD

oly(ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting new classes of agents in development for the treatment of ovarian cancer. Olaparib (Lynparza), the lead oral PARP inhibitor, received accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent germline BRCAmutant ovarian cancer in patients who have received at least three prior lines of chemotherapy.1,2 PARP inhibitors target a cancer cell’s inability to repair DNA, which occurs in cells that have BRCA mutations. Germline BRCA mutations have been identified in up to 17% of women with ovarian cancer and are associated with the high-grade serous histologic subtype, though other histologies can harbor BRCA mutations as well as mutations in other DNA repair genes.3,4 Currently, national guidelines have

with defective BRCA1 or BRCA2 genes cannot perform homologous recombination properly, and thus the cells must use more error-prone DNA repair mechanisms, which then leads to an accumulation of genetic abnormalities.8 PARP inhibitors target these more errant DNA repair mechanisms, leading to cell death.

Emergence of Olaparib Clinically, olaparib was first tested as a single agent in patients with heavily pretreated germline BRCA-mutant ovarian cancer, with observed response rates of up to 33% in both platinumsensitive (platinum-free interval of 6 months or more) as well as platinumresistant (platinum-free interval of less than 6 months) ovarian cancers.9,10 These studies also established the maximally tolerated dose of olaparib capsules—400 mg orally twice a day. Kaufman et al11 tested single-agent

The European Medicines Agency approved olaparib maintenance therapy in both germline BRCAmutant and germline BRCA–wild-type ovarian cancers following response to platinum-based chemotherapy. —Ursula A. Matulonis, MD

recommended that all patients with ovarian cancer regardless of histology undergo genetic testing for detection of high-risk inherited gene mutations.5

Background on PARP Inhibitors Development of PARP inhibitors began in 2005, with the discovery that cancer cells with a BRCA mutation showed PARP inhibitor sensitivity through the concept of synthetic lethality, specifically in the treatment of cancers that harbor a BRCA mutation.6-8 Synthetic lethality occurs when a defect in a gene or protein still allows cell viability but will lead to death if combined with a defect in another gene or protein defect. BRCA1 and BRCA2 genes encode proteins that are important in the repair of DNA double-strand breaks via homologous recombination. Cancer cells Dr. Matulonis is Director of Medical Gynecologic Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

olaparib in cancer patients with germline BRCA mutations. A total of 193 patients with recurrent ovarian cancer were treated in this study, and 137 of these patients had received three or more prior lines of therapy. An accelerated FDA approval of olaparib capsules using the 400-mg dose twice daily was granted in December 2014, as monotherapy in patients with deleterious or suspected deleterious germline BRCAmutant advanced ovarian cancer who had been treated with three or more prior lines of chemotherapy. The indication was approved based on olaparib’s objective response rate of 34% and the median duration of response of 7.9 months in these patients.11 Combined results from olaparib monotherapy trials, including data from Kaufman et al, in the treatment of patients with ovarian cancer who received more than three lines of prior therapy provide additional supportive data for olaparib as monotherapy for recurrent germline BRCA-mutant ovarian cancer.12

PARP Inhibitors for Hereditary Ovarian Cancer ■■ PARP inhibitors are one of the newest and most promising classes of anticancer agents in the treatment of ovarian cancer. ■■ Several phase III studies are testing the efficacy of PARP inhibitors for both newly diagnosed ovarian cancer as well as recurrent germline BRCA-mutant and germline BRCA–wild-type ovarian cancers. ■■ Studies investigating combinations of PARP inhibitors with other agents are also underway and may represent a mechanism to increase the efficacy of single-agent PARP inhibitors, overcome resistance to PARP inhibitors, and further personalize treatment.

Treatment Toxicities Toxicities associated with olaparib included gastrointestinal problems, such as nausea, vomiting, abdominal pain, decreased appetite, diarrhea, and dyspepsia. Hematologic toxicities included anemia, neutropenia, thrombocytopenia, lymphopenia; increases in creatinine, arthralgia, and myalgia were also reported with olaparib.9-13 There have been rare cases of development of acute myeloid leukemia and myelodysplastic syndromes in heavily pretreated patients, so blood cell counts should be carefully monitored. If toxicities occur, the dose of olaparib can be reduced to either 200 mg twice daily or 100 mg twice daily.10

Olaparib Maintenance Therapy A randomized, double-blind, placebo-controlled phase II study to evaluate maintenance therapy with olaparib in patients with or without a documented germline BRCA mutation, with platinum-sensitive, relapsed, high-grade serous ovarian cancer, found significant improvement in median progressionfree survival with olaparib over placebo, 8.4 months vs 4.8 months, respectively (hazard ratio [HR] = 0.35, P < .001).14 To date, there has been no overall survival benefit reported with olaparib maintenance therapy. In another phase II randomized study of olaparib maintenance therapy, women with germline BRCA mutations had an even more pronounced progression-free survival benefit—11.2 months vs 4.3 months (HR = 0.18, P < .0001)—in favor of olaparib maintenance compared with placebo.15 Based on these results, the European Medicines Agency approved olaparib as maintenance therapy in both germline BRCA-mutant and germline BRCA–wild-type ovarian cancer following response to a platinum-based

chemotherapy in women with recurrent ovarian cancer. In a post hoc analysis of these data recently presented at the 2015 Society of Gynecologic Oncology Annual Meeting,16 overall survival was significantly improved in favor of olaparib over placebo in patients with germline BRCA mutations in sites where patients on placebo who went on to receive a PARP inhibitor post disease progression were excluded. The reason for their exclusion might have been that patients originally on placebo who eventually took a PARP inhibitor post disease progression may have had a confounding influence and effect on overall survival interpretation, thus reducing the perceived beneficial impact of olaparib in this population. However, this post-hoc analysis is limited by the small sample size and the need for additional maturity of the data.

Phase III Studies of Single-Agent Olaparib Three international phase III studies of single-agent olaparib in germline BRCA-mutant ovarian cancer are ongoing. They include SOLO1, a randomized, double-blind, placebocontrolled trial of olaparib vs placebo in patients who have completed firstline platinum-based chemotherapy and have responded to upfront chemotherapy; SOLO2, a randomized, double-blind, placebo-controlled trial in patients with platinum-sensitive relapsed disease who have responded to platinum-based therapy; and SOLO3, a randomized, open-label trial of olaparib vs single-agent chemotherapy in patients with platinum-sensitive relapsed disease who have completed at least two lines of platinum-based therapy. SOLO1 and SOLO2 completed accrual at the end of 2014, and SOLO3 is currently accruing patients. continued on page 44

In relapsed multiple myeloma,

TO DISRUPT THE CYCLE OF DIMINISHING RESPONSES,

IS DEPTH THE ANSWER ?

Relapsed multiple myeloma: A COMPLEX AND CHALLENGING DISEASE Today, there is no established cure for multiple myeloma (MM). It is characterized by a recurring pattern of relapse.1,2 The majority of patients with relapsed MM do not achieve optimal responses regardless of treatment regimen, and clinical benefit decreases with each subsequent line of therapy.3

Improving long-term outcomes is a primary goal of relapsed MM treatment.3 Relapsed multiple myeloma: AIMING FOR LONG-TERM SUCCESS Deep responses have been found to statistically correlate to progression-free survival across patient type and treatment setting.3,4 In an analysis of 1175 elderly patients with MM, the impact of complete response on long-term outcome was confirmed regardless of baseline patient characteristics, including age.1 Elderly patients and other high-risk patients with relapsed MM may achieve similar response rates to the rest of the population5; therefore, aiming for deep responses (complete response) for all patients should be the goal.1 Achieving and sustaining responses should be a priority in the treatment of relapsed MM.3 A prolonged or durable complete response is an independent posttreatment variable associated with improved survival.6 Continuous treatment, even after an initial response has been achieved, may further deepen the response.7

As the treatment landscape evolves, both deep and durable responses should be the expectation for relapsed multiple myeloma. LEARN MORE GO TO WWW.WHATMATTERSINMM.COM References: 1. Gay F, Larocca A, Wijermans P, et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood. 2011;117(11):3025-3031. 2. Mohty B, El-Cheikh J, Yakoub-Agha I, Avet-Loiseau H, Moreau P, Mohty M. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia. 2012;26(1):73-85. 3. Chanan-Khan AA, Giralt S. Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol. 2010;28(15):2612-2624. 4. Harousseau JL, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma. Blood. 2009;114(15):3139-3146. 5. Wildes TM, Rosko A, Tuchman SA. Multiple myeloma in the older adult: better prospects, more challenges. J Clin Oncol. 2014;32(24):2531-2540. 6. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008;113(2):355-359. 7. Zago M, Oehrlein K, Rendl C, Hahn-Ast C, Kanz L, Weisel K. Lenalidomide in relapsed and refractory multiple myeloma disease: feasibility and benefits of long-term treatment. Ann Hematol. 2014;93(12):1993-1999. Onyx, Onyx Pharmaceuticals, and Onyx Pharmaceuticals logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-ONYX-101576 March 2015 Printed in USA

The ASCO Post | MAY 25, 2015

PAGE 44

Perspective Ursula A. Matulonis, MD continued from page 42

Additional PARP Inhibitors Under Study In addition to olaparib, there are several other PARP inhibitors being tested in ovarian cancer, including the oral agents niraparib, rucaparib, veliparib, and BMN-673. Currently, niraparib, rucaparib, and veliparib are in phase III studies. Niraparib is being tested in a study called NOVA,17 which is similar in design to SOLO2 with the exception that patients with germline BRCAmutant and germline BRCA–wild-type high-grade serous ovarian cancers are eligible to participate in the trial. Rucaparib is being tested in the ARIEL3 study, which is investigating the drug’s effectiveness in women with high-grade serous platinum-sensitive relapsed ovarian cancer or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer. And veliparib is being studied in patients with newly diagnosed advanced ovarian cancer. Furthermore, PARP inhibitors are being investigated in combination with other agents, including antiangiogenics. The combination of olaparib and cediranib, an oral inhibitor of vascular endothelial growth factor receptor 2, was first tested in a phase I study of patients with recurrent epithelial ovarian or triplenegative breast cancer.18 The anticancer activity observed in that study led to a randomized phase II study of the drug combination vs single-agent olaparib in patients with platinum-sensitive recurrent ovarian cancer.19 The study results showed that the combination regimen resulted in prolonged progression-free survival, 17.7 months vs 9.0 months, over singleagent olaparib (HR = 0.42, P = .005). The overall response rate was higher for

the combination therapy than for single-agent olaparib as well, 80% vs 48%, respectively (P = .002). In addition, the benefit of the combination therapy was especially pronounced in patients with germline BRCA–wild-type ovarian cancer, suggesting that the hypoxia induced by cediranib potentiates the homologous recombination defects of the cell and leads to augmented PARP inhibitor activity. There were more toxicities experienced by patients treated with the combination therapy compared withsingle agent olaparib, and they included hypertension, fatigue, and gastrointestinal side effects. The overall positive results of this phase II study have led to the development of two phase III studies: OVM1403 (for platinum-sensitive recurrent ovarian cancer) and OVM1405 (for platinumresistant recurrent ovarian cancer).

Potential Impact on Overall Survival The explosion of clinical trials investigating PARP inhibitors in the treatment of hereditary ovarian cancer has resulted in significantly improving progression-free survival. n

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

References 1. Liu JF, Konstantinopoulos PA, Matulonis UA: PARP inhibitors in ovarian cancer: Current status and future promise. Gynecol Oncol 133:362-369, 2014. 2. Olaparib (Lynparza) prescribing information, AstraZeneca Pharmaceuticals LP, December 2014. Available at www.lynparza.com. Accessed April 17, 2015. 3. Alsop K, Fereday S, Meldrum C, et al: BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report

from the Australian Ovarian Cancer Study Group. J Clin Oncol 30:2654-2663, 2012. 4. Pennington KP, Walsh T, Harrell MI, et al: Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20:764-775, 2014. 5. National Comprehensive Cancer Network: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Available at http:// www.nccn.org/professionals/physician_ gls/f_guidelines.asp. Accessed April 17, 2015. 6. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005. 7. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005. 8. Lord CJ, Tutt AN, Ashworth A: Synthetic lethality and cancer therapy: Lessons learned from the development of PARP inhibitors. Annu Rev Med 66:455-470, 2015. 9. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123-134, 2009. 10. Audeh MW, Carmichael J, Penson RT, et al: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial. Lancet 376:245-251, 2010. 11. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-250, 2015. 12. Matulonis UA, Penson RT, Domcheck SM, et al: Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: A multistudy subanalysis. 2015 Society of Gynecologic Oncology Meeting. Abstract 14.

13. Kaye SB, Lubinski J, Matulonis U, et al: Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly(ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372-379, 2012. 14. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382-1392, 2012. 15. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852-861, 2014. 16. Matulonis UA, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for post-progression PARP inhibitor therapy. 2015 Society of Gynecologic Oncology Meeting. Abstract 13. 17. Matulonis U, Mahner S, Wenham RM, et al: A phase 3 randomized doubleblind trial of maintenance with niraparib versus placebo in patients with platinumsensitive ovarian cancer (ENGOT-OV16/ NOVA trial). 2014 ASCO Annual Meeting. Abstract TP5625. 18. Liu JF, Tolaney SM, Birrer M, et al: A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972-2978, 2013. 19. Liu JF, Barry WT, Birrer M, et al: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol 15:1207-1214, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Julie Gralow, MD, on HER2-Overexpressing Breast Cancers see page 97

Melanie Royce, MD, PhD, on Disparities in Breast Cancer see page 101

Lori J. Wirth, MD, on Radioiodine-Refractory Thyroid Cancer see page 104

Sean Smith, MD, on the Value of a Physiatrist in Survivorship Care see page 109

Anita O’Donovan, MD, on Guidelines for the Treatment of Older Cancer Patients see page 115

Douglas B. Johnson, MD, MSCI, on Pembrolizumab vs Ipilimumab in Metastatic Melanoma see page 124

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MAY 25, 2015

PAGE 45

Announcements

Karen E. Knudsen, PhD, Named Director of Sidney Kimmel Cancer Center at Thomas Jefferson University

aren E. Knudsen, PhD, has been named the Director of the Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University and the Hilary Koprowski Chair of the Department of Cancer Biology of the Sidney Kimmel Medical College of Thomas Jefferson University. Dr. Knudsen has been serving in these interim roles since January 2015.

prevent or treat lethal prostate cancers. to innovative, biomarker-driven cliniHer studies that identify tumor sup- cal trials. pressor and hormone receptor alteraDr. Knudsen also has joint appointtions have uncovered new targets for ments in the Departments of Urology, Omics Network 20150505.pdf 5/5/15Radiation 10:24 AM Oncology, and Medical treating advanced disease and have1 led

Oncology. She served as the first Vice Provost for Thomas Jefferson University, overseeing and integrating basic and clinical research across the college and schools. n

Karen E. Knudsen, PhD

Dr. Knudsen is committed to ushering in a new era of progress and excellence at SKCC. Under her leadership, wider implementation of precision medicine and greater collaboration in the laboratory are the main goals. In addition to leading SKCC and expanding the Sidney Kimmel Cancer Network, Dr. Knudsen and her team will provide Jefferson’s oncology expertise to patients in Southern New Jersey through our partnership with the Inspira Health Network. The relationship will offer patients greater access to our clinical trials and subspecialty service, such as genetic counseling and oncological surgery. SKCC will also continue its collaboration with the Myrna Brind Center of Integrative Medicine at Jefferson and in fall 2015 Marcus Integrative Health at the Myrna Brind Center at Villanova, to integrate complementary therapies into the care of patients with cancer. Dr. Knudsen received her bachelor’s degree from George Washington University, and her doctorate from the University of California at San Diego. Her postdoctoral studies with National Academy of the Sciences member Webster K. Cavenee, PhD, at the Ludwig Institute for Cancer Research, cultivated a program centered on the molecular basis of prostate cancer growth and progression. Dr. Knudsen joined Jefferson in 2007, after being a tenured Associate Professor at the University of Cincinnati College of Medicine. An expert in the molecular basis of hormone-dependent cancer development and progression, Dr. Knudsen is focused on developing new means to C

The Omics Network is a growing community of health systems, providers, payers, pharma and employers working together to bring 21st century medicine to cancer patients today.

By maximizing our shared knowledge and data we can optimize patient care, improve clinical outcomes and lower costs.

CMY

By joining the Omics Network members will have early access to game-changing innovations such as: Applying genomics and proteomics to guide treatment decisions Novel value based care models (including preferred provider models, reimbursement models etc.) An adaptive, basket style approach to clinical trials Next generation, immuno-oncology platform using novel natural killer cell based therapies JOIN NOW For more information on the Omics Network and how to join contact info@omicsnetwork.org

The ASCO Post | MAY 25, 2015

PAGE 46

JCO Spotlight Genitourinary Oncology

ASCO Endorses American Cancer Society Prostate Cancer Survivorship Care Guidelines By Matthew Stenger

s reported in the Journal of Clinical Oncology by Matthew J. Resnick, MD, of Vanderbilt University Medical Center, and colleagues, ASCO has endorsed the 2014 American Cancer Society Prostate Cancer Survivorship Care Guidelines.1,2 The ASCO endorsement panel was co-chaired by Dr. Resnick and David F. Penson, MD, also of Vanderbilt University Medical Center. The endorsement panel noted that there is limited availability of highquality evidence to support many of the guideline recommendations. The recommendations, with ASCO qualifying statements in bold italics, are provided below.

Health Promotion Assess information needs related to prostate cancer and its treatment, adverse effects, other health concerns, and available support services and provide or refer survivors to appropriate resources to meet these needs. Counsel survivors to achieve and maintain a healthy weight by limiting consumption of high-calorie foods and beverages and promoting increased physical activity. Counsel survivors to engage in at least 150 minutes per week of physical activity, which may include weightbearing exercises. Counsel survivors to achieve a dietary pattern that is high in fruits and vegetables and whole grains. Diet should emphasize micronutrient-rich and phytochemical-rich vegetables and fruits, low amounts of saturated fat, intake of at least 600 IU of vitamin D per day, and adequate (but not excessive) amounts of dietary sources of calcium (not to exceed 1,200 mg/d). Those with nutrition-related challenges (eg, bowel problems that impact nutrient absorption) should be referred to a registered dietitian. Alcohol consumption should be avoided or limited to no more than two drinks per day. Assess for tobacco use and offer and/ or refer survivors to cessation counseling and resources. Counsel survivors to avoid tobacco products.

Surveillance for Prostate Cancer Recurrence Measure serum prostate-specific antigen (PSA) level every 6 to 12 months

for the first 5 years and annually thereafter. Prostate cancer specialists may recommend more frequent PSA monitoring during the early survivorship experience for some men, particularly men with a higher risk of prostate cancer recurrence and/or men who may be candidates for salvage therapy. The exact schedule for PSA measurement should be determined by both the prostate cancer specialist and primary care physician in collaboration. Ensure that survivors with an elevated or rising PSA level are evaluated by their primary treating specialist for fur-

ation therapy. Patients should undergo routine screening for colorectal cancer as suggested by existing evidence-based guidelines and should undergo appropriate evaluation for any signs or symptoms suggestive of either bladder cancer or colorectal cancer. For survivors with hematuria, perform a thorough evaluation to determine the cause of symptoms and to rule out bladder cancer, including urologist referral for cystoscopy and upper urinary tract evaluation. Refer survivors with persistent rectal bleeding, pain, or other symptoms

Patients and physicians should be informed of the increased risk of bladder and colorectal cancers after pelvic radiation therapy. Patients should undergo routine screening for colorectal cancer as suggested by existing evidence-based guidelines and should undergo appropriate evaluation for any signs or symptoms suggestive of either bladder cancer or colorectal cancer. —Matthew J. Resnick, MD (top), David F. Penson, MD (bottom), and colleagues

ther follow-up and treatment. Perform annual digital rectal examination in coordination with cancer specialist to avoid duplication. Primary care physicians should discuss with the prostate cancer specialist the need for annual digital rectal examination, specifically as it relates to detection of disease recurrence in prostate cancer survivors.

Screening for Second Primary Cancers Adhere to American Cancer Society screening and early detection guidelines (cancer.org/professionals). Survivors who underwent radiation therapy may have a slightly higher risk of bladder and colorectal cancers and may need to follow screening guidelines for higher-risk individuals, if available. Patients and physicians should be informed of the increased risk of bladder and colorectal cancers after pelvic radi-

of unknown origin to the appropriate specialist as well as the treating radiation oncologist to conduct a thorough evaluation for cause of symptoms and to evaluate for colorectal cancer.

Anemia: Specific Risk for Men on Androgen-Deprivation Therapy Consider [ASCO Endorsement Panel changed from “perform”] an annual complete blood cell count to monitor hemoglobin levels, particularly in men presenting with symptoms suggestive of anemia.

Bowel Dysfunction Discuss bowel function and symptoms (eg, rectal bleeding) with survivors. For men with a negative colorectal cancer screening result, prescribe stool softeners, topical steroids, or anti-inflammatories for survivors experiencing rectal bleeding. For survivors experiencing rectal bleeding after radiation

therapy, colorectal cancer should be ruled out, and appropriate management should be discussed with the treating radiation oncologist. Management may include corticosteroid suppositories to decrease inflammation, stool softeners, and dietary changes. Refer survivors with persistent rectal symptoms (eg, bleeding, sphincter dysfunction, rectal urgency, and frequency) to the appropriate specialist.

Cardiovascular and Metabolic Effects: Specific Risk for Men Receiving AndrogenDeprivation Therapy Follow U.S. Preventive Services Task Force (USPSTF) guidelines for evaluation and screening for cardiovascular risk factors, blood pressure monitoring, lipid profiles, and serum glucose (uspreventiveservicestaskforce.org/uspstopics.htm).

Distress/Depression/ PSA Anxiety Assess for distress/depression/PSA anxiety at initial visit, at appropriate intervals, and as clinically indicated [ASCO Endorsement Panel removed wording that recommended assessment should occur “periodically, at least annually” and removed suggestion that “simple screening tool” be used “such as the Distress Thermometer”.] Physicians should refer to the ASCO Screening, Assessment, and Care of Anxiety and Depressive Symptoms in Adults With Cancer guideline (www.asco.org/ adaptations/depression) for more information on management of this important problem. Manage distress/depression using in-office counseling resources or pharmacotherapy as appropriate. If office-based counseling and treatment are insufficient, refer survivors experiencing distress/depression for further evaluation or treatment by appropriate specialists.

Fracture Risk/Osteoporosis: Specific Risk for Men Receiving Androgen-Deprivation Therapy Assess risk of fracture for men treated with androgen-deprivation therapy or older radiation techniques through baseline dual-energy x-ray absorptiometry scan and calculation of continued on page 54

indications

ignited we stand with

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a doselimiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non– small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN) Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non–Small Cell Lung Cancer (NSCLC) Study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min) DOSAGE AND ADMINISTRATION • Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN • For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment • For adenocarcinoma of the pancreas, do not administer ABRAXANE to patients who have moderate to severe hepatic impairment • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival In the largest phase III trial in metastatic pancreatic adenocarcinoma1 ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase III MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the pancreatic adenocarcinoma study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

ABRAXANE is also indicated in MBC and NSCLC ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. • The primary end point in the metastatic breast cancer (MBC) phase III trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. • The primary end point in the NSCLC phase III trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms. Reference: 1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment For patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] less than or equal to 10 x ULN), no dose adjustments are required, regardless of indication. Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment. Do not administer ABRAXANE to patients with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN regardless of indication as these patients have not been studied. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreatic c MBC NSCLC c Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.5 x ULN Moderate < 10 x ULN AND > 1.5 to 200 mg/m2 b 80 mg/m2 b not ≤ 3 x ULN recommended Severe < 10 x ULN AND > 3 to 200 mg/m2 b 80 mg/m2 b not ≤ 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 260 mg/m2 for patients with metastatic breast cancer or 100 mg/m2 for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophils less than 500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than Second 50 3 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more Third Discontinue Treatment than 7 days Platelet count less than 50,000/mm3 First 75 4.5 Second Discontinue Treatment Severe sensory Neuropathy – First 75 4.5 Grade 3 or 4 Second 50 3 Third Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: If Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: If Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Febrile Neutropenia: Withhold until fever resolves and ANC ≥ 1500; resume at Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5.6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression. ABRAXANE is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, ABRAXANE is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity of laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b

Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococcal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal

malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment The exposure to paclitaxel may be higher in patients with hepatic impairment than in patients with normal hepatic function. Reduce ABRAXANE starting dose in patients with moderate to severe hepatic impairment. Do not administer ABRAXANE to patients with total bilirubin > 5 x ULN or AST > 10 x ULN [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Do not administer to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment [see Dosage and Administration (2.4)]. 8.7 Patients with Renal Impairment Adjustment of the starting ABRAXANE dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min). 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2014 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_COMBO_HCP_BSv008 12_2014

The ASCO Post | MAY 25, 2015

PAGE 54

JCO Spotlight Prostate Cancer Survivorship Care continued from page 46

a World Health Organization fracture risk assessment (FRAX) score. For men determined to be high risk, prescribe weekly bisphosphonate therapy (oral alendronate at a dose of 70 mg) or annual intravenous zoledronic acid at a dose of 5 mg to increase bone density. Denosumab (Xgeva) is also approved by the U.S. Food and Drug Administration (FDA) to treat men at increased risk of osteoporosis. A collaborative strategy should be developed between the primary care physician and prostate cancer specialist to optimize bone health in men at risk for osteoporosis. This strategy should include a thorough discussion of the benefits and harms of bone-targeted agents.

Sexual Dysfunction/Body Image, Sexual Intimacy Discuss sexual function with survivors. Use validated tools to monitor erectile function over time. [ASCO Endorsement Panel removed reference to Sexual Health Inventory for Men tool.] Erectile dysfunction may be addressed through a variety of options, including penile rehabilitation or prescription of phosphodiesterase type 5 inhibitors (eg, sildenafil, vardenafil, tadalafil). Refer men with persistent sexual dysfunction to a urologist, sexual

health specialist, or psychotherapist to review treatment and counseling options. Encourage couples to discuss their sexual intimacy and refer to counseling or support services as appropriate. Prescribe medication as described previously to address erectile dysfunction. Instruct couples on the use of sexual aids to improve erectile dysfunction for men/male partners as well as postmenopausal symptoms for women. Refer to mental health professional with expertise in sex therapy.

Urinary Dysfunction Discuss urinary function (eg, urinary stream, difficulty emptying the bladder) and incontinence with all survivors. Consider timed voiding, prescribing anticholinergic medications (eg, oxybutynin) to address issues such as nocturia, frequency, or urgency. Consider alpha-blockers (eg, tamsulosin) for slow stream. Refer survivors with postprostatectomy incontinence to a physical therapist for pelvic floor rehabilitation; at a minimum, instruct survivors about Kegel exercises. Refer men with persistent, bothersome leakage or other urinary symptoms to a urologist for further evaluation (eg, urodynamic testing, cystoscopy) and discussion of treatment options including surgical placement of a male urethral sling or artificial urinary sphincter for incontinence.

Vasomotor Symptoms: Specific Risk for Men Receiving Androgen-Deprivation Therapy

and aftercare, focusing on preventive care and the management of preexisting comorbid conditions as well as regularly addressing the patient’s overall physical and psychosocial status and those components of survivorship care that are mutually agreed on with the treating clinicians. Annually assess for the presence of long-term or late effects of prostate cancer and its treatment, including potential urinary, bowel, sexual, and hormonal symptoms. [The ASCO Endorsement Panel removed the following: “Use of a validated tool such as EPIC-CP (Expanded Prostate Cancer Index Composite for Clinical Practice) may be helpful in this assessment.”] Encourage the inclusion of caregivers, spouses, or partners in usual prostate cancer survivorship care. Refer survivors to appropriate community-based and peer-support resources. n

Although not approved by the FDA for this indication, prescription of selective serotonin or noradrenergic reuptake inhibitors or gabapentin may offer symptom relief. The ASCO Endorsement Panel believes further clinical investigation is required to validate this recommendation. Until that time, physicians should be aware of the development of vasomotor symptoms with androgen-deprivation therapy and should discuss with their patients the risks, benefits, and costs of available therapies for possible symptom relief.

Care Coordination and Practice Implications The primary treating specialist is encouraged to provide a treatment summary and survivorship care plan to the primary care clinician when survivorship care is transferred to the primary care clinician. Primary care clinicians and treating oncology specialists should confer regarding the survivorship care plan components and determine roles and responsibilities that are appropriate for the survivor’s condition and the resources available in the primary care setting. Primary care clinicians should maintain their role as general medical care coordinator throughout the spectrum of prostate cancer detection, treatment,

Disclosure: Drs. Resnick and Penson reported no potential conflicts of interest.

References 1. Resnick MJ, Lacchetti C, Bergman J, et al: Prostate cancer survivorship care guideline: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 33:1078-1085, 2015. 2. Skolarus TA, Wolf AM, Erb NL, et al: American Cancer Society prostate cancer survivorship care guidelines. CA Cancer J Clin 64:225-249, 2014.

Prostate Cancer Survivorship: Identifying Opportunities for Improvement By Matthew J. Resnick, MD, MPH

rostate cancer survivors currently approach 3 million in number and comprise 43% of all male cancer survivors in the United States.1 These men face myriad unique oncologic, functional, emotional, and psychological issues that require evaluation and management throughout the survivorship phase of the disease. To address a perceived unmet need in care delivery, the American Cancer Society convened a multidisciplinary panel to develop prostate cancer survivorship care guidelines,2 which were subsequently endorsed by ASCO.3 The American Cancer Society guidelines and subsequent ASCO Dr. Resnick is Assistant Professor of Urologic Surgery and Health Policy, Vanderbilt University Medical Center, Nashville.

endorsement outline multiple domains that merit attention in the delivery of high-quality, comprehensive survivorship care and offer specific recommendations to facilitate both care delivery and care transitions. While the publication and endorsement of the guidelines, without question, serve as a roadmap for optimizing prostate cancer survivorship care, there remain significant limitations to our current knowledge surrounding “what care to deliver to which patients in what setting.”

Recognizing Gaps in Knowledge Despite extensive literature reviews as part of the methodology for the guidelines as well as the ASCO endorsement, many questions remain

As a prostate cancer community, we must begin to routinely and systematically collect patientreported data and use such data to develop survivorship plans tailored to the needs of the individual patient. —Matthew J. Resnick, MD, MPH

unanswered. While the endorsement panel uniformly agreed that routine measurement of serum prostate-specific antigen (PSA) levels to detect disease recurrence was necessary, there is little evidence upon which to base management decisions surrounding appropriateness of the interval between measurements.

The panel agreed upon a qualifying statement encouraging individualizing surveillance schedules to risk of disease recurrence with an eye toward balancing the potential benefits and harms of high-frequency PSA testing. While there may be benefits to early detection of biochemical recontinued on page 55

ASCOPost.com | MAY 25, 2015

PAGE 55

Perspective

Matthew J. Resnick, MD, MPH ment and deployment of novel survicontinued from page 54

currence, particularly in patients who are candidates for salvage local therapy, one must consider the harms of PSA surveillance, including both unnecessary cancer-related anxiety and added financial cost. Oncologic surveillance is just one of many examples of the contemporary knowledge gaps in prostate cancer survivorship. Given the prevalence of prostate cancer survivorship in the United States in the context of both the aging population and improvements in treatment, there is no question that survivorship research will become increasingly important to provide a platform of evidence upon which future recommendations may be based.

Redesigning Prostate Cancer Survivorship Care The American Cancer Society guidelines and ASCO endorsement may ultimately serve as a springboard for redesigning prostate cancer survivorship care. While prostate cancer specialists have historically delivered survivorship care, optimizing comprehensive prostate cancer survivorship care may require creative and novel approaches to care delivery. Gilbert and colleagues recently reported changes in quality of life after deployment of a prostate cancer survivorship clinic incorporating pointof-care patient-reported outcome assessment and dedicated nursing and sexual health therapist engagement.4 Patient-reported sexual function and satisfaction with care were significantly higher among patients treated in the prostate cancer survivorship clinic than in those undergoing routine care. There is high-quality evidence that nurse-led symptom management programs result in consistent improvements in patient-reported outcomes. Andreyev et al randomly assigned patients with new-onset gastrointestinal symptoms after pelvic radiotherapy to usual care, gastroenterologist-led algorithm-based treatment, or nurse-led algorithm-based treatment. Investigators determined that the nurse-led program resulted in significant improvements over usual care and was noninferior to the gastroenterologist-led program.5 These data suggest that the develop-

vorship programs may, ultimately, improve the quality of care we are able to deliver to prostate cancer survivors. Importantly, the American Cancer Society guidelines may provide a platform for care transitions between prostate cancer specialists and primary care physicians, particularly once survivors achieve oncologic, functional, and psychological stability. Indeed, survivorship guidelines may ultimately serve as a basis for the development of pragmatic care plans that may be shared between prostate cancer specialists and primary care physicians to facilitate effective and efficient survivorship care. While there remain no specific recommendations surrounding the optimal time for transition between the prostate cancer specialist and primary care physician, there is little question that the guidelines will encourage highquality transitions of care. Redesigning the process of prostate cancer survivorship care will undoubtedly address unmet needs faced by prostate cancer survivors across multiple domains.

done by Gilbert et al, may serve to underscore those domains and elements that are most important to individual patients. Doing so permits translation of guideline recommendations into patient-centered survivorship care.

Needs of the Individual Prostate cancer survivors face unique physical, psychological, and emotional challenges. The delivery of high-quality, patient-centered survivorship care will undoubtedly require critical evaluation of current practice and engagement of multidisciplinary teams to effectively meet individual unmet needs. Moreover, as a prostate cancer community, we must begin to routinely and systematically collect patient-reported data and use such data to develop survivorship plans tailored to the needs of the individual patient. Doing so will require investment in the development of novel tools for data collection, information technology infrastructure for feedback, and education of both patients and providers. n

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

Need for Reliable Tools The American Cancer Society guidelines and ASCO endorsement also underscore the need for reliable and valid tools to ascertain patient-reported data in routine clinical practice. The development of brief point-of-care instruments that may be used at each clinic visit offers the provider insights into the patient experience and permits targeted evaluation and management. There is no better example of such tools than the EPIC-CP (Expanded Prostate Cancer Index Composite– Clinical Practice), a 16-item questionnaire that correlates strongly with the parent EPIC-26. Additionally, and importantly, the EPIC-CP can be completed quickly and poses little disruption to routine clinical care.6 While the EPIC-CP facilitates point-of-care evaluation of patient-reported prostate cancer–specific function, there are few tools to aid providers in evaluating unmet needs, psychological health, and emotional health related to prostate cancer or its treatment. The development and incorporation of such tools into clinical practice using a real-time dashboard platform, as was

References 1. DeSantis CE, Lin CC, Mariotto

AB, et al: Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252-271, 2014. 2. Skolarus TA, Wolf AMD, Erb NL, et al: American Cancer Society prostate cancer survivorship care guidelines. CA Cancer J Clin 64:225-249, 2014. 3. Resnick MJ, Lacchetti C, Bergman J, et al: Prostate cancer survivorship care guideline: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 33:1078-1085, 2015. 4. Gilbert SM, Dunn RL, Wittmann D, et al: Quality of life and satisfaction among prostate cancer patients followed in a dedicated survivorship clinic. Cancer 121:1484-1491, 2015. 5. Andreyev HJN, Benton BE, Lalji A, et al: Algorithm-based management of patients with gastrointestinal symptoms in patients after pelvic radiation treatment (ORBIT): A randomised controlled trial. Lancet 382:2084-2092, 2013. 6. Chang P, Szymanski KM, Dunn RL, et al: Expanded prostate cancer index composite for clinical practice: Development and validation of a practical health related quality of life instrument for use in the routine clinical care of patients with prostate cancer. J Urol 186:865-872, 2011.

2014–2015 American Association for Clinical Research (AACR) President Carlos L. Arteaga, MD (right), presents the AACR Distinguished Public Service Award to Richard Pazdur, MD (left), Director of the U.S. Food and Drug Administration’s Office of Hematology and Oncology Products. See page 31 for the story.

The ASCO Post | MAY 25, 2015

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Announcements

Stephen Grubbs, MD, to Lead ASCO’s New Clinical Affairs Department

tephen S. Grubbs, MD, a community oncologist and Managing Partner at Medical Oncology Hematology Consultants, PA, has been named the Senior Director of ASCO’s new Clinical Affairs Department. Dr. Grubbs is a longtime ASCO member and volunteer and the Principal Investigator of the Delaware Christiana Care National Cancer Institute Community Oncology Research Program (NCORP). He will begin his new role on a part-time basis in June 2015, before fully transitioning into it in July. “We are delighted that Dr. Grubbs will be joining ASCO to lead our Clinical Affairs Department,” said Allen S. Lichter, MD, Chief Executive Officer

es in oncology practice. The department will provide support to oncology professionals around the country in the areas of business analytics, performance improvement, and practice management, with the ultimate aim of fostering more effective and efficient

delivery of cancer care for the benefit of patients. “I am thrilled to be serving ASCO in this new and vital role,” said Dr. Grubbs. “I look forward to working with the Society’s staff and oncology practices across the country as we

strive to consistently improve cancer care.”

A Background of Service An ASCO member since 1985, Dr. Grubbs serves on the ASCO Board of Directors as the community oncologist

NOW APPROVED

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

I look forward to working with the Society’s staff and oncology practices across the country as we strive to consistently improve cancer care. —Stephen S. Grubbs, MD

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.

of ASCO. “Dr. Grubbs understands and has fully experienced the rewards and challenges of providing care in his community. He has the knowledge and vision needed to assure that this department will provide on-the-ground support to oncology practices across the country.”

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.

Clinical Affairs Department

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.

Announced in late 2014, ASCO’s Clinical Affairs Department is dedicated to providing services, education, and resources to support oncology practices in all settings. The function of the department is to promote the delivery of high-quality, high-value cancer care for people with cancer. To achieve this goal, the Clinical Affairs Department will provide tools and services to facilitate innovation in cancer care delivery and respond to growing economic and administrative challeng-

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.

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 | MAY 25, 2015

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Announcements

representative and is a member of the Finance and Ethics Committees. He has served on the Society’s Government Relations Committee, Cancer Research Committee, and as a Genitourinary Literature Reviewer for ASCO University ®. He has served as Chair of the Clinical Trials Participation Award Selection Subcommittee, Cochair of the NCI/

ASCO Clinical Trial Accrual Symposium, and the Clinical Trials Workshop Planning Committee. Dr. Grubbs serves on the advisory council of the Delaware Cancer Consortium, of which he has been a member since 2003. The Consortium actively worked with the Delaware state government to successfully develop a

system for the uninsured to receive cancer screening and cancer therapy. This has resulted in universal cancer screening and care in Delaware, and has led to the elimination of health-care disparity for colorectal cancer. Dr. Grubbs has served on the NCI’s Clinical Trials Evaluation Working Group and Clinical Trials Advisory

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

Committee, and has been active in the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B), serving on the Board of Directors and Executive Committee. He was President of the Medical Society of Delaware and has held a number of other leadership positions in professional organizations. n

The ASCO Post | MAY 25, 2015

PAGE 58

Announcements

Donald S. Coffey, PhD, Recongized With AACR’s Margaret Foti Award

onald S. Coffey, PhD, was honored with the 9th Annual American Association for Cancer Research (AACR) Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research at the AACR Annual Meeting 2015.

Dr. Coffey, a fellow of the AACR Academy, and the Catherine Iola and J. Smith Michael Distinguished Professor of Urology at Johns Hopkins School of Medicine, was honored for his tremendous leadership and profound contributions to cancer research. His

Donald S. Coffey, PhD

distinct reputation as a natural advocate and leader is evidenced by his tenure as AACR president (1997–1998), which resulted in a number of initiatives for the organization. Likewise, his pioneering work on the structure of the cell nuclei and the pathogenesis of prostate

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

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Announcements

cancer, coupled with his dedication to mentoring young cancer researchers and promoting cancer research nationally, epitomizes the spirit of the award.

Major Discoveries “Dr. Coffey is an internationally recognized research scientist who has made seminal contributions to numer-

ous areas of cancer research,” said Margaret Foti, PhD, MD, Chief Executive Officer of the AACR. “His work on the nuclear matrix established a new paradigm for understanding the biology of normal and cancer cells, while his prostate cancer research helped change the face of that deadly disease. However, Dr. Coffey’s impact on cancer re-

search extends far beyond his scientific achievements. His outstanding leadership skills, dedication to mentoring young investigators, passionate advocacy for sustained increases in funding for cancer research, and remarkable ability to translate complex scientific concepts into lay language make him an icon in the field, and a true champion of can-

” T:14.625” ” S:14.375”

cer research. He is greatly deserving of this award.” “To receive this premier award honoring Dr. Margaret Foti, who has built the AACR into the world’s leading organization to impact the control of cancer, fulfills my lifetime dream. Johns Hopkins University, the AACR, and hundreds of colleagues, supported by private and public donors, have all made this possible,” said Dr. Coffey.

A Background of Service Table 2

Dr. Coffey’s service to the AACR began in 1976. In addition to his tenure as president from 1997 to 1998, he has been a member of the AACR Board of Directors (1993-1996) and Nominating Committee (20012003), Co-chair of the Science Education Committee, Program Chair of the AACR Annual Meeting 1995, and a member of the Public Education Committee and Long-range Planning Committee, as well as Associate Editor of the journal Cancer Research. He has also provided his mentorship in the Scientist↔Survivor Program and for early-career scientists. Dr. Coffey has served in various other leadership positions throughout his career, including the National Cancer Advisory Board, the Board of Directors of the National Coalition for Cancer Research, President of the Society for Basic Urological Research, National Chair of the National Cancer Institute’s National Prostatic Cancer Program, and Director of the Brady Laboratory for Reproductive Biology and the research laboratories in the Department of Urology at Johns Hopkins. While working toward his bachelor’s degree in chemistry from East Tennessee State University, Dr. Coffey was a chemist at the North American Rayon Corporation. He began his tenure at Johns Hopkins in 1959, where he has served since, joining the Johns Hopkins Hospital as Acting Director of the Brady Urological Research Laboratory. He received his doctorate from the university’s medical school in 1964. Additionally, he is currently an Adjunct Professor of Medicine at Howard University in Washington, D.C. 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.

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The ASCO Post | MAY 25, 2015

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Hematology Expert Review Chronic Myelogenous Leukemia

Prognostic Models and Front-Line Treatment Options for Chronic-Phase Chronic Myelogenous Leukemia By Syed A. Abutalib, MD, and Jerald P. Radich, MD

he ASCO Post is pleased to present “Hematology Expert Review,” an occasional feature that includes a case report detailing a particular hematologic condition followed by questions. Answers to each question appear on page 61 with expert commentary. In this installment, we present the case of a 46-year old man with chronic myelogenous leukemia.

GUEST EDITORS

Syed A. Abutalib, MD

Syed A. Abutalib, MD, Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois

Jerald P. Radich, MD

Jerald P. Radich, MD, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Case: A 46-year-old man with diabetes mellitus, hypertension, and hyperlipidemia comes to your clinic for a second opinion. He was recently diagnosed with chronic-phase chronic myelogenous leukemia (CML). He has a history of two cardiac stents and successful cardiac ablation for supraventricular tachycardia. He has a 10 pack/year history of smoking. His local oncologist prescribed dasatinib (Sprycel, 100-mg tablets) approximately 2 weeks ago. Prior to the diagnosis, he presented to his podiatrist with a flare

Prognostic Models in CML Sokal Score1

Euro (Hasford) Score2

EUTOS Score3

• Derives from a multivariate analysis of survival of 813 patients diagnosed with chronic phase CML between 1962 and 1981 • (0.0116 × (age [years] – 43.4)) + (0.0345 × (spleen size [cm] – 7.51) + (0.188 × ((platelets [109/L]/700)^2 – 0.563)) + (0.0887 × (blasts [%] – 2.10)). • Smaller spleen size (0–6 cm vs > 6 cm) and fewer percentage blasts (0%–1% vs > 1%) were most strongly associated with survival. • Sokal et al proposed three risk groups: low-risk (Sokal score < 0.8, 39% of patients), intermediate-risk (Sokal score 0.8–1.2, 38% of patients) and high-risk (> 1.2, 23% of patients).

• Derives from multivariate analysis of survival of 981 patients with early CML who started treatment between 1983 and 1994. • (0.6666 × age [0 when age < 50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 × blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils [0 when basophils < 3%; 1 otherwise]) + (1.0956 × platelet count [0 when platelets < 1,500 × 109/L; 1 otherwise]) × 1,000) • Three risk groups were identified: low-risk (score ≤ 780, 40.6% of patients), intermediaterisk (score 781 – 1480, 44.7% of patients) and high-risk (score ≥ 1481, 14.6% of patients).

• Derived from multivariate analysis of response of 2060 patients treated with imatinib for CML between 2002 and 2006. Score is applied at diagnosis, before therapy. • (7 × basophil [%]) + (4 × spleen [cm]) • Two risk groups were identified: low-risk (score < 87, 79% of patients) and high-risk (score ≥ 87, 21% of patients).

of gout, localized to the left big toe. The gout responded suboptimally to a course of indomethacin. Now, he has no complaints, except pain of 2 on a scale of 10, in his right big toe. Physical examination is remarkable for palpable splenomegaly, measuring 4 cm below the left subcostal margin, with normal examination of the target gout joint. Routine complete blood cell count showed leukocytosis, with a white blood cell count of 69.84 × 109/L with predominance of neutrophils and neutrophil precursors but no basophilia and eosinophilia. His hemoglobin is 10.7 g/dL, and his hematocrit is 33%, with mean corpuscular hemoglobin of 97 fL. The platelet count is normal. The lactate dehydrogenase and uric acid levels are elevated. The peripheral blood smear and bone marrow biopsy are shown in

Fig. 1. Metaphase cytogenetics and fluorescent in situ hybridization studies are consistent with a diagnosis of CML. The reverse transcriptase polymerase chain reaction for BCR-ABL1/ABL1 is 95% on the International Scale. The calculated Sokal, Euro (Hasford), and EUTOS prognostic scores are 0.61, 26.77, and 23, respectively. The electrocardiogram demonstrates a normal heart rate and sinus rhythm, with a corrected QT interval of 499 milliseconds. He has not started dasatinib to date, as he is worried about starting a drug that he may have to take for the rest of his life for an illness that is not currently making him sick.

Question 1 In the current era of tyrosine kinase inhibitor therapy, which prognostic model is best to assess the prognosis of a person with a new diagnosis of CML?

References 1. Sokal JE, Cox EB, Baccarani M, et al: Blood 63: 789-799, 1984. 2. Hasford J, Pfirrmann M, Hehlmann R, et al: J Natl Cancer Inst 90: 850-858, 1998. 3. Hasford J, Baccarani M, Hoffmann V, et al: Blood 118:686-692, 2011.

A. Sokal B. Euro (Hasford) C. EUTOS D. All of the above

Question 2 In this patient, what is the best frontline tyrosine kinase inhibitor therapy? A. Imatinib B. Dasatinib C. Nilotinib

Question 3 If the patient is started on imatinib, what is the best daily dose? A. 400 mg B. 600 mg C. 800 mg See page 61 for answers and expert discussion. n

Fig. 1: Chronic phase of CML. (A) Peripheral blood smear showing leukocytosis and neutrophilic cells at varying stages of maturation but no dysplasia. (B) Bone marrow biopsy showing marked hypercellularity due to granulocytic proliferation. (C) The megakaryocytes in CML are characteristically smaller than normal megakaryocytes. (Courtesy of Mingkui Chen MD, Department of Pathology, Cancer Treatment Centers of America)

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PAGE 61

Hematology Expert Review

Case Report on Chronic Myelogenous Leukemia

Answers From Hematology Expert Review Questions on Page 60 Question 1: In the current era of tyrosine kinase inhibitor therapy, which prognostic model is best to assess the prognosis of a person with a new diagnosis of CML? Correct Answer: D. All of the above

Expert Perspective The choices for front-line tyrosine kinase inhibitor therapy are imatinib, and the more potent second-generation tyrosine kinase inhibitors, nilotinib

(Tasigna) and dasatinib. The selection of the “best” tyrosine kinase inhibitor for newly diagnosed chronic-phase CML is literally and figuratively the “billion dollar question.” However, in

any given case, treatment goals as well as disease and patient characteristics may distill the choices. For instance, for someone older than continued on page 62

Expert Perspective Despite not being perfect, all of these scores are reasonably effective at predicting the behavior of CML and the response to therapy. The Sokal score1 was created to predict the natural history of CML in the era of hydroxyurea and busulfan therapy; the Euro (Hasford) score2 was based on the experience of patients treated with interferon; and the EUTOS score3 is based on modern experience with tyrosine kinase inhibitor therapy. However, it is not tested in patients receiving second-generation tyrosine kinase inhibitor therapy. In reality, we do not ever know how long a person has had CML prior to presentation and diagnosis; thus, the prognostic models reflect a rough measure of initial disease development. For example, leukocytosis and splenomegaly are disease consequences driven by the acquisition of the BCR-ABL abnormality. Patients on tyrosine kinase inhibitor therapy with a low-risk score in any of the three models have better outcomes than those patients with a high-risk score. There are, however, rare cases for which all scores will not be concurrent; in such cases, it is not clear which one to select. In our opinion, the treating physician should exercise at least one of them not only to estimate prognosis but in certain circumstances to select the most appropriate therapy (discussed later). We prefer to use the most current EUTOS model, but it is completely acceptable for a practitioner to use the model with which he or she is more comfortable. This patient’s calculated Sokal, Euro (Hasford), and EUTOS prognostic scores are 0.61, 26.77 and 23, respectively. These numbers imply “low-risk” disease. According to the EUTOS model, the probability of achieving complete cytogenetic remission with imatinib in our patient at 18 months is 88%. Ongoing studies using more sensitive measures to guide therapy will further improve the prognostic models and outcomes. Question 2: In this patient, what is the best front-line tyrosine kinase inhibitor therapy? Correct Answer: A. Imatinib

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The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MAY 25, 2015

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Hematology Expert Review Case Report on CML continued from page 61

age 70, it may be appropriate to control disease and extend short-horizon survival (ie, years not decades), sacrificing higher potency for lesser potential serious toxicities. In someone much younger, achieving a molecular remission may be attractive, as it appears a subset of these patients may

be able to successfully discontinue tyrosine kinase inhibitor therapy.4,5 In such cases, drug potency is paramount. Next, preexisting comorbidities may discourage (or preclude) the use of certain tyrosine kinase inhibitors. For example, it may not be best to prescribe dasatinib or nilotinib, respectively, to a patient with cardiopulmonary prob-

lems or vascular disease. Other important considerations at diagnosis are the phase of the disease (chronic phase vs accelerated or blastic) and in the chronic phase of the disease, the prognostic score. If the patient seems to be on the verge of transition to accelerated or blast phase, there may be a reason to start therapy with a more potent tyro-

sine kinase inhibitor. In patients with a high Sokal, Euro (Hasford), or EUTOS risk score, nilotinib or dasatinib is usually preferred over imatinib. Lastly, personal experience and the comfort level of the physician managing various side effects of specific tyrosine kinase inhibitors remain crucial factors in the decision-making process. Timely at-

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ASCOPost.com | MAY 25, 2015

PAGE 63

Hematology Expert Review

tention to patients’ concerns, medical history, and prognostic scores nicely declares imatinib (with allopurinol) to be the best management strategy in our patient with CML. However, if all things are being considered equal, the second-generation tyrosine kinase inhibitors yield superior progression-free survival over imatinib. Three separate randomized trials6-8

showed that nilotinib or dasatinib yielded more frequent complete cytogenetic responses and major molecular responses by 12%, as well as fewer progressions to accelerated or blast phase, than imatinib. To date, however, no randomized trial has shown a benefit in overall survival of nilotinib or dasatinib over imatinib. This may be because the

differences in survival between imatinib and the second-generation tyrosine kinase inhibitors are so small that it requires significantly longer follow-up and/or a much larger cohort. Question 3: If the patient is started on imatinib, what is the best daily dose? Correct Answer: A. 400 mg

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Expert Perspective Landmark analysis of the phase III IRIS trial9 (which pitted a 400-mg daily dose of imatinib vs interferon and cytarabine—hardly a fair fight in retrospect) demonstrated superior shortterm and long-term responses in the imatinib arm. Given that this trial won imatinib U.S. Food and Drug Administration approval, the 400-mg daily dose became the scientific and regulatory benchmark for the subsequent phase III trials of nilotinib and dasatinib, as well as the U.S. Intergroup trial of imatinib vs dasatinib. Across all of these phase III trials, the cytogenetic, molecular, and survival responses are remarkably similar, and largely because of this large vat of efficacy and toxicity data, both the European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) offer imatinib 400 mg daily as one of the three treatment options for newly diagnosed patients with chronic phase of the disease (along with dasatinib and nilotinib). Several trials have compared the 400mg and 800-mg daily doses of imatinib. The results predictably suggest that the higher dose has more efficacy and compares favorably with second-generation tyrosine kinase inhibitors, but at the expense of substantial toxicity.8,10,11 Another interesting approach pioneered by the Germans is “tolerabilityadapted imatinib dosing” (ie, a daily dose of 800 mg given after 6 weeks of 400 mg to avoid excessive cytopenias).12 In case of imatinib intolerability, the dose was gradually tapered to the best tolerable dose but not less than 300 mg. They showed that the higher median dose density contributed to superior molecular remissions. In lieu of current data, it seems that a 600mg daily dose of imatinib may be the “sweet spot,” but besides its use as the starting point for the Australasia Leukemia and Lymphoma TIDEL studies (I and II)13,14 of dose escalation and tyrosine kinase inhibitor switching in upfront CML treatment, published experience is limited. Thus, currently and in our opinion, imatinib 400 mg daily is the dose of choice for patients with chronic-phase CML. n Disclosure: Drs. Abutalib and Radich reported no potential conflicts of interest.

References are available in the online version of this article at ASCOPost.com.

The ASCO Post | MAY 25, 2015

PAGE 64

Journal Spotlight Genitourinary Cancer

Addition of Lenalidomide to Docetaxel-Prednisone Worsens Survival in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer By Matthew Stenger

n the phase III MAINSAIL trial reported in The Lancet Oncology, Daniel P. Petrylak, MD, of Yale Cancer Center, New Haven, Connecticut, and colleagues found that the addition of lenalidomide (Revlimid) to docetaxel-prednisone in chemotherapy-naive men with metastatic castration-resis-

Australia, South Africa, Israel, Mexico, and Canada were randomized between November 2009 and November 2011 to receive docetaxel 75 mg/m² on day 1 and prednisone 5 mg twice daily on days 1 to 21 and either lenalidomide 25 mg (n = 533) or placebo (n = 526) once daily on days 1 to 14 of each 21-day treatment cy-

Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapynaive men with metastatic, castrationresistant prostate cancer. —Daniel P. Petrylak, MD, and colleagues

tant prostate cancer was associated with significantly worse overall survival.1 The trial was stopped early due to futility.

Study Details In this double-blind trial, 1,059 patients with progressive disease from 223 centers in Europe, United States, Russia,

cle. The primary endpoint was overall survival in the intention-to-treat population. The lenalidomide and placebo groups were generally balanced for age (median 70 years in both), region (North America for 26% in both, Europe and Australia for 62% and 63%), type of disease progression (prostate-

Survival Results From MAINSAIL Trial ■■ The addition of lenalidomide to docetaxel-prednisone resulted in worse overall survival in patients with metastatic castration-resistant prostate cancer. ■■ The investigators concluded that further study of the combination in this setting is not warranted.

specific antigen [PSA] only in 30% and 28%, radiographic in 70% and 72%), metastatic sites (bone only in 32% and 30%, soft tissue in 20% and 18%, both in 49% and 52%), median PSA level (105 and 85 ng/mL), and median circulating tumor cell count (5 cells/7.5 mL vs 11 cells/7.5 mL). At the fourth scheduled protocoldefined safety and efficacy review, the independent data monitoring committee concluded that the study was unlikely to show superiority of lenalidomide and that there was an increased incidence of serious adverse events in the lenalidomide group. In November 2011, the trial was discontinued for futility.

Worse Overall Survival The duration of treatment was shorter in the lenalidomide group than in the placebo group (median 18.0 vs 24.0

weeks), as were the durations of docetaxel treatment (median 20.1 vs 24.0 weeks) and prednisone treatment (19.2 vs 23.9 weeks). Median relative dose intensities for lenalidomide or placebo, docetaxel, and prednisone were similar in the two groups. Dose reductions for lenalidomide or placebo were required in 15% of the lenalidomide group vs 8% of the placebo group, and dose reductions for docetaxel were required in 21% vs 16%. At data cutoff in January 2012, after a median follow-up of 8 months, median overall survival was 17.7 months (95% confidence interval [CI] = 14.8–18.8 months) in the lenalidomide group vs not reached in the placebo group (hazard ratio [HR] = 1.53, P = .0017). Overall survival at 1 year was 71.4% vs 78.2%. Median progression-free survival was 10.4 vs 10.6 months (HR = 1.32, P continued on page 66

MAINSAIL Trial: Worse Outcomes With Addition of Lenalidomide to Docetaxel-Prednisone in Prostate Cancer By Robert J. Jones, MD

he combination of docetaxel plus prednisone has been a standard therapy in advanced prostate cancer since 2004.1 Since then, there have been multiple randomized phase III trials comparing this standard of care with additional drug therapy. None has demonstrated improvement in outcome. Lenalidomide (Revlimid) is an oral derivative of thalidomide (Thalomid), which is widely used in the treatment of myeloma. Its precise mechanism of action is uncertain, but it has immunomodulatory and antiangiogenic properties. Dr. Jones is Senior Lecturer and Honorary Consultant in Medical Oncology at the University of Glasgow College of Medicine and the Institute of Cancer Sciences, Glasgow, Scotland, United Kingdom.

Early trials of thalidomide and lenalidomide in patients with prostate cancer showed some evidence of clinical activity, although the combination of lenalidomide with docetaxel had not been explored beyond a phase I trial with a small, nonrandomized cohort expansion prior to the initiation of the phase III MAINSAIL trial. Preclinical data, however, had shown enhanced cytotoxicity of docetaxel by lenalidomide in models of prostate cancer.

MAINSAIL Details The MAINSAIL trial,2 recently reported by Petrylak and colleagues and reviewed in this issue of The ASCO Post, was a large, randomized, double-blind, placebo-controlled trial of docetaxel plus prednisone with

or without lenalidomide. It failed to demonstrate any benefit from adding lenalidomide to docetaxel plus prednisone in men with metastatic castration-resistant prostate cancer. In fact, patients receiving lenalidomide had a significantly worse outcome for both survival (the primary endpoint of this trial) and progression-free survival than did those receiving placebo in the control arm of the trial. The causes for this apparent detrimental effect of lenalidomide are not clear. Although excess toxicity was seen in the lenalidomide arm, there were few excess deaths during treatment, suggesting that fatal immediate toxicities were not likely to be the cause. This does not rule out the possibility that there were latent toxicities causing excess mortality in those pa-

tients who had received lenalidomide, although there is no particular rationale as to why that might have been the case. Prostate-specific antigen response rates were similar in both arms of the trial, suggesting that lenalidomide was not reducing the efficacy of docetaxel by, for example, a drug interaction. However, the total amount of docetaxel received did differ between the arms—those patients receiving lenalidomide received a median of six cycles, compared to eight in the control arm. Furthermore, there were more dose reductions of all drugs for toxicity in the lenalidomide arm than in the control arm. Therefore, one plausible contributor to the reduced continued on page 66

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References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://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. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

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Journal Spotlight Metastatic Prostate Cancer continued from page 64

= .0187), and progression-free survival at 1 year was 33.8% vs 45.3%. Objective response was observed in 23% vs 25% (odds ratio = 0.884, P = .3975). PSA reduction of at least 50% from baseline occurred in 59% vs 58%.

Adverse Events Adverse events of grade ≥ 3 occurred in 73% of the lenalidomide group vs 58% of the placebo group. Grade 3 or 4 neutropenia (22% vs 16%), febrile neutropenia (12% vs 4%), diarrhea (7% vs 2%), pulmonary embolism (6% vs 1%), asthenia (5% vs 3%), pneumonia (5%

Robert J. Jones, MD continued from page 64

efficacy among patients receiving lenalidomide may have been reduced exposure to docetaxel experienced by those patients.

Lessons Learned Several thousand men with metastatic castration-resistant prostate cancer have now been enrolled in randomized phase III trials of docetaxel with or without an additional agent. This comes at great cost. The first cost, as seen here, is that trial participation may sometimes result in harm to some patients. Some of the men who received lenalidomide in the MAINSAIL trial are likely to have been better off had they not participated. This is, of course, an acceptable risk in ethically conducted trials such as MAINSAIL, but we owe it to our patients to take all reasonable steps to minimize such harm. Second, by participating in these trials, several thousand patients, and countless other finite resources employed in clinical trials, were unavailable for other research, thus, perhaps, delaying the discovery of more impactful treatments. Finally, the financial costs, though largely borne by the pharmaceutical industry in most of these trials, are enormous. It is therefore vital that we learn lessons from these experiences, which will enable us to conduct future clinical trials with greater efficiency while minimizing the number of patients who are exposed to ineffective or even detrimental treatments. There was preclinical evidence of synergy between lenalidomide and docetaxel, but the results of the MAINSAIL trial demonstrated that

vs 1%), and dyspnea (4% vs 2%) were more common in the lenalidomide group. Adverse events led to treatment discontinuation in 29% of the lenalidomide group vs 16% of the placebo group and to discontinuation of docetaxel and prednisone in 32% vs 24%. Death during treatment or at up to 28 days since the last dose occurred in 3% vs 2% of patients, and death at more than 28 days since the last dose, mainly due to disease progression, occurred in 21% vs 15% (P = .016). Treatment-related death occurred in 1% of patients in each group. In both groups, dose reductions of lenalido-

mide or placebo were more frequent in North America (27% vs 18%) than in Europe and Australia (11% vs 5%) and the rest of the world (6% vs 2%). Deaths in the lenalidomide group were more common in North America (33%; 45/137) than in Europe and Australia (21%; 67/325) and the rest of the world (24%; 15/63). By comparison, in the placebo group, the frequency of death in patients from North America (22%; 30/134) was closer to that observed in Europe and Australia (15%; 50/326) and the rest of the world (18%; 11/61). The investigators concluded: “Overall survival with the combination of lenalidomide, docetaxel, and predni-

these data did not in fact predict meaningful clinical synergy. Better preclinical models could assist in testing therapeutic hypotheses prior to clinical development in the future. Although the MAINSAIL trial was terminated early by the independent data monitoring committee, thereby taking steps to minimize harm to trial participants, alternative development pathways could be considered that may result in more

treatment of metastatic castrationresistant prostate cancer, it is easy to question the need to develop new drugs in combination with docetaxel. However, at the time this trial was conceived, docetaxel was the only treatment that had been proven to prolong survival in this disease. Trials of new treatments given earlier in the course of the disease (eg, in the “prechemotherapy” niche) demand long follow-up for

Mortality

There was preclinical evidence of synergy between lenalidomide and docetaxel, but the results of the MAINSAIL trial demonstrated that these data did not in fact predict meaningful clinical synergy. —Robert J. Jones, MD

efficient early stopping of trials of ineffective or harmful treatments. Phase II trials may be used to identify ineffective treatments at an early stage but are limited by the absence of robust intermediate endpoints for survival in prostate cancer and the need to randomize when exploring combination strategies. Furthermore, the need to conclude a phase II trial before initiating a phase III evaluation will result in slower implementation of a truly effective treatment, thus potentially delaying therapeutic progress.

Still a Need for Docetaxel Combinations? During a decade in which five new systemic therapies have been licensed as monotherapy agents for the

which there is no acceptable surrogate endpoint for overall survival, and interventions among those with chemorefractory disease may be impacted by the relative poor health of the participants. Furthermore, placebo-controlled trials may prove unpalatable in a setting in which standard therapy is being delayed (as may be perceived to be the case in the prechemotherapy niche). Thus, it is easy to see how a combination with the standard of care was an obvious developmental pathway at the time the MAINSAIL trial was designed. Recent advances in systemic therapy have changed the positioning of docetaxel in routine practice and have confirmed the value of sequential rather than concurrent combi-

sone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted.” n

Disclosure: The study was funded by Celgene Corporation. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Petrylak DP, Vogelzang NJ, Budnik N, et al: Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): A randomised, doubleblind, placebo-controlled phase 3 trial. Lancet Oncol 16:417-425, 2015.

nation therapies as an effective way of managing this disease. However, what evidence we have would suggest that these new therapies have not negated the role for docetaxel, which remains a useful, life-prolonging therapy for many men with metastatic castration-resistant prostate cancer at some point in the disease pathway. Moreover, recent data from the E3805 CHAARTED trial have suggested that the addition of docetaxel at the point of initial androgen deprivation may dramatically improve outcomes in men with metastatic prostate cancer.3 This may reawaken interest in combining docetaxel with other agents in the hope that the substantial survival gains seen may be further enhanced. n Disclosure: Dr. Jones reported no potential conflicts of interest.

References 1. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004. 2. Petrylak DP, Vogelzang NJ, Budnik N, et al: Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 16:417-425, 2015. 3. Sweeney C, Chen YH, Carducci MA, et al: Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormonesensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol 32(5s suppl):Abstract LBA2, 2014.

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Expert’s Corner Neuro-oncology

Will the PVS-RIPO Poliovirus Be a Game Changer in the Treatment of Recurrent Glioblastoma? A Conversation With Darell D. Bigner, MD, PhD By Jo Cavallo

Darell D. Bigner, MD, PhD

lthough the idea of using viruses to target cancer cells dates back more than 100 years, technologic advances in the genetic engineering of viruses are now making it possible to safely test oncolytic virotherapy as a valid strategy against cancer cells. One type of genetically engineered virus that is getting attention is the PVS-RIPO poliovirus, which is being tested in a phase I clinical trial for recurrent glioblastoma multiforme at Duke University School of Medicine in Durham, North Carolina, and was recently featured on the television program 60 Minutes.1 The study was launched in 2012 by Darell D. Bigner, MD, PhD, Edwin L. Jones, Jr. and Lucille Finch Jones Cancer Research Professor and Director of the Preston Robert Tisch Brain Tumor Center, and his colleagues Allan H. Friedman, MD, The Guy L. Odom Professor of Neurological Surgery; Henry S. Friedman, MD, James B. Powell, Jr. Professor of Neuro-Oncology; Annick Desjardins, MD, FRCPC, Associate Professor of Neurology; and John H. Sampson, MD, PhD, Chief, Division of Neurosurgery and Dr. Robert H. Wilkins and Gloria Wilkins Professor of Neurosurgery, at Duke University Medical Center. To date, 24 patients have been treated with the vaccine, which is delivered via a catheter placed stereotactically directly into the tumor by a method known as convection-enhanced delivery. Dr. Desjardins will be presenting an update of the results from a phase I trial of PVS-RIPO in recurrent glioblastoma at the 2015 ASCO Annual Meeting in Chicago. The PVS-RIPO poliovirus was invented by Matthias Gromeier, MD, Associate Professor of Surgery, Associ-

ate Professor in Molecular Genetics and Microbiology, and Associate Professor of Medicine at Duke University School of Medicine, more than 2 decades ago, when he discovered that many cancer cells, including glioblastoma cells, produce the poliovirus receptor Necl-5/ CD155. The vaccine works by killing tumor cells and initiating an antitumor secondary immune response. After years of preclinical safety studies to prove the vaccine would not infect patients with polio, the U.S. Food and Drug Administration (FDA) granted investigational new drug (IND) status for PVS-RIPO in 2011. The ASCO Post talked with Dr. Bigner about the current results of the poliovirus study, the treatment’s use in other cancer types, and why he thinks PVS-RIPO may prove to be a turning point in the care of patients with glioblastoma.

Early Results What has been the result so far of your phase I study of the poliovirus in patients with recurrent glioblastoma? There were 24 patients enrolled in the study, and 12 patients have died. There are three long-term survivors, meaning patients still alive 22, 34, and 35 months after treatment. Overall, 2 patients have no evidence of disease, 11 are doing well with no disease progression, and 1 had disease progression but is still alive. Can you re-treat the patient whose disease has progressed on the poliovirus? The current protocol is not written for retreatment with the therapy, although we did get a compassionate plea release from the FDA and re-treated one patient. We certainly could re-treat patients with the poliovirus, and that will be something we would probably want to consider in the future. The patient who did have disease progression is being treated with one of the nitrosoureas, and that is proving effective.

Mechanism of Action Why is the PVS-RIPO poliovirus effective against glioblastoma? The vaccine is effective against any tumor that expresses the poliovirus receptor, and we found that all of the

solid tumors we and others tested except for Burkitt’s lymphoma express large amounts of the poliovirus receptor. The genetic alteration of the poliovirus rendered it incapable of killing nerve cells but retained its ability to kill tumor cells. From a mechanistic standpoint, the virus does two things: It kills tumor cells immediately after the injection and then sets up an inflammatory reaction, which sets up a very potent secondary immune response. We think the secondary immune response is the most important part of the antitumor killing mechanism.

Other Cancers and Patient Groups Are you testing the poliovirus therapy in other cancer types? We’ve only tested the vaccine in vitro against melanoma and pancreatic and prostate cancers, and we are in the process of doing animal studies in prostate and pancreatic cancers. Once we have completed those studies and have gotten further along in the glioblastoma clinical trial, we will undertake other

and removal of these catheters. The purpose of this phase I study is to determine the optimal dose of the virus. Because the virus causes an inflammatory reaction, which is a necessary part of its effect, too much virus can cause massive swelling in the brain, and the higher doses did cause cerebral edema that had to be treated. We have now lowered the dose significantly and have reduced the amount of inflammation and cerebral edema. We have to be careful because if you reduce the dose too much and don’t get any inflammatory response, you reduce the therapy’s effect. If patients get too much of an inflammatory reaction, we treat the cerebral edema with bevacizumab (Avastin) in the reduced dose and schedule that we use for treating radiation necrosis of the brain.

Optimizing Treatment Do you have any theories as to why the therapy appears effective in some patients and not in others? At this point, we really don’t, but we are investigating it. We think that

I think [these novel therapies] and immunotherapy for brain tumors in general will result in a paradigm shift in treating brain tumors, probably within the next 10 years. —Darell D. Bigner, MD, PhD

clinical trials, starting with prostate and pancreatic cancers. But these studies are some time away because we have to do the animal studies first. All of the patients in your glioblastoma trial are adults; do you have plans to initiate trials in children? We have tested pediatric tumors, and they do express the poliovirus receptor. So after additional safety studies, yes, ultimately we will be treating children with brain tumors with this therapy.

Safety Profile Are there side effects from the therapy? We have had two adverse events. There was one intracranial hemorrhage on removal of the catheter that was used to administer the virus, which is a known complication of stereotactic biopsies in the brain and implantation

there may be a significant variation in the immune response among the individual patients, which may account for the different responses, and we are investigating that in depth, but at present we don’t have a definitive answer. Some of the early patients we enrolled in the study did not have a restriction on the amount of steroids they had received prior to participation in the study, and some of those patients had severe steroid myopathies. Also, when patients have been heavily pretreated with steroids, they don’t have any functional T lymphocytes left, so we are now significantly limiting the amount of steroids that patients can receive both prior to study enrollment and during treatment. In the future, we will be adding checkpoint inhibitors to the treatment continued on page 68

The ASCO Post | MAY 25, 2015

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Expert’s Corner Darell D. Bigner, MD, PhD continued from page 67

regimen, and we believe that they will enhance the immunotherapeutic effect of the poliovirus.

Looking Ahead What is the next step in this research; are you planning on launching phase II trials? The FDA has suggested that rather than go into a phase II trial we expand the phase I study, and we have just gotten permission to treat a total of 26 additional patients in the phase I study at what we think is the optimal dose of virus. As we get further along, we will request Breakthrough Therapy designation and if it is granted, we may be able to have as few as 200 patients in a multi-institutional setting with a constant virus dose and a constant standard treatment with bevacizumab at the radiation necrosis dose and schedule. That might be a single-arm study with historical controls from each institution. After the 60 Minutes program aired, you received requests from thousands of patients who wanted to enroll in the study. Do you have all the participants you need to expand the study? Even though we received more than 3,000 referrals since the program was broadcast, most do not meet the trial eligibility requirements, so we definitely need all the referrals we can get. The FDA placed quite rigid requirements on eligibility, including tumor size between 1 and 5.5 cm in diameter. Right now, only about 15% of recurrent glioblastoma patients are eligible because of the tumor size restriction. Also, patients cannot have received more than 4 mg of dexamethasone and must have been previously vaccinated against polio. We vaccinate them again once they enter the study.

Turning Point in Glioblastoma? How would you evaluate the effectiveness of this therapy thus far? There are several ways to look at these therapies. The standard way is to look at the median overall survival. In the trial right now, the median is 16 months compared to 10 months in matched historical controls of equivalent eligibility, so this is better than any of the other agents that have been approved for recurrent glioblastoma. Admittedly, the trial is still small. But I’ve never seen a recurrent glioblastoma trial with these types of results, both in terms of median survival and

in these three very long-term survivors, although I have been doing malignant brain tumor research for 45 years. Do you think this treatment is a turning point in care for patients with glioblastoma? Yes, I really do. A lot of improvement is still needed, and my biggest hope is

that the addition of checkpoint inhibitors with this poliovirus is going to be a big turning point. We have a number of other vaccines in trials that we think will be complementary with the poliovirus S:6.75” treatment for glioblastoma. There is also an immunotoxin we will be testing in clinical trials soon, which

should be complementary with this poliovirus. I think this therapy and immunotherapy for brain tumors in general are going to result in a paradigm shift in treating brain tumors, probably within the next 10 years. I’ve spent my whole career getting to this point, and there was no belief in immunotherapy in the treatment of

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

• 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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glioblastoma for most of that time. n Disclosure: Dr. Bigner reported no potential conflicts of interest.

Reference 1. Killing Cancer, Part 1. 60 Minutes, aired March 29, 2015. Available at w w w.cb s n e w s.co m / v i d eo s / k i l l i ngcancer-part-one. Accessed May 1, 2015.

For more information on the PVS-RIPO poliovirus clinical trial and to refer patients, contact the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center at 919-684-5301, or visit S:6.75” www.cancer.duke.edu/btc/modules/ ClinicalTrials4/index.php?id=111.

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

0.7 0.5 0.4

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

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%),

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

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.

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Book Review

Exploring the History and Psychology of Pain: Beyond the Clinical Setting By Ronald Piana

“Pain may even kill. It may overwhelm the nervous system by its mere magnitude & duration.” —Peter Mere Latham, 1871

rom a child’s tears to a burn victim’s agonizing moans, pain is a universal experience deeply enmeshed in what it means to be human. In 1977, the International Association for the Study of Pain

(IASP) called together a diverse group of specialists to definitively answer the question: what is pain? They concluded S:6.75” that pain is an “unpleasant sensory and emotional experience associated with

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.

actual or potential tissue damage, or described in terms of such damage.” Pain comes in varying degrees of hurt, but IASP’s dry academic definition—the most cited in the literature

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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of pain management—certainly does not capture the soul-searing distress associated with untreated late-stage cancer pain. The literature is replete with articles and studies on pain management, and although there are numerous handbooks and reference guides, perhaps the most comprehensive book on pain to date is Cancer Pain: Assessment

and Management, edited by Eduardo D. Bruera, MD, and Russell K. Portenoy, MD. It is intended for a wide range of clinicians with varying degrees of expertise in the care of cancer-related pain. But pain is an intriguing subject that reaches far beyond S:6.75” the clinical setting, and for those readers of The ASCO Post who enjoy a rich and challenging liter-

ary read, prize-winning scholar Joanna Bourke has delivered the goods with her new book, The Story of Pain: From Prayer to Painkillers. Ms. Bourke—a well-known British historian and frequent BBC contributor—has penned nine previous books on subjects including modern warfare, rape, and military medicine. She approaches The Story of

Pain in painstaking prose that delves into the history and psychology of the experience. Be forewarned: This book is not for the casual reader, but after the first 10 or so pages, the book reveals its magic. Aside from a few forgivable missteps, this is a read that nourishes and provokes thought and discussion.

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In chapter 3, “Metaphor,” the author gives a heady interpretation of the language of pain, from militaristic to religious to the deeply human ways in which fragile people try to describe their intimate agony. It took the oncology community decades to finally develop patient-centered tools to describe pain, but a number or a score doesn’t describe what a patient feels inside and how he or she views the cancer that is causing the pain. One of the interesting parts of this chapter describes the gender gap that exists in how patients view cancer, often within carefully circumscribed social norms. One woman interviewed by the author used the domestic sphere to describe her chronic pain: “I visualize my cancer pain as something similar to the cleanup you do before Christmas: You are scrubbing really hard and you are going on and on and you may demolish some jar and scrub the paint away from the furniture and you regret that and think that it may have been enough with only some soft dusting, and then you cry thinking it will never be clean.” For a 30-year-old man, cancer was a battlefield, not housework: “It is some foreign stuff around my body that we will beat and kill. So those soldiers they are sending in now, they will drive it back as far as possible and keep it in place.” Between discussions of pain and perception and the way people communicate about their pain, the author weaves reflective narrations into the content, some of which wax too philosophical, but most serve as an underpinning for the difficult subject she’s dealing with. For instance, “The most common metaphor in pain-speech deifies pain as an independent entity. In this way, pain was something that assailed a non-participating body; it might be omnipotent, but could still be fought while leaving the body intact.” Metaphors aside, pain can be frightful, and its shadow hovers over each page of the book. Although the oncology community has made significant strides in treating cancer pain, under-

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

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

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.

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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

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Book Review The Story of Pain continued from page 71

treated pain remains a challenging issue that needs heightened attention. The unnecessary suffering of undertreated pain was most vividly captured in Ms. Bourke’s book by the words of a terminally ill cancer patient in hospice. The year was 1961: “I would say the pain was so bad that I dreaded anyone touching me and when anyone knocked my bed or came near to me, the first thing I said to them was ‘please don’t touch me. Please don’t move me’…. It was an obsession in a way because it was all around me, I was buried in pain.” Tough to read, especially when this woman’s horrible reality is still shared by millions of cancer patients around the world who don’t have access to morphine.

Religion and War The author’s skill as a historian is on full display in the chapters on religion and war. The graphic descriptions of wounds and surgeries in a preanesthesia era are not for the faint of heart. And while the author’s skill at describing battlefield amputations and operations without anesthesia might make some queasy, her discourse on religion will surely inspire ire, especially in her accounts of pious suffering, when religious followers were

instructed on how they ought to comport themselves when in pain. In fact, pain was thought to be a redemptive tool that brought enlightenment. Ms. Bourke writes about the religious state in the late 1700s: “Suffering has a role in promoting personal as well as spiritual rebirth. Pious acceptance of pain would reap rewards in terms of strengthening moral fiber and stature.” One has to wonder if this morality clause of pious suffering was deemed more beneficial for the wretched poor than for the gentry. Fittingly, the book’s last chapter is called “Pain Relief.” After a brief discussion about the history of analgesics, Ms. Bourke tackles the issue that readers of The ASCO Post will embrace: undertreatment of pain. It is a complex issue filled with sociopolitical minefields, most of which she navigates with assuredness. Sometimes, however, the analysis seems dated or off the mark: “Too often, medical personnel become overly accustomed to suffering or, in psychodynamic terms, attempt to avoid counter-transference when dealing with severely afflicted patients so they keep tight reins on their emotions.” This kind of jargon falls way short when attempting to explain the root causes for undertreatment of pain. Ms.

Bookmark Title: The Story of Pain: From Prayer to Painkillers Author: Joanna Bourke Publisher: Oxford University Press Publication date: 2014 Price: $34.95: hardcover, 416 pages

Bourke should have consulted with oncology nurses about the physiologic processes that occur when dealing with “severely afflicted patients.”

Sensitivities and Biases The author’s most convincing section of “Pain Relief ” is when she explores cultural sensitivities and biases that lead to undertreatment of pain. It’s clear that she knows this area well, and the reader will enjoy her passion. She again wades into choppy waters, however, when trying to explain the economic hurdles of pain relief in developing nations. “Analgesics can be expensive; poorer patients have less

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access to insurance. Sufferers have no real choice.” Wrong. Analgesics are cheap. There are myriad political, social, cultural, and economic reasons for lack of access, none of which are discussed in this volume. Unfortunately, these stumbles come at the end of the book, and it is content that oncologists might judge harshly because it speaks to issues they deal with daily. Ms. Bourke ends her otherwise wonderful book by telling the reader: “A painful world is still a world of meaning.” True, but a less painful world is better, and we have the tools to make it so. That’s a point that the author doesn’t make clear enough. n

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Expert’s Corner

Taking the Next Step in a Storied Career A Conversation With Harold Varmus, MD By Jo Cavallo

Harold Varmus, MD

n March 31, 2015, Harold Varmus, MD, left his position as Director of the National Cancer Institute (NCI) to join the faculty of Weill Cornell Medical College in New York as its Lewis Thomas University Professor of Medicine. Dr. Varmus was also named Senior Associate Core Member of the New York Genome Center, a newly formed consortium of 16 academic and medical institutions to use genomic methods to combat several diseases, including cancer. Douglas R. Lowy, MD, who served as Deputy Director of NCI under Dr. Varmus, became Acting Director of the agency on April 1, 2015. In his nearly 5 years as head of NCI, Dr. Varmus steered the agency through turbulent times, including a government shutdown and a funding cut of 5.5%, which reduced NCI’s budget to $4.78 billion. Still, Dr. Varmus’ accomplishments during his tenure are notable, including the institution of the Provocative Questions initiative; the creation of the Center for Global Health and the Center for Cancer Genomics; the transformation of the Cooperative Group program into the National Clinical Trials Network; and the launch of a large new initiative to study tumors driven by mutant RAS genes, among others. Dr. Varmus’ long association with the National Institutes of Health (NIH) began in 1968, when he studied bacterial gene expression with Ira Pastan, MD, who is now Co-Chief of NCI’s Laboratory of Molecular Biology. Dr. Varmus served as Director of the agency from 1993 to 1999. Before returning to NIH as Director of NCI in 2010, Dr. Varmus was President of Memorial Sloan Kettering Cancer Center in New York. Prior to his appointment to lead NCI, Dr. Varmus was named co-chair of President Barak Obama’s Council of Advisors on Science and Technology,

served on the World Health Organization’s Commission on Macroeconomics and Health, and was Chair of the Scientific Board of the Bill & Melinda Gates Foundation Grand Challenges in Global Health. He is also a member of the National Academy of Sciences and the Institute of Medicine. Recognized for his many contributions to the study of retroviruses and the genetic basis of cancer, Dr. Varmus was co-recipient with J. Michael Bishop, MD, of the 1989 Nobel Prize for Physiology or Medicine for their discovery of the cellular origins of retroviral oncogenes. In addition to the Nobel Prize, Dr. Varmus was the recipient of the National Medal of Science and the Vannevar Bush Award. In his new position at Weill Cornell Medical College, Dr. Varmus will continue his research on lung adenocarcinoma and the cancer-driving mutations

have to remember that NCI still has a budget of about $5 billion. The agency has a public responsibility to use those monies well, and that’s what I tried to do during my tenure. There’s always a lot of justifiable complaining about a declining budget. I’m perfectly happy to say repeatedly that Congress needs to pay attention to the fact that NCI has $177 million less this year than it had the year I became Director. Even if we got the President’s full request for a 3% increase this year, NCI would still not be back to where it was the day I walked into the office. And although that is not good news, I just considered it to be the lay of the land and tried to work within the budget framework. Despite funding constraints, we started a lot of new and interesting programs, including two new centers, one for Cancer Genomics and one for

The past 5 years have been very productive ones. Despite the declines in our budget, we’ve made a lot of good changes at NCI and done a lot of interesting things. We have to remember that NCI still has a budget of about $5 billion. The agency has a public responsibility to use those monies well, and that’s what I tried to do during my tenure. —Harold Varmus, MD

found in the disease in a laboratory he is establishing in the Sandra and Edward Meyer Cancer Center. He will also serve as Senior Advisor to Laurie H. Glimcher, MD, Dean of Weill Cornell. The ASCO Post talked with Dr. Varmus about his tenure as Director of NCI, the future of biomedical research, and this next phase in his career.

Working Within the Budget Framework When you became Director of NCI, the budget for NIH had been stagnant or on the decline for a decade and was reduced by an additional 5.5% in 2012. How were you able to overcome NCI’s funding restrictions and still accomplish your goals? The past 5 years have been very productive ones. Despite the declines in our budget, we’ve made a lot of good changes at NCI and done a lot of interesting things. I wish the budget was rising rather than falling, so we could have done even more, but that didn’t rule my everyday life while I was Director. We

Global Health. I didn’t invent the idea of NCI working abroad; NCI has had programs in developing countries for many years. What I tried to do was to bring a sense of coordination and purpose to these programs. We also attempted to improve the grant-making process in several ways. For example, we are engaging our scientists in identifying inadequately studied but important questions about cancer and providing grants to researchers to answer these questions. At the same time, we are maintaining the numbers of NCI’s traditional research project grants. We revitalized the cooperative clinical trials system—now called the National Clinical Trials Network and the NCI Community Oncology Research Program—to adapt to the advent of targeted drugs and immunotherapies and to enhance the contributions of community cancer centers. And we launched a large new initiative at the Frederick National Laboratory for Cancer Research to study tumors driven by mutant RAS genes.

Improving the Treatment and Control of Cancer Over the next 5 to 10 years, what is one hopeful scientific/clinical area of research that you predict will lead to a major improvement in the outlook for patients with cancer? I try to avoid predictions, especially about a time scale for improved care. However, I think there are things that look especially promising and require bigger investments at the moment, such as targeted therapies carried out with drugs and antibodies, based on our deeper understanding of carcinogenesis. There are still lots of problems; for instance, the genetic profile of a cancer is extremely complex, and we don’t often know what makes cells drug-resistant. Also, we haven’t learned how to give combination therapies effectively and don’t have optimized preclinical models for testing combination therapies. In addition, clinical trials to test new therapies need to be redesigned; NCI is now doing that with MATCH and similar trials. Another area that is promising therapeutically is immunotherapy. I don’t mean just one kind of cancer immunotherapy but those that use antibodies fused to toxic proteins, genetically engineered T cells, and (perhaps most promising) immune checkpoint inhibitors for many types of cancer. I’m encouraged by the fact that as more cancers are analyzed genetically, we are learning some important clues about why some people respond to immune treatment and others do not. So, I think that we will soon have a much better idea of the patients in whom immune therapies should be used, which ones should be used, whether they should be used in combination with conventional chemotherapy or with targeted therapies, and when in the course of an illness immunotherapy should be performed. Everyone is passionate about finding therapies to cure cancer. I understand that and feel the same way, but our greatest gains are often made with the least fanfare in the prevention domain. Early detection also shows promise for certain cancers and perhaps less for others, but there are some opportunities here that are not being as actively pursued as I’d like to see. And certainly more widespread use of prevention strategies that are already at hand, most obviously the human papillomavirus vaccine for the prevention of cervical cancers and oth-

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Expert’s Corner

ers, would be beneficial. It is less dramatic to protect someone from getting a cancer than it is to turn around late-stage metastatic disease, and we need to raise public awareness of the efficacy of prevention.

Biomedical Research Given the current funding climate, what advice do you have for young investigators interested in pursuing a career in cancer research? We are currently in a very difficult situation in the biomedical research ecosystem. We have a Malthusian dilemma: The longstanding assumption that the biomedical research system in the United States will expand indefinitely at a substantial rate has created a crisis. Some colleagues and I have been writing about the issue, and we are actively working on solutions to the problems we discussed in our article.1

We are creating a lot of scientists. That’s a good thing except we can’t accommodate them all in the traditional academic environment. At this point, someone being trained as a biological scientist interested in disease and human biology has about a 1 in 10 chance of becoming an academic principal investigator. So, although the goal is still to attract the best people to consider careers in this field, because the work is incredibly exciting, they should be aware that there are a lot of things that can be done with a PhD in biology and that the chances of becoming an academic scientist aren’t high overall. I could not be more enthusiastic about the scientific opportunities to do great work. But I think people need to go into biomedical research with their eyes open to the competition for jobs and funds and should know that the

ability to work productively in this incredibly exciting field is not going to be available to everybody.

Happy to Be Back in New York Please talk about your new positions as the Lewis Thomas University Professor of Medicine at Weill Cornell Medical College and Senior Associate Core Member of Weill Cornell’s New York Genome Center. About 20% of my time will be spent working in the New York Genome Center. My role there is to facilitate the use of genomics in medical care by offering services to all cancer care providers throughout the New York area. The Genome Center is focused on driving scientific research to improve clinical care, and it is important that this new area of genomics is coordinated in New York, where there is a very strong research base. The rest of

my time will be devoted to running my small laboratory group, teaching, and interacting with other faculty members at the Meyer Cancer Center, which is led by my good friend Lewis C. Cantley, PhD. I think this is going to be a very enjoyable place for me. In addition to my work, I’ll be near all my buddies at The Rockefeller University and Memorial Sloan Kettering Cancer Center, both of which are just across the street. And my wife and sons are here, so I’m enthusiastic about being back in New York. n

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

Reference 1. Alberts B, Kirschner MW, Tilghman S, Varmus H: Rescuing US biomedical research from its systemic flaws. Proc Natl Acad Sci U S A 111:5773-5777, 2014.

Announcements

NIH Names Eliseo J. Pérez-Stable, MD, Director of the National Institute on Minority Health and Health Disparities

ational Institutes of Health (NIH) Director Francis S. Collins, MD, PhD, has announced the selection of Eliseo J. Pérez-Stable, MD, as Direc-

Eliseo Pérez-Stable, MD

tor of the National Institute on Minority Health and Health Disparities (NIMHD). Dr. Pérez-Stable is expected to join NIH in September 2015. “Dr. Pérez-Stable is a highly respected leader with rich experience in advancing efforts to eliminate health disparities,” said Dr. Collins. “He has the passion and vision to guide the NIMHD research agenda in this critically important area.” As NIMHD Director, Dr. PérezStable will oversee the institute’s $270 million budget to conduct and support research, training, research capacity and infrastructure development, public education, and information dissemination programs to improve minority health and reduce health disparities. NIMHD is the lead organization at the

NIH for planning, reviewing, coordinating, and evaluating minority health and health disparities research activities conducted by the NIH institutes and centers. Dr. Pérez-Stable comes to NIH from the University of California San Francisco (UCSF), where he is a Professor of Medicine, Chief of the Division of General Internal Medicine, and Director of the Center for Aging in Diverse Communities. The center

works to alleviate health disparities with a focus on improving health care for aging minority populations and diversifying the scientific workforce addressing these issues. He is also Director of the UCSF Medical Effectiveness Research Center for Diverse Populations, which is addressing issues for African Americans, Asians, and Latinos in the areas of cancer, cardiovascular disease, and reproductive health.

Dr. Pérez-Stable’s personal research interest is in improving the health of poor and minority patients, reducing health risks such as smoking in minority populations, and improving cross-cultural communication skills among health-care professionals. For more information about the National Institute on Minority Health and Health Disparities, visit http://www. nimhd.nih.gov. n

June McKoy Named to NCI Council of Research Advocates

une McKoy, MD, MPH, JD, LLM, MBA, Associate Professor of Medicine and Preventive Medicine at Northwestern University Feinberg School of Medicine and Director of

June McKoy, MD, MPH, JD, LLM, MBA

Geriatric Oncology for the Lurie Cancer Center, has been selected by National Cancer Institute (NCI) Director,

ouglas Lowy, MD, to join the CounD cil of Research Advocates (NCRA). Dr. McKoy is a member of the Institute for Public Health and Medicine at Northwestern University. She is also Program Director for the Geriatric Medicine Fellowship at Northwestern’s McGaw Medical Center. A member of the Illinois Cancer Partnership, she cofounded the Senior Oncology Outcomes Advocacy and Research (SOAR) Program at Lurie and coleads Northwestern Medicine’s Geriatric Fracture Program. She has worked collaboratively with the city of Chicago in its efforts to meet World Health Organization age-friendly standards. The NCRA is a federal advisory committee. NCRA members are chosen for

their expert knowledge of issues of importance to the cancer research community. The NCRA focuses on matters that facilitate research and often identifies and responds to challenges facing the NCI at the request of NCI leadership. In addition, NCRA members bring their unique skills and perspectives by identifying new approaches, promoting innovation, recognizing unforeseen risks or barriers, and identifying unintended consequences that could result from NCI decisions. The NCRA focuses on enhancing community input, optimizing community outreach, and promoting strong collaboration to improve research outcomes. To see a full list of NCRA members, visit http://www.cancer.gov/aboutnci/ organization/oar/ncra. n

When faced with overactive signaling . . .

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi

Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

Inhibit the JAK pathway* in polycythemia vera not controlled with hydroxyurea 1-3

Jakafi® (ruxolitinib) is the first and only FDA-approved treatment for patients who have had an inadequate response to or are intolerant of hydroxyurea3 Jakafi demonstrated superior results in a phase 3 trial vs best available therapy3,4†

Primary Response at Week 323,4 80

* Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 (Janus-associated kinases 1 and 2), which mediate the signaling of cytokines and growth factors important for hematopoiesis and immune function.3 A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy (BAT) in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both hematocrit (Hct) control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value).3,4

P < 0.0001

Jakafi (n = 110) BAT (n = 112)

(n = 66)

38%

21%

20 0

Individual Components of Primary End Point

60%

Patients (%)

†

Composite Primary End Point

(n = 23)

1%b

(n = 22)

(n = 1)

Hct Control + Spleen Volume Reduction

95% CI, 14%-30%

When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy

20%

(n = 42)

(n = 1)

Hct Control Without Phlebotomy

≥35% Spleen Volume Reduction

95% CI, 0%-5%

Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Please see Brief Summary of Full Prescribing Information for Jakafi on the following page. References: 1. Rampal R et al. Blood. 2014;123(22):e123-e133. 2. Keohane C et al. Biologics. 2013;7:189-198. 3. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 4. Vannucchi AM et al. N Engl J Med. 2015;372(5):426-435.

Review the clinical trial data at

www.jakafidata.com

Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi (N=155) Adverse Reactions

Adverse Events

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Edemae

Arthralgia

Asthenia

Epistaxis

Herpes Zosterf

Nausea

a b c d e f

Laboratory Parameter

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Anemia

Thrombocytopenia

Placebo (N=151)

Neutropenia

Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

Grade 4 (%)

Bruisingb

Dizzinessc

Headache

Urinary Tract Infectionsd

Weight Gaine

Flatulence

Herpes Zosterf

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Grade 4 (%)

Chemistry

Grade 3 (%)

Hematology

All Grades (%)

Best Available Therapy (N=111)

All Gradesb (%)

Grade 4 (%)

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

Jakafi (N=110)

Grade 3 (%)

Grade 3-4 (%)

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta

All Gradesa (%)

Best Available Therapy (N=111)

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428a

ASCOPost.com | MAY 25, 2015

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Direct From ASCO

ASCO’s Train the Trainer Program Extends the Reach of Multidisciplinary Cancer Management Education

ultidisciplinary Cancer Management Courses (MCMCs) offered by ASCO International, in collaboration with other organizations, seek to improve cancer care globally through the promotion of interdisciplinary cancer management. Attendees of select MCMCs have the option to attend a 1- to 2-day training workshop called Train the Trainer (TTT). During this workshop, attendees can increase their understanding of multidisciplinary cancer care concepts, learn effective teaching methods and practical skills, and discuss implementation strategies for their own trainings with their communities and institutions. Those who have completed the training are encouraged to disseminate what they have learned by organizing their own courses. ASCO International asked past participants from Chile, Uruguay, Paraguay, and Bolivia to share their TTT workshop experience.

Chile: Christian Caglevic, MD “In 2006, the first MCMC was held in Chile thanks to the efforts of ASCO and numerous Chilean oncologists, es-

Christian Caglevic, MD

pecially Jorge Gallardo, MD, a medical oncologist who in 2010 also brought the new TTT program to Chile. “This was my first time participating in an ASCO activity outside the United States. I didn’t really know what TTT was and what it would mean for me in my professional career years later. I did know, though, that TTT’s purpose was to teach us about how to lead presentations, speak in front of other colleagues, and feel confident when giving a speech. The ASCO delegates leading the course (Hugo V. Villar, MD, FACS; Frank D. Ferries, MD; and Vanessa Eaton, ASCO Manager of International Education) taught us some techniques that we practiced during TTT, including speaking in front of an audience, role-playing different situations, and observing and commenting on the performance of our colleagues.

“My major hope for this course was to be able to stand alone in front of an audience and share something related to my profession so clearly that everyone in the audience could understand the presentation. All my hopes for this course were achieved thanks to the ASCO delegates. I learned so many things that I still practice today. I still remember one of the main messages I took home— that ASCO could have given us a “fish,” but if ASCO taught us “how to fish” it would be much better for our lives. Dr. Villar was right; ASCO gave us the tools,

“I saw being an oncologist as an opportunity to help people who are going through a very hard moment in their lives with a painful disease, where human quality is fundamental. Training in this area allowed me to work in an area of constant growth and development of new therapeutic strategies. Advancements continue to surprise us every day, with an increase in survival and a higher quality of life. “In September 2013, I attended the TTT course in Montevideo, Uruguay, held by ASCO in collaboration with

ASCO gave us the tools, through Train the Trainer, to be able to train our colleagues to be trainers too. —Christian Caglevic, MD

through TTT, to be able to train our colleagues to be trainers too. “Thanks to this opportunity from ASCO’s leaders and my colleagues from other South American countries, I have been a trainer in several activities with ASCO in Paraguay, Bolivia, and Chile. A few years ago, there was a MCMC in Bolivia with a TTT course, and it was the first TTT that I participated in as a trainer. It was a great experience, and my colleagues from Bolivia were very happy with our performance, especially with what they learned. They “learned to fish,” and we gave them the tools to do so. Christian Caglevic, MD, is a medical oncologist at the Fundación Arturo López Pérez de Santiago in Chile.

Uruguay: Noelia Silveyra, MD “Uruguay is a small country in South America with 3.2 million inhabitants. Cancer is a very important health problem in our country. It’s the second most deadly disease in Uruguay (after cardiovascular disease), accounting for 23.8% of all deaths per year in both men and women. The entire population of Uruguay has medical coverage, which includes diagnostic exams, chemotherapy and radiotherapy treatments, and most prescriptions.

Noelia Silveyra, MD

Federación Latinoamericana de Sociedades de Cancerología (FLASCA). I participated in the course while I was in my last year of oncology residency. The knowledge and skills acquired during my TTT experience had a very significant impact on my daily practice. It gave me better communication skills, improved my slides presentations and leadership of group discussions with young residents, and allowed me to contribute in multidisciplinary discussions of patient care. “ASCO courses such as TTT and MCMC are a great contribution to my country because they provide training tools and, more importantly, allow us to conduct better discussions about cancer with our patients and our society as a whole. Personally, I am very grateful for this opportunity and I’d highly recommend the TTT experience to residents-in-training like me.” Noelia Silveyra, MD, is a medical oncologist at the Hospital de Clinicas in Montevideo, Uruguay.

José L. Duarte, MD

sentation. In many cases, participants made vast improvements in their presentation skills. TTT offered us very useful lessons, such as putting together a successful presentation for an audience—big or small—in a way that is attractive and benefits the listeners. “The course is based not only on theory, but also hands-on practice. It emphasized that although the content of a presentation is important, the way one gives the presentation is most important. Whatever topic is being presented—even something very dry— can be interesting for the participant, depending on the skills and quality of the presenter. “I consider the TTT course a highly positive experience. It was motivating to improve the way in which we give a talk in a classroom or in a large conference. For me, and for many of my Paraguayan colleagues who participated, it had a lasting impact and it is easy to recognize the benefits.” José L. Duarte, MD, is the Chair of the Breast Department at the Instituto Nacional del Cancer in Paraguay.

Bolivia: Lena Morillas, MD “The TTT course was a great opportunity that brought together multidisciplinary oncology and training for health

Paraguay: José L. Duarte, MD “The TTT course was, for me, a very enriching experience that has not only improved the quality of my presentations as a speaker, but has also strengthened my skills in leading discussion groups. Without a doubt, my professional life greatly benefitted from TTT. “The experience was so positive in Paraguay that 90% of those who participated in the TTT course (a total of 30 professionals) made a positive change in how they conducted their work and reported that they learned new concepts about how to put together a pre-

Lena Morillas, MD

professionals in Bolivia. Having expert professors from a Society as prestigious as ASCO come to Bolivia was something that seemed like a dream. “In Bolivia, there are only 20 clinical oncologists for a population of almost continued on page 80

The ASCO Post | MAY 25, 2015

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Direct From ASCO

Earn Maintenance of Certification Points on the Go With ASCO MOC App

new app from ASCO University enables clinicians to earn Maintenance of Certification (MOC) points quickly, conveniently, and easily by answering questions on a smartphone, tablet, or computer. The ASCO MOC app, available for iOS and Android devices, as well as on a mobile-friendly responsive website, gives users the flexibility to work toward MOC requirements anytime and anywhere that is most convenient for them. The app utilizes a repetitive spaced-education approach to learning, a proven method for knowledge retention. ASCO University released the first MOC app course in January, and new courses will become available every 6 months. Users may choose to receive either two or five questions every other day, totaling 30 questions per course. Any question that is answered incorrectly will be cycled back into

the pool of questions that the participant receives until he or she is able to answer it correctly. Once a participant has correctly answered all of the questions, he or she will be eligible to claim 10 MOC points, which can be submitted directly to the American Board of Internal Medicine (ABIM) through the app. Questions may be answered at any time—users may choose to receive alerts notifying them when new questions are available. They can also set the app to “vacation mode” if they do not wish to receive new questions for a period of time. To aid the learning process, all questions in the course are linked with corresponding abstracts, providing users the ability to quickly and easily receive more information about the topic. The app also indicates what percentage of participants answered the question correctly, allowing users to track their progress against that

of their peers. “The MOC app is an easy and efficient way to accumulate MOC knowledge points—even for a low-tech person like me,” said Jamie H. Von Roenn, MD, FASCO, ASCO Senior Director of Education, Science, and Career Development.

Train the Trainer

Bolivia has been enduring. The professionals and students that participated in these courses left with a better understanding of what oncology is and the importance of multidisciplinary management for a patient with cancer. Since the TTT course, we have created departmental tumor boards with routine meetings

with different specialists. They are still small, but they are growing.” Lena Morillas, MD, is a clinical oncologist at the Work Center of Diseases Neoplasicas Oncovida in La Paz, Bolivia. To learn more about MCMCs and ASCO International, visit asco.org/ international. n

continued from page 79

10.7 million inhabitants, and there is no postgraduate specialization in oncology. It was great having a multidisciplinary congress and the TTT course so we could reach out to other health professionals. “The impact of the TTT course in

Need for New MOC Opportunities The ASCO University MOC app was born out of the 2013 ASCO App Idea Challenge, in which ASCO members were encouraged to submit concepts for a new oncology-related app for ASCO to develop. David Coffey, MD, of the Fred Hutchinson Cancer Research Center, won the challenge with his suggestion for an app that could offer cancer care providers a convenient and accessible self-assessment opportunity.“ I am always looking for ways to improve my productivity, and mobile phone apps are a great

way to take advantage of the pockets of downtime we have during the day,” Dr. Coffey said. “I envisioned an app that would allow oncologists to catch up on their medical education while earning MOC credit.” The ASCO MOC app can be downloaded for free through Google Play and the Apple App Store. Individual courses can be purchased through the ASCO University Bookstore (store2.asco.org) or as an addon in the ASCO membership renewal form. For more information on the MOC program, visit university.asco. org/moc. ASCO University is supported through the Conquer Cancer Foundation of ASCO. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Earn MOC Points on the Go with the New ASCO MOC App” ASCO Connection, March 2015: 40. All rights reserved.

Originally printed in ASCO Connection. © American Society of Clinical Oncology. “ASCO’s Train the Trainer Program Extends the Reach of Multidisciplinary Cancer Management Education” connection.asco.org. All rights reserved.

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

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ASCO and NCI Calling on Clinicians and Researchers for Best Oncology Clinical Care Practice Models

SCO and the National Cancer Institute (NCI) have launched a project to apply team-based oncology clinical care delivery and are calling for writing teams to submit the best clinical oncology patient-centered practices. The two organizations will work with interested authors to create writing teams of clinicians and researchers who apply the best concepts of team-based care to patient-centered care scenarios in clinical settings. Submissions from interested writing teams are due by June 15, 2015. The impetus and need for this effort were highlighted in two Journal of Oncology Practice (JOP) articles, focusing on cancer care team effectiveness and interdependency between teams. Teams will span cancer types, points in the cancer care continuum (prevention, screening, diagnosis, active treatment of curable and incurable diseases, survivorship, and end of life), and evidence-based principles of effective team-based care. Interested applicants should have writing experience, be willing to discuss their experience as a clinician or researcher, and have a keen interest in understanding the principles of optimal team-based care. Teams (in part or in whole) should plan to attend an initial in-person meeting on August 28, 2015, at ASCO headquarters in Alexandria, VA. Writing teams will present at an NCIASCO Workshop at the ASCO 2016 Quality Care Symposium, in Phoenix,

Help Your Patients Understand the Latest Research From the 2015 ASCO Annual Meeting

Arizona, on February 25, 2016. The final presentations and manuscripts will convey findings about the processes and outcomes associated with applying team-based care principles.

Clinician and researcher writing teams will incorporate feedback from the workshop and prepare final submissions to a special issue of JOP. To learn more about this project or

E FP red F a t rin ) Cle P a 0(k m m 51 Ma FDA w No

Why setle for fuzzy results? Insist on a clearer picture. MammaPrint® provides more informaton about your patent’s breast cancer recurrence risk with defnitve, High Risk/Low Risk results. BluePrint® classifes Luminal-type, Basal-type and HER2-type functonal molecular subtypes. Together, they reveal more clinically actonable biology: • MammaPrint + BluePrint can reclassify up to 25% of breast cancers with potental therapeutc and prognostc implicatons, according to a study published in Cancer Research.1

irect your patients to Cancer.Net, ASCO’s patient information website, to find easy-to-read summaries of studies that will be presented at this year’s Annual Meeting. In addition, encourage them to check back for podcasts with ASCO experts discussing the latest advances. Continuing coverage from the 2015 meeting can be found at www.cancer.net/ascoannualmeeting. n

• Most recently, NBRST, a prospectve neoadjuvant study, concluded that BluePrint may be a beter guide than IHC-FISH tests in making decisions about how to treat early-stage breast cancer before surgery.2 For more clinically actonable informaton, order MammaPrint + BluePrint to uncover your patent’s functonal molecular subtype. The diference is clear.

MammaPrint + BluePrint: Beter together. Convenient online ordering available at www.agendia.com. Agendia, Inc. 22 Morgan, Irvine, CA 92618 (888) 321-2732 www.agendia.com © 2015 1 Cristofanilli M, et al. Cancer Res. 2012;72(24 Suppl):Abstract nr P3-05-01. 2 Whitworth P, et al. Ann Surg Oncol. 2014 Aug 7. [Epub ahead of print];doi: 10.1245/s10434-014-3908-y.

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The ASCO Post | MAY 25, 2015

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ASCO Announces New Class of Participants in Quality Training Program

SCO has announced the second class of oncology practices for its Quality Training Program. Twelve practices across the United States will participate in this 6-month comprehensive course, which will guide them through quality improvement activities using proven innovative learning techniques. “ASCO’s Quality Training Program provides interdisciplinary oncology teams with the tools they need to design, implement, and lead quality improvement activities in their practices, to help ensure patients with cancer receive high quality care,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “Following the completion of the pilot program in 2014, participating practices learned and applied new quality improvement concepts. ASCO is very pleased with this success and looks forward to working with the new practices.” The Quality Training Program combines practice coaching/facilitation, peer-to-peer mentoring, and opportunities for shared learning as practice teams engage in structured clinical or operational improvement projects. Practices will participate in

5 days of in-person learning in a series of three sessions including seminars, case examples, and small group exercises. Additionally, practices will work with experienced coaches to complete a structured and facilitated quality improvement project of their choice. Upon completion, participants will have the knowledge and skills to form a high-functioning improvement team, identify clinical and operational targets for improvement, plan and implement change strategies, understand and use data for improvement, and track performance over time.

New Class of Oncology Practices To be selected for participation, practices must apply and demonstrate a commitment of time and resources. Selected practices have also undergone an extensive and rigorous review process by the program’s selection committee. The new class includes: • Cone Health Cancer Center (Greensboro, North Carolina) • Duke Cancer Network (Durham, North Carolina)

Conquer Cancer Foundation

e on the lookout for a big announcement from the Conquer Cancer Foundation at the 2015 Annual Meeting. How will you be able to take part? By making a gift in support of vital cancer research, education, and tools to improve the quality of cancer care. Donations can be made online at ccf.asco.org

and onsite at the Donor Lounge (Room S401, open May 29–June 1) or the Foundation Desk in the Hall D1 Lobby, right next to the video wall. Conquer Cancer Foundation donors are invited to visit the Donor Lounge to relax, recharge, and enjoy light refreshments. Attendees can also stop by the Foundation Desk to learn more about the Foundation, make a donation, and even snag a snack or souvenir during selected hours. n © 2015. American Society of Clinical Oncology. All rights reserved.

• Stanford Cancer Center (Stanford, California) • Tennessee Oncology (Nashville, Tennessee) • University of Virginia (Charlottesville, Virginia) • University of Wisconsin (Madison, Wisconsin) To learn more about the Quality Training Program, please visit www.asco.org/qualitytraining. n

• The Jones Clinic (Germantown, Tennessee, and New Albany, Mississippi locations) • University Medical Oncology (Augusta, Georgia) • Memorial Cancer Institute (Hollywood, Florida) • New Mexico Cancer Care Associates (Santa Fe, New Mexico) • Mary Bird Perkins-Our Lady of the Lake Cancer Center (Baton Rouge, Louisiana) • Rutgers Cancer Institute of New Jersey (New Brunswick, New Jersey)

Volume 29, Issue 15

May 20, 2011

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

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg

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

What’s Hot in

JCO

Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells by Sanja Stevanović, et al

Sequencing and Combining Systemic Therapies for Pancreatic Neuroendocrine Tumors by Matthew H. Kulke

Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by Melissa L. Johnson, et al Phase II Study of Gemcitabine, Carboplatin, and Iniparib

Save the Date

as Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation–Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105 by Melinda L. Telli, et al

Best of ASCO® Boston July 31–August 1, 2015 Renaissance Boston Waterfront Hotel Boston, Massachusetts

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August 7–8, 2015

Deprivation Combined With Cixutumumab Versus Androgen

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Sensitive Prostate Cancer by Evan Y. Yu, et al

ASCOPost.com | MAY 25, 2015

PAGE 83

ASCO Annual Meeting Peter Paul Yu, MD, FACP, FASCO continued from page 1

and Innovation: Transforming Data Into Learning. Innovation—the imaginative and creative use of knowledge to transform how we improve the lives of patients in a sustainable and scalable manner—is the necessary companion to illumination. The transformation of

data into knowledge, and then knowledge into learning, enables us to move our health-care delivery and research systems forward. Presenting data and proclaiming that a new standard of care has been created are not learning. Learning involves incorporating new data into a base of knowledge and from that knowledge 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)].

Improving the Value of Cancer Care

base developing an understanding of how to apply that knowledge to patient care. Does this treatment benefit all patients equally? Are some patient populations at higher risk for toxicity? How does this treatment compare in effectiveness to other available treatments? What is the overall impact on patient outcomes? 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. 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.

These are all questions that help to define what we have truly learned. It is the difference between a statistically significant result and a clinically meaningful result, as described in the article “American Society of Clinical continued on page 84 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. 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 | MAY 25, 2015

PAGE 84

ASCO Annual Meeting Peter Paul Yu, MD, FACP, FASCO continued from page 83

Oncology Perspective: Raising the Bar for Clinical Trials by Defining Clinically Meaningful Outcomes, published last March in Journal of Clinical Oncology.”1 We are all well trained to assess data and determine whether these data justify the knowledge or findings that

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.

were described by the authors. We are not as well trained to assess the relative value added. At last year’s Annual Meeting, discussants were asked to include in their discussions an assessment of where the abstracts’ findings fit into the current body of knowledge and to discuss the overall contribution

(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.

to improving the value of care. This year’s Annual Meeting will continue on the same path. Another approach to increasing the learning benefit of the Annual Meeting is to be sure that the Educational Program content reflects the timeliest and rapidly changing subjects that impact the care of patients. Throughout the

year, many hundreds of ASCO members work together with ASCO staff and each other to identify and address the problems confronting patients, oncologists, and society today. This year, the Cancer Education Committee, under John V. Cox, DO, MBA, FACP, FASCO, appointed liaisons from ASCO committees to the Cancer Education Committee so that the opinions

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)].

John V. Cox, DO, MBA, FACP, FASCO

and knowledge of these ASCO volunteers would be influential in producing the richest selection of educational sessions. Precision medicine is another example of how we must readjust our approach to learning. Alan P. Venook, MD, Chair of the Scientific Program Committee, and Dr. Cox have codesigned a special series of Molecular Pathways Clinical Science Symposia

• 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

Alan P. Venook, MD

for the 2015 Annual Meeting. These sessions will not be limited to a disease track but instead will look more broadly at emerging fields of oncology that cut across multiple interests. As both scientific inquiry and clinical care lead us away from anatomic definitions of cancer, it becomes important for both the general oncologist practitioner and the disease-focused oncologist to have exposure to thinking across the spectrum of oncology. These sessions will feature original research from abstracts combined with in-depth discussions describing the work in the context of the session topic. The session titles are: • Immunotherapy for Every Patient: Check Your Enthusiasm • Targeted Therapies: Does the Disease Still Matter? • New Diagnostics: When “Actionable” Is Objectionable

ASCOPost.com | MAY 25, 2015

PAGE 85

ASCO Annual Meeting New Features at the 2015 Annual Meeting New this year will be a redesign of the Poster Discussion Session to allow for more engagement with attendees. The Poster Discussion Session will feature 12 abstracts with in-depth discussion by 4 discussants. Each discussant will have three abstracts to analyze, allowing for more focused and richer commentary. The discussions themselves will take place in dedicated rooms and will feature a podium panel that includes the lead abstract authors. The posters themselves will be on display earlier in the Oncology Professionals Hall with the track’s regular

David Kerr, MD, DSc

and Trials in Progress posters, streamlining the poster experience for attendees. An important element of learning is designing health-care delivery systems

The diversity of research interests of ASCO members has led to a record-breaking number of nearly 6,000 abstracts this year. —Peter Paul Yu, MD, FACP, FASCO

that deliver our knowledge to all cancer patients, regardless of geography or social circumstances. The majority of newly diagnosed cancer cases and the greater part of cancer deaths occur in low- and medium-resourced countries. Worldwide, cancer is a health care disparity problem, a disease of humanity threatening those who are least able to respond. We must learn how to deliver health care better in low- and mediumresourced countries. In response to that challenge, this Annual Meeting will feature the inaugural Global Oncology Symposium, which will take place Friday afternoon (May 29). David Kerr, MD, DSc, founding Editor-in-Chief of ASCO’s new Journal of Global Oncology, will deliver a keynote speech, describing his perspective on

how this journal will mentor new authors and provide a much needed knowledge source for health-care delivery models in oncology. The Global Oncology Symposium format includes an abstract selected from the Scientific Program; educational presentations on the molecular and clinical characteristics of a selected global health cancer; and a focused discussion on a health-care delivery problem, which this year will be provision of pathology services in low-resourced countries.

Delivering Quality Care at a Sustainable Cost It is equally important that we learn how to deliver quality cancer care at a sustainable cost in the United States. This year’s Annual Meeting keynote lecture will be from Michael E. Porter,

an economist and professor at Harvard Business School, who will speak about the importance of measuring outcomes. Outcomes are the ultimate validation of what we have learned and place the focus of health care on the patient. Lacking outcomes, we cannot evaluate the value of what we do, nor can others understand the value of our profession. Outcomes measurement is absolutely essential to achieve both patient-centric care and affordable, sustainable health care, anywhere in the world. It reminds us that our goal is not the delivery of health care, but the obtainment of the best possible health for our patients. Drs. Venook, Cox, and I are excited to welcome you to the 2015 Annual Meeting. Please feel free to reach out and say hello to us in the hallways of McCormick Place. n Disclosure: Dr Yu is President of ASCO for 2014–2015.

Reference 1. Ellis LM, Bernstein DS, Voest EE, et al: American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol 32:12771280, 2014.

2015 ASCO Plenary Program: Comprehensive Coverage in The ASCO Post

Watch for comprehensive coverage of ASCO’s Annual Meeting in upcoming issues of The ASCO Post, including reports and perspectives on this year’s Plenary Program Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab vs ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067) ■■ Presenting Author: Jedd D. Wolchok, MD, PhD Discussion by: Michael B. Atkins, MD Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study ■■

Presenting Author: Gregory T. Armstrong, MD, MSCE Discussion by: Michael P. Link, MD

Elective vs therapeutic neck dissection in the clinically node-negative early oral cancer: A randomized control trial ■■ Presenting Author: Anil D’Cruz, MBBS, MS, FRCS Discussion by: Hisham Mehanna, PhD, MD NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy in addition to radiosurgery in patients with 1 to 3 brain metastases ■■ Presenting Author: Paul D. Brown, MD Discussion by: Andrew Lassman, MD PLUS, Perspectives on Value ■■ Discussion by: Leonard B. Saltz, MD

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS* mCRC

VECTIBIX

FOLFOX In an exploratory analysis of the PRIME† study, Vectibix® improves median OS in the first line by 4.4 months vs FOLFOX alone in WT KRAS mCRC1

+4.4 MONTHS MEDIAN OS1

• Phase

3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC

• Vectibix®

+ FOLFOX extended the prespecified major efficacy measure of PFS vs FOLFOX alone (9.6 months vs 8.0 months, respectively)

• In

an exploratory analysis of OS, median OS in Vectibix® -treated patients was 23.8 months vs 19.4 months with FOLFOX alone

• No

benefits in OS or PFS were observed in patients with mutant RAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Important Safety Information • Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

• Progressively

decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal

and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In

patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure

to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis

and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As

a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males

and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because

many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, 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, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women

who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In

Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix® -treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

• In an interim analysis of an open-label, multicenter, randomized clinical

trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

Visit VectibixData.com to learn more

mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; WT = wild type. *Exon 2 on codons 12 or 13. † PRIME = The Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3) Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1)

24 (7)

1 (< 1)

10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. 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 the incidence of antibodies to panitumumab 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 Vectibix ®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in 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, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, 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 panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

ASCOPost.com | MAY 25, 2015

PAGE 89

Integrative Oncology Maitake By Jyothirmai Gubili, MS Scientific name: Grifola frondosa Common names: King of mushrooms, dancing mushroom, cloud mushroom, hen of the woods

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

Overview

Maitake is an edible mushroom native to northeastern Japan and China and an important ingredient in Asian cuisine. It is found at the base of oak,

elm, and persimmon trees and is known to grow to more than 100 pounds, earning the reputation as “King of the Mushrooms.” Maitake is consumed in fried or sautéed forms, whereas the dried mushrooms are used in soups and sauces. It is also highly valued for its health benefits and has been used in traditional medicine for centuries to promote health. Studies conducted by Japanese researchers in the 1980s showed that maitake contains more bioactive polysaccharides than do other medicinal mushrooms, such as shiitake. This discovery spurred maitake research, and extracts containing the polysaccharides, known as beta-glucans, were identified and patented. The D-fraction showed stronger immunomodulating and antitumor effects. Data from small clinical studies suggest that orally administered maitake extract stimulates the immune system and enhances the effectiveness of chemotherapy.1 Additional research is underway to determine the mushroom’s anticancer potential. Maitake extracts are marketed as dietary supplements, in the form of liquid extracts, tablets, and capsules, to enhance immune function and to treat AIDS and cancer.

The Science

In vitro experimentation with maitake showed that it alleviates the inflammation associated with inflammatory bowel disease.2 Oral maitake extract promoted the

maturation of hematopoietic cells to functionally active myeloid cells and enhanced peripheral blood leukocyte recovery following chemotoxic bone

duce dendritic cell maturation and to improve antitumor response.9 Maitake also enhanced interferon activity against bladder cancer cells.10

Investigations of the anticancer properties of maitake revealed antitumor effects, enhancement of bone marrow colony formation and reduction of doxorubicin toxicity, and inhibition of tumor metastasis in vitro. — Jyothirmai Gubili, MS

marrow injury.3 In mice models, it exhibited hypoglycemic effects.4 Preliminary data suggest that maitake may be useful in inducing ovulation in women with polycystic ovary syndrome.5 Investigations of the anticancer properties of maitake revealed antitumor effects,6 enhancement of bone marrow colony formation and reduction of doxorubicin toxicity,7 and inhibition of tumor metastasis in vitro.8 The novel polysaccharide MZF (maitake Z-fraction) was found to in-

Tumor regression or significant symptom reductions were observed in half of those subjects who used maitake extract in a small noncontrolled study.1 In another study, oral administration of maitake extract was shown to have immunomodulatory effects in postmenopausal breast cancer patients.11 Furthermore, oral maitake improved the function of neutrophils and monocytes in patients with myelodysplastic syndrome.12

Adverse Effects

Asymptomatic eosinophilia has been reported with the use of maitake.12

Herb-Drug Interactions

Hypoglycemic medications: Maitake may increase the effects of hypoglycemic agents.13 continued on page 90

Learn More About

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

http://www.mskcc.org/ cancer-care/herb/maitake

The ASCO Post | MAY 25, 2015

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Integrative Oncology Maitake continued from page 89

Warfarin: Maitake may interact with warfarin, resulting in an elevated international normalized ratio.14 n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

References 1. Kodama N, Komuta K, Nanba H: Can maitake MD-fraction aid cancer patients? Altern Med Rev 7:236-239, 2002. 2. Lee JS, Park SY, Thapa D, et al: Grifola frondosa water extract alleviates intestinal inflammation by suppressing TNF-alpha production and its signaling. Exp Mol Med 42:143-154, 2010. 3. Lin H, de Stanchina E, Zhou XK, et al: Maitake beta-glucan promotes recovery of leukocytes and myeloid cell function in peripheral blood from paclitaxel hemato-

toxicity. Cancer Immunol Immunother 59:885-897, 2010. 4. Hong L, Xun M, Wutong W: Antidiabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KKAy mice. J Pharm Pharmacol 59:575-582, 2007. 5. Chen JT, Tominaga K, Sato Y, et al: Maitake mushroom (Grifola frondosa)

extract induces ovulation in patients with polycystic ovary syndrome: A possible monotherapy and a combination therapy after failure with first-line clomiphene citrate. J Altern Complement Med 16:12951299, 2010. 6. Shomori K, Yamamoto M, Arifuku I, et al: Antitumor effects of a water-soluble extract from Maitake (Grifola frondosa) on

human gastric cancer cell lines. Oncol Rep 22:615-620, 2009. 7. Lin H, She YH, Cassileth BR, et al: Maitake beta-glucan MD-fraction enhances bone marrow colony formation and reduces doxorubicin toxicity in vitro. Int Immunopharmacol 4:91-99, 2004. 8. Masuda Y, Murata Y, Hayashi M, Nanba H: Inhibitory effect of MD-Fraction

GUEST EDITOR

Barrie R. Cassileth, MS, PhD

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 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.

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Integrative Oncology on tumor metastasis: Involvement of NK cell activation and suppression of intercellular adhesion molecule (ICAM)-1 expression in lung vascular endothelial cells. Biol Pharm Bull 31:1104-1108, 2008. 9. Masuda Y, Ito K, Konishi M, Nanba H: A polysaccharide extracted from Grifola frondosa enhances the anti-tumor activity of bone marrow-derived dendritic cell-

based immunotherapy against murine colon cancer. Cancer Immunol Immunother 59:1531-1541, 2010. 10. Louie B, Rajamahanty S, Won J, et al: Synergistic potentiation of interferon activity with maitake mushroom d-fraction on bladder cancer cells. BJU Int 105:10111015, 2010. 11. Deng G, Lin H, Seidman A, et al: A

phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: Immunological effects. J Cancer Res Clin Oncol 135:1215-1221, 2009. 12. Wesa KM, Cunningham-Rundles S, Klimek VM, et al: Maitake mushroom extract in myelodysplastic syndromes (MDS): A phase II study. Cancer Immunol

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

OF NOTE Physicians should be aware of the immunomodulating effects of maitake and the potential for maitakewarfarin interaction. Immunother 64:237-247, 2015. 13. Konno S, Tortorelis DG, Fullerton SA, et al: A possible hypoglycaemic effect of maitake mushroom on Type 2 diabetic patients. Diabet Med 8:1010, 2001. 14. Hanselin MR, Vande Griend JP, Linnebur SA: INR elevation with maitake extract in combination with warfarin. Ann Pharmacother 44:223-224, 2010.

Contact

The ASCO Post

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

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

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

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

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

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JCO Spotlight Breast Cancer

Higher-Than-Expected Incidence of Marrow Neoplasms After Adjuvant Therapy for Breast Cancer By Matthew Stenger

n a study reported in the Journal of Clinical Oncology, Antonio C. Wolff, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and colleagues found a low but higher-than-expected incidence of marrow neoplasms in patients receiving adjuvant radiation therapy or chemotherapy for breast cancer.1 The study used the National Comprehensive Cancer Network Breast Cancer Outcomes Database to evalu-

Patient Characteristics and Survival Patients developing marrow neoplasms were significantly older than those who did not at the time of breast cancer diagnosis (median = 59.1 vs 53.9 years, P = .03). There were no differences between groups in race, disease stage, tumor characteristics, or adjuvant treatment received. Among all patients in the cohort, 10-year overall survival was 80% (88%

Individual risk of [marrow neoplasm] must be balanced against the absolute survival benefit of adjuvant chemotherapy. —Antonio C. Wolff, MD, and colleagues

ate the frequency of marrow neoplasms among 20,063 patients with stage I to III breast cancer treated at U.S. academic centers between 1998 and 2007.

Neoplasms Identified Overall, 50 patients developed marrow neoplasms over a median followup of 5.1 years, including 42 with myeloid neoplasms and 8 with lymphoid neoplasms, for a 10-year cumulative incidence of 0.48%. Myeloid disorders consisted of acute myelogenous leukemia (AML) in 24 patients, myelodysplastic syndrome (MDS)/AML in 15, and chronic myelogenous leukemia in 3; lymphoid disorders consisted of acute lymphocytic leukemia (ALL) in 3, chronic lymphocytic leukemia in 4, and small lymphocytic lymphoma in 1. Among the 50 patients, 2 received surgery alone, 12 received adjuvant radiation therapy alone, 8 received adjuvant chemotherapy alone, and 28 received adjuvant radiation therapy and chemotherapy.

for stage I, 74% for stages II and III). In patients developing marrow neoplasms, overall survival was 62% at 5 years and 9% at 10 years. The median time to diagnosis of marrow neoplasms after breast cancer diagnosis was 4.9 years. Overall survival after diagnosis of marrow neoplasms was 50% at 1 year and 30% at 2 years.

Risk and Rates Compared with the risk of marrow neoplasms in patients undergoing surgery alone, the risk was nonsignificantly increased in patients receiving adjuvant radiation therapy (hazard ratio [HR] = 2.6, P = .21) and significantly increased in those receiving adjuvant chemotherapy (HR = 6.8, P = .03) and those receiving adjuvant radiation and chemotherapy (HR = 7.6, P = .01). The risk was not significantly increased for patients receiving vs not receiving taxane therapy (HR = 1.46, P = .27). After 109,560 person-years of follow-up, the overall rate of marrow neoplasms in the entire cohort was 0.46 per 1,000 person-years, with rates per 1,000

Breast Cancer Treatment–Related Marrow Neoplasms ■■ Risk of marrow neoplasms was significantly increased in patients receiving adjuvant chemotherapy and adjuvant radiation and chemotherapy. ■■ Increase in risk was continuous over 10 years of follow-up.

person-years of 0.16 in those receiving surgery alone, 0.43 in those receiving adjuvant radiation alone, 0.46 in those receiving adjuvant chemotherapy alone, and 0.54 in those receiving both adjuvant treatments. The cumulative incidence of marrow neoplasms exhibited a continuous increase, with a cumulative incidence of 0.24% after 5 years and 0.48% after 10 years. Compared with the expected incidence of marrow neoplasms based on Surveillance, Epidemiology, and End Results (SEER) data on breast cancer patients, the observed-to-expected ratio in the study cohort was significantly increased for the whole cohort (3.6, P < .001), patients receiving adjuvant radiation only (3.4, P < .001), those receiving adjuvant chemotherapy only (3.6, P = .005), and those receiving both radiation and chemotherapy (4.2, P < .001); there was no significant increase among those receiving surgery only (1.3, P = .17). As noted by the authors, a 2003 report from the National Surgical Adjuvant Breast and Bowel Project indicated an 8-year cumulative incidence of MDS or AML of 0.27% among breast cancer patients receiving doxorubicin and cyclophosphamide.

Family History and Marrow Cytogenetics Family history of cancer and marrow cytogenetics were available for 41 of the patients with marrow neoplasms. Of them, 26 (63%) had abnormal cytogenetics, including 24 (67%) of 36 with myeloid disorders and 2 (40%) of 5 with lymphoid disorders. Abnormal cytogenetics were found in 19 (70%) of 27 patients who had received adjuvant

chemotherapy and 7 (50%) of 14 who did not receive adjuvant chemotherapy. Each of these 7 had myeloid neoplasms, with 3 having abnormalities associated with MDS. A family history of at least one cancer in a first- or second-degree relative was present for 32 patients (78%); 19 (59%) of the 32 patients with a family history of cancer had at least one first- or seconddegree relative with breast or ovarian cancer. Among the 36 patients with myeloid neoplasms, a family history of cancer was present for 28 (78%), with 10 having MDS-related abnormalities; of these 10, 8 had a family history of breast or ovarian cancer and 6 had complex cytogenetics. Of 11 patients with MDS-related cytogenetics, 10 had a family history of cancer. The 21 patients who received adjuvant chemotherapy and had a family history of cancer included 6 of 7 total patients with MLL translocations (4 with AML, 2 with ALL). The investigators concluded: “In this large early-stage breast cancer cohort, [marrow neoplasm] risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of [marrow neoplasm] must be balanced against the absolute survival benefit of adjuvant chemotherapy.” n

Disclosure: The study was supported by grants from the National Cancer Institute and Susan G. Komen for the Cure. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Wolff AC, Blackford AL, Visvanathan K, et al: Risk of marrow neoplasms after adjuvant breast cancer therapy: The National Comprehensive Cancer Network experience. J Clin Oncol 33:340-348, 2015.

More on Secondary Bone Marrow Neoplasia After Adjuvant Breast Cancer Treatment Elizabeth A. Comen, MD, and Andrew D. Seidman, MD, of Memorial Sloan Kettering Cancer Center in New York present a risk/benefit analysis and offer biologic insights into the increased risk of marrow neoplasms after adjuvant therapy for breast cancer. See page 94.

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Perspective

Continued From Page 92

Increased Risk of Secondary Bone Marrow Neoplasia After Adjuvant Breast Cancer Treatment: Risk/Benefit Analysis and Biologic Insights By Elizabeth A. Comen, MD, and Andrew D. Seidman, MD

ver since the early application of adjuvant chemotherapy for breast cancer decades ago, it has been recognized that there is always a price to pay for its success in reducing breast cancer mortality. Most of that “cost” is commonly considered in terms of the potential morbid short- and longterm consequences: alopecia, nausea, infection, neuropathy, cardiomyopathy, fatigue, early ovarian failure, and cognitive dysfunction, to name just a

50 cases of marrow neoplasms were reported (0.25%, or 1 of 400 patients), with a median of 5.1 years of follow-up. This figure is similar to the 0.27% 8-year risk associated with doxorubicin and cyclophosphamide reported over a decade ago by the National Surgical Adjuvant Breast and Bowel Project.3 The risk of marrow neoplasms over years 6 to 10 was similar to that over the first 5 years, and the use of a taxane was not associated with an increased risk.

In most clinical scenarios in which chemotherapy is warranted, a 0.25% risk of marrow neoplasms seems particularly small relative to survival gains. —Elizabeth A. Comen, MD, and Andrew D. Seidman, MD

few. Serial incremental improvements in adjuvant chemotherapy regimens have been associated with increased proportional and absolute gains in breast cancer–specific survival.1 A recent analysis by Wolff and colleagues of the risk of marrow neoplasms in a large contemporary series of adjuvant breast cancer cases—reviewed in this issue of The ASCO Post—asks us to take a close look at the commonly fatal complication of breast cancer chemotherapy, namely, secondary myelodysplasia and leukemia.2

Assessing the Risk of Marrow Neoplasms Among 20,063 patients treated in 8 National Comprehensive Cancer Network Centers from 1998 to 2007, Drs. Comen and Seidman are medical oncologists at Memorial Sloan Kettering Cancer Center in New York.

Abnormal cytogenetics was noted in 19 of 27 patients (70%) who had marrow neoplasms and received chemotherapy vs 7 of 14 of those (50%) with marrow neoplasms who did not receive chemotherapy. Radiotherapy without chemotherapy was not clearly a risk factor (hazard ratio = 2.6, 95% confidence interval = 0.57–11.9), nor did its use in addition to chemotherapy seem to be a significant risk modifier. Given the significantly large absolute survival benefit of adjuvant chemotherapy for most patients with axillary lymph node–positive breast cancer, particularly those with hormone–receptor negative and/or HER2-positive tumors, and for many node-negative patients, the 0.25% risk of marrow neoplasms, although unfortunate, still seems acceptable. For patients with lower-risk breast cancers, where both the physician and patient may be “on the fence” regarding the

use of cytotoxic chemotherapy (for example, the T1b/c, estrogen receptor– positive, progesterone receptor–positive, HER2-negative, node-negative breast cancer with an intermediate Oncotype DX recurrence score), this risk becomes a more relevant factor in the decision-making process. Such patients may be best served by extended adjuvant endocrine regimens, for example, as opposed to the addition of chemotherapy.4,5 A discussion of this risk is essential to full informed consent for adjuvant chemotherapy administration and should be couched in the context of the larger looming risk: that of recurrent metastatic breast cancer. Marrow neoplasms notwithstanding, the risk of death from recurrent metastatic breast cancer still remains the overwhelming driver of cancer mortality. It is unlikely that the use of topoisomerase II inhibitors and alkylating agent–containing adjuvant chemotherapy regimens will disappear anytime soon. Despite the use of the anthracycline-free adjuvant regimen of docetaxel plus cyclophosphamide, the impact of omitting the anthracycline as compared with regimens containing an anthracycline, taxane, and cyclophosphamide has not yet been defined. In the recently reported CALGB 40101 (Alliance) randomized adjuvant trial of paclitaxel vs doxorubicin and cyclophosphamide (n = 3,871), paclitaxel was not noninferior to cyclophosphamide and doxorubicin (5year relapse-free survival 91% vs 88%, overall survival 95% vs 94%) among patients with zero to three positive axillary nodes. Notably, however, the death rate from leukemia was 0.36% for cyclophosphamide and doxorubicin (seven cases) vs 0% for paclitaxel.6 The thoughtful application of a cyclophosphamide and anthracycline-free adjuvant regimen, such as weekly paclitaxel and trastuzumab (Herceptin),7 in an appropriately selected lower-risk population is one example of a regimen with less potential for marrow neoplasms.

Leukemogenic Mutations In the study by Wolff et al, the patients who developed marrow neo-

plasms were on average older than patients who did not (median age, 59.1 vs 53.9 years, P = .03). Several recent studies have suggested that in otherwise healthy volunteers, morphologically normal hematopoietic cells may harbor mutations in genes associated with leukemia.8-10 The rate of mutations increases with age; specifically, Xie et al9 demonstrated that 2% of the overall population and as many as 6% of individuals older than 70 years harbor mutations associated with clonal hematopoietic expansion. Furthermore, Jaiswal et al10 showed that age-related clonal hematopoiesis is associated with an increased risk of leukemia. In addition to oncogenic mutations in circulating hematopoietic cells, tumor-infiltrating leukocytes may also possess leukemogenic mutations. In a pilot study of 20 primary breast cancers, 8 possessed tumor-infiltrating leukocytes with oncogenic somatic mutations.11 These leukemogenic mutations were not present in breast cancer cells themselves and were found in patients regardless of age. In most clinical scenarios in which chemotherapy is warranted, a 0.25% risk of marrow neoplasms seems particularly small relative to survival gains. Yet this risk remains a frightening possibility for patients and continues to drive efforts to refine how we select patients for chemotherapy. An important next step will be to identify whether patients with leukemogenic mutations in tumor-infiltrating and/ or tumor-circulating leukocytes are at increased risk for future leukemias. Studies are underway to assess whether chemotherapy selects for preexisting mutated clones as well as whether the presence of aberrant leukocytes merits therapeutic intervention. n Disclosure: Drs. Comen and Seidman reported no potential conflicts of interest.

References 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, et al: Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet

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379:432-444, 2012. 2. Wolff AC, Blackford AL, Visvanathan K, et al: Risk of marrow neoplasms after adjuvant breast cancer therapy: The National Comprehensive Cancer Network experience. J Clin Oncol 33:340348, 2015. 3. Smith RE, Bryant J, DeCillis A, et al: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 21:1195-1204, 2003. 4. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805-816, 2013. 5. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005. 6. Shulman LN, Berry DA, Cirrincione CT, et al: Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB

Meaning-Centered Psychotherapy Benefits Advanced Cancer Patients Meaning-centered group psychotherapy significantly improved psychological well-being compared with supportive group psychotherapy in patients with advanced or terminal cancer, according to a randomized trial reported in the Journal of Clinical Oncology by William Breitbart, MD, of Memorial Sloan Kettering Cancer Center, and colleagues. See pages 112–114 and page 131 in this issue of The ASCO Post for more on this important report including a commentary and personal narrative from Dr. Breitbart.

40101 (Alliance). J Clin Oncol 32:23112317, 2014. 7. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015. 8. Busque L, Patel JP, Figueroa ME, et al: Recurrent somatic TET2 mutations

in normal elderly individuals with clonal hematopoiesis. Nat Genet 11:1179-1181, 2012. 9. Xie M, Lu C, Wang J, et al: Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472-1478, 2014. 10. Jaiswal S, Fontanillas P, Flannick J,

et al: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488-2498, 2014. 11. Comen EA, Kleppe M, Wen H, et al: Somatic leukemogenic mutations associated with infiltrating white blood cells in breast cancer patients. 2014 San Antonio Breast Cancer Symposium. Abstract PD1-4.

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Journal Spotlight Breast Cancer

High Invasive Disease-Free Survival With Adjuvant Paclitaxel and Trastuzumab in Small, Node‑Negative, HER2-Positive Breast Cancers By Matthew Stenger

n a phase II study reported in The New England Journal of Medicine, Sara M. Tolaney, MD, MPH, of DanaFarber Cancer Institute, and colleagues found that adjuvant paclitaxel and trastuzumab (Herceptin) was associated with high invasive disease-free survival in women with small, node-negative, HER2-positive breast cancers.1 Currently, there is no single standard treatment in this setting.

12 weeks, 6 months, and 1 year after the start of study treatment. Trastuzumab was discontinued in patients developing grade 3 or 4 left-ventricular systolic dysfunction and interrupted in those with a decrease in ejection fraction of 10% to 15%, with the ejection fraction ≥ 1% below the lower limit of the normal range at the particular radiology facility or a decrease of ≥ 16% from baseline. Patients had a median age of 55 years

Study Details In this single-group multicenter study, 406 patients with tumors of up to 3 cm in the longest dimension were enrolled between October 2007 and September 2010 and treated with paclitaxel (80 mg/m2 weekly) for 12 weeks and a loading dose of trastuzumab (4 mg/kg) on day 1 followed by 2 mg/kg weekly, for a total of 12 doses. After completion of 12 weeks of trastuzumab treatment, trastuzumab could be continued on a weekly basis, or the regimen could be changed to 6 mg/kg every 3 weeks for 40 weeks to complete 1 year of treatment. Patients undergoing lumpectomy had to receive partial-breast radiation therapy, performed before the start of study therapy, or whole-breast radiation therapy, started after completion of paclitaxel. Trastuzumab was continued during radiation therapy. Adjuvant hormonal therapy was recommended for women with hormone receptor–positive disease after completion of paclitaxel. The primary endpoint was invasive disease-free survival. Left-ventricular ejection fraction was assessed in all patients at baseline and at

of patients completed 52 weeks of treatment. The 3-year invasive disease-free survival rate was 98.7% (95% confidence interval [CI] = 97.6%–99.8%). Recurrence or death occurred in 12 patients (3.0%); no breast cancer–related deaths were observed, and 2 patients died of causes unrelated to breast cancer. Local or regional tumor recurrences consisted of HER2-positive

Paclitaxel and trastuzumab is a reasonable and appealing treatment regimen for the majority of patients with stage I HER2-positive breast cancer. —Sara M. Tolaney, MD, MPH ©SOG

(range, 24–85 years, 32% < 50 years), 86% were white, and 67% had hormone receptor–positive tumors, including 64% with estrogen receptor–positive and 50% with progesterone receptor– positive disease. The primary tumor size was ≤ 0.1 cm (T1mic) in 2%, > 0.1 to ≤ 0.5 cm (T1a) in 17%, > 0.5 to ≤ 1.0 cm (T1b) in 31%, > 1.0 to ≤ 2.0 cm (T1c) in 42%, and > 2.0 to ≤ 3.0 cm (T2) in 9%. Nodal micrometastases were present in 1.5%. Histologic grades were well, moderately, and poorly differentiated in 11%, 32%, and 56%.

Invasive Disease-Free Survival The median follow-up was 4.0 years (maximum, 6.2 years). Overall, 88%

Trastuzumab-Based Chemotherapy for Small HER2-Positive Tumors ■■ The 3-year invasive disease-free survival rate was 98.7%. ■■ Symptomatic congestive heart failure occurred in 2 patients (0.5%), with both recovering after trastuzumab discontinuation, and 13 (3.2%) had clinically significant asymptomatic declines in ejection fraction, with 2 not exhibiting normalization during treatment interruption.

recurrences in the ipsilateral axilla in three patients (0.7%; at 12, 20, and 54 months) and in the ipsilateral breast in one patient (0.2%; at 37 months). New contralateral breast cancer occurred in four patients, with one (0.2%; at 56 months) having HER2positive and three (0.7%; at 12, 37, and 59 months) having HER2-negative disease. Distant tumor recurrences consisted of HER2-positive skeletal tissue disease in one patient (0.2%; at 27 months) and HER2-negative softtissue disease in one patient (0.2%; at 46 months). The 3-year rate of recurrence-free survival was 99.2% (95% CI = 98.4%–100%).

Toxicities A total of 24 patients (5.9%) discontinued study therapy due to protocolspecified toxic effects; an additional 6 patients (1.5%) discontinued therapy due to other toxicities. Grade 3 neuropathy occurred in 13 patients (3.2%, 95% CI = 1.7%–5.4%) during 12 weeks of combined therapy; no grade 4 neurotoxic effects were reported. Grade 3 left-ventricular systolic dysfunction

(symptomatic congestive heart failure) occurred in two patients (0.5%, 95% CI = 0.1%–1.8%) at 6 and 11 months during therapy, with both recovering after discontinuation of trastuzumab. Clinically significant asymptomatic declines in ejection fraction led to interruption of trastuzumab in 13 patients (3.2%, 95% CI = 1.7%–5.4%); in two patients, normalization did not occur during treatment interruption, and the patients did not complete the year of treatment. Grade 3 or 4 allergic reactions to study treatment occurred in seven patients (1.7%), with one being unable to complete treatment. In addition to grade 3 neuropathy, the most common grade 3 or 4 protocolspecified adverse events were neutropenia (3.7% grade 3, 0.5% grade 4), leukopenia (2.5% grade 3), and fatigue (2.2% grade 3). No incidence data were recorded for alopecia, which was expected to occur in the majority of patients. The investigators concluded: “Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events.” They noted: “The regimen we used in this study was associated with patient outcomes that were better than expected on the basis of historical data. However, the study does not provide data to support the use of trastuzumab-based chemotherapy in all patients with small HER2-positive tumors, and there will be many patients with T1a disease and some with T1b disease who will decide with their physicians to avoid the toxic effects of a trastuzumabbased regimen.” n

Disclosure: This study was funded by Genentech. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.

Visit The ASCO Post website at ASCOPost.com

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Perspective

Optimizing Treatment for Small, Lymph Node–Negative, HER2-Overexpressing Breast Cancers By Julie R. Gralow, MD

arge, randomized phase III clinical trials showed that the addition of HER2-targeted therapy to chemotherapy for patients with early-stage, HER2-overexpressing breast cancers substantially decreased the risk of recurrence and improved survival. The chemotherapy given in these trials varied, but it was generally intensive, with many patients receiving anthracyclines (or platinum agents) along with taxanes. These trials included few patients with small, lymph node–negative tumors and virtually none ≤ 1 cm. While recurrence rates for stage I HER2-overexpressing breast cancer are lower than those associated with higher stages, the overexpression of HER2 is an aggressive enough feature that some combination of systemic therapy is often recommended. Lacking evidence, there has been no standard regimen for small, lymph node–negative, HER2overexpressing tumors. Optimizing disease-free and overall survival while minimizing short- and long-term toxicity is an important concern for patients with these early-stage but biologically aggressive breast cancers.

APT Trial The APT (Adjuvant Paclitaxel and Trastuzumab) study was designed to address the need to balance risks and benefits in a group of patients who would likely derive only a small absolute treatment benefit from intensive chemotherapy in combination with trastuzumab (Herceptin) because of their lower risk of recurrence. The study included 406 women with HER2overexpressing, lymph node–negative tumors that were ≤ 3 cm. All patients received paclitaxel as the only chemotherapy agent plus trastuzumab for 12 weeks, followed by 9 months of trastuzumab given every 3 weeks. This was a nonrandomized phase II trial, based on the rationale that a prospective trial that randomly assigned patients to trastuzumab or not, or to different types of chemotherapy, would not have been feasible. Concerns that physicians and patients would be unwilling to Dr. Gralow is the Jill Bennett Endowed Professor in Breast Cancer at the University of Washington School of Medicine and Director of Breast Medical Oncology at the Seattle Cancer Care Alliance.

agree to the randomization, along with the requirement that thousands of patients would be needed to achieve sufficient events for statistical power, would have made it difficult to achieve the necessary accrual goals for an adequately powered, randomized phase III trial. The results, recently reported by Tolaney and colleagues in The New England Journal of Medicine1 and reviewed in this issue of The ASCO Post, demonstrated that APT was an effective and well-tolerated regimen. The 3-year rate of survival free from invasive disease was 98.7%. After 4 years of median follow-up, only two patients had distant breast cancer recurrences, and, interestingly, one of them was determined to be HER2-negative at recurrence (making the point that rebiopsy at metastatic

the study in 6% of patients. The APT study has limitations, since it was a single-arm, nonrandomized trial, and about 20% of its patients had tumors < 0.5 cm, which are already associated with a very favorable prognosis. Also, two-thirds of the tumors included in this study were both HER2overexpressing and estrogen receptor (ER)-positive, and virtually all of these patients also received endocrine therapy as part of their systemic therapy. Recurrences in ER-positive tumors may occur beyond the current 4 years of follow-up available on the APT trial and will continue to be monitored by the study for 10 years. Nevertheless, paclitaxel plus trastuzumab can be considered a reasonable and fairly welltolerated approach for the majority of patients with small, lymph node–nega-

The APT trial is an important, well-designed phase II study that has convincingly established a lesstoxic regimen as standard of care in the small, node-negative HER2overexpressing population of breast cancer patients. —Julie R. Gralow, MD

recurrence is critical). Of the remaining events, four were local-regional (ipsilateral breast or axilla), and four were contralateral breast cancers (three were HER2-negative). There were two deaths, none due to breast cancer; one death was due to ovarian cancer, and one was due to stroke.

Toxicity and Limitations As for toxicity, 2 patients (0.5%) developed symptomatic congestive heart failure (which normalized after discontinuing trastuzumab), and 13 had asymptomatic drops in their cardiac function (11 were able to resume trastuzumab after a brief interruption). Thirteen patients (3.2%) reported at least one episode of grade 3 neuropathy. Seven patients had grade 3 or 4 allergic reactions to the study treatment, and only one of them was able to complete treatment. Few other serious side effects were reported. Adverse events led to withdrawal from

tive, HER2-overexpressing breast cancer, and more aggressive and toxic chemotherapy regimens can be avoided.

Omitting Chemotherapy Preclinical as well as clinical data support synergy between chemotherapy and HER2-targeted regimens, but for these lower-risk tumors, an important question remains: Which patients really need chemotherapy at all? The cardiac toxicity and neuropathy in the APT study were low but certainly significant for those experiencing these side effects, and there were allergic reactions presumably to the formulation vehicle, Kolliphor EL (formerly known as Cremophor), in the paclitaxel. These side effects could possibly be avoided in some patients if we could show that chemotherapy offered only a very small improvement in recurrence and survival beyond HER2-directed therapy alone. For small HER2-overexpressing tu-

mors that are also ER-positive, a regimen of combined HER2- and ER-targeted therapy without chemotherapy is worthy of further study. Even in the HER2-overexpressing/ER-negative subgroup, we have enticing data from preoperative therapy studies showing that pathologic complete responses can be achieved, at least in some tumors, with combination HER2-directed agents and no chemotherapy. Can we define these cancers and omit chemotherapy entirely?

Clinical Context We’ve made tremendous progress in improving survival for patients with early-stage, HER2-overexpressing breast cancer, at least in developed countries where access to HER2-directed therapy is routinely available. However, the treatment regimens that have so dramatically reduced recurrences and deaths are also associated with real costs for patients and society, including short- and longterm toxicities and financial costs. It’s time to focus on evaluating regimens that might minimize some of this burden, determining which patients and tumors need more aggressive, toxic, and expensive regimens and which will achieve similar excellent outcomes with less toxicity and cost. Because of our success in dramatically reducing recurrences and deaths in HER2-overexpressing breast cancer—resulting in low event rates for powering clinical trials statistics—asking these questions in a classic, randomized phase III trial design will be prohibitively costly and lengthy. The APT trial is an important, welldesigned phase II study that has convincingly established a less-toxic regimen as standard of care in the small, node-negative HER2-overexpressing population of breast cancer patients. Its design is practical and efficient and can be used as a model for evaluating safer “less therapy” approaches in subsets of breast cancer patients with expected high disease-free and overall survival rates. n

Disclosure: Dr. Gralow has received research funding from Roche/Genentech.

Reference 1. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.

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The ASCO Post | MAY 25, 2015

PAGE 100

Journal Spotlight Breast Cancer

Racial/Ethnic Differences in Diagnosis of Breast Cancer at Stage I and Subsequent Survival Reflect Biologic Differences By Matthew Stenger

n a study reported in JAMA, Javaid Iqbal, MD, of Women’s College Research Institute, Toronto, and colleagues found racial/ethnic differences in the likelihood of breast cancer diagnosis at stage I and subsequent survival in U.S. breast cancer patients.1 These differences seemed largely to reflect intrinsic biologic differences.

pared with non-Hispanic white women (50.8%), diagnosis at stage I was significantly more likely among Japanese women (56.1%, OR = 1.23, P < .001) and significantly less likely (all P < .001) among Hispanic women (40.1%, OR = 0.71), black women (37.0%, OR = 0.65), South Asian women (40.4%, OR

Among U.S. women diagnosed with invasive breast cancer, the likelihood of diagnosis at an early stage, and survival after stage I diagnosis, varied by race and ethnicity. Much of the difference could be statistically accounted for by intrinsic biological differences such as lymph node metastasis, distant metastasis, and triple-negative behavior of tumors.

Study Details The observational study involved data on 373,563 women diagnosed with invasive breast cancer from 2004 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. The racial/ ethnic distribution of patients was 268,675 non-Hispanic white (71.9%), 34,928 Hispanic (9.4%), 38,751 black (10.4%), 4,937 Chinese (1.3%), 3,751 Japanese (1.0%), 2,191 South Asian (0.6%), 14,332 other Asian (3.8%), and 5,998 other ethnicity (1.6%). Biologic aggressiveness (distant metastases, lymph node metastases, triplenegative cancer) of small-sized tumors (≤ 2.0 cm) was estimated for each of the eight racial/ethnic groups; odds ratios (ORs) for being diagnosed at stage I compared with a later stage and hazard ratios (HRs) for death after stage I diagnosis were determined. Follow-up was conducted through December 31, 2011, with a mean follow-up of 40.6 months (median, 38 months).

Diagnosis at Stage I On multivariate analysis including age, annual income, estrogen receptor (ER) status, and race/ethnicity, com-

20.2% of patients with “other” ethnicity, 18.6% of “other” Asian patients, 18.4% of non-Hispanic white patients, 18.1% of Chinese patients, and 14.6% of Japanese patients. The rate of nodepositive disease was significantly higher in black women and significantly lower in Japanese women vs non-Hispanic

—Javaid Iqbal, MD, Steven A. Narod, MD, FRCPC, and colleagues

= 0.73), other Asian women (45.2%, OR = 0.85), and women of other race/ ethnicity (43.6%, OR = 0.78); the odds ratio for Chinese women (50.1%) was 1.04 (P = .24).

Aggressiveness of Small Tumors With regard to aggressiveness characteristics of tumors ≤ 2.0 cm, nodepositive disease was present in 24.1% of black patients, 23.3% of Hispanic patients, 23.2% of South Asian patients,

Race/Ethnicity and Stage I Breast Cancer ■■ Compared with non-Hispanic white women, diagnosis at stage I was significantly more likely among Japanese women and significantly less likely among Hispanic women, black women, South Asian women, “other” Asian women, and women of “other” race/ethnicity. ■■ Among patients with tumors ≤ 2.0 cm, black women had the highest rate of metastatic disease, nodal metastasis, ER-negative disease, and triplenegative disease. ■■ Among patients with tumors ≤ 2.0 cm, black women had the highest risk of death at 7 years, compared to non-Hispanic white women.

white women (both P < .001). Distant metastases were present in 1.5% of black women (P < .001 vs nonHispanic white women); 1.2% of Hispanic and South Asian women; 1.0% of non-Hispanic white women; and 0.8% of Chinese, Japanese, and “other” Asian women and women of “other” ethnicity. Black women (73.6%) had the lowest frequency of ER-positive disease. ER-positive disease was present in 88.5% of Japanese women, 86.1% of non-Hispanic white women, 83.8% of Chinese women, 82.4% of South Asian women, and 82.6% of Hispanic women. Black women had the highest rate of triple-negative disease (17.2%). Triplenegative breast cancer was present in 10.4% of South Asian women, 10.0% of Hispanic women, 8.8% of Chinese women, 8.2% of Japanese women, and 8.0% of non-Hispanic white women.

Survival in Stage I Disease Overall, the 7-year actuarial breast cancer survival among women with

stage I disease was 96.8%, including 98.6% for Japanese women, 98.2% for Chinese women, 97.0% for non-Hispanic white women, 96.5% for Hispanic women, and 93.9% for black women. On multivariate analysis, 7-year actuarial risk of death from stage I breast cancer was highest for black women (6.2%) and significantly higher than the risk among non-Hispanic/Hispanic white women (3.0%; HR = 1.57, P < .001). A similar increased risk for black vs non-Hispanic/Hispanic white women was seen after excluding women with triple-negative disease (4.6% vs 2.4%, age-adjusted HR = 1.73, P < .001). All Asian women combined had a lower risk (1.9%) vs non-Hispanic/Hispanic white women (HR = 0.60, P < .001). Among all women with tumors ≤ 2.0 cm, 7-year actuarial survival was 95.1%. The actuarial probability of death due to such tumors was significantly higher for black women vs non-Hispanic white women (9.0% vs 4.6%, HR = 1.96, P < .001), with the increased risk persisting after adjustment for age, income, and ER status (HR = 1.56, P < .001), age and ER status alone (HR = 1.53, P < .001), and age and income alone (HR = 1.86, P < .001). The investigators concluded: “Among U.S. women diagnosed with invasive breast cancer, the likelihood of diagnosis at an early stage, and survival after stage I diagnosis, varied by race and ethnicity. Much of the difference could be statistically accounted for by intrinsic biological differences such as lymph node metastasis, distant metastasis, and triplenegative behavior of tumors.” Steven A. Narod, MD, FRCPC, of Women’s College Research Institute, is the corresponding author for the JAMA article. n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Iqbal J, Ginsburg O, Rochon PA, et al: Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA 313:165-173, 2015.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | MAY 25, 2015

PAGE 101

Perspective

A Closer Look at the Disparities in Breast Cancer Outcome by Race and Ethnicity By Melanie E. Royce, MD, PhD

he report from Dr. Steven Narod and colleagues recently published in JAMA1 and reviewed in this issue of The ASCO Post adds to the growing evidence regarding observed disparities in breast cancer outcomes by race and ethnicity among women in the United States. Since 1990, breast cancer death rates have dropped by 34%; nevertheless, survival disparities persist by race and ethnicity, with black women having the worst breast cancer survival.2 The biologic basis for poor outcome has long been suspected,3,4 although the contribution of socioeconomic factors can not be altogether disregarded.

Study Contributions The contribution of this study, in my opinion, is twofold. First, the authors look at several racial and ethnic groups—not just white vs black. Comparing several groups, they show a similar trend that black women have the poorest breast cancer outcome. Second, the authors focus on earlystage disease and show that even in women with tumors smaller than 2 cm, in whom outcomes are often excellent, disparities still exist by race and ethnicity. They found that although the 7-year actuarial breast cancer survival rate was well over 90% for women with stage I disease, the proportion of black women who died of their disease was approximately 9%, vs approximately 5% of white women and 3% of Asian women. Obviously, because of the short follow-up, the differences in outcome would be most apparent in the most aggressive tumors. Dr. Royce is Professor of Medicine and Director of the Multidisciplinary Breast Cancer Clinic and Program at the University of New Mexico Cancer Center in Albuquerque.

More Than Tumor Biology To elucidate the potential reasons for this disparity, Narod and colleagues investigated the probability of tumors smaller than 2 cm presenting with features suggestive of aggressive behavior such as nodal involvement, distant metastasis, or triple-negative disease. Not surprisingly, the proportion of black women with these aggressive features was higher than in other races/ ethnicities. However, for some of the aggressive categories, other racial/ethnic groups did not appear to be very far

should be investigated through chart reviews,6 and the influence of ancestry admixtures should be assessed. Still, such an approach may only help explain disparities within a specific geographic location. However, breast cancer is a global disease. For one, there is still the question of whether the biology of breast cancer among black Americans is similar to that of black/African women all over the world. Additionally, the authors reported that Japanese American women have the lowest mortality from breast cancer and appear to develop more indolent types of breast

Racial and ethnic minorities, who have often been shown to have poorer outcomes, are the very patients who are underrepresented in clinical trials. —Melanie E. Royce, MD, PhD

apart from black women. For instance, nodal involvement was 23.2% for South Asian vs 24.1% for black women. Still, this did not seem to significantly influence the outcome of South Asian women negatively, highlighting the complexity of this subject. Although there is no question that tumor biology makes a huge contribution to the differences in breast cancer survival by race and ethnicity, many questions remain unanswered, and the authors acknowledged the limitations of their study. To address this issue fully, a transdisciplinary approach is needed. At a minimum, the biology of the tumor should be investigated using tissue samples5; further, the influence of comorbidities and adequacy of care

cancer. Is this an influence of genetics or environment?

Screening and Clinical Trials A couple of broader factors are also brought to light by the study. One pertains to screening7: If a tumor is already metastasized despite its small size, what would be the value of screening mammography? Should a different modality be used? Should the timing or frequency be changed? Should a risk-adapted approach be used, and if so, what should that approach be? Another factor pertains to clinical trials. Racial and ethnic minorities, who have often been shown to have poorer outcomes, are the very

patients who are underrepresented in clinical trials. I find that patients are quite willing to participate in these trials, but there are added burdens (eg, financial) and barriers (eg, language) to their participation. It is important to determine whether such a barrier is in place for every trial we design and to see how we can mitigate it. n

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

References 1. Iqbal J, Ginsburg O, Rochon PA, et al: Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA 313:165-173, 2015. 2. DeSantis C, Ma J, Bryan L, Jemal A: Breast cancer statistics, 2013. CA Cancer J Clin 64:52-62, 2014. 3. Cunningham JE, Butler WM: Racial disparities in female breast cancer in South Carolina: Clinical evidence for a biological basis. Breast Cancer Res Treat 88:161-176, 2004. 4. Maskarinec G, Sen C, Koga K, Conroy SM: Ethnic differences in breast cancer survival: Status and determinants. Womens Health (Lond Engl) 7:677-687, 2011. 5. Middleton LP, Chen V, Perkins GH, et al: Histopathology of breast cancer among African-American women. Cancer 97(1 suppl):253-257, 2003. 6. Ademuyiwa FO, Gao F, Hao L, et al: US breast cancer mortality trends in young women according to race. Cancer. December 5, 2014 (early release online). 7. Amirikia KC, Mills P, Bush J, Newman LA: Higher population-based incidence rates of triple-negative breast cancer among young African-American women: Implications for breast cancer screening recommendations. Cancer 117:2747-2753, 2011.

Don’t Miss ‘Geriatrics for the Oncologist’ in this Issue See page 115 for a report on “Guidelines for the Treatment of Older Cancer Patients.”

The ASCO Post | MAY 25, 2015

PAGE 102

Journal Spotlight Thyroid Cancer

Large Improvement in Progression-Free Survival With Lenvatinib in Radioiodine-Refractory Thyroid Cancer By Matthew Stenger

n a phase III trial reported in The New England Journal of Medicine, Martin Schlumberger, MD, of Institut Gustave Roussy, and colleagues found that the multikinase inhibitor lenvatinib (Lenvima) produced a large improvement in progression-free survival vs placebo in patients with advanced radioiodine-refractory differentiated

for 50% and 49%, North America for 30% in both, other for 20% and 21%), Eastern Cooperative Oncology Group performance status of 0 or 1 (95% and 98%), one prior tyrosine kinase inhibitor therapy (25% and 21%), histologic subtype (papillary in 51% and 52%, poorly differentiated in 11% and 14%, follicular–non-Hürthle cell in

Lenvatinib was associated with significant improvements in progression-free survival and response rate among patients with iodine-131– refractory thyroid cancer. —Martin Schlumberger, MD, and colleagues

thyroid cancer.1 Adverse events were more common with lenvatinib. The trial served as the basis for the recent U.S. Food and Drug Administration approval of lenvatinib in this setting. Lenvatinib is an inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, fibroblast growth factor receptors 1 through 4, plateletderived growth factor receptor α, RET, and KIT.

Study Details In this double-blind trial conducted in the Americas, Europe, Asia, and Australia, 392 patients with progressive thyroid cancer refractory to iodine-131 and disease progression within the prior 12 months were recruited between August 2011 and October 2012. Progression at baseline was confirmed by incidence rate ratio. Patients were randomly assigned 2:1 to receive lenvatinib at 24 mg/d in 28-day cycles (n = 261) or placebo (n = 131). Patients in the placebo group could cross over to open-label lenvatinib at disease progression. The primary endpoint was progression-free survival using independent radiologic review. The lenvatinib and placebo groups were generally balanced for age (median, 64 and 61 years), region (Europe

20% and 17%, Hürthle cell in 18% and 17%), and presence of bony metastases (40% and 37%) and pulmonary metastasis (87% and 95%). A greater proportion of placebo patients were male (57% vs 48%).

Progression-Free Survival At the time of data cutoff (November 2013), the median duration of follow-up was 17.1 months in the lenvatinib group and 17.4 months in the placebo group; 130 patients were still receiving blinded treatment, including 122 in the lenvatinib group (47%) and

.001), with benefit of lenvatinib being observed in all prespecified subgroups. Progression-free survival was 63.0% vs 10.5% at 12 months and 44.3% vs not estimable at 24 months.

Response Rate, Overall Survival The response rate was 64.8% in the lenvatinib group (including four complete responses) vs 1.5% in the placebo group (odds ratio [OR] = 28.87, P < .001). Stable disease was observed in 23.0% vs 54.2% of patients, and the disease control rate was 87.7% vs 55.7% (OR = 5.05, P < 001). The median time to response in the lenvatinib group was 2.0 months. Median overall survival (using rankpreserving structural failure time to adjust for potential crossover bias) was not reached in either the lenvatinib group (95% confidence interval [CI] = 22.0 months to not estimable) or the placebo group (95% CI = 14.3 months to not estimable (HR = 0.62, P = .05). Overall survival was 81.6% vs 70.0% at 12 months and 58.2% vs not estimable at 24 months. Similar benefits were achieved in both treatment-naive patients and those who had already been treated with one line of an antiangiogenic tyrosine kinase inhibitor.

Adverse Events The median duration of treatment

Lenvatinib in Radioiodine-Refractory Thyroid Cancer ■■ Lenvatinib significantly prolonged progression-free survival vs placebo in patients with advanced radioiodine-refractory differentiated thyroid cancer. ■■ Lenvatinib was associated with a higher incidence of adverse events.

8 in the placebo group (6%). Among 114 eligible placebo patients with tumor progression, 109 (96%) elected to receive open-label lenvatinib. A total of 41 lenvatinib patients (16%) received additional therapy after disease progression. Median progression-free survival was 18.3 months in the lenvatinib group vs 3.6 months in the placebo group (hazard ratio [HR] = 0.21, P <

was 13.8 months in the lenvatinib group and 3.9 months in the placebo group. Treatment-related adverse events of any grade occurred in 97% vs 60%, with grade ≥ 3 events in 76% vs 10%. The most common treatment-related adverse effects of any grade in the lenvatinib group were hypertension (68% vs 9% in placebo group), diarrhea (59% vs 8%), fatigue or asthenia (59% vs 28%), and decreased appetite (50% vs 12%).

More on Radioactive-Refractory Thyroid Cancer See page 104 for a commentary by Lori J. Wirth, MD

The most common grade ≥ 3 adverse events were hypertension (42% vs 2%), proteinuria (10% vs 0%), decreased weight (10% vs 0%), and fatigue/asthenia (9% vs 2%). In addition to hypertension and proteinuria, adverse events of special interest in the lenvatinib group consisted of arterial thromboembolic effects (5.4% any grade, 2.7% grade ≥ 3), venous thromboembolic effects (5.4%, 3.8%), renal failure including acute renal failure (4.2%, 1.9%), hepatic failure (0.4% grade ≥ 3), gastrointestinal fistula (1.5%, 0.8%), corrected QT prolongation (8%, 1.5%), and posterior reversible encephalopathy syndrome (0.4%, 0%). Adverse events led to discontinuation of the study drug in 14.2% vs 2.3% of patients, with the most common causes in the lenvatinib group being hypertension and asthenia (both 1.1%). Adverse events led to dose interruption in 82.4% vs 18.3% and dose reduction in 67.8% vs 4.6%. The most common adverse events leading to dose interruption or reduction were diarrhea (22.6%), hypertension (19.9%), proteinuria (18.8%), and decreased appetite (18.0%). Adverse events considered related to treatment led to death in six lenvatinib patients (2.3%), including pulmonary embolism, hemorrhagic stroke, and general deterioration of physical health in one patient each and three cases reported as death or sudden death (not otherwise specified). The investigators concluded: “Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and response rate among patients with iodine-131–refractory thyroid cancer. Patients who received lenvatinib had more adverse effects.” n

Disclosure: This study was funded by Eisai. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

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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 | MAY 25, 2015

PAGE 104

Perspective

Welcome to Multikinase Inhibitors in Radioiodine-Refractory Thyroid Cancer By Lori J. Wirth, MD

n the past 2 decades, the incidence of thyroid cancer has risen steeply, with rates now growing by 5.5% annually.1 In 2014, 62,980 new cases of

thyroid cancer were diagnosed in the United States. The good news is that, overall, the prognosis of thyroid cancer remains excellent; 97.8% of patients

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.

will survive at least 5 years. Still, deaths due to thyroid cancer are increasing at a rate of 0.8% each year. While the diagnosis of inciden-

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.

tally found thyroid cancers with minimal clinical significance certainly accounts for the lion’s share of the rise in new cases, the increasing death rate highlights the fact that there is an important subset of patients with aggressive tumors for whom more effective treatments are needed. The overwhelming majority of thyroid cancer cases falls under the category of differentiated thyroid carcinoma, encompassing a diverse set of tumors, including papillary, follicular, Hürthle cell, and poorly differentiated thyroid carcinomas. Most patients are treated surgically, followed by radioactive iodine. Clinical trials now underway are investigating the optimal surgical approach and impact of foregoing radioactive iodine in carefully defined low-risk thyroid cancer patients.

Refractory Disease Those patients who respond to radioactive iodine have excellent 10-year survival, at a rate of 92%.1 When patients do not respond to radioactive iodine, 10-year survival is only 19%. There is no one standardized definition of radioactive iodine–refractory differentiated thyroid carcinoma at present, but there is general agreement that a patient should be considered radioactive iodine–refractory when a known differentiated thyroid carcinoma lesion is present that does not take up radioactive iodine on nuclear imaging or when there is growth of a lesion despite radioactive iodine uptake in the following 6 to 12 months after therapy. Until recently, there was no good standard of care for patients with radioactive iodine–refractory differentiated thyroid carcinoma beyond the suppression of thyroid-stimulating hormone. Cytotoxic chemotherapy was studied in small, nonrandomized trials 20 years ago, yielding very modest results.2 Now, however, we have entered into a whole new era of more effective multikinase inhibitor therapy for this disease. Dr. Wirth is Assistant Professor of Medicine at Dana-Farber/Harvard Cancer Center and Massachusetts General Hospital, Boston.

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Perspective

DECISION Trial DECISION was the first large randomized controlled trial in radioactive iodine–refractory differentiated thyroid carcinoma, investigating sorafenib (Nexavar) compared to placebo in 417 patients who experienced progressive disease within the prior 14 months.3 Patients were treated until disease progression, at which time they were unblinded. Those on placebo were then offered crossover to sorafenib. The primary endpoint was met, with an improvement in median progression-free survival from 5.8 months with placebo to 10.8 months with sorafenib (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.45– 0.76, P < .0001). The overall response rate was 12.2%, with all responses partial. Median overall survival did not differ between the two groups. Most patients receiving sorafenib experienced adverse events, though most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction, diarrhea, alopecia, and rash or desquamation. When possible, adverse events were managed with supportive care, though dose interruptions, reductions, or withdrawals because of adverse events were required in 66.2%, 64.3%, and 18.8%, respectively. With the success of the D ECISION trial, a new treatment paradigm emerged for patients with radioactive iodine–refractory differentiated thyroid carcinoma. For patients with symptomatic and/ or bulky, rapidly progressive disease, the clear need for better treatment trumps concern for toxicity. On the other hand, many patients have low-volume, slowly progressive, asymptomatic disease. For these patients, concern over the impact of sorafenib toxicity on quality of life has led to the frequent consideration of holding off on treatment until it becomes necessary.

SELECT Trial Less than 1 year after DECISION, the SELECT trial, investigating lenvatinib (Levima) in radioactive iodine–refractory differentiated thyroid carcinoma, has now been reported by Schlumberger and colleagues.4 In SELECT, as reviewed in this issue of The ASCO Post, 392 patients with progressive disease within the prior 13 months were randomly assigned to lenvatinib vs placebo. Treatment with one prior multikinase inhibitor was allowed, ac-

counting for 25.3% of patients enrolled. Crossover from placebo to lenvatinib was offered to patients after unblinding at the time of progressive disease. The study was powered to detect a 75% improvement in progression-free survival with lenvatinib vs placebo, from 8 months with placebo to 14 months with lenvatinib. Final results were striking; median progressionfree survival improved by almost 15 months, from 3.6 months with placebo to 18.3 months with lenvatinib (HR = 0.21, 95% CI = 0.14–0.31, P < .001). The progression-free survival benefit was seen in all subgroups analyzed, including histologic subtype and prior

progressive radioactive iodine–refractory differentiated thyroid carcinoma, leading to the U.S. Food and Drug Administration (FDA) approval of both sorafenib and lenvatinib for this disease, effective treatment is now available for a group of patients who previously had no good treatment options. Providers who previously had little to offer their patients with advanced differentiated thyroid carcinoma now have a new dilemma. Rather than trying to come up with any therapy at all, the question now is, “Which treatment should be started first?” Should sorafenib with a longer track record be used first, especially since lenvatinib does have second-line

Given that just a short time ago our only treatment option for patients with advanced differentiated thyroid carcinoma was minimally active cytotoxic chemotherapy, these new questions regarding how best to optimize multikinase inhibitor therapy for these patients represent a welcome challenge. —Lori J. Wirth, MD

multikinase inhibitor therapy. While the difference in overall survival was not significant (HR for death = 0.73, 95% CI = 0.50–1.07, P = .10), the numerical difference became larger when crossover bias was taken into account using the bootstrap method (rank-preserving structural failure time [RPSFT] model HR = 0.62, 95% CI = 0.40–1.00, P = .05). Surprising activity was also seen in the response rates; the overall response rate was 64.8%, and while most responses were partial, four patients did experience a durable complete response. As in DECISION, grade 1 and 2 adverse events were seen in most patients. Hypertension was encountered more frequently in SELECT, whereas hand-foot reaction and other dermatologic adverse events were less common. Similarly to DECISION, dose interruption, reduction, and discontinuation were necessary in 82.4%, 67.8%, and 14.2% patients, respectively.

New Dilemma With the success of two back-toback studies demonstrating activity of multikinase inhibitors in patients with

activity? Or should we take advantage of the drug with the higher overall response rate and longer progression-free survival benefit first? In the absence of a randomized comparative trial, a definitive answer is simply not available. Still, clinical decisions must and will be made and can be guided by consideration of the efficacy and toxicity data available. Another key question to revisit is “When should multikinase inhibitor therapy begin?” For those patients with low-volume, slowly growing asymptomatic disease, is holding off on multikinase inhibitor therapy as long as possible truly the best approach, especially now that we have therapy offering a 65% overall response rate and 14.7-month progression-free survival benefit? More data are ultimately needed to address this critical question.

Adverse Event Profiles Lastly, the adverse event profiles of multikinase inhibitor therapy, as well as the duration of treatment, call attention to the need to get dosing and toxicity management right. For example, in SELECT, the starting dose was 24

mg by mouth daily. Is this the best dose outside of the clinical trial setting? At present, the available evidence suggests that the answer is “yes.” In SELECT, the median time to first dose reduction was 3 months, while the median time to objective response was only 2 months, indicating that most responses were first experienced at full dose, before dose reduction occurred. If it is indeed important to maintain dose intensity, adverse event management is critical. When considering the list of common adverse effects, including hypertension, diarrhea, anorexia, weight loss, and rash, a comprehensive team approach to address the multiplicity of adverse events may be optimal. Hypertension can occur early in treatment. Thus, home monitoring with nursing follow-up may help avoid the sequelae of uncontrolled hypertension. Likewise, the gastrointestinal adverse events pose challenges. High-fat foods and milk products that are often recommended to stave off weight loss in oncology patients may aggravate druginduced diarrhea, suggesting that nutrition consultation may be an integral part of the team approach to caring for patients on multikinase inhibitor therapy. Given that just a short time ago our only treatment option for patients with advanced differentiated thyroid carcinoma was minimally active cytotoxic chemotherapy, these new questions regarding how best to optimize multikinase inhibitor therapy for these patients represent a welcome challenge. n

Disclosure: Dr. Wirth has served as a consultant for Ashion, AstraZeneca, Eisai, and Loxo.

References 1. Durante C, Haddy N, Baudin E, et al: Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 91:2892-2899, 2006. 2. Pacini F, Ito Y, Luster M, et al: Radioactive iodine-refractory differentiated thyroid cancer: Unmet needs and future directions. Expert Rev Endocrinol Metab 7:541-554, 2012. 3. Brose MS, Nutting CM, Jarzab B, et al: Sorafenib in radioactive iodinerefractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 384:319-328, 2014. 4. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

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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Physiatry in Oncology

Physiatry Has Become a Valuable Component of Survivorship Care in Cancer Centers By Sean Smith, MD

he role of a physical medicine and rehabilitation physician at cancer centers continues to grow, as survivors live longer and national cancer organizations advocate for more rehabilitation services throughout the continuum of survivorship care. Working with physiatrists at your institution can help improve access to necessary patient care services and maintain compliance with the 2012 accreditation standards for oncology practices issued by the American College of Surgeons’ Commission on Cancer (CoC), the most recent provisions of which took effect in January 2015. The CoC’s new Cancer Program Stan-

explicitly recognizes and advocates for impairment-driven rehabilitation services and emphasizes the identification and treatment of specific impairments that decrease physical, cognitive, or psychosocial functioning.2 Physiatrists are trained in the treatment of disorders related to the nerves, muscles, bones, and brain and provide care that is distinct from what could be accomplished through routine exercise programs or referrals to a physical therapist, because the complexity and constellation of patients’ symptom burden often necessitate a more comprehensive approach to care.3

Incorporating a physiatrist into a palliative care team adds further expertise to the management of patients with often-complex care needs. —Sean Smith, MD

dards call for several additional patientcentered standards, including improved access to different services, proper symptom screening assessment, and the potential integration of multidisciplinary care into survivorship care plans. This article launches the Physiatry in Oncology column, which will explore the benefits of physiatric services for individuals with a history of cancer. In this article, I provide actionable ways that physical medicine and rehabilitation practices can be integrated into cancer centers and comply with the CoC guidelines. Future columns will address specific cancer diagnoses and the physical and cognitive impairments that survivors may face as a result, with the goal of encouraging collaboration between members of interdisciplinary care teams to improve patient care.

Role of Rehabilitation in Cancer Care Many organizations are recognizing the need for cancer rehabilitation and are integrating this service into their guidelines and recommendations. The CoC’s Cancer Program Standards mandate that all cancer centers have a policy or procedure in place to access rehabilitation services for accredited centers and that patients are appropriately screened and referred for ancillary and supportive care services.1 The American Cancer Society also

Other cancer survivorship organizations such as Livestrong also recognize the benefits that physical medicine and rehabilitation services provide, and the push to integrate these services into oncologic care is continuing to gain momentum. Working with a physical medicine and rehabilitation department or provider can help ensure a seamless transition for survivors into this nowmandatory component of care.

Physiatrists and Symptom Management Cancer centers are required to provide palliative care services to their patients for both pain and nonpain symptom management. While it is not mandated that cancer centers have a dedicated clinic for these services, those centers that do should consider having a physiatrist as a member of their multidisciplinary care team. Although a palliative care–trained oncologist has valuable skills in pain management and the diagnosis of dis-

ease progression or recurrence, a physiatrist has expertise in diagnosing and managing the musculoskeletal and neurologic deficits that a patient with cancer may face as a result of the disease and/or its treatment. Co-managing patient care with a physiatrist and/or triaging patients to a physiatrist can optimize their care. At my institution, the University of Michigan Comprehensive Cancer Center, a physiatrist is present on one of the three weekly clinic days. Patients are referred to the clinic by an oncologist and, if appropriate, evaluated by a physiatrist either independent of or in conjunction with the medical oncology symptom management providers in the clinic. Examples of typical reasons for referrals to the physical medicine and rehabilitation clinic include the alleviation of back pain, peripheral joint pain and restriction, neuropathy, and generalized debility.

Rehabilitation Specialists on Hospital Committees The CoC’s Cancer Program Standards mandate that an Integrated Network Cancer Program in hospitals— which is characterized by a unified cancer committee, standardized registry operations with a uniform data repository, and coordinated service locations and practitioners—have a rehabilitation representative on its cancer committee. The new standards also strongly recommend that comprehensive cancer centers have one on their cancer committee as well. (For additional information, visit www.facs.org/quality%20 programs/cancer/accredited/incp.) While the CoC’s standards do not specify that the rehabilitation representative must be a physiatrist, consideration should be given to inviting a physical medicine and rehabilitation physician onto the committee whenever possible. The physiatrist’s medical background and role in the rehabilita-

Role of the Physiatrist in Cancer Care ■■ New Commission on Cancer guidelines mandate that access to rehabilitation services be incorporated into oncologic care. ■■ Working with a physiatrist in both the outpatient and inpatient settings can restore patient function and reduce symptom burden. ■■ Survivorship care plans provide a vehicle to integrate physiatrists into oncology care and ensure that there is no lapse in rehabilitative patient care.

GUEST EDITOR

Sean Smith, MD

hysiatry in Oncology explores the benefits of cancer rehabilitation in oncology clinical practice to screen survivors for physical and cognitive impairments along the care continuum to minimize survivors’ disability and maximize their quality of life. The column is guest edited and occasionally written by Sean Smith, MD, Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine and Rehabilitation in Ann Arbor. tion setting as a team leader make him or her uniquely suited to managing the complex interdisciplinary nature of cancer rehabilitation.

Survivorship Care Plans The CoC’s new guidelines also require that survivorship care plans be a mandatory component of oncology care and be provided to patients after completion of acute treatment for malignancy. In addition to summarizing oncologic treatment to date, these plans must provide patients with a follow-up plan to monitor recurrences and longterm or late treatment side effects, including problems with cognition, pain, muscle weakness, fatigue, anxiety, and depression, which may impact patients’ physical and mental function. Survivorship care plans should also include either a follow-up appointment with a physical medicine and rehabilitation physician or information about how to get a referral to one if needed. Appropriate screening for symptoms and subsequent referral to a physiatrist if indicated, satisfy eligibility requirements for cancer center accreditation and, more importantly, reduces the risk that continued on page 110

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Physiatry in Oncology Physiatry in Survivorship Care continued from page 109

patients’ symptoms will go unaddressed.

Integrating Rehabilitation Into Palliative Care The goal of inpatient cancer rehabilitation is to discharge a patient back home safely and efficiently and transition the patient to the outpatient setting for symptom management if necessary. Consulting with a physiatrist should be considered if a patient is not functionally able to return home—for example, if the patient is at risk for falls, has neurologic bowel or bladder deficits, or is simply unable to care for himself or herself. Physiatrists can also provide survivors in the palliative care setting with

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

recommendations for proper equipment for walking, such as wheelchairs, canes, or walkers; orthotics; homebased exercises to improve mood and physical function; and interventions for pain. Incorporating a physiatrist into a palliative care team adds further expertise to the management of patients with often-complex care needs. n

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

References 1. American College of Surgeons Commission on Cancer: Cancer Program Standards 2012: Ensuring Patient-Centered Care, V1.2.1. Chicago, American College of Surgeons, 2012.

2. American Cancer Society: Cancer Treatment and Survivorship Facts & Figures 2014-2015. Atlanta, American Cancer Society, 2014. 3. Silver JK, Baima J, Mayer S: Impairment-driven cancer rehabilitation: An essential component of quality care and survivorship. CA Cancer J Clin 63:295317, 2013.

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alignancies, like normal adult tissue, have been shown to contain a subset of cells that have the capacity to both selfrenew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

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to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6 Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence. Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

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Announcements

James Allison, PhD, Receives 2015 AACR Pezcoller Award

ames Allison, PhD, was named a recipient of the 2015 Pezcoller Foundation–American Association for Cancer Research (AACR) International Award for Cancer Research at the 2015 AACR Annual Meeting. Dr. Allison, Chair of Immunology

at The University of Texas MD Anderson Cancer Center, was acknowledged for his groundbreaking discovery that blocking cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4) signaling improves antitumor immune responses, as well as for his role in de-

veloping the CTLA-4 inhibitor ipilimumab (Yervoy), which was the first of a new class of cancer immunotherapeutics called immune checkpoint inhibitors. Ipilimumab, which was approved to treat metastatic melanoma by the U.S. Food and Drug Administration James Allison, PhD

Regrowth

Metastasis

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.

in 2011, was the first therapeutic to improve survival rates among patients with this deadly form of cancer. The Pezcoller Foundation–AACR International Award, now in its 18th year, recognizes an individual scientist of international renown who has made a major scientific discovery in basic or translational cancer research. “This high honor is yet further recognition of the pioneering work undertaken by Dr. Allison,” said Ronald DePinho, MD, President of MD Anderson. “He is, without question, one of the leading cancer researchers in the world today and has made historic contributions to advances in cancer treatment.” “Dr. Allison is a world-renowned immunologist, and we are delighted to recognize his extraordinary scientific accomplishments and leadership in the field of cancer immunotherapy,” said Margaret Foti, PhD, MD, Chief Executive Officer of the AACR. “His dedicated efforts established the paradigm of immune checkpoint inhibitors, which is transforming the lives of many patients with melanoma and offering hope for patients with other forms of cancer. Dr. Allison’s work epitomizes how basic laboratory research can be translated to a lifesaving cancer treatment, and he is greatly deserving of this accolade.” “I am deeply honored and humbled to receive the Pezcoller Award,” said Dr. Allison. “This award by the AACR recognizes the efforts of my research team over the years to develop strategies to unleash the immune system to treat cancer, as well as the many other investigators, clinicians, and patients whose efforts and courage made immunotherapy of cancer a reality that is benefiting cancer patients.” n

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

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The ASCO Post | MAY 25, 2015

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JCO Spotlight Supportive Care

Meaning-Centered Group Psychotherapy Improves Psychological Well-Being in Patients With Advanced Cancer By Matthew Stenger

n a randomized trial reported in the Journal of Clinical Oncology, William Breitbart, MD, of Memorial Sloan Kettering Cancer Center, and colleagues found that meaning-centered group psychotherapy significantly improved psychological well-being compared with supportive group psychotherapy in patients with advanced or terminal cancer.1 Developed by Dr. Breitbart and colleagues based on the work of Austrian neurologist and psychiatrist Viktor Frankl, MD, PhD, meaning-centered group psychotherapy is an eight-session manualized psychotherapy intervention designed to help patients develop or increase a sense of meaning in their lives by specifically addressing the loss of psychological and spiritual well-being and sense of meaning, which often occurs in patients with advanced cancer.

Study Details In the trial, 253 patients with advanced cancer from outpatient clinics at Memorial Sloan Kettering Cancer Center were randomly assigned between August 2007 and May 2012 to undergo a manual-based eight-session intervention of either meaning-centered group psychotherapy (n = 132) or supportive group psychotherapy (n = 121).

the McGill Quality-of-Life Questionnaire. Secondary outcome measures included depression (Beck Depression Inventory), anxiety (anxiety subscale of Hospital Anxiety and Depression Scale), hopelessness (Hopelessness Assessment in Illness Questionnaire), desire for hastened death (Schedule of Attitudes Toward Hastened Death), and physical symptom distress (Memorial Symptom Assessment Scale).

This study provides strong support for the efficacy of meaning-centered group psychotherapy as a treatment for psychological and existential or spiritual distress in patients with advanced cancer. —William Breitbart, MD, and colleagues

Analyses of treatment effects included the a priori covariates of sex, social support, cognitive functioning, and level of religiosity to control for potential confounding influences. Patients were assessed before and after completing the intervention and at 2 months after the intervention. The meaning-centered group psychotherapy and supportive group psychotherapy groups were generally balanced for gender (71% and 68% female), age

Benefits of Meaning-Centered Group Psychotherapy ■■ Among patients attending at least three sessions, meaning-centered group psychotherapy was associated with significantly greater benefit in quality of life, spiritual well-being, depression, hopelessness, desire for hastened death, and physical symptom distress compared with supportive group psychotherapy. ■■ Significant positive effects vs baseline in spiritual well-being, overall quality of life, depression, anxiety, hopelessness, and physical symptom distress were observed among all patients attending at least three sessions.

The primary outcome measures were spiritual well-being, assessed by the Functional Assessment of Chronic Illness Therapy Spiritual Well-Being Scale, and overall quality of life, assessed by

er, 11% and 8% none), primary cancer diagnosis (breast in 32% and 27%, pancreas in 14% and 22%, lung in 18% and 13%, colorectal in 16% and 15%, other in 21% and 22%), and Karnofsky performance score (mean, 83 and 82). Overall, 70% of the meaning-centered group psychotherapy group and 65% of the supportive group psychotherapy group attended at least one session; of those who began treatment,

(mean, 57 and 60 years), race/ethnicity (71% and 67% white, 13% and 15% African American), religion (39% and 32% Catholic, 14% and 11% other Christian, 22% and 27% Jewish, 14% and 22% oth-

74% and 73% completed the post-treatment assessment. There was no significant difference between the groups in the mean number of sessions completed (5.55 and 5.28, P = .43).

Significant Improvements Analyses including only patients who attended at least three sessions showed significant group X time interaction effects for all but one of the outcome measures, with significantly stronger treatment effects for meaning-centered group psychotherapy (all P < .05) being observed for quality of life (B value = 0.26), spiritual well-being (B = 0.26), depression (B = −0.28), hopelessness (B = −0.30), desire for hastened death (B = −0.23), and physical symptom distress (B = −0.22); no significant treatment effect was observed for anxiety symptom severity (B = −0.16, 95% confidence interval = −0.33 to 0.02). A significant main effect for time (all P < .05) was observed for spiritual wellbeing, overall quality of life, depression, anxiety, hopelessness, and physical symptom distress, indicating improvement over time in these areas for all

study patients. On intent-to-treat analysis excluding the a priori covariates, significantly greater benefit was still observed for meaning-centered group psychotherapy in quality of life, depression, and hopelessness but not for other outcome measures. Significant within-group improvement after treatment was observed in the meaning-centered group psychotherapy group for spiritual well-being (d = 0.54, P < .001), quality of life (d = 0.40, P < .001), depression (d = −0.67, P < .001), anxiety (d = −0.52, P < .001), hopelessness (d = −0.53, P < .001), desire for hastened death (d = −0.31, P < .05), and physical symptom distress (d = −0.35, P < .01) and in the supportive group psychotherapy group only for depression (d = −0.34, P < .05). At 2-month follow-up, the significant improvements persisted in the meaning-centered group psychotherapy group for spiritual well-being (d = 0.48, P < .001), quality of life (d = 0.35, P < .01), depression (d = −0.54, P < .001), anxiety (d = −0.36, P < .01), hopelessness (d = −0.55, P < .001), desire for hastened death (d = −0.27, P < .05), and physical symptom distress (d = −0.57, P < .001) and in the supportive group psychotherapy group only for depression (d = −0.39, P < .05). The investigators concluded: “This large randomized controlled study provides strong support for the efficacy of meaning-centered group psychotherapy as a treatment for psychological and existential or spiritual distress in patients with advanced cancer.” n

Disclosure: The study was supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Breitbart W, Rosenfeld B, Pessin H, et al: Meaning-centered group psychotherapy: An effective intervention for improving psychological well-being in patients with advanced cancer. J Clin Oncol 33:749-754, 2015.

“In Search of Meaning: A Personal Journey” See pages 113 and 131 in this issue of The ASCO Post for more on meaning-centered psychotherapy, including a personal narrative by Dr. William Breitbart.

ASCOPost.com | MAY 25, 2015

PAGE 113

Perspective

Potential Power of Meaning-Centered Group Psychotherapy in Patients With Advanced Cancer By William Breitbart, MD

he recent publication of the results of our National Cancer Institute (NCI) RO1-funded randomized controlled trial of meaningcentered group psychotherapy for advanced cancer patients in the Journal of Clinical Oncology,1 and the accompanying summary published in this issue of The ASCO Post, represent the culmination of many years of effort. This clinical research effort was born out of clinical experience with thousands of patients with advanced cancer, who taught us the importance of sustaining meaning to maintain the courage and will to live life, even in the face of death. These patients taught us that experiencing meaningful moments could be accompanied by the emotion of joy, which made it possible to better tolerate suffering and uncertainty. This recent trial of meaningcentered group psychotherapy in fact demonstrates the power of sustaining meaning in the amelioration of suffering and despair.

Importance of Meaning in End-of-Life Care Our research group at Memorial Sloan Kettering Cancer Center has conducted a series of studies examining the importance of meaning and spiritual well-being in end-of-life care.2-4 We demonstrated a central role for spiritual well-being, and, in particular, meaning, as a buffering agent, protecting against depression, hopelessness, and desire for hastened death among terminally ill cancer patients. We also found that spiritual wellbeing was significantly associated with end-of-life despair (as defined by hopelessness, desire for hastened death, and suicidal ideation), even after controlling for the influence of depression. Moreover, when spiritual well-being was divided into two components—one measuring a sense of meaning and another measuring spirituality linked to religious faith—the inability to maintain a sense of meaning was much more strongly associated with end-of-life despair than was Dr. Breitbart is the Jimmie C Holland Chair in Psychiatric Oncology and Chairman, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York.

the faith component of spiritual wellbeing. That is, the ability to sustain a sense of meaning was associated with lower levels of hopelessness, desire for hastened death, and suicidal ideation. These findings are significant in the face of what we have come to learn about the consequences of depression and hopelessness in cancer patients. Depression and hopelessness are associated with dramatically higher rates of suicide, suicidal ideation, and desire for hastened death and interest in physician-assisted suicide.2,5 Our findings2 demonstrate that hopelessness is an independent and synergistic predictor of desire for death that is as powerful an influence on desire for death as (and independent of) depression.

Meaning-Centered Psychotherapy for Advanced Cancer Patients The importance of spiritual wellbeing and the role of “meaning” in particular in moderating depression, hopelessness, and desire for death in terminally ill cancer and AIDS patients

meaning and spirituality clearly, in our view, had applications in psychotherapeutic work with advanced cancer patients. Dr. Frankl’s main contributions to human psychology have been to raise awareness of the spiritual component of human experience and the central importance of meaning (or the will to meaning) as a driving force or instinct in human psychology. His basic concepts include the following ideas: • Life has meaning and never ceases to have meaning even up to the last moment of life; meaning may change in this context, but it never ceases to exist. • The desire to find meaning in human existence is a primary instinct and basic motivation for human behavior. • We have the freedom to find meaning in existence and to choose the attitude toward suffering. • The three main sources of meaning in life are creativity (work, deeds, dedication to causes), experience (art, nature, humor, love, relation-

We demonstrated a central role for spiritual well-being, and, in particular, meaning, as a buffering agent, protecting against depression, hopelessness, and desire for hastened death among terminally ill cancer patients. —William Breitbart, MD

demonstrated by our research group led us to look beyond the role of antidepressant treatment for depression in this population. We chose to focus new efforts on developing nonpharmacologic (psychotherapeutic) interventions that can address such issues as hopelessness, loss of meaning, and spiritual well-being in patients with advanced cancer at the end of life. This effort led to an exploration and analysis of the work of Viktor Frankl and his concepts of “logotherapy” or meaning-based psychotherapy.6,7 While Dr. Frankl’s logotherapy was not designed for the treatment of cancer patients or those with lifethreatening illness, his concepts of

ships, roles), and attitude (the attitude one takes toward suffering and existential problems). • Meaning exists in a historical context—thus, legacy (past, present, and future) is a critical element in sustaining or enhancing meaning. The novel intervention we developed and call “meaning-centered psychotherapy” is based on the concepts described above and the principles of Dr. Frankl’s logotherapy. It is designed to help patients with advanced cancer sustain or enhance a sense of meaning, peace, and purpose in their lives, even as they approach the end of life.8-10 We initially conducted a pilot randomized trial of an 8-week (1½-hour

weekly sessions) meaning-centered group psychotherapy intervention, based on the concepts of meaning as elucidated by Viktor Frankl, which utilized a highly developed treatment manual incorporating a mixture of didactics, discussion, and experiential exercises that focus on particular themes related to meaning and advanced cancer. Our findings1,12 demonstrate that meaning-centered group psychotherapy is a highly effective intervention, increasing a sense of meaning, spiritual well-being, and hope, while decreasing end-of-life despair. That said, during the course of the meaning-centered group psychotherapy clinical trial, it became quite obvious to us that the group format for psychotherapy interventions in patients with advanced cancer near the end of life posed limitations. We therefore developed and tested, in a pilot randomized controlled trial, an individual format of meaning-centered psychotherapy, which proved highly effective.13

Goals of Psychotherapy in Palliative Care The nature and scope of the clinical goals of psychotherapeutic or counseling interventions in the palliative care setting have been evolving. Most psychotherapists and counselors would agree that, until recently, there were two basic constructs that were universally accepted as the basis of the counseling intervention with a dying patient: support and nonabandonment. In essence, supportive counseling allies with a patient’s defenses and coping strategies, supporting or reinforcing them. For example, the patient who is dying and is using denial in the face of the proximity of death would be supported by the therapist in this way of coping. We all find ourselves allying with hopes, even unrealistic ones, expressed by patients and families in the dying process. However, experienced clinicians also create possibilities for patients to discuss death and dying by gentle questioning. Nonabandonment or presence is a second basic principle of counseling the terminally ill. The therapist makes a commitment to escort or accompany the patient through the course continued on page 114

The ASCO Post | MAY 25, 2015

PAGE 114

Perspective

William Breitbart, MD continued from page 113

of treatment and the dying process. There is power in the presence of the therapist in accompanying the patient on this too-often lonely path. The question many of us have asked in recent years is “Can we accomplish something more ambitious in psychotherapy with the terminally ill?” The “more ambitious” goal of psychotherapy with the terminally ill is to help patients come to a sense of acceptance of a life lived and, ultimately, an acceptance of death (ie, being able to face death with a sense of peace and equanimity). Many suggest such a goal of care is not achievable by all and perhaps inappropriate for many. I would suggest that tasks of life completion are achievable and essential at this phase of life. Acknowledging or facing death (ie, the finiteness of life) is the impetus for transformation. Facing death forces us to turn around and face life—the life one has lived. When one examines the life one has lived and struggles to accept that

lived life, one is faced with a number of challenges and tasks of dying. Facing death can enhance the process of pursuing a sense of coherence, meaning, and completion of one’s life. It allows for realization that the last chapter of one’s life is the last opportunity to live to one’s full potential, to leave behind an authentic legacy, to connect with the beyond, and to transcend life as we know it. The goal is to preserve the idea that there is still life to be lived—still time to become—so that one can die with a sense of peace, equanimity, and acceptance of the life one lived. The paradox of the end-of-life dynamic is that through acceptance of the life one has lived comes acceptance of death. The lessons of the dying can inform the living of the value of life. Perhaps we die so that we can appreciate the importance of living. n Disclosure: Dr. Breitbart reported no potential conflicts of interest.

References 1. Breitbart W, Rosenfeld B, Pessin H, et al: Meaning-centered group psy-

chotherapy: An effective intervention for reducing despair in patients with advanced cancer. J Clin Oncol 33:749754, 2015. 2. Breitbart W, Rosenfeld B, Pessin H, et al: Depression, hopelessness, and desire for hastened death in terminally ill cancer patients. JAMA 284:29072911, 2000. 3. Nelson C, Rosenfeld B, Breitbart W, et al: Spirituality, depression and religion in the terminally ill. Psychosomatics 43:213-220, 2002. 4. McClain C, Rosenfeld B, Breitbart W: The influence of spirituality on endof-life despair among terminally ill cancer patients. Lancet 361:1603-1607, 2003. 5. Breitbart W, Rosenfeld B: Physician-assisted suicide: The influence of psychosocial issues. Cancer Control 6:146-161, 1999. 6. Frankl VF: Man’s Search for Meaning, 4th ed. New York, Simon & Schuster, 1959. 7. Frankl VF: The Will to Meaning, 2nd ed. New York, Penguin Books, 1969. 8. Greenstein M, Breitbart W: Cancer and the experience of meaning: A group psychotherapy program for

people with cancer. Am J Psychother 54:486-500, 2000. 9. Breitbart W: Spirituality and meaning in supportive care: Spirituality- and meaning-centered group psychotherapy interventions in advanced cancer. Support Care Cancer 10:272-280, 2002. 10. Breitbart W, Gibson C, Poppito SR, et al: Psychotherapeutic interventions at the end of life: A focus on meaning and spirituality. Can J Psychiatry 49:366-372, 2004. 11. Breitbart W, Rosenfeld B, Gibson C, et al: Meaning-centered group psychotherapy for patients with advanced cancer: A pilot randomized controlled trial. Psychooncology 19:21-28, 2010. 12. Breitbart W, Poppito S, Rosenfeld B, et al: Pilot randomized controlled trial of individual meaningcentered psychotherapy for patients with advanced cancer. J Clin Oncol 30:1304-1309, 2012.

For more on meaning-centered psychotherapy, see Dr. Breitbart’s personal narrative on page 131.

Don’t Miss These Important Reports in This Issue of The ASCO Post Lorraine A. Chantrill, MD, on Whole Genomic Sequencing and the Future of Targeted Treatment see page 22

Richard J. O’Reilly, MD, on Adoptive T-Cell Therapy see page 24

Joaquin Mateo, MD, on Genetic Abnormalities and Olaparib in Metastatic Prostate Cancer see page 32

Larry Norton, MD, on the State of Breast Cancer in 2015 see page 33

Erich M. Sturgis, MD, MPH, on the Rise of HPV-Related Anal Cancer see page 35

Elizabeth M. Swisher, MD, on PARP Inhibitor Benefits in Ovarian Cancer and BRCA Mutations see page 37

Ursula A. Matulonis, MD, on PARP Inhibitors in Ovarian Cancer see page 42

Daniel P. Petrylak, MD, on Lenalidomide Addition to Docetaxel-Prednisone in Prostate Cancer see page 64

Darrell D. Bigner, MD, PhD, on PVS-RIPO Poliovirus in Glioblastoma Treatment see page 67

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | MAY 25, 2015

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Geriatrics for the Oncologist

Guidelines for the Treatment of Older Cancer Patients: Task Forces of the International Society of Geriatric Oncology By Anita O’Donovan, MD

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.

he Task Forces of the International Society of Geriatric Oncology (SIOG) are active in various fields of geriatric oncology and have produced position papers, consensus statements, and clinical practice guidelines on issues related to cancer in the elderly, which guide clinicians regarding the optimal management of older patients and important age-related considerations. Until recently, older patients were underrepresented in clinical trials, so optimal therapeutic approaches for these patients were generally extrapolated from those for younger patients. The underlying theme or common thread in many of the guidelines, summarized here, is the need for a more objective baseline assessment of older cancer patients to estimate physiologic reserve. It is important to note that the summaries below represent the expert views provided by the respective Task Forces of multidisciplinary expert panels, who developed evidence-based recommendations through a systematic review of the current literature. Further details may be found in the individual publications, as cited. The last three guidelines mentioned in this report, related to taxanes, radiopharmaceuticals in prostate cancer, and chronic lymphocytic leukemia (CLL), and are currently in press.

Comprehensive Geriatric Assessment (CGA) In 2014, SIOG composed a panel with expertise in geriatric oncology to develop consensus statements of key evidence on the role of geriatric assessment in oncology. The panel concluded that there are mounting data regarding the utility of geriatric assessment in oncology practice; however, additional research is needed to conDr. Donovan is Assistant Professor, Applied Radiation Therapy Trinity (ARTT) research group, School of Medicine, Trinity College, Dublin, Republic of Ireland.

tinue to strengthen the evidence base. The main findings demonstrating the value of geriatric assessment in oncology practice include the following benefits: detection of impairment not identified on routine history or physical examination, ability to predict severe treatment-related toxicity, ability to predict survival in a variety of tumors and treatment settings, and ability to influence treatment choice and intensity. The panel recommended that the following domains be evaluated as part of a geriatric assessment: functional status, comorbidity, cognition, mental health status, fatigue, social status and support, nutrition, and presence of geriatric syndromes. Several combinations of tools and various models are available for implementation of geriatric assessment in oncology practice.1

Prostate Cancer In 2013, SIOG updated previous guidelines, including recommendations on assessing individual health status based on physiologic age, rather

Radiation Oncology Radiotherapy is a key component of the management of older cancer patients. The following radiotherapy-specific adaptations/recommendations for various cancer sites may be suitable for older patients.3 It should be noted that the literature to date related to CGA and toxicity in radiotherapy is scant, and this should be addressed in future studies in radiation oncology. • Fit older patients are candidates for postoperative whole-breast radiotherapy after breast-conserving surgery for invasive cancer and higherrisk ductal carcinoma in situ, although it may be acknowledged that the absolute risk of locoregional or distant recurrence is lower in women over the age of 70, compared to younger patients. Shorter courses of hypofractionated whole-breast radiotherapy have proved to be both safe and effective in certain categories of patients, offering greater convenience, and similar local control. Partial breast irradiation should be considered investigational, as there is insufficient

The panel concluded that there are mounting data regarding the utility of geriatric assessment in oncology practice; however, additional research is needed to continue to strengthen the evidence base. —Anita O’Donovan, MD

than chronologic age. On the basis of a validated rapid health status screening instrument (based on the G8 questionnaire [cutoff of < 14] screening score) and simple geriatric assessment, the Task Force recommends that patients be classed into three groups for treatment: (1) healthy or fit patients, who should have the same treatment options as younger patients; (2) vulnerable patients with reversible impairment, who should receive standard treatment after medical intervention; and (3) frail patients with nonreversible impairment, who should receive adapted treatment. This guideline provides recommendations for all treatment modalities.2 [These guidelines are dedicated to the memory of our dear friend Prof. John M. Fitzpatrick, who died on May 14, 2014.]

evidence to support it in the elderly. In relation to comorbidities, threedimensional computed tomography (CT)-based planning is advised to minimize cardiac and lung irradiation, in conjunction with appropriate positioning and immobilization. • Stereotactic body radiation therapy, which delivers higher-than-conventional doses to small-target volumes in much fewer treatments, is transforming the management of non– small cell lung cancer (NSCLC) in older patients, particularly those for whom comorbidities preclude the use of radical surgery. For inoperable locoregionally advanced NSCLC, concomitant chemoradiation is appropriate in fit elderly patients. • From a treatment planning view-

GUEST EDITOR

Stuart M. Lichtman, MD

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). point, adaptive radiation therapy (ART) uses a feedback process for dynamic treatment planning with each fraction. Treatment plans are re-optimized to account for daily variations in physical setup and in internal tumor and normal tissue location and biologic changes. ART may be particularly useful for older patients whose treatment set-up varies due to impaired mobility or unpredictable internal organ motion. Likewise, techniques limiting respiratory motion include controlled breathhold and abdominal compression, which, while effective, are frequently not tolerated by the elderly. Incorporation of four-dimensional planning CT scans permits better integration of tumour and normal tissue respiratory motion as well as other predictable motion captured during scanning into treatment p lanning. • Modern involved-field radiotherapy for lymphoma, based on pretreatment positron-emission tomography data, has resulted in a significant decrease in toxicity, an important consideration in elderly patients. • Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer. Management should be guided by geriatric assessment and life expectancy. For intermediate-risk disease, 4 to 6 months of hormones are comcontinued on page 116

The ASCO Post | MAY 25, 2015

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Geriatrics for the Oncologist Treatment Guidelines continued from page 115

•

bined with external-beam radiotherapy (EBRT). For high-risk prostate cancer, combined-modality therapy is advised. For high-intermediate risk endometrial cancer, vaginal brachytherapy alone (rather than EBRT) is recommended as the adjuvant treatment of choice in older patients, without an associated reduction in toxicity. Elderly patients with locally advanced rectal cancer benefit from chemoradiation, with prospective data showing that preoperative radiation therapy is associated with significantly better local control and less acute and late toxicity than postoperative radiation therapy. For primary brain tumors, shorter courses of postoperative radiotherapy following maximal debulking may provide equivalent survival to longer schedules. The MGMT (O-6-methylguanine-DNA-methyltransferase) methylation status may help to select older patients for temozolomide alone. Stereotactic radiosurgery provides an alternative to whole-brain radiotherapy in patients with limited brain metastases. This may be an especially suitable option for older patients at increased risk of cognitive impairment. Intensity-modulated radiation therapy is now the standard of care in head and neck cancer and provides an excellent technique to reduce the dose to the carotid arteries, salivary glands, and other critical structures.

Colorectal Cancer The colorectal cancer guidelines provide a summary of the Task Force report in 2013, to update the existing expert recommendations published in 2009, and include overviews of the recent data on best practice4: • Embracing the concept of individualized treatment is an absolute requirement for further improvements in the management of patients with colorectal cancer in older patients. • Multidisciplinary teams are key to

enabling individualized treatment. There is a need to utilize some form of geriatric assessment to inform clinical decision-making. • The potential for comorbidities and the options if serious complications do occur, or treatments fail, should be fully discussed in advance, as the consequences of colorectal surgery can lead to significant quality-of-life issues for older adults, especially when a permanent stoma is required. • Investigators should be encouraged to design not only clinical trials using low-toxicity treatments that maintain most of the efficacy of full-dose treatments but patientcentered assessments to expand the evidence base in the treatment of older patients with colorectal cancer. • Radiotherapy can be used effectively to manage inoperable patients as well as in the palliative setting for advanced disease.

Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common nonHodgkin lymphoma subtype in the elderly and is of increasing prevalence in the older patient population. The newly developed treatment guidelines5,6 address initial therapy for DLBCL, in both limited- and advanced-stage disease, as well as approaches to the relapsed and refractory patient. Some of the suggestions for optimal care of older patients include the use of alternative regimens for those unable to tolerate R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone). Anthracycline-based chemotherapy is complicated by comorbidities and alterations in functional status in older adults, therefore alternative regimens may be considered. At present, there is no clear-cut role for maintenance therapy for DLBCL. In the relapsed setting, there is increasing recognition that select elderly patients may be candidates for high-dose treatment approaches. Geriatric assessment has a role to play in stratifying patients in this setting. Palliative treatment approaches may be considered for those unable to tolerate such therapy.

Taxanes in Breast Cancer Balancing the efficacy of therapy against toxicity is especially difficult in elderly patients who have diminished

physiologic reserve and significant comorbidities. In the adjuvant setting, taxane toxicity is greater in older than in younger patients, but taxanes can be added to anthracylines in healthy highrisk patients or can be used instead of them to reduce cardiac risk. In HER2positive patients, paclitaxel or docetaxel plus cyclophosphamide is an alternative to anthracylines and reduces trastuzumab (Herceptin)-related cardiotoxicity. In metastatic disease, weekly paclitaxel or three-weekly docetaxel is a cornerstone of treatment. Nab-paclitaxel (Abraxane) offers efficacy comparable to that with solvent-based taxanes, but there are limited study data in the elderly. Neuropathy remains a significant problem.

Radiopharmaceuticals: Focus on the Prostate Radiopharmaceutical imaging has a clear role in diagnosis and monitoring and involves doses that are pharmacologically inactive. However, the therapeutic use of radionuclides in elderly patients who may be frail and have impaired organ function and bone marrow reserve raises specific issues related to short-term toxicity. On the other hand, limited life expectancy means that elderly patients are less likely than their younger counterparts to be concerned about the long-term consequences of radiation. Efficacy, tolerability, and ease of use are being considered in the context of newly introduced agents, notably the alpha-emitter radium-223 dichloride (Xofigo), which has shown survival benefits in patients with castration-resistant prostate cancer and symptomatic bone metastases.7

Chronic Lymphocytic Leukemia Elderly patients with CLL do not differ substantially from younger patients with CLL in the stage distribution or molecular biology of their disease, but many are frail, and comorbidities shorten survival independently of factors that are prognostic for CLL. Impaired nutrition and mobility are present in up to 50% of older patients with CLL, and they may not be able to tolerate aggressive therapy. For fit patients, purine-based chemoimmunotherapy remains a standard, with bendamustine (Treanda)/rituximab as an alternative. However, in relapsed or refractory CLL, novel small molecules targeting abnormal signalling in the B-cell recep-

tor pathway are changing management. For the full guidelines from the Task Forces of the International Society of Geriatric Oncology, visit http:// www.siog.org/index.php?Itemid=92. n

Disclosure: Dr. O’Donovan reported no potential conflicts of interest. For full disclosures of the guideline authors, visit www.siog.org.

References 1. Wildiers H, Heeren P, Puts M, et al: International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 32:2595-2603, 2014. 2. Droz JP, Aapro M, Balducci L, et al: Management of prostate cancer in older patients: Updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol 15:e404-e414, 2014. 3. Hoskin P, Sartor O, O’Sullivan JM, et al: Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: A prespecified subgroup analysis from the randomised, doublebline, phase 3 ALSYMPCA trial. Lancet Oncol 15:1397-1406, 2014. 4. Papmichael D, Audisio RA, Glimelius B, et al: Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 26:463-476, 2015. 5. Morrison VA, Hamlin P, Soubeyran P, et al: Approach to therapy of diffuse large B-cell lymphoma in the elderly: The International Society of Geriatric Oncology (SIOG) expert position commentary. Ann Oncol. January 29, 2015 (early release online). 6. Morrison VA, Hamlin P, Soubeyran P, et al: Diffuse large B-cell lymphoma in the elderly: Impact of prognosis, comorbidities, geriatric assessment, and supportive care on clinical practice. An International Society of Geriatric Oncology (SIOG) Expert Position Paper. J Geriatr Oncol 6:141-152, 2015. 7. Kunkler IH, Audisio R, Belkacemi Y, et al: Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: The International Society of Geriatric Oncology (SIOG) task force. Ann Oncol 25:21342146, 2014.

Watch future issues of The ASCO Post for continued discussion on geriatrics for the oncologist and practical tools to use with your older patients.

Estrogen is a key driver of tumor growth and survival in HR+ breast cancer1,2

Mutations in the PI3K/Akt/mTOR pathway are found in

UP TO

70%

Abbreviations: Abbreviations: HR+, HR+, hormone hormone receptor-positive; receptor-positive; mTOR, PFS, mammalian progression-free target ofsurvival. rapamycin.

of breast cancer cases; hyperactivation of this pathway can contribute to endocrine resistance.1,3-6

DOUBLE INHIBITION In advanced disease, targeting one pathway may not be enough Aromatase inhibition

Typical ER Pathway Blockade

Estrogen

In HR+ breast cancer, NSAI treatments (eg, letrozole or anastrozole) inhibit the production of estrogen, thereby reducing ER signaling, a key driver of tumor growth and survival in breast cancer.1,2

Nucleus Cell Proliferation and Survival Aromatase inhibition

Key Mechanism of Progression

Estrogen

P ER

In the advanced setting, multiple signaling pathways and hyperactivation of the PI3K/Akt/mTOR pathway can give tumor cells alternate pathways for progression.1,4-6

mTOR

P ER

Nucleus Cell Proliferation and Survival

Cell Proliferation and Survival

AFINITOR + exemestane Estrogen

Double Inhibition

Exemestane

AFINITOR

mTOR

Cell Proliferation and Survival

In patients who have progressed on an NSAI, AFINITOR® (everolimus) Tablets plus exemestane is the only regimen to deliver dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways, providing synergistic inhibition of tumor survival signaling.7-9

Nucleus

Only AFINITOR plus exemestane offers dual inhibition of the ER and mTOR pathways7 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients • Manage noninfectious pneumonitis by dose interruption until treated with AFINITOR. The incidence of Common Terminology symptoms resolve, follow with a dose reduction, and consider Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up the use of corticosteroids. Discontinue AFINITOR if toxicity to 4.0% and up to 0.2%, respectively. Fatal outcomes have been recurs at grade 3 or for grade 4 cases. For patients who require observed. Monitor for clinical symptoms or radiological changes use of corticosteroids, prophylaxis for PJP may be considered • Opportunistic infections such as Pneumocystis jiroveci pneumonia • The development of pneumonitis has been reported even at a (PJP) should be considered in the differential diagnosis reduced dose Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; ER, estrogen receptor; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; NSAI, nonsteroidal aromatase inhibitor; P, phosphorylation; PFS, progression-free survival.

DOUBLE MEDIAN PFS AFINITOR plus exemestane more than doubled median PFS over exemestane alone7

55%

Median PFS in BOLERO-2 (Investigator Radiological Review)7 100

reduction in risk of progression or death 7

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

PFS curves

began to diverge at

6 weeks (the ﬁrst tumor assessment)7,9

PFS Probability (%)

Median PFS

7.8 months

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

0 0

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

62% reduction in risk of progression or death 7

Independent central assessment conﬁrmed beneﬁt 7 Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)7

Important Safety Information (cont) Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

•

• •

Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required

Important Safety Information . AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes • Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis • Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids. Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases. For patients who require use of corticosteroids, prophylaxis for PJP may be considered • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment • PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: • Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment) • In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Impaired Wound Healing: • Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma • These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared with 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age • Careful monitoring and appropriate dose adjustments for adverse reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelﬁnavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, ﬂuconazole, verapamil, diltiazem). •

Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less Hepatic Impairment: • Exposure to everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired beneﬁt outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST, 69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT, 51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%) Please see Brief Summary of Prescribing Information on adjacent pages. •

To learn more, please visit www.AFINITOR.com. References: 1. Johnston SRD. Enhancing the efﬁcacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9(suppl 1):S28-S36. 2. Miller TW, Hennessy BI, González-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-2413. 3. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224. 4. Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: importance of heterogeneity. Nat Rev Clin Oncol. 2010;7(3):139-147. 5. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptorHER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96(12):926-935. 6. De Laurentiis M, Arpino G, Massarelli G, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11(13):4741-4748. 7. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015. 8. Fedele P, Calvani N, Marino A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? Crit Rev Oncol Hematol. 2012;84:243-251. 9. Data on ﬁle. AFINITOR CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals Corp; March 2012.

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AFB-1109394

AFINITOR® (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information] . For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Phophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required. Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Impaired Wound Healing Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period. Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] .

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] . Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). Embryo-fetal Toxicity Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders b 67 8 0 11 0.8 0 Stomatitis Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations c 50 4 1 25 2 0 Infections Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median duration of treatmente 23.9 weeks 13.4 weeks Grading according to CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter

Hematologyb Hemoglobin decreased WBC decreased Platelets decreased Lymphocytes decreased Neutrophils decreased Clinical chemistry Glucose increased Cholesterol increased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Triglycerides increased Albumin decreased Potassium decreased Creatinine increased

AFINITOR (10 mg/day) + exemestanea N=482 All grades Grade 3 Grade 4 % % %

Placebo + exemestanea N=238 All grades Grade 3 Grade 4 % % %

68 58 54 54 31

6 1 3 11 2

0.6 0 0.2 0.6 0

40 28 5 37 11

0.8 5 0 5 0.8

0.4 0.8 0.4 0.8 0.8

69 70 69

9 0.6 4

0.4 0.2 0.2

44 38 45

0.8 0.8 3

0.4 0.8 0.4

0.2

50 33 29 24

0.8 0.8 4 2

0 0 0.2 0.2

26 16 7 13

0 0.8 1 0

0 0 0 0

Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions]. Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in disease-related symptoms and overall survival

in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information]. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITORtreated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology in the full prescribing information]. Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (ChildPugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Revised Jan 2015 © Novartis T2015-17/T2015-18 January 2015/January 2015

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Journal Spotlight Dermatologic Oncology

Anti–PD-1 Antibody Pembrolizumab Improves Progression-Free and Overall Survival vs Ipilimumab in Advanced Melanoma By Matthew Stenger

n the phase III KEYNOTE-006 trial reported in The New England Journal of Medicine,1 Caroline Robert, MD, PhD, Head of the Dermatology Unit at the Institut Gustave Roussy, Paris, and colleagues found that the anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab (Keytruda) increased progression-free and overall survival compared with ipilimumab (Yervoy) in patients with advanced melanoma.

pembrolizumab every 2 weeks, 151 days for pembrolizumab every 3 weeks, and 50 days for ipilimumab.

Progression-Free Survival On first interim analysis for progression-free survival, estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio [HR] = 0.58, P < .001 for

Study Details

T:14”

B:14.25”

S:13”

In this open-label trial, 834 patients from 16 countries were randomly assigned 1:1:1 between September 2013 and March 2014 to receive pembrolizumab at 10 mg/kg every 2 weeks (n = 279) or 3 weeks (n = 277) or four doses of ipilimumab at 3 mg/kg every 3 weeks (n = 278). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status, line of therapy, and PD-1 ligand (PDL1) expression. The primary endpoints were progression-free and overall survival. The three groups were generally balanced for age (median, 61–63 years), sex (58%–63% male), ECOG performance status (0 for 68%–70%, 1 for 30%–32%), elevated LDH (29%–35%), metastasis stage (M0 in 3%–5%, M1not otherwise specified in 1%–2%, M1a in 8%–12%, M1b in 15%–23%, M1c in 64%–68%), PD-L1–positive status (80%–81%), BRAF V600E–mutant status (35%–38%), brain metastases (8%–

Overall Survival At the second interim analysis for overall survival, estimated 12-month overall survival rates were 74.1% (HR = 0.63, P = .0005, vs ipilimumab),

The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. —Caroline Robert, MD, PhD, and colleagues

both pembrolizumab vs ipilimumab comparisons). Median progressionfree survival was 5.5 months (95% confidence interval [CI] = 3.4–6.9 months), 4.1 months (95% CI = 2.9– 6.9 months), and 2.8 months (95% CI = 2.8–2.9 months) for the three groups, respectively. Benefit of both pembrolizumab regimens vs ipilimumab was evident in all examined subgroups. For the every2-week and every-3-week pembrolizumab groups vs ipilimumab, hazard ratios were 0.53 (95% CI = 0.41–0.67) and 0.52 (95% CI = 0.40–0.66) among

Pembrolizumab vs Ipilimumab in Advanced Melanoma ■■ Pembrolizumab treatment was associated with significantly better progression-free survival and overall survival than ipilimumab. ■■ Pembrolizumab treatment was associated with less toxicity than ipilimumab.

10%), previous lines of systemic therapy (0 in 65%–67%, 1 in 33%–35%), and type of previous systemic therapy (chemotherapy in 10%–15%, immunotherapy in 3%–4%, BRAF or MEK inhibitor or both in 16%–20%). Median duration of follow-up at the time of data cutoff was 7.9 months (range = 6.1–11.5 months). The mean duration of exposure was 164 days for

Among patients with BRAF mutation who had received BRAF inhibitor therapy, the hazard ratio was significantly better for the every-2-week group (0.58) but not for the every-3-week group (0.87, 95% CI = 0.53–1.40).

PD-L1–positive patients and 0.67 (95% CI = 0.41–1.11) and 0.76 (95% CI = 0.47–1.24) among PD-L1–negative patients. Hazard ratios were also significantly in favor of the pembrolizumab groups among patients with wild-type BRAF (0.58 and 0.57) and among patients with BRAF mutation who had received no BRAF inhibitor (0.54 and 0.44).

68.4% (HR = 0.69, P = .0036, vs ipilimumab), and 58.2%. Due to the superiority of pembrolizumab, the independent data and safety monitoring committee recommended stopping the study early to permit patients in the ipilimumab group to receive pembrolizumab. Median overall survival was not reached in any group. Hazard ratios favored pembrolizumab for all subgroups, except in the comparison of every-3-week pembrolizumab vs ipilimumab in patients with PD-L1–negative tumors; among these patients, hazard ratios were 0.91 (95% CI = 0.49–1.69) for every-2-week pembrolizumab and 1.02 (95% CI = 0.56–1.85) for every-3-week pembrolizumab. Among patients with PD-L1–positive tumors, hazard ratios were 0.55 (95% CI = 0.40–0.76) and 0.58 (95% CI = 0.42–0.79). Hazard ratios were significantly in favor of the two pembrolizumab groups among patients with wild-type BRAF and nonsignificantly in favor of pembrolizumab among patients with BRAF mutation irrespective of whether they had received BRAF inhibitor treatment.

Response Rate Response rates were 33.7% for pembrolizumab every 2 weeks, 32.9% for pembrolizumab every 3 weeks, and

11.9% for ipilimumab (P < .001 for both comparisons), with complete response rates of 5.0%, 6.1%, and 1.4%. Median times to response were 86, 85, and 87 days. Median duration of response was not reached in any group, with 89.4%, 96.7%, and 87.9% of responses ongoing at the time of analysis.

Adverse Events The most common treatment-related adverse events of any grade in the pembrolizumab groups were fatigue (20.9% in the every-2-week group and 19.1% in the every-3-week group), diarrhea (16.9% and 14.4%), rash (14.7% and 13.4%), and pruritus (14.4% and 14.1%). The most common events in the ipilimumab group were pruritus (25.4%), diarrhea (22.7%), and fatigue (15.2%). Treatment-related grade ≥ 3 adverse events occurred in 13.3%, 10.1%, and 19.9% of patients; the most common events in pembrolizumab recipients were diarrhea (2.5% and 1.1%), colitis (1.4% and 2.5%), and hepatitis (1.1% and 1.8%), and the most common events in ipilimumab recipients were colitis (7.0%), diarrhea (3.1%), hypophysitis (1.6%), and fatigue (1.2%). The most common autoimmune or immune-related adverse events of special interest in the pembrolizumab groups were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5% and 3.2%). Treatment-related adverse events led to discontinuation of the study drug in 4.0%, 6.9%, and 9.4% of patients. One treatment-related death occurred in an ipilimumab patient (cardiac arrest from diarrhea-related metabolic imbalances in a patient with diabetes). The investigators concluded: “The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less highgrade toxicity than did ipilimumab in patients with advanced melanoma.” n

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. April 19, 2015 (early release online). See commentary on page 124

The ASCO Post | MAY 25, 2015

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Perspective

Continued from page 123

Pembrolizumab vs Ipilimumab: Good vs Better By Douglas B. Johnson, MD, MSCI

he treatment landscape for metastatic melanoma has recently undergone a remarkable transformation. Prior to 2011, clinicians and patients were presented with difficult decisions between therapies without proven survival benefit. Now, similarly difficult but much more hopeful choices are posed among multiple potentially effective therapies (as well as promising clinical trials). Although outcomes are still far from optimal, we are now in a position to compare between clinically active agents.

Promising New Therapies Treatment options for advanced melanoma include genetically targeted agents and immune therapies. Selective small-molecule inhibitors blocking BRAF and MEK have improved clinical outcomes for the 40% to 50% of patients harboring a BRAF mutation, and MEK inhibitors are showing activity in other genetic subsets.1-3 Perhaps more promising, new immune therapies cause durable antitumor responses in some patients by unleashing suppressed immune responses. Ipilimumab (Yervoy), a monoclonal antibody to cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4), was the first of these novel therapeutics to receive regulatory approval, based on its survival benefit in patients with advanced melanoma who experienced disease progression on prior therapies.4 Antibodies blocking the interaction of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have more recently displayed clinical activity. Pembrolizumab (Keytruda) and nivolumab (Opdivo) were both U.S. Food and Drug Administration (FDA)approved, largely based on randomized studies that demonstrated improved clinical outcomes compared with chemotherapy for patients who had previously received ipilimumab.5,6 In addition, nivolumab produced superior response rates and overall survival compared with chemotherapy in a randomized phase III study in treatment-naive, BRAF–wild-type melanoma patients.7 Dr. Johnson is Assistant Professor of Medicine at Vanderbilt University Medical Center and a hematologist/oncologist at VanderbiltIngram Cancer Center, Nashville.

These and other early-phase studies, in fact, suggested that anti–PD-1 agents have favorable efficacy and safety compared to ipilimumab. However, until recently, these agents had not been compared against one another, and the optimal sequence had been unclear.

KEYNOTE-006 As reviewed in this issue of The ASCO Post, Robert and colleagues have begun to address some of these questions. In the randomized phase III KEYNOTE-006 clinical trial, which they recently reported in The

Remaining Questions

Biomarkers Needed

Several questions remain, particularly in light of the smaller, randomized study published concurrently in The New England Journal of Medicine by Postow and colleagues.9 This study compared the combination of nivolumab and ipilimumab with ipilimumab alone and noted superior overall survival and objective response rates for the combination. Nivolumab and ipilimumab produced a 61% response rate and 22% complete response rate in the BRAF–wildtype cohort—unprecedented activity for immune therapies. For several rea-

These studies also highlight the need for predictive molecular biomarkers to assist with treatment selection. An accurate marker for anti–PD-1 therapy would be particularly useful to clinicians. Such a marker could be envisioned to stratify patients to singleagent pembrolizumab or nivolumab if positive or immune combinations or genetically targeted therapy if negative. This “precision immunotherapy” type of approach could maximize therapeutic benefits and allow avoidance of more toxic combination regimens. Initially, great excitement surrounded stratifying patients based on PD-L1 expression by tumor cells.11 Several subsequent studies, however, have diminished enthusiasm for using PD-L1 in treatment decision-making. While response rates are generally higher in the PD-L1–positive cohort, a large number of PD-L1–negative patients still benefit. Furthermore, PD-L1 status has essentially no predictive capacity for patients treated with nivolumab and ipilimumab.9 Although PD-L1 expression may have utility in other malignancies or in combination with other predictors, it is unlikely to have a major role in guiding melanoma treatment selection. Several promising strategies may help identify more accurate predictive markers of anti–PD-1 response. Snyder and colleagues profiled melanomas treated with ipilimumab and found an array of neoantigens generated by tumor mutations present only in patients who benefited from ipilimumab.12 Individual mutant peptides may represent specific targets for activated T cells and therefore may predict anti–PD-1 response as well. Tumeh and colleagues reported that tumor-infiltrating CD8positive T cells, particularly at the invasive margin, correlated with pembrolizumab responses.13 In this same study, pretreatment clonal expansion of infiltrating T cells, likely representing a preexisting tumor-specific T-cell population, also predicted benefit from pembrolizumab.

Pembrolizumab has now demonstrated superior efficacy and tolerability compared with ipilimumab in a randomized phase III clinical trial [and] therefore, should be strongly considered as a preferred front-line treatment option for patients with metastatic melanoma. —Douglas B. Johnson, MD, MSCI

New England Journal of Medicine, two schedules of pembrolizumab were compared with ipilimumab in 834 patients.8 Both pembrolizumab arms were superior to ipilimumab in terms of response rate (33.7% and 32.9% vs 11.9%), median progression-free survival (5.5 months and 4.1 months vs 2.8 months), and 12-month overall survival (74.1% and 68.4% vs 58.2%). Pembrolizumab improved clinical outcomes across all prespecified subgroups, with the possible exception of PD-L1–nonexpressing tumors. Consistent with prior studies, immune-related adverse events and other severe drug-related toxicities occurred less often in the pembrolizumab arms, despite more prolonged exposure. This study is the first to demonstrate superiority of an anti–PD-1 agent compared to ipilimumab and establishes that pembrolizumab (and likely nivolumab) should be preferred over ipilimumab as front-line therapy.

sons, however, it would be premature to conclude that the combination is superior to anti–PD-1 monotherapy. First, the trial by Postow and colleagues was comparatively small, enrolling 142 patients (with 95 receiving combination therapy). Second, negative prognostic features were less common in this study than in KEYNOTE-006, including stage IV M1c disease (46% vs 65%), prior brain metastases (3% vs 9%), and prior therapies for metastatic disease (0% vs 34%). Third, grade 3 or 4 immune-related adverse events and other toxicities occurred much more frequently with the combination, although they were manageable with corticosteroids in most cases. Still, the activity of nivolumab and ipilimumab in combination appears quite impressive, with rapid and deep responses occurring even after just one cycle of therapy.10 Ongoing randomized trials will clarify whether an anti– PD-1 agent should be given alone or in combination with ipilimumab.

Closing Thoughts Pembrolizumab has now demonstrated superior efficacy and tolerability compared with ipilimumab in

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Perspective

a randomized phase III clinical trial. Pembrolizumab, therefore, should be strongly considered as a preferred front-line treatment option for patients with metastatic melanoma. We also eagerly await the results from ongoing randomized clinical trials that will elucidate the role of combination treatment with anti–PD-1 agents and ipilimumab. n Disclosure: Dr. Johnson reported no potential conflicts of interest.

References 1. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-2516, 2011. 2. Robert C, Karaszewska B, Schachter

J, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39, 2014. 3. Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: A non-randomised, open-label phase 2 study. Lancet Oncol 14:249-256, 2013. 4. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010. 5. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet

Oncol 16:375-384, 2015. 6. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:11091117, 2014. 7. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015. 8. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. April 19, 2015 (early release online). 9. Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipilimumab in untreated melano-

ma. N Engl J Med. April 20, 2015 (early release online). 10. Chapman PB, D’Angelo SP, Wolchok JD: Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N Engl J Med. April 20, 2015 (early release online). 11. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012. 12. Snyder A, Makarov V, Merghoub T, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189-2199, 2014. 13. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.

Announcements

Mario R. Capecchi, PhD, Recognized With AACR Lifetime Achievement in Cancer Research Award

ario R. Capecchi, PhD, was honored for his tremendous scientific contributions, which have had a profound impact on the understanding of cancer, with the 12th annual American Association for Cancer Research (AACR) Award for Lifetime Achievement in Cancer Research at the AACR Annual Meeting 2015.

has made significant contributions to cancer research, either through a single scientific discovery or a body of work. Dr. Capecchi is the Distinguished Professor of Biology and Human Genetics at the University of Utah School of Medicine, an Investigator with Huntsman Cancer Institute, a Howard Hughes Medical Institute Investigator, and a fellow of the AACR Academy. His pioneering work in the development of gene targeting technology in the mouse has led to a revolution in our ability to study the function of cancer genes, as well as the mechanisms of cancer development.

Contributions to Research Mario R. Capecchi, PhD

The AACR established the Award for Lifetime Achievement in Cancer Research to honor an individual who

A leader in the field of molecular genetics, Dr. Capecchi is best known for his pivotal role in the creation of gene-targeting technology, sometimes referred to as knockout technology.

By manipulating specific genes within mouse-derived embryonic stem cells, he discovered how to genetically engineer a mouse devoid of a specific gene. This technology has spurred studies whereby researchers can analyze the specific function of a particular gene by investigating the biological repercussions of its absence. It has also proven to be a vital asset in the analysis of genetic mutations common in cancer patients. His work in this area was recognized in 2007 with the Nobel Prize in Physiology or Medicine. Dr. Capecchi has also been involved in pioneering studies involving the Hox gene family. His studies of these genes have offered unique insights into the genetics of development within various organ systems, primarily the brain. “Dr. Capecchi is a world-renowned scientist and Nobel laureate, and we are delighted to recognize his remarkable

contributions to biomedical research and the field of cancer research through this award,” said Margaret Foti, PhD, MD, Chief Executive Officer of the AACR. “Gene targeting has been used in the study of numerous diseases, including cancer, and will be central to many future lifesaving advances.” “It is a great honor to be recognized by the AACR for lifetime achievements in cancer research, an institution that has done so much to advance cancer research,” Dr. Capecchi said. He is also an Elected Fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science. A native of Verona, Italy, Dr. Capecchi graduated from Antioch College, and received his doctorate from Harvard University. He has been at the University of Utah since 1973, beginning his tenure as a Professor of Biology. n

Taking the Trauma Out of Cancer Care for Children and Adolescents See page 142 in this issue of The ASCO Post for a report on how cancer centers are implementing programs to help their youngest patients cope with the psychological and physical effects of cancer and its treatment.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

Indication KyprolisÂŽ (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis, and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ÂŠ2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100826J November 2014 Printed in USA

for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results* n

22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

7.8-MONTH MEDIAN DURATION OF RESPONSE (95% CI: 5.6, 9.2)1

Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event1,2 - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each)1

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved. Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of full Prescribing Information on adjacent pages. References: 1. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012. 2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761.

The ASCO Post | MAY 25, 2015

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FDA Update

Venetoclax Receives Breakthrough Therapy Designation in Relapsed/Refractory CLL With 17p Deletion

he U.S. Food and Drug Administration has granted Breakthrough Therapy Designation to AbbVie’s investigational agent venetoclax (ABT-199) for the treatment of relapsed or refrac-

tory chronic lymphocytic leukemia (CLL) in patients with 17p deletion. Venetoclax is an investigational oral B-cell lymphoma-2 (BCL-2) inhibitor currently being evaluated for the treat-

ment of patients with a number of different cancers. The drug is designed to selectively inhibit the BCL-2 protein, which prevents apoptosis of some cells, including lymphocytes, and can be ex-

B:16.75”

pressed in some cancer types. Breakthrough Therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. n

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a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor during Toxicity KYPROLIS duringTreatment KYPROLIS(continued) Treatment (continued) Renal Toxicity Renal Toxicity • Withhold until renal function has • Withhold until renal function has recovered to recovered Grade 1 to Grade 1 to baseline and monitor monitor renal function.renal function. • Serum creatinine • Serum creatinine equal to or equal toororto baselineorand • Iftoattributable KYPROLIS, at the next scheduled • If attributable KYPROLIS,to restart at the restart next scheduled than 2 × baseline greater than 2greater × baseline 2 at a reduced (from treatment at atreatment reduced dose (from 27dose mg/m to 27 mg/m2 to Adverse Reactions] [see Adverse [see Reactions] 2 202,mg/m OR from to 15 20 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m KYPROLIS™KYPROLIS™ (carfilzomib) (carfilzomib) for Injectionfor Injection Brief Summary BriefofSummary Prescribing of Prescribing Information.Information. Please see Please the KYPROLIS see the package KYPROLISinsert package insert • If not attributable • If nottoattributable KYPROLIS,torestart KYPROLIS, at the restart dose used at the dose used for full prescribing for full prescribing information.information. prior to the event. prior to the event. INDICATIONS INDICATIONS AND USAGE: AND KYPROLIS USAGE:is KYPROLIS indicated for is indicated the treatment for theof treatment patients with of patients multiplewith multiple • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the myeloma who myeloma have received who haveat received least twoat prior least therapies two prior including therapiesbortezomib including and bortezomib an and an previous doseprevious at the discretion dose at the of the discretion physician. of the physician. immunomodulatory immunomodulatory agent and have agentdemonstrated and have demonstrated disease progression disease on progression or within on 60 ordays within of 60 Peripheral days of Neuropathy Peripheral Neuropathy • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. completion ofcompletion the last therapy. of the Approval last therapy. is based Approval on response is based rate on response [see Clinical rate Studies [see Clinical section Studies of fullsection of full • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced • Grade 3 or• 4 Grade 3 or 4 PI]. Clinical benefit, PI]. Clinical such benefit, as improvement such as improvement in survival or in symptoms, survival orhas symptoms, not beenhas verified. not been verified. 2 2 dose (from 27dose mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20 mg/m2 [see Adverse [see Reactions] Adverse Reactions] DOSAGE AND DOSAGE ADMINISTRATION: AND ADMINISTRATION: Dosing Guidelines. Dosing Guidelines. KYPROLIS is KYPROLIS administered is administered intravenously intravenously 2 2 to 15 mg/m ),toat15themg/m discretion ), at the of the discretion physician. of the physician. over 2 to 10 over minutes, 2 to on 10two minutes, consecutive on twodays, consecutive each week days,foreach threeweek weeks for (Days three weeks 1, 2, 8,(Days 9, 15,1,and 2, 8, 9, 15, and • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the 16), followed 16), by a followed 12‑day rest by aperiod 12‑day (Days rest 17 period to 28). (Days Each 1728‑day to 28). Each period28‑day is considered period isone considered treatmentone treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician. 2 cycle (Table 1). cycle In Cycle (Table1,1). KYPROLIS In Cycle is 1, administered KYPROLIS is administered at a dose of 20 at mg/m a dose2.ofIf tolerated 20 mg/min . IfCycle tolerated 1, thein Cycle 1, the Other Other • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. dose should be dose escalated should to be27 escalated mg/m2 beginning to 27 mg/m in2 Cycle beginning 2 andincontinued Cycle 2 and at 27 continued mg/m2 in at subsequent 27 mg/m2 in subsequent • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade non‑hematological 3 or 4 non‑hematological cycles. Treatment cycles. may Treatment be continued may be untilcontinued disease progression until diseaseorprogression until unacceptable or until unacceptable toxicity occurstoxicity [see occurs [see 3 or• 4 Grade 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to toxicities toxicities Dosage and Administration]. Dosage and Administration]. The dose is calculated The dose isusing calculated the patient’s using the actual patient’s body surface actual body area surface at area at 2 2 2 2 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m2). 20 mg/m , OR20from mg/m baseline. Patients baseline. with Patients a body surface with a body area surface greater than area 2.2 greater m2 should than 2.2 m2 should receive a dosereceive basedaupon doseabased upon a 2 • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the body surface body area of surface 2.2 marea of 2.2 m2. Dosedo . Dose adjustments adjustments not need todobenot made needfortoweight be made changes for weight of less changes than of less than previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or equal to 20%. or equal to 20%. a Table 1: KYPROLIS Table 1:Dosage KYPROLIS Regimen Dosage forRegimen Patients for with Patients Multiple with Myeloma Multiple Myeloma National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. Administration Administration Precautions.Precautions. The quantity The of KYPROLIS quantity ofcontained KYPROLIS in contained one single‑use in onevial single‑use (60 mg vial (60 mg Cycle 1 Cycle 1 carfilzomib) may carfilzomib) exceed may the required exceed the dose. required Cautiondose. should Caution be used should in calculating be used inthe calculating quantity the quantity Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 delivered to prevent delivered overdosing. to prevent Do overdosing. not mix KYPROLIS Do not mix with KYPROLIS or administer with or as administer an infusion as with an infusion other with other DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days Days Day Day Day medicinal Theproducts. intravenous Theadministration intravenous administration line should beline flushed shouldwith be normal flushed saline with normal or 5% saline or 5% 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 medicinal 22–28 products. 1 Dextrose Injection, Dextrose USPInjection, immediately USP before immediately and after before KYPROLIS and after administration. KYPROLIS administration. KYPROLIS should KYPROLIS not should not KYPROLIS KYPROLIS 20 20 No 20 20 No20 20No 20 20 No 20 20 No 20 No No No 20 administered be administered as a bolus. KYPROLIS as a bolus. should KYPROLIS be administered should be administered over 2 to 10 minutes. over 2 toReconstitution 10 minutes. Reconstitution (20 mg/m2):(20 mg/m2): Dosing Dosing Dosing Dosing Dosing Dosing Dosing be Dosing and Preparation and Preparation for Intravenous for Intravenous Administration. Administration. KYPROLIS vials KYPROLIS containvials no antimicrobial contain no antimicrobial a Cycles 2 andCycles Beyond 2 and Beyonda preservativespreservatives and are intended and are onlyintended for singleonly use.forUnopened single use. vials Unopened of KYPROLIS vials of areKYPROLIS stable until arethe stable until the Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 date indicated date on the indicated package on when the package stored in when the original stored inpackage the original at 2°C package to 8°Cat(36°F 2°C to to 8°C 46°F). (36°F Theto 46°F). The DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days reconstituted Days Day Day Day reconstituted solution contains solution carfilzomib contains atcarfilzomib a concentration at a concentration of 2 mg/mL.ofRead 2 mg/mL. the complete Read the complete 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 preparation 22–28 1 instructions preparationprior instructions to reconstitution. prior to reconstitution. Reconstitution/Preparation Reconstitution/Preparation Steps: 1. Remove Steps:vial 1. Remove vial KYPROLIS KYPROLIS 27 27 No 27 27 No27 27No 27 27 No 27 27 No 27 No No No refrigerator 27 from fromjust refrigerator prior to use. just prior 2. Aseptically to use. 2.reconstitute Aseptically each reconstitute vial by each slowlyvial injecting by slowly 29 injecting mL 29 mL Dosing Dosing Dosing Dosing Dosing Dosing Sterile DosingWater Sterile (27 mg/m2):(27 mg/m2): Dosing Water USP, for Injection, the solution ontoWALL the INSIDE OFminimize THE VIAL to minimize for Injection, directingUSP, the directing solution onto the INSIDE OF THEWALL VIAL to a If previous cycle a If dosage foaming. Gently invert swirl and/or slowly for about 1 minute, or until complete dissolution foaming. 3. Gently swirl3.and/or the vialinvert slowlythe forvial about 1 minute, or until complete dissolution previousiscycle tolerated. dosage is tolerated. of powder any cakeoccurs. or powder occurs. DO to NOT SHAKE avoid foamIfgeneration. If foaming cake or DO NOT SHAKE avoid foamtogeneration. foaming occurs, allowoccurs, allow Hydration and Hydration Fluid Monitoring. and Fluid Monitoring. Hydrate patients Hydrate to reduce patients thetorisk reduce of renal the toxicity risk of renal and oftoxicity tumor andofofany tumor solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, lysis syndrome lysis (TLS) syndrome with KYPROLIS (TLS) withtreatment KYPROLIS [see treatment Warnings[see andWarnings Precautions]. and Precautions]. Maintain adequate Maintain adequate KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, fluid volume status fluid volume throughout statustreatment throughout andtreatment monitor blood and monitor chemistries bloodclosely. chemistries Prior closely. to each Prior dose to in each dose in colorless If any discoloration particulate matter do is observed, not use the reconstituted colorless If anysolution. discoloration or particulateormatter is observed, not use thedoreconstituted Cycle 1, give Cycle 250 mL 1, give to 500 250mLmLoftointravenous 500 mL ofnormal intravenous salinenormal or othersaline appropriate or otherintravenous appropriatefluid. intravenous fluid.solution. product. 5. When administering in anbag, intravenous calculated dose and [see Dosage and product. 5. When administering in an intravenous withdrawbag, the withdraw calculatedthe dose [see Dosage Give an additional Give an250 additional mL to 250 500 mL mL to of 500 intravenous mL of fluids intravenous as needed fluids following as neededKYPROLIS following KYPROLIS and50dilute into Dextrose 50 mL 5% Dextrose USP bag. intravenous bag. from the vialfrom and the dilutevialinto mL 5% Injection, USPInjection, intravenous administration. administration. Continue intravenous Continue hydration, intravenousashydration, needed, in as subsequent needed, in cycles. subsequent Also cycles. monitorAlsoAdministration] monitor Administration] 6. Immediately the vialthe containing unused of reconstituted 6. Immediately discard the discard vial containing unused the portion. The portion. stabilitiesTheof stabilities reconstituted patients during patients this period during for thisfluid period overload for fluid [seeoverload Warnings [see andWarnings Precautions]. and Precautions]. Dexamethasone Dexamethasone KYPROLIS various and temperature container shown variousunder temperature containerand conditions areconditions shown in are Table 3. in Table 3. Premedication. Premedication. Pre‑medicatePre‑medicate with dexamethasone with dexamethasone 4 mg orally or4intravenously mg orally or intravenously prior to all doses priorofto allKYPROLIS doses of under Table of 3: Reconstituted Stability of Reconstituted Table 3:toStability KYPROLIS KYPROLIS KYPROLIS during KYPROLIS Cycle during 1 and prior Cycleto1alland KYPROLIS prior to all doses KYPROLIS during doses the first during cyclethe of dose first cycle escalation of dose to escalation 2 27 mg/m2 to 27 mg/m reduce the toincidence reduce the andincidence severity ofand infusion severity reactions of infusion [seereactions Warnings[see andWarnings Precautions]. and Precautions]. a Stabilitya perStability Container per Container Reinstate dexamethasone Reinstate dexamethasone premedicationpremedication (4 mg orally or(4intravenously) mg orally or intravenously) if these symptoms if these develop symptoms or develop or Storage of Conditions of Reconstituted Storage Conditions Reconstituted reappear during reappear subsequent during cycles. subsequent Dosecycles. Modifications Dose Modifications based on Toxicities. based on Recommended Toxicities. Recommended IV Bag IV Bag KYPROLIS KYPROLIS actions and dose actions modifications and dose modifications are presentedare in Table presented 2. in Table 2. Vial Vial Syringe Syringe (D5Wb) (D5Wb) a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor Toxicity during KYPROLIS duringTreatment KYPROLIS Treatment RefrigeratedRefrigerated (2°C to 8°C;(2°C 36°Ftoto8°C; 46°F) 36°F to 46°F) 24 hours 2424 hours hours 2424hours hours 24 hours HematologicHematologic Toxicity Recommended Action Toxicity Recommended Action

• Withhold dose. • Withhold dose. • Grade 3a or Neutropenia • 4Grade 3a or 4 Neutropenia Room Temperature Room Temperature (15°C to 30°C; (15°C 59°F to to 30°C; 86°F) 59°F to 86°F) 4 hours 4 hours 4 hours 4 4hours hours 4 hours • If fully recovered • If fully before recovered next scheduled before next dose, scheduled continue dose, continue • Grade 4 Thrombocytopenia • Grade 4 Thrombocytopenia a b b Total time fromaTotal reconstitution time fromtoreconstitution administration to should administration not exceed should 24 hours. not exceed 5% 24 Dextrose hours.Injection, 5% Dextrose USP. Injection, USP. at same doseatlevel. same dose level. [see Warnings[see andWarnings Precautions] and Precautions] AND PRECAUTIONS: AND PRECAUTIONS: Cardiac Arrest, Cardiac Congestive Arrest, Congestive Heart Failure, Heart Myocardial Failure, Myocardial • If recovered • toIf recovered Grade 2 neutropenia to Grade 2 or neutropenia Grade 3 or Grade 3 WARNINGS WARNINGS Ischemia. Death Ischemia. due toDeath cardiacdue arrest to cardiac has occurred arrest has within occurred a day of within KYPROLIS a day of administration. KYPROLIS administration. New New thrombocytopenia, thrombocytopenia, reduce dose by reduce one dose level by one dose level onset onset or of worsening pre‑existingofcongestive pre‑existingheart congestive failure with heartdecreased failure withleftdecreased ventricularleftfunction ventricular or function or 2 2 2 (from 27 mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from to 20 mg/m to or worsening myocardial ischemia myocardial have ischemia occurred have following occurred administration following administration of KYPROLIS. of Cardiac KYPROLIS. failure Cardiac events failure events 15 mg/m2). 15 mg/m2). (e.g., cardiac (e.g., failurecardiac congestive, failurepulmonary congestive,edema, pulmonary ejection edema, fraction ejection decreased) fractionwere decreased) reportedwere in 7% reported in 7% • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the of patients. Monitor of patients. for cardiac Monitorcomplications for cardiac complications and manage and promptly. manage Withhold promptly. KYPROLIS Withhold forKYPROLIS Grade 3 for Grade 3 previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or 4 cardiac events or 4 cardiac until recovery events until and recovery consider and whether consider to restart whether KYPROLIS to restart based KYPROLIS on a benefit/risk based on a benefit/risk Non-Hematologic Non-Hematologic Toxicity Toxicity Recommended Recommended Action Action assessment [see assessment Dosage [see and Administration]. Dosage and Administration]. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and Class III and IV heart myocardial failure,infarction myocardial in infarction the preceding in the6 preceding months, and 6 months, conduction and abnormalities conduction abnormalities Cardiac Toxicity Cardiac Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. IV heart failure, by uncontrolled medications by were medications not eligible werefornottheeligible clinicalfortrials. the clinical These patients trials. These may patients be at greater may be at greater • After of: resolution, • Afterconsider resolution, if restarting considerKYPROLIS if restarting at KYPROLISuncontrolled at Grade 3 or 4, new Grade onset 3 oror4,worsening new onsetof: or worsening 2 risk for cardiac riskcomplications. for cardiac complications. Pulmonary Pulmonary Hypertension. Hypertension. Pulmonary arterial Pulmonary hypertension arterial hypertension (PAH) (PAH) a reduced is appropriate dose is(from appropriate 27 mg/m (from to 27 mg/m2 to • congestive•heart congestive failure; heart failure; a reduced dose 2 2 2 2 2 was reported was in 2% reported of patients in 2% treated of patients with KYPROLIS treated with and KYPROLIS was Grade and 3 was or greater Grade in 3 less or greater than 1% in less of than 1% of 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m ). mg/m • decreased•leftdecreased ventricularleft ventricular 20 mg/m , OR20from patients. withEvaluate cardiac with imaging cardiac and/or imaging other and/or tests as other indicated. tests asWithhold indicated. KYPROLIS WithholdforKYPROLIS for • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedpatients. to the Evaluate function; function; pulmonary hypertension until resolveduntil or returned resolved to or baseline returned and to baseline considerand whether consider to restart whether to restart at the discretion dose at the of the discretion physician. of the physician.pulmonary hypertension • or myocardial • orischemia myocardial ischemia previous doseprevious KYPROLIS based KYPROLIS on a based benefit/risk on a assessment benefit/risk assessment [see Dosage[see and Dosage Administration]. and Administration]. Pulmonary Pulmonary [see Warnings[see andWarnings Precautions] and Precautions] Complications. Complications. Dyspnea wasDyspnea reported was in 35% reported of patients in 35% enrolled of patients in clinical enrolled trials. in clinical Grade 3trials. dyspnea Grade 3 dyspnea occurred no Grade in 5%; 4 events, no Grade and4 1events, death and (Grade 1 death 5) was (Grade reported. 5) was Monitor reported. and Monitor manage and manage Pulmonary Hypertension Pulmonary Hypertension • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. occurred in 5%; dyspnea immediately; dyspnea immediately; interrupt KYPROLIS interrupt until KYPROLIS symptoms until have symptoms resolved have or returned resolved to or baseline returned [see to baseline [see • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced [see Warnings[see andWarnings Precautions] and Precautions] 2 2 Administration and Administration and Adverse and Reactions]. AdverseInfusion Reactions]. Reactions. Infusion Infusion Reactions. reactions Infusion were reactions were to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20Dosage mg/m2 and Dosage dose (from 27dose mg/m (from 2 by a spectrum by ofa systemic spectrum symptoms of systemicincluding symptoms fever, including chills, arthralgia, fever, chills, myalgia, arthralgia, facialmyalgia, facial to 15 mg/m2),toat15themg/m discretion ), at the of the discretion physician. of the physician.characterizedcharacterized edema,facial vomiting, edema, weakness, vomiting, shortness weakness, of breath, shortness hypotension, of breath, syncope, hypotension, chest syncope, tightness, chest tightness, • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedflushing, to the facialflushing, or angina. reactions These canreactions occur immediately can occur following immediately or up following to 24 hours or up after to 24administration hours after administration of of previous doseprevious at the discretion dose at the of the discretion physician. of the physician.or angina. These KYPROLIS.dexamethasone Administer dexamethasone prior to KYPROLIS prior toto KYPROLIS reduce theto incidence reduce the andincidence severity and of severity of Pulmonary Complications Pulmonary Complications • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS. Administer reactions [seereactions Dosage [see and Administration]. Dosage and Administration]. Inform patients Inform of thepatients risk and of symptoms the risk andand symptoms to contactand to contact • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade 3 or• 4 Grade 3 or 4 physician if symptoms physicianofif symptoms an infusionofreaction an infusion occurreaction [see Patient occurCounseling [see PatientInformation]. Counseling Tumor Information]. LysisTumor Lysis 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to [see Warnings[see andWarnings Precautions] and Precautions] Syndrome. Tumor Syndrome. lysis syndrome Tumor lysis (TLS) syndrome occurred (TLS) following occurred KYPROLIS following administration KYPROLIS administration in < 1% of in < 1% of 2 202,mg/m OR from to 20 15 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m patients. Patients patients. withPatients multiple with myeloma multiple andmyeloma a high tumor and aburden high tumor should burden be considered should betoconsidered be at to be at • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedgreater to the risk for greater TLS. Prior risk for to receiving TLS. PriorKYPROLIS, to receivingensure KYPROLIS, that patients ensure that are well patients hydrated are well [seehydrated Dosage [see Dosage previous doseprevious at the discretion dose at the of the discretion physician. of the physician.and Administration]. and Administration]. Monitor for evidence Monitor for of TLS evidence duringoftreatment, TLS duringand treatment, manage and promptly. manage Interrupt promptly. Interrupt Hepatic Toxicity Hepatic Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS until KYPROLIS TLS is resolved until TLS[see is resolved Dosage [see and Dosage Administration].Thrombocytopenia. and Administration].Thrombocytopenia. KYPROLIS KYPROLIS • After consider resolution, if restarting considerKYPROLIS if restarting is KYPROLIS iscauses thrombocytopenia • Grade 3 or• 4 Grade elevation 3 orof4 elevation•of After resolution, causes thrombocytopenia with platelet with nadirsplatelet occurring nadirs around occurring Day 8around of each Day28‑day 8 of each cycle28‑day and cycle and may appropriate; be reinitiated may at beareinitiated reduced dose at a reduced (from doserecovery (from to baseline transaminases, transaminases, bilirubin or other bilirubin orappropriate; other recoverybytothe baseline start ofbythe thenext start28‑day of the cycle. next 28‑day In patients cycle. with In patients multiple with myeloma, multiple 36% myeloma, of 36% of 2 27 mg/m2 to 20 27 mg/m22, to OR20from mg/m 202mg/m , OR from to 15 20 mg/m mg/m22) to 15patients mg/m2) experienced liver abnormalities liver abnormalities patients experienced thrombocytopenia, thrombocytopenia, including Grade including 4 in 10%. Grade Thrombocytopenia 4 in 10%. Thrombocytopenia following following with frequentwith monitoring frequentofmonitoring liver function. of liver function. KYPROLIS administration KYPROLIS administration resulted in aresulted dose reduction in a dose in reduction 1% of patients in 1% and of patients discontinuation and discontinuation of of [see Warnings[see andWarnings Precautions] and Precautions] • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedtreatment to the with treatment KYPROLIS within KYPROLIS < 1% of patients. in < 1%Monitor of patients. platelet Monitor counts platelet frequently countsduring frequently treatment during treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician.with KYPROLIS. withReduce KYPROLIS. or interrupt Reduce dose or interrupt as clinically dose indicated as clinically [seeindicated Dosage [see and Dosage Administration]. and Administration]. Hepatic Toxicity Hepatic andToxicity Hepaticand Failure. Hepatic Cases Failure. of hepatic Cases failure, of hepatic including failure, fatalincluding cases, have fatalbeen cases, have been (continued) (continued)

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FDA Update

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FDA Grants Fast Track Designation to Evofosfamide for Advanced Pancreatic Cancer

he U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of evofosfamide (TH-302), administered in combination with gemcitabine,

for previously untreated patients with metastatic or locally advanced unresectable pancreatic cancer. Evofosfamide is an investigational drug that is thought to be activated under severe

tumor hypoxic conditions, a feature of many solid tumors. The new agent currently is being evaluated in pancreatic cancer in the phase III MAESTRO study, which ran-

The ASCO Post Wants to Hear From You B:11.25”

T:10.875”

S:10” B:11.25”

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. S:10”

One event wasbOne Grade event 5 severity. was Grade 5 severity.

domly assigned patients to either gemcitabine plus placebo or gemcitabine plus evofosfamide. The primary efficacy endpoint is overall survival, and secondary endpoints include efficacy measured by progression-free survival, overall response rate and disease control rate. It is anticipated that the number of protocol-specified events for the trial may be reached in the second half of 2015, with primary efficacy analyses to be available shortly thereafter. The compound is being developed by Merck KGaA, Darmstadt, Germany, in collaboration with Threshold Pharmaceuticals, Inc. n

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reported (< 1%). reported KYPROLIS (< 1%).can KYPROLIS cause elevations can causeof elevations serum transaminases of serum transaminases and bilirubin.and Withhold bilirubin.Description Withhold Description of SelectedofAdverse Selected Drug Adverse Reactions. Drug Renal Reactions. Events: Renal The Events: most common The most renal common renal KYPROLIS in KYPROLIS patients experiencing in patients experiencing Grade 3 or greater Gradeelevations 3 or greater of elevations transaminases, of transaminases, bilirubin, or other bilirubin,adverse or otherreactions adverse were reactions increasewere in blood increase creatinine in blood (24%) creatinine and renal (24%) failure and (9%), renal which failurewere (9%),mostly which were mostly liver abnormalities liver abnormalities until resolveduntil or returned resolved to or baseline. returned to After baseline. resolution, Afterconsider resolution, if restarting consider if restarting Grade 1 or Grade Grade 21 inorseverity. Grade 2Grade in severity. 3 renalGrade adverse 3 renal reactions adverse occurred reactions in 6% occurred of patients in 6%and of patients and KYPROLIS is KYPROLIS appropriate. is appropriate. Monitor liver Monitor enzymesliver frequently enzymes[see frequently Dosage [see and Dosage Administration and Administration and Gradeand 4 events Grade occurred 4 events in 1%. occurred Discontinuations in 1%. Discontinuations due to increased due to blood increased creatinine blood andcreatinine acute renal and acute renal Adverse Reactions]. AdverseEmbryo-fetal Reactions]. Embryo-fetal Toxicity. KYPROLIS Toxicity. canKYPROLIS cause fetal canharm cause when fetaladministered harm when administered to a failuretowere a 1% failure each. were In 1% one each. patient, In death one patient, occurred death withoccurred concurrent withsepsis concurrent and worsening sepsis andrenal worsening renal pregnant woman pregnant basedwoman on its mechanism based on itsofmechanism action and of findings actioninand animals. findings There in animals. are no adequate There are and no adequate and[see function function Dosage and [seeAdministration]. Dosage and Administration]. Peripheral Neuropathy: Peripheral Neuropathy: Peripheral neuropathy Peripheral(including neuropathy (including well‑controlledwell‑controlled studies in pregnant studieswomen in pregnant usingwomen KYPROLIS. using Carfilzomib KYPROLIS.caused Carfilzomib embryo‑fetal caused toxicity embryo‑fetal in all toxicity in of all events peripheral events ofsensory peripheral neuropathy sensoryand neuropathy peripheral andmotor peripheral neuropathy) motor occurred neuropathy) in 14% occurred of in 14% of pregnant rabbits pregnant at doses rabbits that were at doses lower thatthan were in patients lower than receiving in patients the recommended receiving the recommended dose. Femalesdose. of Females patientsofenrolled patients in clinical enrolled trials. in clinical Grade 3trials. peripheral Grade neuropathy 3 peripheraloccurred neuropathy in 1% occurred of patients. in 1%Serious of patients. Serious reproductive potential reproductive should potential be advised should to be avoid advised becoming to avoid pregnant becoming whilepregnant being treated while being with KYPROLIS. treated with KYPROLIS. peripheral neuropathy peripheralevents neuropathy occurred events in <occurred 1% of patients, in < 1%which of patients, resulted which in dose resulted reduction in dose in <reduction 1% in < 1% If this drug isIfused this drug duringis pregnancy, used duringorpregnancy, if the patient or ifbecomes the patient pregnant becomes while pregnant taking this whiledrug, taking thethis and drug,treatment the and discontinuation treatment discontinuation in < 1%. Withhold in < 1%. or discontinue Withhold or treatment discontinue as treatment recommended as recommended [see [see patient shouldpatient be apprised shouldofbethe apprised potential of hazard the potential to the hazard fetus [see to the Usefetus in Specific [see Use Populations]. in Specific Populations]. Dosage and Administration]. Dosage and Administration]. Herpes VirusHerpes Infection: Virus Herpes Infection: zosterHerpes reactivation zosterwas reactivation reportedwas in 2% reported in 2% ADVERSE REACTIONS: ADVERSE REACTIONS: The following adverse The following reactions adverse are discussed reactions are in greater discussed detail in in greater other detail sections in otherofsections patients. Consider of patients. antiviral Consider prophylaxis antiviralfor prophylaxis patients who for patients have a history who have of herpes a history zoster of herpes infection. zoster infection. of the labeling:of the labeling: DRUG INTERACTIONS: DRUG INTERACTIONS: Carfilzomib isCarfilzomib primarily metabolized is primarily via metabolized peptidasevia andpeptidase epoxide and hydrolase epoxide hydrolase • Cardiac Arrest, • Cardiac Congestive Arrest,Heart Congestive Failure,Heart Myocardial Failure,Ischemia Myocardial [seeWarnings Ischemia [see andWarnings Precautions] and Precautions] activities, andactivities, as a result, and the as apharmacokinetic result, the pharmacokinetic profile of carfilzomib profile ofiscarfilzomib unlikely toisbeunlikely affectedto by be affected by • Pulmonary •Hypertension Pulmonary Hypertension [seeWarnings [see andWarnings Precautions] and Precautions] concomitant administration concomitant administration of cytochromeofP450 cytochrome inhibitors P450 andinhibitors inducers.and Carfilzomib inducers.isCarfilzomib not expected is not expected • Pulmonary •Complications Pulmonary Complications [seeWarnings [see andWarnings Precautions] and Precautions] to influence exposure to influence of other exposure drugsof[see otherClinical drugs Pharmacology [see Clinical Pharmacology section of fullsection PI]. of full PI]. • Infusion Reactions • Infusion [see Reactions Warnings [see andWarnings Precautions] and Precautions] USE IN SPECIFIC USE IN POPULATIONS: SPECIFIC POPULATIONS: Pregnancy. Pregnancy. Pregnancy Category PregnancyD Category [see Warnings D [seeand Warnings and • Tumor Lysis•Syndrome Tumor Lysis [see Syndrome Warnings [see andWarnings Precautions] and Precautions] Females of potential reproductive potential shouldtobe advised to avoid becoming pregnant while Precautions].Precautions]. Females of reproductive should be advised avoid becoming pregnant while • Thrombocytopenia • Thrombocytopenia [seeWarnings [see andWarnings Precautions] and Precautions] treated withBased KYPROLIS. on itsofmechanism action and findingsKYPROLIS in animals, KYPROLIS being treatedbeing with KYPROLIS. on its Based mechanism action andoffindings in animals, • Hepatic Toxicity • Hepatic and Hepatic Toxicity Failure and Hepatic [seeWarnings Failure [see andWarnings Precautions] and Precautions] can harm causewhen fetal administered harm when administered a pregnant woman.caused Carfilzomib caused embryo‑fetal can cause fetal to a pregnanttowoman. Carfilzomib embryo‑fetal The most common The most adverse common reactions adverse (incidence reactions of (incidence 30% or greater) of 30%toorKYPROLIS greater) to observed KYPROLIS in clinical observed toxicity in clinical toxicity rabbits in pregnant rabbits doses thatthan wereinlower thanreceiving in patients the recommended in pregnant at doses thatatwere lower patients thereceiving recommended trials of patients trialswith of patients multiple with myeloma multiple were myeloma fatigue,were anemia, fatigue, nausea, anemia, thrombocytopenia, nausea, thrombocytopenia, dyspnea, dose. dyspnea, dose. Ifis KYPROLIS is pregnancy, used duringorpregnancy, or ifbecomes the patient becomes pregnant If KYPROLIS used during if the patient pregnant while taking while this taking this diarrhea, anddiarrhea, pyrexia. and Clinical pyrexia. Trials Clinical SafetyTrials Experience. Safety Experience. Because clinical Because trials clinical are conducted trials are conducted drug,should the patient shouldofbethe apprised of hazard the potential to the fetus.was Carfilzomib was administered drug, the patient be apprised potential to the hazard fetus. Carfilzomib administered under widely under varyingwidely conditions, varyingadverse conditions, reaction adverse ratesreaction observed rates in the observed clinicalintrials the of clinical a drugtrials cannot of a drug cannot intravenously to pregnant ratsduring and rabbits during period of organogenesis at doses intravenously to pregnant rats and rabbits the period of the organogenesis at doses of 0.5, 1, andof 0.5, 1, and be directly compared be directlywith compared rates in with the clinical rates intrials the clinical of another trialsdrug, of another and may drug, not and reflect maythenotrates reflect 2themg/kg/day rates 2inmg/kg/day in rats and 0.8inmg/kg/day in rabbits.was Carfilzomib was notatteratogenic at rats and 0.2, 0.4,and and0.2, 0.8 0.4, mg/kg/day rabbits. Carfilzomib not teratogenic observed in medical observed practice. in medical A total practice. of 526Apatients total of with 526 relapsed patients with and/or relapsed refractory and/or multiple refractory myeloma multiple any myeloma any dose tested.there In rabbits, was in an pre‑implantation increase in pre‑implantation at ≥ 0.4 mg/kg/day dose tested. In rabbits, was anthere increase loss at ≥ 0.4loss mg/kg/day received KYPROLIS received as KYPROLIS monotherapy as monotherapy or with pre‑dose or with dexamethasone. pre‑dose dexamethasone. Patients received Patients a median received of a median and in anearly increase in earlyand resorptions and post‑implantation loss andina fetal decrease in at fetal weight at and an ofincrease resorptions post‑implantation loss and a decrease weight four treatment fourcycles treatment with acycles median withcumulative a medianKYPROLIS cumulativedose KYPROLIS of 993.4 dose mg.ofDeaths 993.4 due mg. to Deaths all due to all thetoxic maternally of 0.8The mg/kg/day. of 0.4 and 0.8inmg/kg/day the maternally dose oftoxic 0.8 dose mg/kg/day. doses ofThe 0.4doses and 0.8 mg/kg/day rabbits arein rabbits are causes withincauses 30 days within of the30last days dose of the of KYPROLIS last dose of occurred KYPROLIS in 37/526 occurred (7%) in 37/526 of patients. (7%)Deaths of patients. not Deaths not approximately 20% and 40%, of respectively, of the recommended doseof in27humans 27 mg/m2 based approximately 20% and 40%, respectively, the recommended dose in humans mg/m2 of based attributed to disease attributed progression to diseasewere progression cardiac were in 5 patients cardiac (acute in 5 patients coronary (acute syndrome, coronary cardiac syndrome, arrest,cardiac on arrest, body surface on body area.surface Nursing area. Mothers. Nursing It isMothers. not known It iswhether not known KYPROLIS whetheris KYPROLIS excreted inishuman excreted in human cardiac disorder), cardiac end‑organ disorder),failure end‑organ in 4 patients failure in(multi‑organ 4 patients (multi‑organ failure, hepatic failure, failure, hepatic renal failure, failure),renalmilk. failure), Since many milk.drugs Since are many excreted drugs are in human excreted milkin and human because milk and of the because potential of for the serious potentialadverse for serious adverse infection in infection 4 patientsin (sepsis, 4 patients pneumonia, (sepsis, pneumonia, respiratory tract respiratory bacterial tract infection), bacterialdyspnea infection), anddyspnea and in nursing reactions reactions infants in nursing from KYPROLIS, infants from a decision KYPROLIS, should a decision be made should whether be made to discontinue whether tonursing discontinue nursing intracranial hemorrhage intracranial in hemorrhage 1 patient each, in 1 patient and 1 each, patientand found 1 patient dead offound unknown dead causes. of unknown Serious causes.orSerious to discontinue or tothe discontinue drug, taking the into drug,account taking into the importance account theofimportance the drug toofthe themother. drug toPediatric the mother. Pediatric adverse reactions adverse were reactions reportedwere in 45% reported patients. in 45% The patients. most common The most serious common adverse serious reactions adverse were reactions Use.were The safety Use.and Theeffectiveness safety and effectiveness of KYPROLISofin KYPROLIS pediatric patients in pediatric havepatients not been have established. not been established. pneumonia (10%), pneumonia acute (10%), renal failure acute (4%), renal pyrexia failure (4%), (3%),pyrexia and congestive (3%), andheart congestive failure (3%). heart Adverse failure (3%).Geriatric Adverse Use. Geriatric In studies Use. of KYPROLIS In studies there of KYPROLIS were nothere clinically weresignificant no clinically differences significantobserved differences in safety observed in safety reactions leading reactions to discontinuation leading to discontinuation of KYPROLIS occurred of KYPROLIS in 15% occurred of patients in 15% and of included patients and congestive included congestive and efficacy between and efficacy patients between less than patients 65 years less than of age 65 and yearspatients of age 65 andyears patients of age 65 and yearsolder. of age Renal and older. Renal heart failure (2%), heart failure cardiac(2%), arrest, cardiac dyspnea, arrest, increased dyspnea, blood increased creatinine, bloodand creatinine, acute renal andfailure acute (1% renal failure (1% Impairment. Impairment. The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS evaluated were in evaluated a Phase 2intrial a Phase in 2 trial in each). Adverse each). reactions Adverse occurring reactions at aoccurring rate of 10% at a or rate greater of 10% areorpresented greater are in Table presented 4. in Table 4. patients withpatients normal with renal normal functionrenal and function those with andmild, thosemoderate, with mild,and moderate, severe renal and severe impairment renal impairment on chronic patientsdialysis. on chronic On average, dialysis. patients On average, werepatients treated were for 5.5 treated cyclesforusing 5.5 cycles KYPROLIS using KYPROLIS Table 4: Incidence Table 4:ofIncidence Adverse Reactions of AdverseOccurring ReactionsinOccurring ≥ 10% of in Multiple ≥ 10% Myeloma of Multiple Myelomaand patients and 2 doses of 15 doses mg/m2ofon15Cycle mg/m 1,2 20 on mg/m Cycle 21,on20Cycle mg/m 2,2 and on Cycle 27 mg/m 2, and on27Cycles mg/m32 on andCycles beyond. 3 and beyond. Patients Treated Patients withTreated KYPROLIS with KYPROLIS The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS not influenced were notbyinfluenced the degreebyofthe baseline degreerenal of baseline renal Patients Patients (N = 526) (N = 526) impairment, including impairment, the including patients on thedialysis. patientsSince on dialysis. dialysisSince clearance dialysis of clearance KYPROLIS ofconcentrations KYPROLIS concentrations [n (%)] [n (%)] has not beenhas studied, not been the studied, drug should the drug be administered should be administered after the dialysis after procedure the dialysis[see procedure Clinical [see Clinical Grade Grade 3 4 GradePharmacology 4 All Grade 3 All Pharmacology section of fullsection PI]. Hepatic of full Impairment. PI]. Hepatic Impairment. The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of of a a EventsEvents Events Event GradesEvents Event Grades KYPROLIS have KYPROLIS not been have evaluated not been in evaluated patients with in patients baselinewith hepatic baseline impairment. hepatic Patients impairment. withPatients the with the following laboratory following values laboratory were excluded values were fromexcluded the KYPROLIS from theclinical KYPROLIS trials:clinical ALT/AST trials: ≥ 3ALT/AST × upper ≥ 3 × upper Fatigue Fatigue 292 (55.5) 292 (55.5) 38 (7.2) 38 (7.2)2 (0.4) 2 (0.4) limit of normallimit (ULN) of normal and bilirubin (ULN) ≥ and 2× bilirubin ULN [see ≥ 2Clinical × ULN Pharmacology [see Clinical Pharmacology section of fullsection PI]. Cardiac of full PI]. Cardiac Anemia Anemia 246 (46.8) 246 (46.8) 111 (21.1) 111 (21.1)7 (1.3) 7 (1.3) Impairment.Impairment. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and IV Class heartIII failure and IV were heartnot failure eligible were not eligible Nausea Nausea 236 (44.9) 236 (44.9)7 (1.3) 7 (1.3) 0 0 for the clinicalfortrials. the clinical Safety in trials. this Safety population in thishas population not beenhas evaluated. not been evaluated. Thrombocytopenia Thrombocytopenia 191 (36.3) 191 (36.3) 69 (13.1) 69 (13.1) 54 (10.3) 54 (10.3) OVERDOSAGE: OVERDOSAGE: There is no known There isspecific no known antidote specific for KYPROLIS antidote foroverdosage. KYPROLIS In overdosage. the event of In the an event of an b overdosage, monitor overdosage, the patient monitorand theprovide patientappropriate and providesupportive appropriatecare. supportive care. Dyspnea Dyspnea 182 (34.6) 182 (34.6) 25 (4.8) 25 (4.8)1 (0.2)b 1 (0.2) NONCLINICAL NONCLINICAL TOXICOLOGY: TOXICOLOGY: Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, and Impairment and Impairment of Fertility. of Fertility. Diarrhea Diarrhea 172 (32.7) 172 (32.7)4 (0.8) 4 (0.8)1 (0.2) 1 (0.2) Carcinogenicity Carcinogenicity studies have studies not beenhave conducted not beenwith conducted carfilzomib. withCarfilzomib carfilzomib.was Carfilzomib clastogenic wasinclastogenic the in the Pyrexia Pyrexia 160 (30.4) 160 (30.4)7 (1.3) 7 (1.3)2 (0.4) 2 (0.4) in vitro chromosomal in vitro chromosomal aberration testaberration in peripheral test in blood peripheral lymphocytes. blood lymphocytes. Carfilzomib was Carfilzomib not mutagenic was not mutagenic in the in vitro in bacterial the in vitro reverse bacterial mutation reverse (Ames) mutation test and (Ames) was test not and clastogenic was not in clastogenic the in vivo in the in vivo mouse mouse Upper respiratory Uppertract respiratory infectiontract infection 149 (28.3) 149 (28.3) 17 (3.2) 17 (3.2) 0 0 marrow micronucleus Fertility withhave carfilzomib have not beenNo conducted. No micronucleus assay. Fertilityassay. studies with studies carfilzomib not been conducted. Headache Headache 145 (27.6) 145 (27.6)7 (1.3) 7 (1.3) 0 0 bone marrowbone effects on reproductive were noted during 28‑day repeat‑dose rat and monkey toxicity effects on reproductive tissues weretissues noted during 28‑day repeat‑dose rat and monkey toxicity Cough Cough 137 (26.0) 137 (26.0)1 (0.2) 1 (0.2) 0 0 studies or in studies in and 6‑month rat and 9‑month monkey chronic toxicity studies. Animal and/ Toxicology and/ 6‑monthorrat 9‑month monkey chronic toxicity studies. Animal Toxicology Blood creatinine Blood increased creatinine increased 127 (24.1) 127 (24.1) 13 (2.5) 13 (2.5)1 (0.2) 1 (0.2) or Pharmacology. Monkeys administered single bolusdose intravenous dose ofatcarfilzomib or Pharmacology. Monkeys administered a single bolusa intravenous of carfilzomib 3 mg/kg at 3 mg/kg 2 2 1.3 times recommended doseofin27humans 27 mg/m (approximately(approximately 1.3 times recommended dose in humans mg/m ofbased on body based surface on body area) surface area) LymphopeniaLymphopenia 126 (24.0) 126 (24.0) 84 (16.0) 84 (16.0) 11 (2.1) 11 (2.1) experienced hypotension, experienced increased hypotension, heart increased rate, andheart increased rate, and serum increased levels of serum troponin‑T. levels ofThe troponin‑T. repeated The repeated Edema peripheral Edema peripheral 126 (24.0) 126 (24.0)3 (0.6) 3 (0.6) 0 0 bolus intravenous bolus administration intravenous administration of carfilzomibofatcarfilzomib ≥ 2 mg/kg/dose at ≥ 2 in mg/kg/dose rats and in 2 mg/kg/dose rats and 2 mg/kg/dose in in Vomiting Vomiting 117 (22.2) 117 (22.2)5 (1.0) 5 (1.0) 0 0 monkeys using monkeys dosingusing schedules dosingsimilar schedules to those similar usedto clinically those used resulted clinically in mortalities resulted inthat mortalities were that were due occurring to toxicities in occurring the cardiovascular in the cardiovascular (cardiac failure, (cardiac cardiac failure, fibrosis, cardiac pericardial fibrosis,fluid pericardial fluid Constipation Constipation 110 (20.9) 110 (20.9)1 (0.2) 1 (0.2) 0 0 due to toxicities accumulation,accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Neutropenia Neutropenia 109 (20.7) 109 (20.7) 50 (9.5) 50 (9.5)4 (0.8) 4 (0.8) (glomerulonephropathy, tubular necrosis, and pulmonary (glomerulonephropathy, tubulardysfunction), necrosis, dysfunction), and(hemorrhage/inflammation) pulmonary (hemorrhage/inflammation) Back pain Back pain 106 (20.2) 106 (20.2) 15 (2.9) 15 (2.9) 0 0 systems. The systems. dose of 2inmg/kg/dose in rats is approximately half the recommended dose in humans dose of 2The mg/kg/dose rats is approximately half the recommended dose in humans 2 Insomnia Insomnia 94 (17.9) 94 (17.9) 0 0 0 0 of 27 mg/m2ofbased 27 mg/m on body based surface on body area.surface The dose area. of 2The mg/kg/dose dose of 2 in mg/kg/dose monkeys isinapproximately monkeys is approximately equivalent to equivalent the recommended to the recommended dose in humans dose based in humans on body based surface on body area. surface area. Chills Chills 84 (16.0) 84 (16.0)1 (0.2) 1 (0.2) 0 0 PATIENT COUNSELING INFORMATION: INFORMATION: Discuss the following Discuss the withfollowing patients with priorpatients to treatment prior with to treatment with Arthralgia Arthralgia 83 (15.8) 83 (15.8)7 (1.3) 7 (1.3) 0 0 PATIENT COUNSELING KYPROLIS: Instruct KYPROLIS: patients Instruct to contact patients their to contact physiciantheir if they physician develop if they any of develop the following any of the symptoms: following symptoms: Muscle spasms Muscle spasms 76 (14.4) 76 (14.4)2 (0.4) 2 (0.4) 0 0 fever, chills, rigors, fever, chills, chest rigors, pain, cough, chest or pain, swelling cough,oforthe swelling feet oroflegs. the Advise feet or patients legs. Advise that patients KYPROLIS that KYPROLIS HypertensionHypertension 75 (14.3) 75 (14.3) 15 (2.9) 15 (2.9)2 (0.4) 2 (0.4) may cause fatigue, may cause dizziness, fatigue, fainting, dizziness, and/or fainting, drop inand/or blooddrop pressure. in blood Advise pressure. patients Advise not topatients drive ornot to drive or operate machinery operate if they machinery experience if theyany experience of these symptoms. any of theseAdvise symptoms. patients Advise that they patients maythat experience they may experience Asthenia Asthenia 73 (13.9) 73 (13.9) 12 (2.3) 12 (2.3)1 (0.2) 1 (0.2) shortness of shortness breath (dyspnea) of breath during (dyspnea) treatment during with treatment KYPROLIS. withThis KYPROLIS. most commonly This mostoccurs commonly withinoccurs within Hypokalemia Hypokalemia 72 (13.7) 72 (13.7) 14 (2.7) 14 (2.7)3 (0.6) 3 (0.6) a day of dosing. a day Advise of dosing. patients Advise to contact patientstheir to contact physicians theirif physicians they experience if theyshortness experience of shortness breath. of breath. Hypomagnesemia Hypomagnesemia 71 (13.5) 71 (13.5)2 (0.4) 2 (0.4) 0 0 Counsel patients Counsel to avoid patients dehydration, to avoid dehydration, since patientssince receiving patients KYPROLIS receivingtherapy KYPROLIS may therapy experience may experience vomiting and/or vomiting diarrhea. and/or Instruct diarrhea. patients Instruct to seek patients medical to seek advice medical if theyadvice experience if theysymptoms experience symptoms Leukopenia Leukopenia 71 (13.5) 71 (13.5) 27 (5.1) 27 (5.1)1 (0.2) 1 (0.2) lightheadedness, dizziness, lightheadedness, or fainting spells. or fainting Counsel spells. females Counsel of reproductive females of reproductive potential to use potential to use Pain in extremity Pain in extremity 70 (13.3) 70 (13.3)7 (1.3) 7 (1.3) 0 0 of dizziness, of effective contraceptive effective contraceptive measures to measures prevent pregnancy to preventduring pregnancy treatment during with treatment KYPROLIS. withAdvise KYPROLIS. the Advise the b Pneumonia Pneumonia 67 (12.7) 67 (12.7) 52 (9.9) 52 (9.9)3 (0.6)b 3 (0.6) patient that ifpatient she becomes that if she pregnant becomes during pregnant treatment, duringto treatment, contact hertophysician contact her immediately. physician immediately. Advise Advise Aspartate aminotransferase Aspartate aminotransferase increased increased 66 (12.5) 66 (12.5) 15 (2.9) 15 (2.9)1 (0.2) 1 (0.2) patients not topatients take KYPROLIS not to take treatment KYPROLIS while treatment pregnant while or breastfeeding. pregnant or breastfeeding. If a patient wishes If a patient to restart wishes to restart breastfeeding breastfeeding after treatment, after advise treatment, her to advise discuss her the to appropriate discuss the timing appropriate with her timing physician. with her Advise physician. Advise Dizziness Dizziness 66 (12.5) 66 (12.5)5 (1.0) 5 (1.0)1 (0.2) 1 (0.2) patientswith to discuss their physician with their anyphysician medication anythey medication are currently they are taking currently prior to taking starting prior to starting HypoesthesiaHypoesthesia 64 (12.2) 64 (12.2)3 (0.6) 3 (0.6) 0 0 patients to discuss treatment withtreatment KYPROLIS, withorKYPROLIS, prior to starting or prior anytonew starting medication(s) any new medication(s) during treatment during withtreatment KYPROLIS. with KYPROLIS. Anorexia Anorexia 63 (12.0) 63 (12.0)1 (0.2) 1 (0.2) 0 0 Pain Pain 63 (12.0) 63 (12.0) 12 (2.3) 12 (2.3) 0 0 Hyperglycemia Hyperglycemia 62 (11.8) 62 (11.8) 16 (3.0) 16 (3.0)3 (0.6) 3 (0.6) Chest wall pain Chest wall pain 60 (11.4) 60 (11.4)3 (0.6) 3 (0.6) 0 0 Hypercalcemia Hypercalcemia 58 (11.0) 58 (11.0) 13 (2.5) 13 (2.5)8 (1.5) 8 (1.5) Manufactured Manufactured for: Onyx Pharmaceuticals, for: Onyx Pharmaceuticals, Inc., 249 EastInc., Grand 249Avenue, East Grand Avenue, Hypophosphatemia Hypophosphatemia 55 (10.5) 55 (10.5) 24 (4.6) 24 (4.6)3 (0.6) 3 (0.6) South San Francisco, South San CAFrancisco, 94080 CA 94080 HyponatremiaHyponatremia 54 (10.3) 54 (10.3) 31 (5.9) 31 (5.9)3 (0.6) 3 (0.6) U.S. Patent Numbers: U.S. Patent7,232,818; Numbers:7,417,042; 7,232,818;7,491,704; 7,417,042;7,737,112 7,491,704; 7,737,112 05‑1088‑00 05‑1088‑00 a National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. ©2014 Onyx©2014 Pharmaceuticals, Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J Inc. TROPIC‑KYPR‑100826J November 2014 November 2014

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

The ASCO Post | MAY 25, 2015

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In the Clinic Gastrointestinal Oncology

Ramucirumab With FOLFIRI in Metastatic Colorectal Cancer 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 April 24, the monoclonal antibody ramucirumab (Cyramza) was approved for use in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan) for treatment of patients with metastatic colorectal cancer with disease progression on a first-line line regimen including bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine.1,2 The drug was initially approved to treat patients with gastric cancer and, subsequently, to treat non–small cell lung cancer.

Supporting Trial Approval was based on results of the phase III RAISE trial showing significantly increased overall survival with ramucirumab treatment in this setting.2,3 In the trial, 1,072 patients were randomly assigned to FOLFIRI plus ramucirumab (n = 536) or FOLFIRI plus placebo (n = 536) given in 2-week cycles. Ramucirumab was given every 2 weeks at 8 mg/kg via intravenous infusion until disease progression or unacceptable toxicity. Patients had a median age of 62 years, 57% were male, 76% were white and 20% were Asian, 49% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, 49% had KRASmutant tumors, and time to disease progression after beginning first-line treatment was < 6 months in 24%. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4–14.5 months) in the ramucirumab group vs 11.7 months (95% CI = 10.8–12.7 months) in the placebo group (hazard ratio [HR] = 0.85, P = .023). Progression-free survival was also significantly prolonged in the ramucirumab group (median, 5.7 vs 4.5 months, HR = 0.79, P < .001).

OF NOTE Ramucirumab inhibits ligand-stimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells.

How It Works Ramucirumab is a recombinant human IgG1 monoclonal antibody that acts as a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. It specifically binds VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D. As a result of receptor blockade, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells. Ramucirumab inhibited angiogenesis in animal models.

How It Is Given The recommended dose of ramucirumab in metastatic colorectal cancer is 8 mg/kg every 2 weeks via intravenous infusion over 60 minutes prior to FOL-

OF NOTE Ramucirumab carries boxed warnings for hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events, gastrointestinal perforation, and impaired wound healing.

nal perforation, grade 3 or 4 bleeding, or reversible posterior leukoencephalopathy syndrome.

Safety Profile In the phase III trial, patients received a median of 8 doses (range, 1–68) of ramucirumab. Median duration of exposure was 4.4 months, with 32% of patients receiving ramucirumab for ≥ 6 months. Safety data were gen-

Expanded Approval for Ramucirumab ■■ Ramucirumab (Cyramza) was recently approved for use in combination with FOLFIRI to treat metastatic colorectal cancer with disease progression on a first-line line regimen including bevacizumab, oxaliplatin, and a fluoropyrimidine. ■■ The recommended dose of ramucirumab in metastatic colorectal cancer is 8 mg/kg every 2 weeks via intravenous infusion over 60 minutes prior to FOLFIRI administration.

FIRI administration. Ramucirumab should be continued until disease progression or unacceptable toxicity. All patients should be premedicated with an intravenous histamine H1 antagonist (eg, diphenhydramine hydrochloride) prior to each infusion; patients who have a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen. The infusion rate should be reduced by 50% for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be interrupted in patients with severe hypertension and prior to surgery until wounds are fully healed. Treatment should be interrupted in patients with urine protein levels ≥ 2 g/24 hours and restarted after improvement to < 2 g/24 hours at 6 mg/kg upon first occurrence and at 5 mg/kg upon second occurrence. Ramucirumab should be permanently discontinued in patients with severe hypertension that cannot be managed with antihypertensive therapy, proteinuria of > 3 g/24 hours or nephrotic syndrome, arterial thromboembolic events, gastrointesti-

erally consistent with the safety profile of ramucirumab in other approved indications. An exception is thyroid dysfunction (hypothyroidism), which was reported in 2.6% of patients based on thyroid monitoring in patients with metastatic colorectal cancer. The most common adverse events of any grade in patients receiving ramucirumab-FOLFIRI that occurred with an incidence ≥ 2% higher vs the placeboFOLFIRI group were diarrhea (60% vs 51%), neutropenia (59% vs 46%), decreased appetite (37% vs 27%), epistaxis (33% vs 15%), and stomatitis (31% vs 21%). The most common grade ≥ 3 adverse events were neutropenia (38% vs 33%), diarrhea (11% vs 10%), and hypertension (11% vs 3%). Granulocyte colony-stimulating factor treatment was required in 20% of patients in the ramucirumab group. Adverse events led to discontinuation of any study drug in 29% vs 13% of patients, with the most common being neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2% vs 0.8%); the most common events leading to discontinuation of ramucirumab were proteinuria (1.5%) and gastrointestinal perforation (1.7%). The most

common serious adverse events in the ramucirumab group were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%). Ramucirumab carries boxed warnings for hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events, gastrointestinal perforation, and impaired wound healing. It also has warnings/precautions for arterial thromboembolic events (sometimes fatal), hypertension, infusion-related reactions, clinical deterioration in patients with cirrhosis (including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome), reversible posterior leukoencephalopathy syndrome, proteinuria, thyroid dysfunction, and embryofetal risk. Patients should be monitored for hypertension, proteinuria, and thyroid function during treatment and for infusion-related reactions. n References 1. U.S. Food and Drug Administration: Ramucirumab mCRC. Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm444496.htm. Accessed May 4, 2015. 2. Cyramza® (ramucirumab) injection prescribing information, Eli Lilly and Company, April 2015. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2015/125477s011lbl.pdf. Accessed May 4, 2015. 3. Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015 5:499-508, 2015.

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

ASCOPost.com | MAY 25, 2015

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Perspective

In Search of Meaning: A Personal Journey By William Breitbart, MD

William Breitbart, MD

famous Talmudic question asks: “What is truer than the truth?” The answer: “The story.” This is the story of my personal journey in search of meaning and the development of an approach to care for patients with advanced cancer, which I came to call “meaning-centered psychotherapy.” In terms of the scientific rationale, structure, and practice of meaning-centered psychotherapy, see page 112 in this issue for a report on my paper published recently in the Journal of Clinical

me. It is what life has given me, and I have made the choice to respond to this legacy of death, loss, and perceived meaninglessness by using it as a source for compassion to ease those in despair with advanced cancer and help them reclaim a life of meaning in the face of loss, suffering, and limitations. My parents, Rose and Moses Breitbart, were Holocaust survivors. After their lives were disrupted at ages 14 and 17, respectively, my parents survived by fighting as partisans in the forests of Poland and finally wound up in a displaced persons camp outside of Munich called Fahrenwald. In 1949, they married there and spent their wedding night in a borrowed “wedding bed.” Arriving on the Lower East Side of Manhattan, they had nothing of their own but the will to live and the courage to love; they created a life of meaning in a seemingly meaningless world. I was the firstborn of two sons. The legacy of the Holocaust remained alive and lived with us in our two-bedroom apartment on Grand Street. The Ho-

The essence of meaning-centered psychotherapy is the conviction that there is always the possibility for meaning, the experience of meaning, and the creation or search for meaning, even in the setting of advanced cancer and despite the limitations of time in the face of death. —William Breitbart, MD

Oncology.1 Here, I discuss the evolution of meaning-centered psychotherapy, beginning with the story of a personal journey in search of meaning.

Legacy of the Holocaust I am a child of Holocaust survivors. This is an identity that has defined me, because of the profound legacy and source of meaning it has imparted to Dr. Breitbart is the Jimmie C. Holland Chair in Psychiatric Oncology and Chairman, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York.

locaust did not have its own room; it lived in every room, on the walls, in the drawers, in pictures, in documents, and in prayer books and tefillin saved from the flames of war.

Meaning and Purpose “Why am I here?” My mother asked this question of herself every morning of my childhood and urged me to ask the same question of myself every day. “Why am I here? And so many others are not!” This, in fact, is the more complete question my mother asked. Both of my parents lost so much—their own parents, siblings, cousins, aunts, uncles,

schoolmates, and friends. I grew up with a legacy of loss and suffering but in a home filled with love, compassion, and the need to find meaning, purpose, and significance. I accepted the responsibility and the burden of living not only my life, but also the lives of those who did not survive. I am trained and certified in both internal medicine and general psychiatry. I began my training in 1984 as a clinical fellow in psycho-oncology at Memorial Sloan Kettering Cancer Center in New York. My mentor, Dr. Jimmie Holland, had a mission to create and develop the field of psycho-oncology in order to provide comprehensive psychosocial care to patients with cancer globally. I made Dr. Holland’s mission my own mission as well and have worked toward this purpose for almost 30 years, as a clinician, researcher, educator, administrator, writer, lecturer, and advocate. Over the years, I have been searching to find a way to ameliorate the despair of patients with advanced cancer who saw no meaning, value, or purpose in living in the face of the limitations of approaching death. In my search, I found that the belief in the possibility of experiencing or creating meaning, even in the last months or days of life, sustained hope and diminished despair and suffering.

Will, Meaning, and Care In the process of searching for a means to integrate the concepts of will, meaning, and care into an approach to ameliorating the despair experienced by patients facing death, I had a transformative experience when I came across Viktor Frankl’s seminal work, Man’s Search for Meaning.2 This experience led me to appreciate the importance of caring for myself and my family while still “being in the world.” Dr. Frankl’s book reminds us that finding meaning in our existence is a defining characteristic of human beings. One cannot give meaning to another human being, but rather, each of us must go through the process

Rose and Moses Breitbart, Holocaust survivors, married in 1949.

of searching for the meaning in our own lives. The story of meaning-centered psychotherapy for cancer patients, like many stories, involves multiple characters as well as twists and turns in the narrative; and like all stories, it has its origins in an important legacy. The inspiration of the work of Viktor Frankl and his elucidation of the importance of meaning in human behavior and existence are that legacy. The essence of meaning-centered psychotherapy is the conviction that there is always the possibility for meaning, the experience of meaning, and the creation or search for meaning, even in the setting of advanced cancer and despite the limitations of time in the face of death. n Disclosure: Dr. Breitbart reported no potential conflicts of interest.

References 1. Breitbart W, Rosenfeld B, Pessin H, et al: Meaning-centered group psychotherapy: An effective intervention for reducing despair in patients with advanced cancer. J Clin Oncol 33:749-754, 2015. 2. Frankl VF: Man’s Search for Meaning, 4th ed. New York, Simon & Schuster, 1959.

Meaning-Centered Group Psychotherapy Improves Psychological Well-Being in Patients With Advanced Cancer See pages 112 to 114 in this issue of The ASCO Post for more on Dr. Breitbart’s research in meaning-centered psychotherapy.

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Cutaneous Lymphoma Compiled by Liz Janetschek

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with newly diagnosed or relapsed or refractory lymphoma of the skin. The studies include observational, phase I, and phase II trials investigating single-agent and combination chemotherapies, extracorporeal photopheresis, graft-vs-host disease in photodynamic treatment, focal radiation therapy, nonmyeloablative hematopoietic stem cell transplantation, and high-throughput sequencing. There are also studies investigating tissue and blood banking protocols and the development of a patient registry to collect and store tissue samples from patients with rare or cutaneous non-Hodgkin lymphoma. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

OBSERVATIONAL Study Type: Observational Study Title: Peripheral Blood and Skin Sample Collection for Cutaneous Lymphoma Research Study Sponsor and Collaborators: University of Pittsburgh Purpose: To create a tissue and blood banking protocol for patients with cutaneous T-cell lymphoma (CTCL) for current and future CTCL research Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Proteomics of Cutaneous T-cell lymphoma (time frame: ongoing) Principal Investigator: Lisa M. Grandinetti, MD, University of Pittsburgh; contact Sue A. McCann, MSN, RN, 412864-3681, mccannsa@upmc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00177268 Study Type: Observational Study Title: Outcomes of Cutaneous T-Cell Lymphoma and Chronic GraftVersus-Host Disease in Patients Treated With Extracorporeal Photopheresis Study Sponsor and Collaborators: Dartmouth-Hitchcock Medical Center

Purpose: To study the outcomes (response rates) of extracorporeal photopheresis (ECP) as a treatment for cutaneous T-cell lymphoma (CTCL) and graft-vs-host disease (GVHD) and other factors relating to their disease and treatment, as well as procedural events, such as complications Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Response rates (time frame: 1 year) Principal Investigator: Frederick Lansigan, MD, Dartmouth-Hitchcock Medical Center; 800-639-6918, cancer. research.nurse@dartmouth.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01460914 Study Type: Observational Study Title: Rare and Cutaneous Non-Hodgkin Lymphoma Registry Study Sponsor and Collaborators: Children’s Oncology Group, National Cancer Institute Purpose: To collect and store tissue samples from patients with rare or cutaneous non-Hodgkin lymphoma Ages Eligible for the Study: Up to 21 years Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Clinical features, treatment, and outcomes (time frame: length of study; study ends January 2100) Principal Investigator: Amanda M. Termuhlen, MD, Nationwide Children’s Hospital; 562-933-8605 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01000753 Study Type: Observational Study Title: Analysis of Cutaneous and Hematologic Disorders by HighThroughput Nucleic Acid Sequencing Study Sponsor and Collaborators: Stanford University Purpose: To identify genetic changes associated with the initiation, progression, and treatment response of cutaneous and hematologic disorders using recently developed high-throughput sequencing technologies Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No

Primary Outcome Measures: Number of mutations (time frame: 2 years) Principal Investigator: Paul Khavari, MD, Stanford University; contact Alexander Ungewickell, 650-723-6661, ungewica@stanford.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01556828 Study Type: Observational Study Title: Longitudinal Assessment of Ovarian Reserve in Adolescents With Lymphoma Study Sponsor and Collaborators: Children’s Oncology Group, National Cancer Institute Purpose: To study blood sample markers of reproductive hormones in assessing ovarian reserve in younger patients with newly diagnosed lymphomas. Studying samples of blood from patients with cancer in the laboratory may help measure the effect of curative therapy for lymphoma on ovarian failure. Ages Eligible for the Study: Up to 29 years Genders Eligible for the Study: Female Accepts Healthy Volunteers: No Primary Outcome Measures: Comparison of the measures of ovarian reserve (AMH, FSH, and E2) to that of health controls (time frame: up to 12 months) Principal Investigator: Jennifer Levine, MD, Children’s Oncology Group; study is multisite and state locations are listed on ClinicalTrials.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01793233

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: Phase I Dose-Escalation Study of CPI-613, in Combination With Bendamustine, in Patients With Relapsed or Refractory T-Cell NonHodgkin Lymphoma or Classic Hodgkin Lymphoma Study Sponsor and Collaborators: Comprehensive Cancer Center of Wake Forest University, National Cancer Institute Purpose: To study the side effects and best dose of CPI-613 when given together with bendamustine hydrochloride in treating patients with relapsed or refractory T-cell non-Hodgkin lympho-

ma or Hodgkin lymphoma Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose of 6,8-bis(benzylthio)octanoic acid when used in combination with bendamustine hydrochloride, defined as the dose level immediately below the dose level that induced a dose-limiting toxicity in < 2 patients (time frame: up to 28 days) Principal Investigator: Zanetta S. Lamar, MD, Wake Forest University; 336-716-7448, zlamar@wakehealth.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02168140 Study Type: Phase I/interventional/ single-group assignment Study Title: Silicon Phthalocyanine Pc4 for Photodynamic Therapy of Cutaneous T-cell Lymphoma: Single and Repeated Photoexposures Study Sponsor and Collaborators: Case Comprehensive Cancer Center, National Cancer Institute Purpose: To study the side effects and best dose of silicon phthalocyanine 4 and photodynamic therapy in treating patients with stage IA-IIA cutaneous Tcell non-Hodgkin lymphoma Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose defined as the dose immediately below the dose in which two or more of six patients experience a grade 4 toxicity assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (time frame: up to 30 days) Principal Investigator: Elma D. Baron, MD, Case Comprehensive Cancer Center; 800-641-2422, elma.baron@ case.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01800838 Study Type: Phase I/interventional/ parallel assignment Study Title: A Pilot Study of a Novel Multimodality Immuno-Chemotherapy Platform for Patients With Advanced

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Clinical Trials Resource Guide

Cutaneous T-Cell Lymphoma Study Sponsor and Collaborators: New York University School of Medicine, Ludwig Institute for Cancer Research Purpose: To evaluate the safety and tolerability of the addition of immunostimulatory therapy consisting of focal radiation with or without the Toll-like receptor (TLR) agonist Poly ICLC in patients with cutaneous T-cell lymphoma (CTCL) receiving concurrent therapy with the histone deacetylase inhibitor (HDACI) romidepsin Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose (MTD) (time frame: 21 days) Principal Investigator: Catherine Diefenbach, MD, New York University School of Medicine; 212-731-5670, catherine.diefenbach@nyumc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02061449 Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase 1 and Pharmacokinetic Single-Agent Study of Romidepsin in Patients With Lymphomas, Chronic Lymphocytic Leukemia and Select Solid Tumors and Varying Degrees of Liver Dysfunction Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of romidepsin in treating patients with lymphoma, chronic lymphocytic leukemia, or solid tumors with liver dysfunction Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose of romidepsin in groups of patients with varying degree of hepatic dysfunction according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (time frame: 28 days) Principal Investigator: Roisin Connolly, Johns Hopkins University/Sidney

Kimmel Comprehensive Cancer Center; 410-614-9217; rconno12@jhmi.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01638533 Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase I Trial of the Combination of Everolimus (RAD001) and Bortezomib (Velcade) for Relapsed or Refractory Lymphoma Study Sponsor and Collaborators: National Cancer Institute, The Leukemia and Lymphoma Society Purpose: To study the side effects and best dose of everolimus when given together with bortezomib in treating patients with relapsed or refractory lymphoma Ages Eligible for the Study: 18 Years and Older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerated dose of everolimus in combination with bortezomib (time frame: after one course [21 days]) Principal Investigator: Brian Hill, MD, PhD, Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center; 216-444-6833, hillb2@ ccf.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00671112

Schieke, MD, Medical College of Wisconsin; contact MCW Cancer Center Clinical Trials Office, 414-805-8900, cccto@mcw.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01843998 Study Type: Phase II/interventional/single-group assignment Study Title: Doxycycline in Patients With Relapsed Cutaneous T-cell Lymphoma Study Sponsor and Collaborators: University of Rochester Purpose: To study the efficacy of doxycycline for the treatment of cutaneous T-cell lymphomas Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Efficacy of doxycycline in relapsed CTCL (time frame: from baseline to 5 months or a year, depending on response) Principal Investigator: Brian Poligone, MD, PhD, University of Rochester; contact Carolina V. Alexander Rodriguez, BS, 585-489-2883, carolina_alexander@urmc.rochester.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02341209

Study Type: Phase II/interventional/ single-group assignment Study Title: A Phase II Study of Nonmyeloablative Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) in Patients with Cutaneous T Cell Lymphoma Study Sponsor and Collaborators: Stanford University Purpose: To study hematopoietic stem cell transplantation using a nonmyeloablative preparative regimen, TLI/ATG Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: To evaluate the graft-vs-lymphoma effect by monitoring the rate of clinical response, event-free, and overall survival (time frame: 2 years) Principal Investigator: Wen-Kai Wang, MD, PhD, Stanford University; contact Physician Referrals, 650-7230822 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00896493 Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, visit ClinicalTrials.gov. n

PHASE II Study Type: Phase II/interventional/ single-group assignment Study Title: Therapeutic Efficacy of Topical Sirolimus in Early-Stage Cutaneous T-cell Lymphoma (CTCL) Study Sponsor and Collaborators: Medical College of Wisconsin Purpose: To determine whether sirolimus reduces the symptoms of cutaneous T-cell lymphoma and whether it causes any side effects Ages Eligible for the Study: 18 years and older Genders Eligible for the Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Overall response rate (time frame: 6 months) Principal Investigator: Stefan

“Very bad hair day” (baby tricolored heron). Photo submitted by Michael Ross, MD. Submit your high-resolution photo and caption to editor@ASCOPost.com

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Build a treatment plan with extended survival* from the start1-3

Establish extended survival with ALIMTA/cisplatin in 1st line1,2 Extended survival was seen in four phase III trials for patients with advanced nonsquamous† NSCLC*2-6 * Only patients with stable disease or better were eligible for continuation maintenance with ALIMTA single agent. †

Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Learn more at

Continue treatment.* Extend survival.1,7 For patients with advanced nonsquamous NSCLC Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

Patients* with advanced nonsquamous NSCLC who achieve stable disease or better during ALIMTA/cisplatin induction therapy may benefit from continuing treatment until progression with ALIMTA single agent.3 Continue until disease progression, unacceptable toxicity, or patient-physician decision

4 Cycles

• Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA • Patients must also receive one intramuscular injection of vitamin B12 (1000 mcg) 1 week prior to the first dose of ALIMTA and every three cycles thereafter • Patients should receive dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration1

Select Important Safety Information Warnings and Precautions ALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modifications, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities.

Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the Important Safety Information and Brief Summary for ALIMTA on the following pages. References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551. 3. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 4. Scagliotti G, et al. Oncologist. 2009;14(3):253-263. 5. Ciuleanu T, et al. Lancet. 2009;374(9699):1432-1440. 6. Hanna N, et al. J Clin Oncol. 2004;22(9):1589-1597. 7. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities. Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function. Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency. Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

PM95234

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/ stomatitis (5% vs 2.4%); and edema (5% vs 3.6%). For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page. PM_HCP_ISI_NSCLC1M_17OCT2012

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FDA Update

FDA Accepts Supplemental Biologics License Application for Nivolumab in Patients With Previously Untreated Advanced Melanoma

he U.S. Food and Drug Administration (FDA) has accepted for filing and review Bristol-Myers Squibb’s supplemental Biologics License Application (sBLA) for nivolumab (Opdivo)

for the treatment of previously untreated patients with unresectable or metastatic melanoma. The FDA also granted Priority Review for this application. The projected FDA action date is August 7, 2015.

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information. 2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

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Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.) Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. 5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

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FDA Update Nivolumab continued from page 137

with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) and, if BRAF V600–mutation positive, a BRAF inhibitor. This initial indication was approved under accelerated approval based on tumor response rate and dura-

bility of response from CheckMate-037 clinical trial results. The new sBLA accepted by the FDA includes data from CheckMate-066, which evaluated nivolumab in treatmentnaive patients with BRAF–wild-type advanced melanoma as compared to dacarbazine chemotherapy. In the trial, safety and tolerability were well characterized,

Use in Other Cancers Nivolumab is also approved in lung cancer: On March 5, 2015, the drug received FDA approval for the treatment of patients with metastatic squamous

platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)]. 5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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 of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/ pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa Reactionb

non–small cell lung cancer (NSCLC) with progression on or after platinumbased chemotherapy. Bristol-Myers Squibb has a broad, global development program to study nivolumab in multiple tumor types consisting of more than 50 trials, in which more than 7,000 patients have been enrolled worldwide. n

with fewer treatment-related grade 3/4 adverse events observed with nivolumab than dacarbazine.

Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Non-Small Cell Lung Cancer (NSCLC) – Maintenance ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction Therapy Table 5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy Reactionb

All Adverse Reactions Laboratory Hematologic Anemia Neutropenia Leukopenia Hepatic Increased ALT Increased AST Clinical Constitutional Symptoms Fatigue Gastrointestinal Nausea Anorexia Vomiting Mucositis/stomatitis Diarrhea Infection Neurology Neuropathy-sensory Dermatology/Skin Rash/Desquamation

ALIMTA/cisplatin Gemcitabine/cisplatin (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) 90 37 91 53

ALIMTA Placebo (N=438) (N=218) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) 66 16 37 4

15 6 6

3 3 2

6 0 1

1 0 1

10 8

0 0

4 4

0 0

19 19 9 7 5 5

1 2 0 1 1 2

6 5 1 2 3 2

1 0 0 0 0 0

All Adverse Reactions Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology. In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity. No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%). Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen. Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%). The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation General Disorders — edema, fever (in the absence of neutropenia) Hematologic — thrombocytopenia Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate

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FDA Update

Cobas KRAS Mutation Test Receives FDA Approval

oche announced that the U.S. Food and Drug Administration (FDA) has approved the cobas KRAS Mutation Test for diagnostic use. The real-time polymerase chain reaction (PCR) test is designed to identify KRAS mutations in tumor samples

from patients with metastatic colorectal cancer and aid clinicians in determining a therapeutic path for them. The new assay is intended to be used as an aid in the identification of patients with metastatic colorectal cancer for whom treatment with cetuximab (Erbitux) or

panitumumab (Vectibix) may be effective if no KRAS mutation is present.

Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo b NCI CTCAE Criteria version 3.0 Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm. Incidence 1% to 5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence Less than 1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%). Additional Experience Across Clinical Trials Sepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions occurred with ALIMTA when used as a single-agent and in combination therapies. Blood and Lymphatic System – Immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory — interstitial pneumonitis Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal. 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)]. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)]. Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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 of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults. 8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients

ALIMTA® (pemetrexed for injection)

Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy Table 6 provides the frequency and severity of adverse reactions reported in >5% of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial. The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12. Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy Adverse Reaction Organ System and Term All Adverse Reactions Laboratory Hematologic Anemia Neutropenia Clinical Constitutional Symptoms Fatigue Gastrointestinal Nausea Vomiting Mucositis/stomatitis General Disorders Edema

ALIMTA Placebo (N=333) (N=167) All Gradesa Grade 3-4a All Gradesa Grades 3-4a Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) 53 17 34 4.8

15 9

4.8 3.9

4.8 0.6

0.6 0

4.5

0.6

12 6 5

0.3 0 0.3

2.4 1.8 2.4

0 0 0

3.6

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The cobas KRAS Mutation Test is a TaqMelt assay, a PCR-based diagnostic test intended for the detection of mutations in codons 12 and 13 of the KRAS gene. The test, which is performed on the cobas 4800 System, can be conducted in less than 8 hours. n

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News

ASCO, ACCC Respond to Repeal of Medicare Sustainable Growth Rate Formula

he American Society of Clinical Oncology (ASCO) and the Association of Community Cancer Centers (ACCC) responded to the approval of H.R.2, a Medicare-reform bill to end the program’s sustainable growth rate (SGR) formula.

ASCO’s Statement ASCO President Peter Paul Yu, MD, FACP, FASCO, praised the historic Congressional vote that restored stability to one of cancer care’s most vital programs. “Today’s courageous vote by the

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients. 8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia. • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. • Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch. Additional information can be found at www.AlimtaHCP.com

U.S. Senate to finally end the SGR formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease. With Congress passing this historic legislation to finally end the 13year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier, knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.” “We praise the 92 Senators for voting ‘yes’ on The Medicare Access and CHIP Reauthorization Act of 2015 (H.R.2), and for joining the 392 House members who voted earlier to support this longawaited legislation. The Congressional bipartisan, bicameral leadership that forged this much-anticipated resolution has taken an important step to restore stability and confidence in Medicare.” “ASCO looks forward to working with policymakers to ensure that this new law is effectively implemented, and paves the way to new payment models that foster high-quality, value-based health care for all Americans with cancer.”

ACCC’s Statement ACCC also applauded the lawmakers who voted “yes” on H.R.2. “Last night’s historic 92-to-8 vote by the Senate is a long-awaited critical step in the right direction, restoring stability for physicians serving Medicare patients in communities across the country,” said ACCC President Steven L. D’Amato, BSPharm, BCOP. “ACCC thanks the legislators in both houses who voted in support of SGR repeal. We also salute our ACCC members for their persistent, multi-year advocacy efforts on behalf of SGR reform.” In recent weeks, ACCC members were on Capitol Hill making more than 80 visits with congressional and committee staff as Congress negotiated the bill, and sent hundreds of letters to members of Congress urging support of H.R.2. ACCC looks forward to working with members to effectively implement the bill, and transitioning towards a new future for physician reimbursement. n

Poster sessions generate traffic and enthusiasm each year among attendees to the American Society of Clinical Oncology Annual Meeting, taking place May 29–June 2, 2015, in Chicago. See next month’s issue of The ASCO Post for comprehensive coverage from the 2015 Annual Meeting. Photo by © ASCO/ Scott Morgan.

Send Us Your NEWS Write to editor@ASCOPost.com. Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved. PM HCP BS NSCLC1M 18Nov2013 ALIMTA® (pemetrexed for injection)

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ASCOPost.com | MAY 25, 2015

PAGE 141

Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The Anesthesia Era: 1845–1875.” To view additional photos from this series of books, visit burnsarchive.com.

THE Anesthesia Era: 1845–1875 Sarcoma of the Arm, Circa 1874

he face of this young man mirrors the suffering typical in bone sarcoma patients of the 19th century. Surgery was so dangerous and cancer treatment so haphazard, patients often did not present themselves until the disease was far advanced. Surgeons knew that only wide excision offered any chance of a cure, although infection killed most patients in the postoperative period. This frightened, cachexic patient consented to surgery for the removal of his massive arm tumor when the lesion became extremely painful. He died in the postoperative period. It was not until the 19th century that bone and soft-tissue tumors were distinguished from other cancers. Alexis Boyer, MD (1757–1833), coined the word “osteosarcoma” in describing bone tumors. Astley Paston Cooper, MD (1768–1841), the most important surgeon in London in the first quarter of the 19th century, was a pioneer in vascular, ear, and experimental surgery. Among his achievements was dividing bone tumors into two groups: intramedullary and extramedullary. In 1829, John Lobstein, MD (1777–1835), described soft-tissue sarcomas that arise in the retroperitoneal space. A major step forward in differentiating bone tumors was also

Excerpted from Oncology Tumors & Treatment, A Photographic History, The Anesthesia Era: 1845–1875 by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive.

made in 1829, with the publication of a text on cancer by Joseph C.A. Recamier, MD (1774–1852). He was the first to recognize the process of metastasis and separated primary bone tumors from metastatic tumors. Rudolf L.C. Virchow, MD (1821–1902), the legendary founder of cellular pathology (1858), set in motion a new way of looking at the body as a “cell state.” Between 1863 and 1867, he wrote his main thesis

on cancer, Die Krankhaften Geschwulste. He was the first to recognize the sarcomas as connective tissue cancers, separating them into six major types: fibrosarcoma, gliosarcoma, melanosarcoma, myxosarcoma, chondrosarcoma, and osteosarcoma. One of his few mistakes was his theory of the connective-tissue origin of carcinoma. In 1872, Moritz Kaposi, MD (1837–1902), described “idiopathic multiple hemorrhagic sarcoma.” Dur-

ing the 20th century, numerous other connective tissue cell types were identified as sources of sarcoma. Sarcomas are rare, malignant tumors, consisting of only 1% of all neoplasms. Bone sarcomas represent about half of sarcomas. Treatment of bone and soft-tissue sarcomas requires specific pathologic diagnosis, but it wasn’t until the 1970s that histologic analysis became reliable enough to make differential diagnosis accurate. n

“Sarcomas are rare, malignant tumors, consisting of only 1% of all neoplasms. Bone sarcomas represent about half of sarcomas.”

The ASCO Post | MAY 25, 2015

PAGE 142

Reflections Pediatric and Adolescent Oncology

Taking the Trauma Out of Cancer Care for Children and Adolescents Cancer centers are implementing programs to help their youngest patients cope with the psychological and physical effects of cancer and its treatment.

etting a cancer diagnosis and going through treatment are difficult for patients of any age, but the experience can be especially traumatizing for the nearly 16,000 infants, children, and adolescents diagnosed each year with cancer,1 especially during the early days of treatment. Young cancer patients who need an imaging test typically enter a stark room filled with scary-looking medical machinery and are told to lie still while the test is performed. The loud noises and close enclosure of the imaging machine can be so frightening for children, they may require sedation to safely complete the examination. Now physicians at the new University of California, San Francisco (UCSF) Benioff Children’s Hospital are hoping to make the experience less frightening for young patients. Enter-

ing the hospital’s child-friendly scanning suites, instead of intimidating medical equipment, the first thing children see is a colorful cable car. During their scans, images projected on the wall help distract children by letting them take in the sights of San Francisco, the majestic Muir Woods, or the Pacific Ocean while listening to the soothing sounds of nature or music. “Instead of kids hopping up on a table surrounded by medical equipment, they imagine they’re going for a boat ride,” said John MacKenzie, MD, Chief of Pediatric Radiology at UCSF, who helped design the new treatment suites. “And a medical technician says ‘Hi, I’m the captain. Can you please hop on?’” If the children prefer, they can don video goggles and watch a movie instead. Although the treatment suites have only been open for a short time,

By Beth Howard

John MacKenzie, MD

Lisa Scherber

Dr. MacKenzie said he is already seeing how the new child-friendly environment is resulting in helping to calm young patients. “We are seeing more young patients below the age of 6 (who typically need anesthesia) go through an MRI without any anesthesia or sedation, and some of our older children who previously needed medication for anxiety now complete the MRI comfortably without anxiolytics or anesthesia,” said Dr. MacKenzie.

The new facility is just one example of how hospitals around the country are re-imagining cancer care to make it less stressful and traumatic for children with cancer and their families. “Being treated for cancer is a shock at any age,” said Lisa Scherber, Director of Patient and Family Programs at DanaFarber/Boston Children’s Cancer and Blood Disorders Center. “But children lose their childhood, their innocence, their feeling of ‘I can do anything.’” continued on page 144

8 Steps to Help Children Cope With Cancer and Its Treatment

ere are several steps for helping pediatric and adolescent patients to cope with cancer and its treatment. • Give young patients control whenever possible, suggests Shawna Grissom, MS, CCLS, CEIM, Director of the Child Life Program at St. Jude Children’s Research Hospital, and offer them realistic choices for their treatment. “There are not many things patients can control while in the hospital,” said Ms. Grissom. “But they can choose who they want to support them during a procedure. Do they want to know what is going to happen or not? Where do they want to sit when the nurse starts their IV, and should we count to three first? Should we put the blood pressure cuff on the left or right arm?” • Tell children what is happening and explain what is going to happen next using the five senses. “In any preparation situation, we try to let children know what they will see, hear, feel, taste, or smell,” said Ms. Grissom. “This helps patients have a better idea of what they can expect, rather than making up their own story of

what they think will happen.” • For instance, before an IV is placed in a child’s vein, “we might say who he or she will see during the procedure and what types of medical equipment will be used,

and Blood Disorders Center. “No one falls in the same category.” • When speaking to parents include the patient in the discussion, if appropriate. “Get down on the [patient’s] level and engage him or

In any preparation situation, we try to let children know what they will see, hear, feel, taste, or smell. This helps patients have a better idea of what they can expect. —Shawna Grissom, MS, CCLS, CEIM Photo by Seth Dixon

explaining step-by-step what will happen. We will say that the nurse will put some numbing medicine on his or her arm first—it makes a popping noise and explain what things will feel like, for example, wet or cold, and that he or she might smell the cleaning solution.” • Respect children’s privacy. • Treat children as individuals, advises Lisa Scherber, Director of Patient and Family Programs at DanaFarber/Boston Children’s Cancer

her,” said Ms. Grissom. “Don’t act like children cannot hear you— they can.” However, if you need to, talk to parents separately from the children. • Take part in hospital events involving patients and their families. “When you see your patient outside of the clinic or hospital smiling and enjoying life, it allows you to understand him or her better,” said Ms. Scherber. • Don’t forget the psychological

needs of parents, who are often more distressed than their children, said Robert B. Noll, PhD, Professor of Pediatrics, Psychiatry, and Psychology at the University of Pittsburgh Cancer Institute in Pennsylvania. He recommends a research-based intervention called Bright IDEAS: ProblemSolving Skills Training, which is rooted in cognitive-behavioral therapy. In a study of mothers of children recently diagnosed with cancer, those who participated in an 8-week training program in the intervention experienced fewer symptoms of depression and post-traumatic stress disorder and less total mood disturbance than those who received the usual psychosocial care.1 n

Disclosure: Ms. Grissom, Ms. Scherber, and Dr. Noll reported no potential conflicts of interest.

Reference 1. Sahler OJ, Dolgin MJ, Phipps S, et al: Specificity of problem-solving skills training in mothers of children newly diagnosed with cancer: Results of a multisite randomized clinical trial. J Clin Oncol 31:1329-1335, 2013.

The goal seemed insurmountable: to find a way to unleash the immune system’s power to fight cancer.

And we achieved it at Dana-Farber.

To many physician-researchers and scientists, finding a way to get the body’s immune system to attack cancer cells is a momentous achievement. And Dana-Farber researchers helped make it happen. We found that some cancer cells elude the body’s immune defenses by cloaking themselves in the proteins PD-L1 and PD-L2. This discovery led to the development of several immunotherapies that are already demonstrating promising results and better quality of life for some people with deadly cancers. In fact, the new therapies have improved outcomes for many patients with advanced metastatic melanoma, kidney cancer, Hodgkin lymphoma, bladder cancer, stage IV lung cancer, and more. And the sky is the limit. Videos, whitepapers and more at DiscoverCareBelieve.org/PD-1.

The ASCO Post | MAY 25, 2015

PAGE 144

Reflections Easing Pediatric Trauma continued from page 142

Healing Environments Many hospitals are turning to technology to help distract young children from challenging procedures. The theater-like Infusionarium at Children’s Hospital of Orange County in Orange, California, lets young patients access five broadcast channels, use social media, watch movies, or play video games on giant screens while they sit in comfortable recliners getting their chemotherapy. “Kids are very resilient,” said Leonard Sender, MD, Director of the Adolescent and Young Adult Cancer Programs at the hospital. “They take to their environment pretty well. But the hospital is still the hospital. We want to change the environment for children to see if it changes their stress levels or makes getting chemotherapy easier.” The hospital is now studying

sic, the 10,000 square-foot outpatient clinic features a Snoezelen room, a controlled multisensory environment that combines sounds, scents, colors, and lighting effects to stimulate and soothe young patients who may be coping with pain or fear. The facility also has nine rooms where children can experience a variety of modalities to fight pain and other symptoms, including biofeedback, physical therapy, massage therapy, aromatherapy, and acupuncture.

Putting the Human Touch on Cancer However, helping pediatric cancer patients cope better with their disease and treatment does not require a lot of technologic bells and whistles to be successful. Hospitals and cancer centers have long used visits from clowns and magicians as well as music and art

We want to change the environment for children to see if it changes their stress levels or makes getting chemotherapy easier. Many of the kids who used to be anxious can’t wait to be up here now. —Leonard Sender, MD

whether patients who use the facility experience less pain or nausea, but according to Dr. Sender, it appears the Infusionarium is already making a difference. “Many of the kids who used to be anxious can’t wait to be up here now,” he said. Like the Infusionarium, the new Kiran Stordalen and Horst Rechelbacher Pediatric Pain, Palliative, and Integrative Medicine Clinic at Children’s Hospitals and Clinics of Minnesota in Minneapolis is tackling children’s pain and fears by caring for both their physical and emotional well-being. Built with natural materials, including wood walls and rock, and designed throughout with nature photos and soothing mu-

therapists to bring at least a brief respite from the fear many children go through during cancer treatment. Like other medical facilities, St. Jude Children’s Research Hospital in Memphis, Tennessee, relies heavily on a team of child life specialists focused on the psychosocial needs of children facing a challenging illness to minimize the stress and fear that often accompany hospital stays. “[The child life specialists] are with the patients from the time they walk through the door to the end of their journey,” said Shawna Grissom, MS, CCLS, CEIM, Director of the Child Life Program at St. Jude Children’s Research

Hospital. “We help children understand at an age-appropriate level why they’re here and prepare them for everything that’s happening, so they can get through it in the best way possible.” When children face scary or painful procedures, depending on the child’s age, the team employs a number of tools, from toys and games to guided imagery and deep breathing, to comfort them. “We also do our best to normalize the environment, for instance by helping parents keep infants and toddlers on feeding and napping schedules and keeping them on track developmentally,” said Ms. Grissom. The hospital also has a program specifically designed for teenagers, which includes staging big events like graduation ceremonies and formal dances to provide activities “they would be doing if they were not here,” said Ms. Grissom. The hospital designs play and activity areas for different age groups to specially meet developmental milestones and allow for socialization with their peers.

Getting Creative Young children and adolescents with cancer receive age-appropriate treatment at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center as well. “Being an adolescent with cancer is very different from being a 5-year-old with cancer,” said Ms. Scherber. “A diagnosis of cancer makes you feel and look different. It makes you miss all those things that make you who you are.” At Dana-Farber, there are myriad programs designed to ease the stress of young patients with cancer, including treatment lounges with computers, iPads, and video cameras children can use to make films. The hospital also sponsors out-of-town trips during the year, including one to see the Boston Red Sox at spring training in Fort Myers, Florida, accompanied by a team of doctors and nurses. “These events make treatment more bearable,” said Ms. Scherber. “And they give teens time away from cancer to feel like regu-

lar kids.” And oncologists benefit from these outings, too. “A doctor will say ‘I feel like I’m a better doctor because of this trip,’” said Ms. Scherber. The hospital also holds holiday celebrations throughout the year for patients

Robert B. Noll, PhD

in all age groups, their families, and their care team members. “At Christmas, the doctors dress as elves,” said Ms. Scherber. “One of the goals is to show the children that even though the doctors are the ones giving treatments, they also want to make the children feel happy. As soon as the first-year fellows start their training, they are fitted for their tights,” laughed Ms. Scherber. “Programs such as these make kids’ lives better when they’re feeling awful,” said Robert B. Noll, PhD, Professor of Pediatrics, Psychiatry, and Psychology at the University of Pittsburgh Cancer Institute in Pennsylvania. “They make it easier to go through these experiences.” Dr. Sender adds, “Whether it’s a sophisticated Infusionarium, a visit from a clown, or just a hug, we’re all working toward the same goal [to ease the trauma of cancer and its treatment on young patients].” n

Disclosure: Dr. MacKenzie has received research support from General Electric Healthcare to study PET/MRI in pediatric patients. Dr. Sender, Ms. Grissom, Dr. Noll, and Ms. Scherber reported no potential conflicts of interest.

Reference 1. National Cancer Institute: Cancer in Children and Adolescents Fact Sheet. Available at http://www.cancer.gov/cancertopics/factsheet/Sites-Types/childhood. Accessed March 6, 2015.

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PAGE 145

Palliative Care in Oncology The Mechanisms Driving Cancer Pain

A Conversation With Patrick W. Mantyh, PhD, JD By Jo Cavallo

or over a decade, Patrick W. Mantyh, PhD, JD, has been investigating the molecular and cellular mechanisms that are involved in cancer-related pain, especially bone pain caused by advanced breast, prostate, and lung cancers. His early laboratory work using mouse models of bone cancer led to an understanding of the multiple mechanisms involved in the generation of pain, including allogeneic substances released from the cancer and its associated stromal cells as well as the destruction and sprouting of nerve fibers near the tumor.

trolling pain; and the emergence of targeted symptom therapy in alleviating cancer pain.

Start Pain Management Early When should pain management strategies for patients in the palliative care setting be started, and how long should they last? Pain management in the cancer setting should be started as early as possible and continue into survivorship. If chronic cancer pain is allowed to develop, not only will the pain fibers innervating the tumor-bearing organ change, both the spinal cord and higher centers

The earlier you effectively treat the pain, the less reorganization occurs, which makes the pain less severe and more tractable to effective control. —Patrick W. Mantyh, PhD, JD

“Just as the tumor is constantly changing and evolving with disease, so too are the nerve fibers that innervate the tumor-bearing organ,” said Dr. Mantyh. “Tumors not only injure nerve fibers as they invade a tissue, they also cause a dramatic sprouting of sensory and sympathetic nerve fibers. Once you get this hyperinnervation of the cancer environment, if there are tumor and stromal factors being released that excite these nerve fibers, the cancer pain will continue to increase in intensity with time.” These mechanistic insights into the causes of metastatic bone pain have led to the development of new treatments for bone pain, including bisphosphonates and denosumab (Prolia), antiresorptive compounds that simultaneously reduce bone cancer pain, tumor-induced bone destruction, and tumor growth within the bone; and anti–nerve growth factor (NGF) molecules, such as the monoclonal antibody tanezumab currently in phase III clinical trials. The ASCO Post talked with Dr. Mantyh, Professor of Pharmacology at the University of Arizona Cancer Center in Tucson, about when pain management strategies should be started in the palliative care setting; what the most effective therapies are for con-

of the brain will undergo reorganization, all of which contributes to further amplification of the pain. In general, the earlier you effectively treat the pain, the less reorganization occurs, which makes the pain less severe and more tractable to effective control. The earlier you treat the pain, the easier it is for the clinician and the patient to control the pain, which can dramatically increase the quality of life and functional status of the patient.

‘Analgesic Ladder’ What is the most effective therapy for cancer pain management? Currently, most cancer pain is managed using an “analgesic ladder,” which begins with nonsteroidal antiinflammatory drugs (NSAIDs), then an NSAID plus a mild opiate, and, finally, when the pain becomes severe, an NSAID plus a strong opiate. In addition to this three-step ladder approach, adjuvant therapies, including steroids, radiation therapy, radioisotopes, nerve block, antiepileptics, and bisphosphonates, are commonly used in an attempt to control cancer pain. Even with these therapies, cancer pain can be difficult to control fully 24/7, and the majority of patients with advanced cancer will still experience significant cancer pain. A major reason is because as the cancer advances, so too does the cancer pain, requiring ever-increasing doses of opiates. Although opiates can be effective in controlling cancer pain, they also have many unwanted side effects, such as constipation, respiratory depression, and mental clouding, which can reduce a patient’s quality of life and functional status.

A Viable Therapeutic Target Are pharmaceutical companies starting to develop specific targeted symptom therapies to control cancer pain? With the development of preclinical models of cancer pain, enormous strides have been made in understanding the mechanisms that drive cancer

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

pain. A little more than a decade ago, we had no idea of any specific mechanism that drove cancer pain. Now, we understand that acidosis, tumor-released products, and tumor-induced nerve reorganization all play major roles in driving cancer pain. This increase in knowledge has allowed biotech and pharmaceutical companies to develop targeted therapies that have fewer side effects than opiates to treat cancer pain, such as bisphosphonates, denosumab, gabapentin, and anti-nerve growth factor therapies. And many other promising therapies are in development and in clinical trials. Thus, pharmaceutical and biotech companies now look upon cancer pain as a viable therapeutic target. As patients with cancer are living much longer than ever before, targeted therapies to control cancer pain have the potential to dramatically improve their quality of life and functional status.

Pain Relief and Beyond

This image was obtained using confocal microscopy and shows prostate cancer cells in bone (green) along with exuberant tumor-induced sprouting of calcitonin gene-related protein–positive sensory nerve fibers (red). Sensory nerve fibers drive bone cancer pain and may also play a role in regulating tumor growth and metastasis.

What is your current area of research? We are focusing on developing more targeted therapies to relieve cancer pain. We are also attempting to understand whether unique mechanisms drive cancer pain in different types of cancer. For example, do the same mechanisms that drive bone cancer pain also drive head and neck cancer pain? Initial data suggest there are similarities in the continued on page 146

The ASCO Post | MAY 25, 2015

PAGE 146

FDA Oncology Initiative Professional Development

Building a Better Federal Oncology Workforce By Ronald Piana

he process of delivering novel treatments for patients with cancer involves a multifaceted and long-term interaction between three distinct entities: clinical researchers, who conduct the trials which test treatments; drug developers, including the pharmaceutical industry, which takes cancer drugs from the laboratory, through nonclinical studies, to the clinical trials; and the U.S. Food and Drug Administration (FDA), tasked with ensuring that drug development is

cialized clinician-scientists to hold joint appointments at the Office of Hematology and Oncology Products and at the Center for Cancer Research, at the Bethesda, Maryland, campus of the National Cancer Institute (NCI).

A Unique Career Choice Specifically, at the Center for Cancer Research, candidates will continue their careers as academic clinicians in the NCI’s intramural program, serving as independent, tenure-track, princi-

We’ve historically had difficulty attracting people to enter at the midlevel career range. So the purpose of creating a joint NCI-FDA position was to provide a unique job opportunity for talented people outside of the government. —Richard Pazdur, MD

conducted according to statutory standards, and that only safe and effective new treatments are approved for use in the United States.This is a rigorous process that involves the thousands of patients who make the trials possible and is constantly evolving as a result of increased scientific knowledge, discovery of novel drug targets and pathways, and improving clinical outcomes. Its complexity creates the need for new and flexible approaches to clinical trial and drug development. In response, the Director of FDA’s Office of Hematology and Oncology Products, Richard Pazdur, MD, has initiated an oncology workforce project designed to recruit and train highly spe-

pal investigators with the opportunity to develop cutting-edge clinical trials supported by the Center’s infrastructure. Similarly, at the FDA, candidates will develop an expertise in regulatory science with a focus on their area of clinical expertise as Associate Direc-

Patrick W. Mantyh, PhD, JD

cer-induced bone fracture. Another example is radionuclide radium-223 chloride (Xofigo), which not only reduces bone pain from prostate cancer but also is associated with a clear increase in overall survival. We are also very interested in the question of whether nerve fibers in bone are involved in metastasis of the tumor to bone as well as tumor vascularization and growth. For years, we have known that nerve fibers appear to serve as the scaffolding by which tumors escape from their primary site and metastasize to other organs. The two most

continued from page 145

mechanisms that drive pain in different cancer types, but just like the cancers themselves, there will probably be some unique aspects in pain arising from distinct cancers. Another area we are exploring is whether novel therapies developed to relieve cancer pain also have significant effects on disease progression. Probably the best examples of these therapies are bisphosphonates and denosumab, which can reduce bone cancer pain and also significantly delay the time to can-

tors in the Office of Hematology and Oncology Products, which was reorganized in 2011 following a diseasespecific model, similar to most large academic centers, to better meet the demands of an increasingly complex and rapidly changing knowledge base in the diagnosis and treatment of malignant diseases. According to Dr. Pazdur, the impetus for the oncology workforce initiative was to address an inherent problem of recruiting experienced, disease-specific clinical trialists into its workforce. “We’ve historically had difficulty attracting people to enter at the mid-level career range. So the purpose of creating a joint NCI-FDA position was to provide a unique job opportunity for talented people outside of the government. Obviously, the mid-level salary structure is one impediment for attracting outside talent, so we have to offer unique opportunities that they wouldn’t see in the private sector. For instance, they can create and run a clinical trial at NCI’s Center for Cancer Research and then do review work at the FDA,” said Dr. Pazdur. Asked how this initiative will help the overall drug approval process, Dr. Pazdur responded, “It’s important to note that these candidates, although

Logistics and Application • FDA will serve as chair of the search committee, and the Center for Cancer Research will participate in search and selection. Official position will be in FDA. • During recruitment, each candidate will identify a clinical branch with mutual interest and then meet and discuss areas of mutual interest with the Center for Cancer Research Branch Chief. • Questions? Contact: NCI: Dr. Susan Bates, 301-496-5941; FDA: Dr. Sanjeeve Bala, 240-402-4975.

they will go through a training process, will be chosen from academic levels equal to associate professors and professors with a background in oncology or hematology, with 5 to 10 years of clinical experience post completion of an oncology or hematology fellowship. Moreover, these candidates will be Board certified or recognized as experts in a specific area of oncology. So the FDA is looking to strengthen its ranks by integrating these individuals who have proven real-world experience.”

Susan Bates, MD

Susan Bates, MD, a Senior Investigator in the Developmental Therapeutics Branch of the Center for Cancer Research, stated that this exciting initiative is a wonderful opportunity for the NCI as well. “For decades, the NCI program in Bethesda has helped train many of our drug development investigators—both in academia and in industry. By providing the unique opportunity to work and train alongside FDA medical officers, this new initiative will bring an exciting and fresh perspective to the Center for Cancer Research. Our mutual goal is to create better therapies for patients, and we envision that by better understanding the FDA viewpoint on drug development, both investigators and trainees continued on page 149

studied examples of that are in prostate and pancreatic cancers. However, a study1 in Science investigating the role of nerves in prostate cancer growth and dissemination found that the formation of new nerve fibers within and around prostate tumors can alter tumor behavior and that nerves within the prostate promote early stages of tumorigenesis as well as cancer dissemination. Do nerves in bone play a similar role in allowing metastatic tumors to preferentially metastasize, proliferate, and colonize the bone? We don’t know the answer to that yet, but given the impor-

tance of bone metastasis in many common cancers, this is an exciting time to be involved in the discovery and development of new therapies that decrease pain, improve quality of life, and potentially increase survival of patients with metastatic cancer. n Disclosure: Dr. Mantyh reported no potential conflicts of interest.

Reference 1. Magnon C, Hall SJ, Lin J, et al: Autonomic nerve development contributes to prostate cancer progression. Science 341:1236361, 2013.

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FDA Oncology Initiative Federal Oncology Workforce continued from page 146

at the NCI will be able to achieve greater alignment with that goal. This can include avoiding the use of resources on clinical trials that do not advance an agent toward FDA approval. It is hoped that by interweaving FDA and Center for Cancer Research investigators, new ideas and energy will accrue to the development of clinical trials.” Sanjeeve Bala, MD, a Medical Officer at the Office of Hematology and Oncology Products and former clinician in the Developmental Ther-

have a strong history of collaboration with translational s cientists.”

Two Agencies Working Together Dr. Bala noted that both he and Dr. Pazdur have discussed ways in which the new investigators could help develop new dialog between the FDA, the Center for Cancer Research, and the pharmaceutical industry, aiding in the development of a more sophisticated drug development process. By bringing to the table their real-world clinical research experience, these in-

Ideal candidates will have developed and conducted their own investigatorinitiated clinical trials and have a strong history of collaboration with translational scientists. —Sanjeeve Bala, MD

apeutics Branch at NCI, added, “In order to be successful in the Center for Cancer Research, we’re looking for doctors who are experienced in disease-specific clinical research and who have successfully competed in a high-energy academic atmosphere. Also, ideal candidates will have developed and conducted their own investigator-initiated clinical trials and

vestigators will develop their careers as thought leaders in regulation for their specific disease areas. Moreover, given the focus of the new workforce initiative, both the FDA and the Center for Cancer Research—separate government agencies—acknowledge the mission for the advancement of medical research and, in particular, the development of new therapies for

cancer treatment. To that end, the two agencies, through this program, have agreed to increase opportunities for sharing information, material, and intellectual resources. Dr. Pazdur explained, in a nutshell, that the staff of the Office of Hematology and Oncology Products consists of over 130 highly trained physicians, scientists, and regulatory project managers with expertise in oncology, hematology, internal medicine, pharmacology/toxicology, and regulatory affairs. As for the Center for Cancer Research, it supports more than 250 scientists and clinicians, organized into more than 50 branches and laboratories, conducting basic, clinical, and translational science. The Center’s researchers pursue high-risk, highimpact research and translate their discoveries into clinical applications using the infrastructure provided by the National Institute of Health’s Clinical Center, the largest clinical research hospital in the world.

Possible Expansion Into Other Sectors According to Dr. Pazdur, the oncology workforce program could be a model for other sectors in the government. “The reason I called this initiative the oncology workforce program was because if it is successful, I can see it branching outside of the FDA into

New Investigators Will Serve in Two Capacities • At FDA: Become an expert in regulatory processes focusing on a specific disease type, from investigational new drug (IND) to new drug application (NDA) and postmarketing; develop pivotal role in guiding industry and academia in their approach to drug development. • At NCI: In collaboration with existing clinical teams, FDA/ NCI investigators will develop and execute clinical trials, identify translational correlates, enroll and treat patients, and analyze and publish data. other areas of the Health and Human Services department and perhaps the Centers for Medicare & Medicaid Services. But those discussions have not taken place at this time.” Drs. Pazdur and Bala said that the recruitment process was ongoing. “Given the multiple responsibilities involved and having to work within two government cultures, we are not in any rush. We just want to find the best candidates possible,” said Dr. Bala. n Disclosure: Drs. Pazdur, Bala, and Bates reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Harold Varmus, MD, on Leaving the NCI and What’s Next see page 74

Jyothirmai Gubili, MS, on Maitake see page 89

Sara M. Tolaney, MD, MPH, on Adjuvant Paclitaxel and Trastuzumab in Small, NodeNegative, HER-2 Positive Breast Cancer see page 96

Javaid Iqbal, MD, on Racial and Ethnic Differences in Diagnosis of Stage I Breast Cancer see page 100

Martin Schlumberger, MD, on Lenvatinib in RadioiodineRefractory Thyroid Cancer see page 102

Sean Smith, MD, on Physiatry and Survivorship see page 109

Shawna Grissom, MS, CCLS, CEIM, on Helping Pediatric Cancer Patients Cope see page 142

Patrick W. Mantyh, PhD, JD, on the Origins of Cancer Pain see page 145

Sandra M. Swain, MD, on CLEOPATRA Phase III Trial Results see page 168

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | MAY 25, 2015

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2015-2016 Oncology Meetings May

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

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org 13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

Yale ASCO® Review 2015: Highlights of the Annual Meeting June 19 • New Haven, Connecticut For more information: https://transact.med.yale.edu/cme/ conferences/conference_index. asp?ID=1149&linkID=0

2015 ASCO State Affiliates’ Reception May 31 • Chicago, Illinois For more information: www.asco.org/about-asco/ state-affiliate-leadership-conference

EACR-AACR-SIC Special Conference June 20-23 • Florence, Italy For more information: www.ecco-org.eu/eas2015

June

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 International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org

2015-2016

International Conference on Prostate Cancer June 22-24 • Orlando, Florida For more information: http://prostatecancer.cancersummit.org International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ The World NSCLC Summit 2015 Boston June 23-24 • Boston, Massachusetts For more information: http://nsclc.skygenix.com MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/ ASCO Review 2015 June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/2015/ASCO15/default.asp 2nd EACR Special Conference on Cancer Genomics June 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org IO360–Immuno-Oncology 360o June 29-June 30 • New York, New York For more information: http://theconferenceforum.org/ conferences/immuno-oncology-360/ overview/

July

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp Gynecologic Oncology Group July 15-19 • Denver, Colorado For more information: www.gog.org/meetinginformation. html 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

For more information, visit http://www.lymphcon.ch

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2015-2016 Oncology Meetings Palliative Medicine and Supportive Oncology 2015 July 23-25 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/pallmed15/overview.asp APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: 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

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

Advances in Cancer Immunotherapy™ July 31 • Pittsburgh, Pennsylvania For more information: www.sitcancer.org/sitc-meetings/ aci2015/pa

August

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

American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

September

International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/internationalprograms/international-palliativecare-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

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/

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org 25th World Congress of Lymphology September 7-11 • San Francisco, California For more information: www.lymphology2015.com

2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

2015-2016

ILCA 2015 —The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org

American Society of Hematology (ASH) Meeting on Hematologic Malignancies September 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/ ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting HPV 2015–30th International Papillomavirus Conference September 17-21 • Lisbon, Portugal For more information: www.hpv2015.org 2nd International Symposium of the Cancer Research Center of Lyon (CRCL) September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr 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 5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer.global-summit.com/ america/

October CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists) October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/ future_congress/future 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 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10 • Athens, Greece For more information: www.spandidos-publications.com/ pages/conference Congress of the International Society of Pediatric Oncology October 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com continued on page 152

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2015-2016 Oncology Meetings continued from page 151

Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: http://pallonc.org National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default. aspx

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org

Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

November

2015-2016

ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

December 9th European Colorectal Congress (ECC) December 1-4 • St.Gallen, Switzerland For more information: www.colorectalsurgery.eu Chemotherapy Foundation Symposium November 4-6 • New York, New York For more information: www. chemotherapyfoundationsymposium .org SITC 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.ncer.org/sitc-meetings/sitc2015

57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, Massachusetts For more information: www.integrativeonc.org/index.php/ events

Genitourinary Cancers Symposium January 7-9 • San Francisco, California For more information: http://gucasym.org Gastrointestinal Cancers Symposium January 21-23 • San Francisco, California For more information: http://gicasym.org

February Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org

March

Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org Best of ASTRO November 13-14 • San Diego, California For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index.aspx

January 2016

American Society for Cell Biology Annual Meeting December 12-16 • San Diego, California For more information: http://ascb.org/2015meeting/ European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ESMOAsia-2015-Congress

Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org Society of Gynecologic Oncology Annual Meeting on Women’s Cancer March 19-22 • San Diego, California For more information: www.sgo.org

Save the Date November 5-8, 2015 JW Marriott Phoenix Desert Ridge

Learn more at jadprolive.com A CE/CME Conference for Advanced Practitioners in Oncology

For conference exhibitor or sponsorship opportunities, contact David Horowitz at 631-935-7658 or email at david@harborsidepress.com

BECAUSE YOU CAN’T DO THIS TO FL…

THERE’S ZYDELIG

A first-in-class selective inhibitor of PI3Kδ, a protein that is expressed in normal and malignant B cells

ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed FL after ≥2 systemic therapies The FL indication was granted accelerated approval based on ORR; improvement in patient survival or disease-related symptoms has not been established. FL=follicular B-cell non-Hodgkin lymphoma; ORR=overall response rate; PI3Kδ=phosphatidylinositol 3-kinase delta.

IMPORTANT SAFETY INFORMATION BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended • Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation

Please see the following pages for additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING.

IMAGINE WHAT’S POSSIBLE

FDA approved in relapsed FL after ≥2 systemic therapies

Imagine what’s possible: ZYDELIG®—A first-in-class PI3Kδ inhibitor ZYDELIG is the FIRST AND ONLY

KINASE INHIBITOR APPROVED IN FL.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) RECOMMEND IDELALISIB MONOTHERAPY AS AN OPTION for appropriate patients with relapsed/refractory FL.1*

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN®=National Comprehensive Cancer Network®. *Please see the complete version of the NCCN Guidelines® for Non-Hodgkin’s Lymphomas available on NCCN.org for specific recommendations.

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development

of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash • Most frequent serious adverse reactions (SAR) were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions • Most common lab abnormalities (incidence ≥30%; all grades) were neutrophils decreased and ALT/AST elevations

Median time— the first follow-up, per protocol

Powerful efficacy, chemotherapy free 0

1.9

months 1

Demonstrated single-agent efficacy in an open-label, pivotal, phase 2 trial2† Range=1.6 to 8.3 months ZYDELIG in FL (n=72)

ORR

Response (%)

POWER of response

(95% CI, 42%-66%) 8% CR, 46% PR

Median DoR

Not reached

DURATION of response 0

Range=0.0+ to 14.8+ months CI=confidence interval; CR=complete response; DoR=duration of response; PR=partial response. †Results of a single-arm, open-label trial of ZYDELIG (150 mg, twice daily) in patients with FL who failed to respond or relapsed after ≥2 prior therapies (which must have included both rituximab and an alkylating agent). Primary end point was ORR, as assessed by an independent review committee. ORR was defined as the proportion of subjects who achieved CR or PR. Secondary end point was DoR. DoR was measured from the onset of first documented response (CR or PR) to disease progression or death.2

• Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash; 53% of patients discontinued or interrupted therapy due to adverse reactions Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations,

bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued Please see the following pages for Brief Summary of full Prescribing Information, including BOXED WARNING. VISIT ZYDELIG.COM

IMAGINE WHAT’S POSSIBLE

S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions]. INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities. • ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies. • ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies. • Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information. Adult Starting Dose: One 150 mg tablet taken orally twice daily (BID), swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who required treatment longer than several months is unknown.

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration]. Fatal and serious pneumonitis occurred in ZYDELIG-treated patients. Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids. Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation. Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions. Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration]. Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations]. ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

The safety assessment of ZYDELIG 150 mg BID + rituximab (up to 8 doses) is based on data from 110 adult subjects with relapsed CLL (Study 1). The median duration of exposure to ZYDELIG was 5 months.

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment. Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge. CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN). WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis. • Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%). Subjects with Indolent Non-Hodgkin Lymphoma (iNHL):

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%). DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine). • CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration]. • CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered. USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm. In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions]. Nursing Mothers: It is not known whether idelalisib 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 ZYDELIG, a decision should be made whether to discontinue nursing or ZYDELIG, taking into account the importance of ZYDELIG to the mother. Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established. Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed. • In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%). • In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%). Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions]. Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min. Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration]. 205858-GS-000-PI July 2014

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed January 7, 2015. 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. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months). • Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

Gilead, the Gilead logo, and ZYDELIG are trademarks of Gilead Sciences, Inc., or one of its related companies. All other trademarks referenced herein are the property of their respective owners. © 2015 Gilead Sciences, Inc. All rights reserved. ZYDP0068 02/2015

S:13”

DOSAGE AND ADMINISTRATION:

treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use of ZYDELIG with hepatotoxic drugs. In all patients, monitor ALT and AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. If ALT or AST >3x ULN, monitor weekly until elevation resolves; if ALT or AST >5x ULN, withhold ZYDELIG and monitor AST, ALT and total bilirubin weekly until elevation resolves [See Dosage and Administration].

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Book Review

A Less Is More View of Medicine By Ronald Piana He’s the best physician that knows the worthlessness of most medicines. —Benjamin Franklin

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any think the biggest problem in medical care is that it costs too much or that health insurance is too expensive, too uneven, or too complicated. But according to nationally regarded health-care expert H. Gilbert Welch, MD, the central problem is that too much medical care delivers too little value. Drawing on his 25 years of medical practice and research, Dr. Welch noted that while economics and onerous regulations and laws contribute to the excesses of American medicine, the problem is essentially created by our general public, who steadfastly clings to the notion that more medical tests and care are better care. Dr. Welch soundly debunks this mindset in his new book, Less Medicine, More Health: 7 Assumptions That Drive Too Much Medical Care. Dr. Welch knows this territory well, as he is the author of two previous books: Should I Be Tested for Cancer? Maybe Not and Here’s Why and the highly acclaimed Overdiagnosed: Making People Sick in the Pursuit of Health. And he is a frequent guest contributor to national newspapers and television shows. As expected, aside from an introduction and conclusion, the book is structured around Dr. Welch’s “7 Assumptions,” which makes for a modular, easy-to-follow format. Dr. Welch is Professor at Dartmouth Medical School but writes in the style of a trustworthy country doctor, urging readers to reject the temptation of trying to reduce all health risks by insisting on the latest technologies and tests. The informed health-care consumer must also be cautiously skeptical.

Challenging Common Assumptions In “Assumption 1, All Risks Can Be Lowered,” he challenges its potential dangers with an example of preventive measures gone awry that readers of The ASCO Post will appreciate. After explaining the rudiments of the randomized clinical trial, Dr. Welch made his point, stating that the history of hormone therapy serves as “exhibit A.” During the 1980s and 1990s, hundreds of studies linking hormone re-

placement to a lower risk of cardiovascular disease were published. “That’s what led Mom’s doctor—and thousands of others—to start millions of women on hormone replacement…. Soon after the new millennium, the results of follow-up studies were published, showing that hormone therapy on women like my mother caused as many problems as it solved. Millions of women like my mom were given the drug to prevent future problems…and that turned out to be a huge mistake.” As we know, one major problem was that hormone replacement increased the risk of breast cancer, and following the publication of the follow-up trials, millions of women went off hormone replacement therapy. Dr. Welch writes, “You could see the effect from space: The rate of breast cancer dropped nationwide.” This isn’t a newsflash for the oncology community, but it’s good to revisit past mistakes, and Dr. Welch’s interesting use of anecdotes makes for an enriching read. After a discussion about cardiovascular issues, in which Dr. Welch debated whether doctors should “manage the problem of angina or try to fix it,” he boiled it down to the underlying theme of much of the book: money. In this case, balloon angioplasties done by cardiologists are, in effect, taking ad-

Bookmark Title: Less Medicine, More Health: 7 Assumptions That Drive Too Much Medical Care Author: H. Gilbert Welch, MD Publisher: Beacon Press Publication date: March 3, 2015 Price: $24.95; hardcover, 241 pages

chapters, Dr. Welch challenges the readers’ assumptions about screening, specifically cancer screening, an area he is passionate about. “I know I sound like a broken record on this issue…. For a quarter of a century, cancer screening has been a central thrust of my research and writing for the public. Nevertheless, I know that a lot of misconceptions about cancer screening persist. Your intuition might be that cancer screening is a no-brainer…. In this chapter, I’m going to ask you to think again.” And he does, over and over again. Although much of this material about the risks of false-positive results,

The truth is screening is a mixed bag. It makes more sense for some cancers than others and for some individuals than others. But it should always be an informed voice. —H. Gilbert Welch, MD

vantage of our generous fee-for-service system. To make his point, he cited a trial that found “the patients who had their obstruction ‘fixed’ with balloon angioplasty were no less likely to die of or have a heart attack than patients who had their obstruction ‘managed’ with medications.”

Misconceptions About Cancer Screening Most of Dr. Welch’s book is interesting and written in a way that’s accessible to the smart lay public. In several

overdiagnosis, and lead-time bias will be like watching reruns for the readers of The ASCO Post, it does provide a thorough overview of our current screening environment, warts and all. Will Dr. Welch’s take on this complicated issue clear the air of contentious debate? No, but it will add a wellreasoned voice. He ends the chapter, “The truth is screening is a mixed bag. It makes more sense for some cancers than others and for some individuals than others. But it should always be an informed voice.”

‘Strive to Live, Not Avoid Death’ The chapter “Assumption 7: It’s All About Avoiding Death” is perhaps the book’s strongest, giving the reader a prescription: strive to live, not avoid death. Here, in a compelling narrative, Dr. Welch shared his father’s struggle and ultimate death from colon cancer, which unfolded during Dr. Welch’s first year of medical school and “quickly turned into one of the hardest years of my life—and one of the most important.” Even now, the oncology community struggles with imminent death and when to tell patients there are no more curative or life-extending options. It is one of the defining issues in the evolving practice of cancer care, and Dr. Welch offers sound and compassionate counseling. “Embrace life. And don’t dwell on death—recognize that it’s part of life.”

A Recommended Read Once again, Dr. Welch has turned out a fine book on health care. He put more of himself on these pages than in his previous books. It’s always a gamble for an author to get personal with his readers in this type of book, but it was worth it, because readers will come away liking Dr. Welch. This is a recommended read for the layperson and the professional health provider. Many of his messages and ideas should be carefully considered, as we endeavor to create a better health-care system. Incidentally, all the proceeds from his books go to charities. Another reason to like this author. n

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Reflections

Courage Under Fire By Kishore K. Dass, MD

The following essay by Kishore K. Dass, 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.

by willpower. My goals were to force myself to learn English, excel in high school and college, and make something of myself. Most children model themselves on the professional paths of their parents. Being a welder like my father never appealed to me. I wanted to impact lives. Anything else would equate to complete failure in my mind. But which career to choose?

Oncology Is My Calling

orn in Myanmar (Burma), an impoverished country, I was the eldest son of seven children in a destitute family. My parents were of firm Hindu faith, but I grew up in a Buddhist society until the age of 15. We then immigrated to Chicago, with great hopes and anticipation of achieving the American Dream. At the tender age of 7, I lost my Nani, my maternal grandmother, to what I now presume was liver cancer. I remember telling my mother with immense anger, “I miss Nani so much! When I grow up, I want to learn about and destroy cancer so that no one loses their [sic] Nani ever again!” I was a teenager when we moved to Chicago. I could not read or write, let alone speak, English. Despite this, I was placed in the ninth grade. One’s teenage years are challenging; here I was from a different country, facing a language barrier, and unimaginable culture shock. The human mind is a powerful engine: Faced with adversity or situations in which there is no option but to survive, the mind has the ability to overcome any obstacle. Failure was not an option. I was determined to succeed, even if purely Dr. Dass is Medical Director of South Florida Radiation Oncology in Wellington, Florida.

When I was in high school, two of my uncles—both oncologists— gave me the opportunity to shadow them at their outpatient clinics in the Chicago suburbs. On my first day, as my uncle entered a patient’s room, I saw the patient’s eyes light up, beaming with the utmost hope. My uncle answered questions thoroughly and with compassion. I noticed his words soothed all the patient’s fears. At that moment, I knew this was where I belonged. This was my calling. This is how I wanted to live the rest of my life, influencing lives and fulfilling the promise I’d made to my mother as a child. I’ve never looked back. Fast-forward through the years. I’ve successfully completed my medical training, and I’ve been hired as a radiation oncologist into a private group practice in West Palm Beach, Florida. In my 20 years in practice, I’ve had the privilege of caring for patients from all walks of life, afflicted with all varieties of cancers. Like all oncologists, I have experienced as many patient success stories as I have failures, but I’ve always tried to learn from each of my patients. They are responsible for the person I am today and the physician I’ve become. I will cherish these men and women eternally.

Lessons From a Nurse With Cancer I would like to share the story of one patient who taught me the essence of courage, resilience, and optimism. Several years ago, while tending to a patient—he’d undergone a prostate radioactive implant procedure—in the post anesthesia care unit, I overheard a stern, yet soft, voice say, “Bed 5 is in extreme pain! Are you going to order something or what?” I looked up and saw a petite young woman smile, then giggle. Like the surgeon she was addressing, I chuckled to

myself. This was nurse Andrea. I observed her interactions with patients and physicians. She exuded incredible energy, channeled through a bubbly personality. I watched her multitask with precision and ease: checking on patients, taking vital signs, answering phone calls, joking with staff members, and relaying patient updates to the surgeons. She possessed this positive magnetic force. I was drawn to her. Andrea was also very good at what she did and loved every minute of it. I decided I needed Andrea working side-by-side with me. I pleaded with her to transfer to my center. A perfectionist, she hesitated, feeling she didn’t have enough background or experience in oncology

tachment to the word cancer, but this was painful news to bear. On the other hand, Andrea looked at me and said, “Dr. Dass, don’t worry. Everything will be fine. I was meant to be at this cancer center. That’s why God sent me here. I’m a fighter, and I need your help to fight.”

Coping With Cancer Andrea always saw the bright side of things. She opted for breast conservation and started systemic chemotherapy with doxorubicin and cyclophosphamide, followed by paclitaxel. Despite experiencing fatigue, nausea, and alopecia, Andrea never missed a day of work. She wore her pink cap every day with great pride and dealt with

What I’ve learned from Andrea and so many other patients over the years continues to shape and refine me. It enhances my ability to be a better physician each and every day. —Kishore K. Dass, MD

to do the position justice. I promised I’d teach her and send her for oncology-certified nurse training. She finally agreed. I was amazed at how quickly Andrea learned oncology from pathophysiology to treatment and management (perhaps a little too much for her own good). Often she’d joke that if she grew extra appendages or developed cancer from the radiation, it would be my fault. Obviously, I’d discredit these nonsensical comments. We both knew it wasn’t possible, but it always made me smile. Andrea had this gift of making those around her relax, even if it was at her expense. Within 2 months of joining my practice, Andrea was diagnosed with stage IIIA, locally advanced breast cancer with multiple lymph node involvement. She was 32 years old, a wife, and a mother of 4-year-old twin boys. Besides working full time, she was a homemaker and cared for her aging father. I was devastated. I couldn’t help thinking, would she have this cancer if she still worked at the hospital recovery room? As medical providers, we often develop a numbness or de-

her hair loss by saying, “I never liked my hair anyway.” There was a time when extremely swamped at work, she suffered peripheral neuropathy. I watched her struggle to pick up a pen. Instead of getting emotional or frustrated, Andrea stopped, closed her eyes, took a deep breath, and was able to finally grasp the pen. I was staggered by her tremendous determination. After completing her chemotherapy, Andrea approached me for advice regarding radiation as part of breastconservation therapy. She requested I be her radiation oncologist. Surprised, I asked, “Wouldn’t you prefer to be under the care of one of my partners since we work together?” “Absolutely not!” she said. “If I’m to have radiation treatment, it will be under your supervision.” Reluctantly, I accepted her as my patient. Assuming it would be strenuous for her to juggle work, her personal life, and radiation treatment, I suggested she take some time off. Unyielding, Andrea worked right through her treatment. To ensure her patients were taken care of, she underwent treatment during her lunch breaks.

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Reflections

Andrea endured the side effects of radiation, including lymphedema in her arms. She took it in stride and immediately went to see a lymphedema specialist. Never did she ever suggest quitting her job or taking a leave of absence. She picked up her kids from preschool every day, dropped them off for after-care, and came right back to work. She never lost that great smile and positive demeanor. She tended to her patients as if nothing serious was going on in her life. She put their well-being before her own and gave them the undivided attention they deserved, day in and day out. She taught me that no matter the circumstance, patients take priority. I never saw Andrea cry. She never asked, “Why is this happening to me?” She never stopped living.

free for 5 years. She works with the Susan G. Komen Foundation. Oftentimes, when one of my patients is having a very difficult time accepting a newly diagnosed breast cancer, I have Andrea speak with her. After hearing Andrea’s story, I’ve seen patients come out with a completely different outlook: a willingness to de-

feat cancer; fear replaced with hope; anger replaced with humility; tears of sadness replaced with tears of joy. Recently, I asked Andrea about the secret of her bravery. She gave me that mysterious yet warm smile and said, “I stick around for my husband, my boys, family, friends, and even you. Imagine how bored you all would be!”

What I’ve learned from Andrea and so many other patients over the years continues to shape and refine me. It enhances my ability to be a better physician each and every day and motivates me to continue the journey I began 20 years ago with the same level of enthusiasm and interest I had as a young resident physician. n

The Gifts of Optimism and Perseverance Andrea reminded me that life has its ups and downs. That it’s okay if things are not always perfect. One must go on living. And yes, there is a happy ending to this story. Now 37 years old, Andrea has been cancer-

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The ASCO Post | MAY 25, 2015

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Patient’s Corner

Living With a Rare Cancer—My Dr. Seuss World

From cancer survivor to patient advocate, oh, the places I have gone. By Josh Mailman

o one ever expects to hear the words “you have cancer,” but over the course of the day, over 5,000 people in the United States are given that news.1 I first heard those words in the summer of 2007 and have been living with cancer ever since. At the time of my diagnosis, I knew this would forever change my life and my family’s life, but it has done so in ways I could hardly have imagined. Little did I know that my life would be transformed into two of Dr. Seuss’ books—Did I Ever Tell You How Lucky You Are? and Oh, The Places You’ll Go. Let me explain.

How Lucky I Am My first stroke of luck came with my diagnosis—pancreatic neuroendocrine tumor. That part is not lucky, but the fact that my internal medicine physician picked it up as part of my annual physical exam is. Those with neuroendocrine tumors routinely go 5 to 10 years with symptoms being misdiagnosed before finally getting a correct diagnosis. Most

roendocrine tumors, only a handful of medical centers have oncologists dedicated to the care of these patients. At the time of my diagnosis, there were no approved drugs or treatments for those without symptoms who have unresectable primary and innumerable liver metastases. Given that I was stable and the disease not yet progressing, my UCSF oncologist suggested a “wait and see” approach to my care, and if I was interested, I could see an integrative oncologist at UCSF. “Wait and see” is challenging to most patients and their families who are newly diagnosed with cancer, as they are bombarded by messaging from the popular press that if they are not fighting cancer, they have given up on their lives. My meeting with the integrative oncologist was more about taking care of me as a whole person than taking care of just my cancer. My cancer care was in the hands of my oncologist, whereas supportive care, from nutrition to my level of stress, was in his hands. “Wait

My goal in working with the patient and medical communities is to ensure that the next person diagnosed with a rare cancer does not need to live in a Dr. Seuss world of luck and travel to get the best outcome. —Josh Mailman

of those who are misdiagnosed are told they have other diseases such as Crohn’s or celiac, are going through menopause, or are just plain crazy. I was lucky and had a physician who picked up something and followed through with it, even though her patient had no symptoms and no abnormal blood markers. My luck continued in that I live in the San Francisco Bay area, where I had access to not one but two medical centers (University of California, San Francisco [UCSF] and Stanford), with specialists dedicated to neuroendocrine tumors. It would not be until much later that I learned that even though the incidence of neuroendocrine tumors makes it a rare disease, the prevalence of these tumors makes it the second most common gastrointestinal cancer after colon cancer in the United States.2 Even with over 100,000 patients living with neu-

and see” turned into “wait and learn.” At the time, I did not fully appreciate how lucky I was to live in an area with an excellent supportive care infrastructure. One of the biggest challenges for those with rare cancers is finding support and others willing to share their experiences. Although more and more patients turn to the Internet to find information and support, seeing and interacting face to face with others who are going through what you are experiencing is much more satisfying. In another stroke of luck, soon after my diagnosis, a local support group was forming and holding its first meeting at the Cancer Support Center in Walnut Creek, California. For the first time in over 6 months since my diagnosis, I was meeting face-to-face and sharing information with others who were going through what I was facing.

The NorCal CarciNET Community (my local neuroendocrine tumor support community) emphasized learning as much as you can about the disease, from clinical trials to clinical guidelines. The community encourages its members to attend national and international patient meetings on neuroendocrine tumors and to bring back information to benefit the entire community. With the group’s encouragement and eight other NorCal CarciNET Community members traveling together, I attended my first patient conference, hosted by the Canadian Neuroendocrine Tumor Society in Toronto, Canada, in October 2008.

The Places I Have Gone Little did I know that this first trip to Toronto would be the start of a global experience for me. On the third day of the conference, I listened to a lecture by the director of nuclear medicine in Bad Berka, Germany, about a gallium-68 (68Ga) positron-emission tomography/computed tomography (PET/CT) scan that is routinely used to track progression of my disease in Europe but was not yet available in the United States. Following the lecture, I asked about the availability of the scan for those visiting from the United States and was told I could arrange an appointment in a matter of weeks. I travelled to Germany in December 2008 and had a 68Ga PET/CT scan. The scan did not change the management of my disease, but it gave me more information about future treatment options should my condition change. Six months after my first scan, my condition worsened, and without too many options available in the United States, I returned to Germany in May 2009 for my first of what would be three rounds of peptide receptor radionuclide therapy. Improved health gave me the ability to give back to the communities that had helped me in my journey. In 2009, I joined the board of NorCal CarciNet Community. In 2011, we obtained nonprofit status, allowing us to better serve those in our community by providing facilitated support group meetings for patients, caregivers, and children of those whose parents are living with neuroendocrine tumors. Our community hosts an annual patient education conference for over 150 participants. Honoring our commitment to education, we also provide travel grants to

patients and medical professionals in our area to attend national meetings on neuroendocrine tumors. I also reached out to those physicians who helped me to see how I could support them and their patients. In 2009, I was nominated to the board of the Society for Integrative Oncology (SIO) and soon thereafter was asked to join its executive board for 4 years. The SIO works to advance evidence-based, comprehensive, integrative health care, improving the lives of people affected by cancer. Nearly all patients receiving a cancer diagnosis will likely research Internet remedies for managing their disease. Having guidelines and resources provided by the SIO and members of its community enables patients and patient advocates to better understand what complementary health care can and cannot do for a patient. In 2011, I was asked to attend the First Theranostics World Congress in Bad Berka, Germany, as a patient advocate. Attended by over 400 medical professionals and a few patients, this was the start of my association with those in the nuclear medicine and molecular imaging field. Shortly after that meeting, I became a member of the Patient Advisory Board of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and in 2013, I was elected the first chair of this group. As a group, we hold a patient education day at the SNMMI’s annual meeting, drawing over 100 patients and their families/friends. The SNMMI has been supportive of patient advocacy, including me in the outreach committee as well as in 68Ga and targeted radiotherapy working groups. My work in advocacy in the patient community has led to meetings and speaking invitations from patient groups and medical societies around the world. In the past 4 years, I have spoken at conferences in England, Austria, Mexico, India, Singapore, and the Philippines as well as countless conferences in the United States.

A Clearer Perspective The places I have visited have given me a clearer perspective of just how many people are working toward bringing better diagnostics and therapies to those with rare cancers. As a cancer patient, you see your oncologist and a few specialists and perhaps read a few papers and recognize some of the key authors.

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Patient’s Corner

We tend to think only a few specialists are following our disease and that not much progress is being made, but there is a bigger picture to appreciate. In 2014, I became a published author. I contributed an article from the patient perspective to the Integrative Oncology Monograph of the Journal of the National Cancer Institute.3 I also

to the last day of the 3rd Theranostics World Congress on 68Ga diagnostics and peptide receptor radionuclide therapy (wcga68.org) in Baltimore. After the daylong session, patients in attendance had a much better appreciation of the many people from different parts of the world with different areas of expertise who are working on their

Even with over 100,000 patients living with neuroendocrine tumors, only a handful of medical centers have oncologists dedicated to the care of these patients. —Josh Mailman

wrote an article for SNMMI’s publication Pathways, highlighting my experience on the 68Ga working group and trying to shed light on how professionals work together to bring new imaging and treatments such as 68Ga to the United States. This year, thanks in part to a grant from the Caring for Carcinoid Foundation and the Carcinoid Cancer Foundation, I was able to invite 80 patients

rare cancer in the nuclear medicine and molecular imaging specialty. Over these past 8 years, all of the places I have been have shown me just how lucky I am. Most of those facing a rare cancer diagnosis are not as lucky. My goal in working with the patient and medical communities is to ensure that the next person diagnosed with a rare cancer does not need to live in a Dr. Seuss world of luck and travel

to get the best outcome. The NorCal CarciNET Community and other groups across the country continue to raise awareness about the symptoms and signs of neuroendocrine tumors. Our goal is to reduce time to diagnosis so those who are suffering can be identified and helped much sooner by medical professionals who understand these rare tumors.

How You Can Help Reach out to local support groups in your area. Offer to give a talk and make sure your patients know where they can find disease-specific information and community resources. If no local support group is available, assist your patients in working with a national nonprofit to start one. Let your patients know that their rare disease is being studied, and help them become better educated about their disease. n References 1. Cancer Facts & Figures 2013. Available at www.cancer.org/acs/groups/ content/@epidemiologysur veilance/

Wants to Hear From You

• 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.

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

• 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.

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

Josh Mailman is President of NorCal CarciNET Community (NorCal CarciNET.org) and is Chair of both the Patient Advocacy Board for the Society of Nuclear Medicine and Molecular Imaging and the Society of Integrative Oncology Patient Task Force. He is also a member of the National Cancer Institute Task Force for Neuroendocrine Tumors and a Board Member of the Education and Research Foundation for Nuclear Medicine and Molecular Imaging and the Piedmont Yoga Community. Josh lives in Oakland, California, with his wife, Juliette, and their young son.

The ASCO Post

Patient Guides Available Through ASCO University Bookstore

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

documents/document/acspc-036845.pdf. Accessed April 16, 2015. 2. Yao JC, Hassan M, Phan A, et al: One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-3072, 2008. 3. Mailman J: A patient’s perspective on integrative oncology: Getting past the “war,” living with and beyond cancer. J Natl Cancer Inst Monogr 2014:291, 2014.

Write to The ASCO Post at editor@ASCOPost.com

2015 Women of Influence—The T.J. Martell Foundation honored seven distinguished women at The Women of Influence Awards & Luncheon held in New York earlier this month. Robin Quivers (seen far left) hosted the annual event, which honored (left to right) radio host and author Delilah, StriVectin Operation CEO JuE Wong, Jimmie C. Holland MD, of Memorial Sloan Kettering Cancer Center, T.J. Martell Foundation CEO Laura Heatherly, SESAC Executive Vice President and Chief Financial Officer Kelli Turner, Designer Elaine Turner, and the Third Highest Ranking Officer in New York City's Transit Union Local 100 Latonya Crisp-Sauray. NBC Today Show's Natalie Morales was also honored but could not attend the event. For more, visit www.tjmartell.org. The T.J. Martell Foundation is a nonprofit foundation that funds innovative medical research focused on finding cures for leukemia, cancer, and AIDS. Photo credit: Getty Images.

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The ASCO Post | MAY 25, 2015

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Expert’s Corner Professional Development

Learning to Communicate Science More Effectively A Conversation With Alan Alda By Jo Cavallo

Alan Alda

lan Alda’s passion and appreciation for science extend nearly as far back to his early life as his love of acting. The son of actor Robert Alda, Mr. Alda began his acting career at the age of 16. Although he has appeared in such widely acclaimed films as The Seduction of Joe Tynan, Crimes and Misdemeanors, and The Aviator, for which he received an Academy Award nomination, he is perhaps best known for his role as the wise-cracking surgeon Hawkeye Pierce in the long-running television series M*A*S*H. Science became a parallel passion when Mr. Alda was in his 20s, and he began pouring through issues of Scientific American cover to cover. In 1993, Mr. Alda became the host of the PBS series Scientific American Frontiers. He conducted hundreds of interviews with scientists during 11 seasons of the program. Mr. Alda found that when scientists discussed their work one on one, they usually gave lively and engaging explanations but would occasionally slip into lecture mode, and he wondered whether a program could be designed to help them use conversational skills to communicate their research more effectively with the public. This experience led Mr. Alda, 79, to suggest to university presidents that they offer courses to teach scientists to become more capable communicators. In 2007, Stony Brook University in Stony Brook, New York, expressed interest in developing a graduate program to improve public communication of science. Two years later, with the cooperation of Brookhaven National Laboratory and Cold Spring Harbor Laboratory, both on Long Island, New York, the University launched the Alan Alda Center for Communicating Science. The program requires all medical students to receive 10 hours of training and

includes Improvisation for Scientists, a workshop pioneered by Mr. Alda that uses improvisational theater techniques to help scientists speak more spontaneously and directly with their audience, as well as workshops in Writing About Science for the Public and Media Interview Skills. The Alan Alda Center also offers these workshops to academic and medical institutions across the country, including The Rockefeller University in New York, the University of Michigan Medical School in Ann Arbor, and the University of California in Los Angeles. The program has proved to be so beneficial to students that Dartmouth College, the University of Vermont, and the Robert Wood Johnson Medical School have become affiliates of the center, and other universities are considering developing similar programs. The ability to describe science effectively, said Mr. Alda, can result in providing not just the general public with a greater understanding of science but policymakers in charge of research funding as well. “There isn’t anyone who would give out money for something he doesn’t understand,” said Mr. Alda. Mr. Alda’s work in helping to broaden the public’s appreciation for science has garnered him the Sagan Award; the AAAS Kavli Science Journalism Award for the PBS series, The Human Spark; and the Scientific American Lifetime Achievement Award.

The ASCO Post spoke with Mr. Alda, Co-Founder of the Alan Alda Center for Communicating Science and Visiting Professor at Stony Brook University, about the development of the center; the need for scientists to hone their communication skills; and how more effective communication can improve the public’s understanding of science.

Cultivating Scientists and Communicators Why is it important for you to help future scientists learn to communicate their ideas more clearly? By the time I finished hosting Scientific American Frontiers, I realized that we had almost by accident stumbled upon a good way for scientists to communicate with the public, which was through

warm human contact they had had in a conversation with someone, even when they were up alone on a stage peering into an audience or when they were writing for the public. The second thing I wondered was whether we could teach scientists to become effective communicators from the time they are learning about science, so they would leave school as both accomplished scientists and accomplished communicators. In the improvisational workshops we have developed, we are not asking scientists to be funny or make up stories, which is the usual notion of what improvisation is, but rather we use theater games to help them talk about their work more directly. And what is interesting to see is that they gladly engage in the process of making real contact with

Clarity and accuracy don’t go against each other. I don’t think science was ever hurt by more clarity. —Alan Alda

conversation. Speaking one on one with scientists made them much less likely to go into lecture mode, which is usually difficult to understand but also does not have the same human flavor to it. And I wondered two things: One was whether scientists could benefit from exposure to a program that would help them experience the same sense of

the people with whom they are playing these games, which then results in better contact with the audience. The games and acting exercises are designed to help scientists build up a certain amount of empathy with the person they are talking to and the theory of mind, so they can actually anticipate what the other person is thinking and determine whether the person is getting what is being said. And the most important thing is not what the scientist is saying but what the other person understands, because you can say the most brilliant things, but if what you are saying is jargon to your audience, if it sounds like you are speaking a foreign language, or if you are putting the person off with your manner, you might as well have not said anything.

More Clarity and Empathy

The Improvisation for Scientists workshop at the Alan Alda Center for Communicating Science at Stony Brook University trains scientists at all career levels to communicate their work more effectively to the public, the media, and scientists outside their field. Top: Alan Alda helps workshop participants develop skills to connect with their audience. Photo credit: Courtesy of the Alan Alda Center for Communicating Science

How can participation by oncologists in the Improvisation for Scientists workshops help them communicate more effectively with their patients, colleagues, the media, and public officials? There is an especially strong need for oncology researchers to communicate effectively with policymakers in charge of issuing grants and determining research funding. I saw in the PBS documentary Cancer: The Emperor of All Maladies that research funding has gone

ASCOPost.com | MAY 25, 2015

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Expert’s Corner

down 25% instead of going up, and that’s a disaster. (See “Bringing the History of Cancer to Film,” in the March 10, 2015, issue of The ASCO Post.) Part of the problem might be due to poor communication of the idea the researcher is proposing, because so many proposals are full of jargon and specific details of biologic processes that policymakers don’t understand and cannot be expected to know. Scientists have to be able to translate what they are saying so it is understood. There isn’t anyone, I don’t think, who would give out money for a project he or she does not understand. It is the job of the communicators to make clear what they are saying. On the first point you made about communicating more effectively with patients, we all have had encounters with doctors, with some being outstanding communicators and some having been wanting. And what we have found through our work with a lot of medical schools is that the difference, to a great extent, is the physician’s ability to make a real connection with the patient and to understand what the patient is feeling. There are several definitions of empathy, but I think of empathy as two different experiences. One is the cool kind, where you are cognitively aware of what the other person is going through, and the other is the hot kind, where you take on the emotions of the other person. The hot kind is probably detrimental, because, for example, if your doctor looks as your x-ray and says, “Oh, my God, no,” that is not a good response. Conversely, if the second the doctor comes into the room he can tell from the patient’s face and body language that the patient is anxious and he can speak to that anxiety, the experience for the patient will be a lot better. In terms of relaying scientific information to the media, I think better communication is the answer to poor reporting. Scientists need practice talk-

ing with the media, so they can describe their work briefly, clearly, and accurately and not dumb it down. That’s very important, and we stress that constantly. Clarity and accuracy don’t go against each other. I don’t think science was ever hurt by more clarity.

Improving Public Speaking and Writing What have you observed in the way scientists communicate their work before and after they have participated in your improvisational workshops? We were conducting a workshop at a university, and a scientist there had had a breakthrough in his work that had been reported in his university press. After he took our workshop, he talked about his work and wrote about it in a completely different way. It was still accurate, but his words had imagery that the public could understand, and his work was later reported in publications around the world. The techniques scientists learn in our workshops that improve their public speaking can also be used to improve their writing, because the same process is at work, which is being aware of what the person listening to or reading the work is thinking. Is the person ready to hear the next idea, and how can the scientist prepare the audience for the next idea? And scientists need to more clearly communicate their ideas not just to lay people but to other scientists as well. One of the observations I’ve made, and it was kind of surprising when I realized it was true, is that scientists often don’t understand one another unless they are in the exact same field—and sometimes unless they are in the same laboratory—because they develop an academic shorthand. This saves time and it’s a way to communicate easily with people familiar with the work, but it can cause trouble when people are not all on the same page. When the National Institutes of Health was starting up the Brain Re-

Steps to More Effective Communication

lan Alda, Co-Founder of the Alan Alda Center for Communicating Science and Visiting Professor at Stony Brook University, suggests these steps to improve scientific communication. The ability to be empathic and imagine what someone else might be thinking or feeling is the key to becoming a more effective communicator. • Jargon is gibberish. You have to speak the same language as your audience. • The public is on a blind date with science—make them fall in love with science. With effective communication, you can attract people to your ideas. You want people to love the work as much as you do. • Confidence comes from being able to relate to your audience. • Defeat the curse of knowledge in which people with a specific knowledge incorrectly assume that other people have the same information by using concrete language to express your ideas. • Use emotion to communicate science. Information is more easily retained if there is an emotional connection to the idea that is being conveyed. • Tell a compelling story about your study results, including the obstacles you encountered. • No matter how good your communication skills are, they can always be improved. • Scientific knowledge is one of the greatest achievements of human kind and one of the greatest gifts we have to share with each other. When you communicate effectively, you make science exciting and more accessible. • The ability to communicate a message effectively is what makes us human and allows technology to advance.

search Through Advancing Innovative Neurotechnologies (BRAIN) initiative, a group of neuroscientists and nanoscientists got together and wasted hours discussing the word “probe,” because they couldn’t agree on its meaning. That’s awful. So scientists need to communicate more effectively with each other and, very importantly, across disciplines, as well as with the public at large.

Building Familiarity and Trust Less than 5% of Americans participate in clinical trials, in some cases because they have a misunderstanding of trial information. How can scientists involved in oncology care help patients have a better understanding of the true risks and benefits of scientific research so they can make informed decisions? This is just a guess, because we don’t have hard data on this issue, but

we are beginning to understand that if you build familiarity and trust with the people you are trying to help understand complex information, you will have greater success. If they think a stranger in a white coat is forcing some dangerous experiment on them, people become self-protective, so establishing a familiarity with the scientist as a caring, trustful person can help break through the barrier. I don’t think people can be convinced by arguing them into complying with what you want them to do, but if the information is presented clearly and compassionately, it might make a difference. For more information about the Alan Alda Center for Communicating Science, visit www.centerforcommunicatingscience.org. n Disclosure: Mr. Alda reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Peter Paul Yu, MD, FACP, FASCO, on the 2015 Annual Meeting see page 1

Robert W. Carlson, MD, And Others on 2015 NCCN Guidelines Updates see page 12

Visit The ASCO Post online at ASCOPost.com

Edward B. Garon, MD, on Pembrolizumab and NSCLC see page 20

The ASCO Post | MAY 25, 2015

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Journal Spotlight Breast Cancer

CLEOPATRA Overall Survival Analysis: Significant Benefit for Pertuzumab Plus Trastuzumab/Docetaxel in HER2-Positive Metastatic Breast Cancer By Matthew Stenger

s reported in The New England Journal of Medicine by Sandra M. Swain, MD, of Washington Cancer Institute, MedStar Washington Hospital Center, and colleagues, the final prespecified overall survival analysis in the phase III CLEOPATRA study showed a significant 15.7-month increase in median overall survival over 50 months of follow-up with the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and docetaxel in the first-line treatment of women with HER2-positive metastatic breast cancer.1 An earlier report from CLEOPATRA showed significant improvement in the primary endpoint of progression-free survival with the pertuzumab-containing regimen.2

Study Details In the double-blind trial, 808 patients were randomly assigned between February 2008 and July 2010 to receive pertuzumab, trastuzumab, and docetaxel (n = 402) or placebo, trastuzumab, and docetaxel (n = 406) in 3-week cycles. Study drug doses were pertuzumab at 840 mg on day 1 of cycle 1 followed by 420 mg on day 1 of subsequent cycles, trastuzumab at 8 mg/kg on day 2 of cycle 1 followed by 6 mg/ kg on day 1 of subsequent cycles, and docetaxel at 75 mg/m2 on day 2 of cycle 1 and day 1 of subsequent cycles. Patients had to have left-ventricular ejection fraction ≥ 50% at baseline and could not have received more than one hormonal treatment for metastatic disease. Adjuvant or neoadjuvant chemotherapy with or without trastuzumab was permitted.

Overall Survival Improvement Median follow-up was 49.5 months (range, 0–70 months) in the pertuzumab group and 50.6 months (range, 0–69 months) in the control group. Median overall survival was 56.5 months (95% confidence interval [CI] = 49.3 months to not reached) in the pertuzumab group vs 40.8 months (95% CI = 35.8–48.3 months) in the control group

(difference = 15.7 months; hazard ratio [HR] = 0.68, P < .001) in an intent-totreat analysis. Estimated survival rates were 94.4% vs 89.0% at 1 year, 80.5% vs 69.7% at 2 years, 68.2% vs 54.3% at 3 years, and 57.6% vs 45.4% at 4 years.

Subgroup and Sensitivity Analyses Exploratory subgroup analyses generally showed a consistent benefit of the addition of pertuzumab according to prior neoadjuvant/adjuvant treatment, study region, age, race/ethnicity,

Overall, subsequent therapy was received by 77% of patients in the pertuzumab group and 79% in the control group after discontinuation of study treatment, including HER2-targeted treatment (usually trastuzumab) in 73% and 71% and capecitabine in 55% and 58% of those receiving subsequent treatment. Investigator-assessed median progression-free survival was 18.7 vs 12.4 months (HR = 0.68, P < .001). Median duration of response among 275 patients in the pertuzumab group and

In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. —Sandra M. Swain, MD, and colleagues

and hormone receptor status. Hazard ratios were 0.59 among patients with visceral disease and 1.11 among those with nonvisceral disease (P = .03 for interaction). Among 47 patients in the pertuzumab group and 41 in the control group who had received previous trastuzumab treatment, the hazard ratio was 0.80 (95% CI = 0.44–1.47). Sensitivity analyses were performed to adjust for outcomes in 48 patients (12%) without disease progression who crossed over from the control group to receive pertuzumab. All had been receiving study treatment for at least 2 years. Median overall survival was 56.5 vs 39.6 months (HR = 0.63, P < .001) when data from these patients were censored at the time of first pertuzumab dose and 56.5 vs 34.7 months (HR = 0.55, P < .001) when the data were excluded.

associated with docetaxel administration. Overall, left-ventricular dysfunction was observed in 6.6% of patients in the pertuzumab group and 8.6% of patients in the control group. One new case of symptomatic left-ventricular dysfunction was observed in a patient in the pertuzumab group after 40 months, with the event resolving at 3 months after discontinuation of pertuzumab and trastuzumab. Reductions in leftventricular ejection fraction of ≥ 10% from baseline to an absolute value of < 50% were observed in 6.1% and 7.4% of patients, with the reductions being reversed in 21 (87.5%) of 24 patients in the pertuzumab group and 22 (79%) of 28 in the control group. Death due to febrile neutropenia or infection occurred in 1.7% of patients in the pertuzumab group and 1.5% of patients in the control group. The investigators concluded: “In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination.” n

233 in the control group with response on independent assessment was 20.2 vs 12.5 months.

Disclosure: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of the study authors, visit www.nejm.org.

No New Safety Signals

References 1. Swain SM, Baselga J, Kim S-B, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015. 2. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

Rates of adverse events were consistent with those reported in the primary progression-free survival analysis, with any-grade headache, upper respiratory tract infection, and muscle spasm occurring at an incidence ≥ 5% higher in the pertuzumab group. Most adverse events in both groups were grade 1 or 2 and were

CLEOPATRA Trial Update ■■ The addition of pertuzumab to trastuzumab and docetaxel significantly prolonged overall survival. ■■ Estimated overall survival was 94.4% vs 89.0% at 1 year, 80.5% vs 69.7% at 2 years, and 68.2% vs 54.3% at 3 years.

More on the CLEOPATRA Trial in Metastatic Breast Cancer Javier Cortés, MD, of Vall d'Hebron Institute of Oncology in Barcelona, discusses the unexpectedly huge survival benefit observed with pertuzumab and trastuzumab in HER2-positive metastatic breast cancer. See page 173.

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

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Perspective

Continued from page 168

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

Unexpectedly Huge Survival Benefit With Pertuzumab and Trastuzumab in HER2-Positive Metastatic Breast Cancer By Javier Cortés, MD

n my opinion, the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) is one of the most important advances in the field of metastatic breast cancer in the past 10 years. As recently reported by Swain, my other colleagues, and me and reviewed in this issue of The ASCO Post, the CLEOPATRA trial, designed to demonstrate the benefit of pertuzu mab, trastuzumab, and chemo-based therapy over trastuzumab and chemo-

—Javier Cortés, MD

based therapy in terms of progressionfree survival, also showed an improvement in overall survival.1 However, what was absolutely unexpected was the huge survival benefit observed. Usually, an improvement in progression-free survival does not translate into a statistically significant difference in overall survival. Many reasons might explain that, including the prolonged post-progression survival observed in patients with metastatic breast cancer. However, in this case, even with a very prolonged post-progression survival, improvement in overall survival was not only statistically significant, but it represents an impressive absolute improvement. To the best of my knowledge,

these are the best overall survival data in the history of metastatic breast cancer trials. Median overall survival was 56.5 months (95% confidence interval [CI] = 49.3 months to not reached) in the pertuzumab group vs 40.8 months (95% CI = 35.8–48.3 months) in the control group (difference = 15.7 months, hazard ratio [HR] = 0.68, P < .001). The improvement in median progression-free survival was amazing

To the best of my knowledge, these are the best overall survival data in the history of metastatic breast cancer trials.

Dr. Cortés is Head of the Breast Cancer Program at Vall d’Hebron Institute of Oncology and Medical Oncologist, Medica Scientia Innovation Research (MedSIR), in Barcelona, Spain.

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as well but shorter (18.7 vs 12.4 months, HR = 0.68, P < .001). How is this possible? How is it possible to achieve an improvement in median progression-free survival that is much shorter than the improvement in median overall survival? This is clearly something that investigators should be studying. However, in the meantime, pertuzumab, trastuzumab, and taxanes should be considered the new standard of care for first-line treatment in patients with HER2-positive metastatic breast cancer. n

Disclosure: Dr. Cortés is a consultant for Roche/Genentech and Celgene; has received honoraria from Roche/Genentech, Novartis, Eisai, and Celgene; and has stock in MedSIR.

Reference 1. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724734, 2015.

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Art of Oncology

The Paradox of Positive Thinking By Eliezer M. Van Allen, MD

The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays. To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.” For information on how you can submit your own essay for consideration in JCO’s Art of Oncology, visit http:// jco.ascopubs.org/site/ifc/ determine-my-article-ty pe. xhtml#art-of-oncology

lthough his symptoms had been festering for months, it was not until James sank his teeth into a peanut butter and jelly sandwich that he finally knew with certainty that something was horribly wrong. His nose had been draining incessantly, but numerous evaluations and attempts at treatment—including a septoplasty and course after course of antibiotics—had not solved the problem. He kept smiling his increasingly crooked smile while explaining himself to a multitude of physicians. Eventually, on that fateful day, James felt a sharp twinge while taking a bite and quickly pulled the sandwich out of his mouth. He inspected the slice of bread and found one of his teeth buried inside of it. I first met 35-year-old James about 3 weeks later, after at long last the necrotic mass that was at the root of his problem had been discovered near his hard palate. Detection of the mass was quickly followed by a biopsy—two biopsies, actually, because the first sample was nondiagnostic. After soliciting an array of pathologist opinions, a specific diagnosis was finally made: natural killer/T-cell lymphoma, nasal type. Dr. Van Allen is from the Dana-Farber Cancer Center in Boston. Article reprinted with permission from the Journal of Clinical Oncology. © 2015. American Society of Clinical Oncology. All rights reserved.

Natural killer/T-cell lymphomas are rare neoplasms that carry a poor prognosis even when detected at an early stage, and are usually rapidly fatal when metastatic. At that point, we did not know much else, but that did not stop me from facing James and a hospital room filled with his family and friends to explain the basics of his diagnosis. I described the type of tumor he had, the likely severity of its involvement in his skull, and the need for many additional tests. I suspect I was appropriately morose. Yet after my somber monologue stirred the growing tension that had been simmering in his room since he was admitted to the hospital, James turned to me and said, “I feel great, so this won’t be a problem. I’ve got to stay positive.” I smiled, offered encouragement, and left the room. The next day, James underwent a positron emission tomography/computed tomography scan. I was still hopeful that he had only localized disease, but the mass had likely been present for quite a while, and I felt compelled to remain properly pessimistic. When the imaging study showed a suspicious liver mass, I was not surprised. I returned to the patient’s room, again faced an explosion of family and friends standing at his bedside, and explained the bad news. “I understand it has spread. That won’t stop me. I’m going to be fine.” His crooked smile, which had become slightly more jagged with the continued invasion of the tumor into his palate, returned. Was I communicating the bad news ineffectively? Did he truly understand his grim situation? I repeated the information and the need for another procedure to biopsy the liver mass. He laughed and reassured his family that everything would be fine. I did not correct him. Although I knew I was explaining his scenario in approachable terms, he was not responding in kind. I smiled, offered further encouragement, and left the room. I began wondering whether James’ stay-positive coping strategy was part of a larger accepted modality among patients with cancer. I discovered that numerous investigators have attempted to correlate the way patients handle a cancer diagnosis with the patients’ eventual outcomes. Although a few smaller studies have suggested a survival benefit in maintaining a persistently positive mental approach no matter how grim

the situation, the bulk of data strongly supports the notion that there is no difference in outcome, regardless of the coping mechanism a patient chooses.1 In fact, many of the claims made in the positive psychology literature have been refuted or are so vague that they are not testable with any degree of scientific rigor.2 Perhaps, I thought, for some patients like James, positive thinking is a reflex, a means of facing the seemingly insurmountable struggle that lies ahead. Was it then my responsibility to meet him where he was and try to sustain his artificially created state of mind or instead to try to force him to convert to my own more realistic view of his situation? The liver mass was biopsied, and it confirmed metastatic disease. After the findings were explained to the patient, he turned to his family and smiled. They smiled back at him. “It’s just a small bump in the road. I’m going to be fine.” Was he suffering under the weight of his family’s expectations to fight on, a com-

I was the problem because I was not being positive enough. Although honesty required that I acknowledge the dire nature of his disease, by offering no possibility for a positive outcome, was I merely projecting my own pessimistic nature onto a vital physicianpatient interaction? The next day, James was being transported to his first simulation for planned palliative radiotherapy treatment when he developed a high fever. The orderly rushed him back to his hospital room, and the house officers obtained cultures and administered broad-spectrum antibiotics. I came into James’ room a little later, dejected, and explained that although we had hoped to begin radiation treatment, we could not do so safely that day. I began making what, in retrospect, was a rather meager attempt at sounding hopeful, when James cut me off. “I’m not worried. I’ll get it done tomorrow, and then I’ll be doing well.” When James, his gurney, and his

Ultimately, this is a very hopeful film and one that will make people feel better about cancer … and about what would happen today if they or their loved ones were diagnosed with the disease. —Eliezer M. Van Allen, MD

mon phenomenon among patients with cancer that many find unbearable yet simultaneously immutable?3 I explained to him that I admired his steadfast positivity in the wake of this challenge, which he seemed to appreciate greatly. Yet after leaving the room, I contemplated the disparate trajectories our respective tones had taken; the more hopeless and desperate I made his outlook sound, the more hopeful and determined he seemed to become. Even more, I felt that each attempt to instill my conceptual understanding of James’ grim prognosis to him only served to reinforce his increasingly positive spin on the situation. Perhaps, faced with the increasing certainty of his mortality, his focused optimism was the only response he could imagine. Seen in that light, I wondered whether

nurse reached the elevator the next day to once again attempt radiation simulation, he suffered a seizure. He was once again rushed back upstairs, where he was administered antiseizure medications and observed carefully in his room for the remainder of the day. The second attempt to initiate palliative radiotherapy had been thwarted. Later that day, I returned to his hospital room and involuntarily let out a prolonged sigh. Before I could speak, James turned to me. His face had become markedly more swollen, his remaining teeth now projected in increasingly awkward directions, and his neck was covered in sweat. “I know I will do well. I can overcome this.” It was difficult to understand him the first time he mumbled something, so I asked him to repeat it. His father, sitting at his bedside, nodded approvingly.

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Art of Oncology Was James delusional? Was he trying to cheer me up or to put on a good show for his family? Or worse, was he in fact not capable of even understanding his situation, something I had assumed this entire time? Maybe he could not grasp the enormity of his condition, and his positive attitude was merely the reflection of a complete lack of understanding. I pulled his father aside privately and asked his opinion of his son’s capacity to appreciate his situation. The father sternly brushed aside any suggestion of incompetence or denial. I quickly apologized for making this suggestion, but I did not understand how he could remain so positive while facing the increasingly dire situation. More head imaging and a lumbar puncture confirmed the worst: CNS involvement. His disease was rapidly evolving, even in the few interim days between scans, and he was in no shape to receive any treatment without suffering grave adverse effects. With his family at his side, the attending physician and I explained the bad news and his equally

untenable options: succumb now or a little later by attempting to treat the disease via methods that are themselves potentially lethal. I feared more positive thinking that I could not understand, influence, or conquer. I worried that his relentless positivity would, just like his tumor, permeate his inner thoughts and point him toward the latter choice. Instead, he chose comfort. “I get it. I’m done.” With that statement, his gathered family erupted in tears. I fought back my own tears—my first as an oncologist—and after some time, I left the room to give the family privacy. When I returned the next day to check in on James, I asked him if he was comfortable. “I am, and I want to apologize to you.” I was shocked. Apologize to me? I felt like I was the one who needed to apologize—for not being able to provide treatment, for repeatedly crushing his hope for a future, for not validating his positive thinking. With tears running down his cheeks, colliding with his beads of sweat and the swollen mountains his cheeks had become, he mumbled, “I

am sorry that I can’t be positive today.” He died 3 days later. When patients state their fears and anxieties about treatments, I often find myself validating these sentiments, stating that I would be far more worried if they were incessantly cheerful and bordering on delusional, completely denying the grave realities they are facing and the diseases threatening their lives. I rarely hear patients discuss the positive aspects of their treatments and care, as James did repeatedly. Beyond citing survival statistics and quality-of-life measures during the initial visit, I rarely validate these positive sentiments myself. After all, I do not want to get caught up in the irrational positivity of pink ribbons or yellow bracelets, and before I met James, I naively did not want to believe that the emotional sentiments I conveyed had a lasting effect on my patients. However, after having the privilege of being involved in James’s care and seeing his courage and dignity even while facing an impossible challenge, I

now counsel differently. Positive thinking can be an important part of being a patient with cancer, or a patient facing any serious disease, if only for the comfort it provides the patient, the family, and the physician when reality forces increasingly negative choices on all of us. And just as valuable is balancing that optimism with realistic pessimism, such that during any given encounter, patient and physician can work collectively to connect these two disparate coping worlds and reach a more enlightened space, together. n References 1. Petticrew M, Bell R, Hunter D: Influence of psychological coping on survival and recurrence in people with cancer: Systematic review. BMJ 325:1066, 2002. 2. Coyne JC, Tennen H: Positive psychology in cancer care: Bad science, exaggerated claims, and unproven medicine. Ann Behav Med 39:16–26, 2010. 3. Holland JC, Lewis S: The Human Side of Cancer: Living With Hope, Coping With Uncertainty, 1st ed, p 340. New York, HarperCollins, 2001.

More From the Art of Oncology in JCO The Night Before the First Day of School Adam S. Levy JCO May 1 2015: 1509-1510 Palliative Oncologists: Specialists in the Science and Art of Patient Care David Hui, Esmé Finlay, Mary K. Buss, Eric E. Prommer, Eduardo Bruera JCO Apr 27 2015 Profound Answers to Simple Questions Ceilidh Eaton Russell, and Eric Bouffet JCO Apr 10 2015: 1294-1296 Poison Abby R. Rosenberg JCO Apr 6 2015: JCO.2015.61.2465v1-JCO.2015.61.2465 A Bag of Chips Daniel Rayson JCO Apr 1 2015: 1214-1215 You Have Nothing to Lose Lee N. Newcomer JCO Mar 30 2015: JCO.2014.60.5634v1-JCO.2014.60.5634.

Visit http://jco.ascopubs.org/cgi/collection/a007

The ASCO Post | MAY 25, 2015

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Lab Notes

Ongoing Molecular Research in the Science of Oncology

BLEED

BIOMARKERS Bispecific Antibody Recruitment to Increase Antitumor Activity of Adoptive T-Cell Transfer In a study reported in the Journal of the National Cancer Institute, Kobold and colleagues assessed whether combining tumor-specific T cells modified with a marker antigen and a bispecific antibody that selectively recognizes transduced T cells and tumor cells could improve Tcell recruitment to tumors and antitumor activity of adoptive T-cell transfer. SV40 T antigen–specific T cells from T-cell receptor-I transgenic mice were transduced with truncated human epidermal growth factor receptor (EGFRa) as a marker protein. Targeting and killing with combined adoptive T-cell therapy and anti-EGFR/anti-epithelial cell adhesion molecule bispecific antibody therapy were investigated in C57BL/6 mice with murine gastric cancer cell line GC8 (positive for both SV40 and epithelial cell adhesion) subcutaneous tumors. Anti-EGFR/anti-c-Met bispecific antibody was used for targeting of human tumorspecific T cells to c-Met–positive human tumor cell lines. The bispecific antibody linked EGFR-transduced T cells to tumor cells and increased tumor cell lysis. In mouse models, the combination of adoptive T-cell transfer and bispecific antibody increased T-cell infiltration of tumors, inhibited tumor growth, and prolonged survival compared with adoptive T-cell transfer with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, the bispecific antibody strategy increased recruitment of human EGFR-transduced T cells to immobilized c-Met and improved recognition of tyrosinase-positive melanoma cells by T-cell receptor–modified T cells and carcinoembryonic antigen–positive colon cancer cells by chimeric antigen receptor–modified T cells. The investigators concluded: “Bispecific antibody recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of [adoptive T-cell transfer].” Kobold S, et al: J Natl Cancer Inst 107:364, 2014 (print January 2015).

IGF2 May Be Target in Colorectal Cancer With Stable Disease As Response to Anti-EGFR Therapy In a study exploring the mechanisms of stabilized disease vs tumor re-

gression with targeted anti–epidermal growth factor receptor (EGFR) therapy in colorectal cancer reported in Science Translational Medicine, Zanella and colleagues found that stable disease as response was characterized by

overexpression of insulin growth factor (IGF) 2. Studies in patient-derived xenografts from samples that did not harbor established resistance mutations showed that those from patients re-

sponding to cetuximab (Erbitux) with disease stabilization exhibited high levels of EGFR family ligands and receptors. Of 21 stabilized disease models with particularly high expression of EGFR and EGFR fam-

TRIM:

SAFETY

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Lab Notes

D: 15.4” 15.15”

Y: 14.15”

ily members, 5 (24%) had tumor regression after intensified EGFR blockade with cetuximab and a smallmolecule inhibitor. Of 16 models in which enhanced EGFR inhibition did not result in tumor regression, 6 (37.5%) exhibited marked overexpression of IGF2. Enrichment of IGF2 overexpres-

sion in cases with stabilized disease was demonstrated in the entire set of patient-derived xenografts and was confirmed in colorectal cancer patients using clinical gene-expression data sets. In functional studies, IGF2 overproduction reduced the efficacy of cetuximab, and abrogation of IGF2-dependent signaling in IGF2-

overexpressing models potentiated the effects of cetuximab. The investigators concluded: “The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of re-

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duced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.” Zanella ER, et al: Sci Transl Med 7:272ra12, 2015.

TARGETED THERAPIES EGFR Amplification/ Overexpression Associated With Improved Response of Glioblastoma to Metronomic Temozolomide

Making the human connection

TRIM: 10.575”

Introducing

BLEED: 10.825”

SAFETY: 9.575”

In a study reported in Journal of the National Cancer Institute, Cominelli and colleagues found that EGFR amplification/overexpression was associated with improved response of glioblastoma to adjuvant metronomic (every day of a 28 day cycle at a dosing of 50-75 mg/m2) but not standard (5 consecutive days of temozolomide in a 28 day cycle at a dosing of 150-200 mg/m2) temozolomide schedules. Analysis of a cohort of glioblastoma patients showed no relationship of survival with gene classifiers associated with molecular glioblastoma subtypes in those receiving temozolomide in a standard schedule. However, EGFR amplification/ overexpression was associated with significantly better progression-free survival and overall survival (hazard ratio = 0.22, P = .001, for high vs low) in those receiving metronomic treatment. Long-term survival in those receiving metronomic treatment was independent of MGMT and EGFRvIII-mutant status and was more likely in those with EGFR overexpression with PTEN loss. In studies in vitro, temozolomidetreated EGFR-positive human-derived glioblastoma cancer stem cells exhibited selective dose- and timedependent reductions in survival, mediated by inhibition of NF-κB (nuclear factor kappa B) transcriptional activity. Analysis of samples from recurrent metronomic-treated EGFR-overexpressing patients showed reductions in EGFR-amplified cells and NF-κB/p65 e xpression. The investigators concluded: “ EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.” n Cominelli M, et al: J Natl Cancer Inst 107:pii: djv041, 2015. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

The ASCO Post | MAY 25, 2015

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In Memoriam

Remembering Multiple Myeloma Patient Advocate Michael S. Katz, MBA By Jo Cavallo

first met Michael Katz, MBA, in 2004, 3 years after my brother, Dom, was diagnosed with multiple myeloma, and we were at a crossroads in his care and needed advice. Although an experimental regimen of thalidomide (Thalomid) and dexamethasone had successfully put Dom in remission for a year (the combination was U.S. Food and Drug Administration [FDA] approved in 2006), and a course of bortezomib (Velcade) had also been briefly success-

Michael Katz, MBA

ful in containing his myeloma, now the cancer was on the move, and we were looking for treatment options. Dom’s oncologist was recommending a bone marrow transplant, but the idea of going through the rigors of a transplant, which offered no guarantee of a cure and carried potentially lifethreatening risks, was so daunting to Dom, he wanted to try less aggressive therapy if possible. It was through a patient network at the Multiple Myeloma Research Foundation that I learned about Mike Katz and the multiple myeloma support group he was leading at St. Vincent’s Cancer Center in New York, where Dom was receiving his treatment. It is not an exaggeration to say that meeting Mike was a turning point in what turned out to be a 10-year odyssey of hope and despair as the disease toggled between stable and active, and I have no doubt that Mike’s unfailing advice and support helped extend Dom’s life 5 years beyond his prognosis. Mike was the epitome of what could be accomplished when patients become active participants in their health care, and his take-no-prisoners approach when it came to out-smarting myeloma was legendary. After all, he had been outsmarting the disease for 25 years,

a feat he attributed to unprecedented treatment advances in the cancer, until his death from complications of myeloma on April 26, 2015. Mike had also been successfully treated for colorectal cancer in 2008.

Advocating for Patients When Mike was first diagnosed with myeloma in 1990, treatment options were limited to chemotherapy, bone marrow transplantation, and radiation therapy, and there were no patient advocacy groups or Internet resources to turn to for information and help. “It was a very scary and lonely time,” Mike said when we talked last year, soon after he received ASCO’s 2014 Partners in Progress Award in recognition of the contribution he had made in cancer awareness and public advocacy. (See “Cancer Survivor and Patient Advocate Michael S. Katz, MBA, Has Helped Alter the Standard of Care for Myeloma Survivors,” in the August 15, 2014, issue of The ASCO Post.) Mike was drawn to patient advocacy after receiving advice from the late Francesca M. Thompson, MD, who was a myeloma survivor and among the first to undergo an autologous bone marrow transplant. Dr. Thompson had helped Mike reach a decision about his

of the Coalition of Cancer Cooperative Groups’ Patient Advisory Board. Mike was also appointed to serve as Chair of the Director’s Consumer Liaison Group at the National Cancer Institute and selected as a member on the Drug Development Patient Consultant Program at the FDA.

Changing the Lives of Multiple Myeloma Survivors Mike’s work with ECOG led him to propose a clinical trial comparing lenalidomide (Revlimid) and standarddose dexamethasone with lenalidomide and low-dose dexamethasone in newly diagnosed multiple myeloma patients. The low-dose dexamethasone regimen had been successful in keeping Mike’s myeloma from progressing, and he had been getting similar feedback from patients in the IMF’s support groups and on the listservs of the Association of Cancer Online Resources he was overseeing, and he wanted to test the two doses in a randomized study. The results from ECOG’s E4A03 clinical trial,1 which found a clear survival advantage in the lower-dose dexamethasone arm, led to a change in the standard of care for the use of dexa-

The results from ECOG’s E4A03 clinical trial led to a change in the standard of care for the use of dexamethasone, improving the quality of life for myeloma survivors and earning Mike a lasting legacy as a champion of patient care. own treatment strategy, and the experience of talking with her “was so powerful and I felt so grateful, it got me thinking that I could do the same for others,” said Mike. He began working with the International Myeloma Foundation (IMF) and became a member of its Executive Board. His involvement in the IMF led to his work as a patient advocate for the Eastern Cooperative Oncology Group (ECOG), where he was elected Chair of its Patient Representative Committee and was later made Chair

methasone in all disease settings and in all dexamethasone-containing combination drug regimens, improving the quality of life for myeloma survivors and earning Mike a lasting legacy as a champion of patient care. Mike was also instrumental in raising awareness of bisphosphonate-related osteonecrosis of the jaw, a rare but serious side effect linked to the use of pamidronate and zoledronic acid. And in 2007, in response to concern over bisphosphonate-related side effects, ASCO updated its clinical practice

guideline on bisphosphonate treatment for multiple myeloma to include a discussion of osteonecrosis of the jaw, recommending that most patients receive bisphosphonate treatment for no longer than 2 years.2

A Source of Courage For me, Mike was a lifeline when Dom’s disease was escalating out of control, and I questioned whether we had chosen the appropriate course of treatment. He was the example I could point to of someone who had beaten the odds and was seemingly indestructible, overcoming cancer not once but twice. His resolve gave us the courage to keep pushing forward, even as Dom’s cancer overwhelmed him. When I saw Mike at the 2014 ASCO Annual Meeting, the challenge of keeping his myeloma from overtaking his body was clearly taking a toll. He looked a bit older and more fragile than he did a few years ago, and he was dependent on a mobility scooter to get around. But his determination to live and his dedication to serving the needs of myeloma survivors were as intact as ever. “I’ve always chosen to live my life as if I didn’t have cancer,” said Mike. “I just face forward and try to do everything I want to do, working around symptoms and treatment side effects. I’ve been a patient for so long, I’m much better now at managing those things.” Mike Katz is survived by his wife, Susie, and sons, Jason, Jeffrey, and Jonathan. n References 1. Rajkumar SV, Jacobus S, Callender N, et al: Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. 2007 ASCO Annual Meeting. Abstract LBA8025. 2. Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25:24642472, 2007. Obituaries continued on page 180

Learn more

The ASCO Post | MAY 25, 2015

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In Memoriam

Andrew Parsa, MD, PhD, Chair of Neurological Surgery at Northwestern, Dies at 48

ndrew Parsa, MD, PhD, the Michael J. Marchese Professor and Chair of the Departments of Neurological Surgery at Feinberg and Northwestern Memorial Hospital, passed away on April 13. He was 48 years old.

Andrew Parsa, MD, PhD

“We are all shocked and saddened by this great loss. Dr. Parsa was a distinguished scholar, an extraordinarily talented surgeon, and a dedicated mentor to students and faculty alike,” said Eric G. Neilson, MD, Vice President for Medical Affairs and Lewis Landsberg Dean at Feinberg. “He was a pioneering neurosurgeon and an innovative inves-

tigator who pushed the boundaries of scientific understanding. His presence will be sorely missed within the Northwestern Medicine community and across the country.”

[Dr. Parsa] was a pioneering neurosurgeon and an innovative investigator who pushed the boundaries of scientific understanding. —Eric G. Neilson, MD

Pioneering Research “He spent his whole life trying to solve the problem of treating brain tumors [and] glioblastoma multiforme,” Dr. Neilson continued. “He got interested in [glioblastoma multiforme in] medical school with one of his faculty members at that time, and he learned surgery could not cure this cancer. He began thinking how the immune system could be activated. It turned out to be an extremely novel approach.” Dr. Parsa was renowned for his research in tumors of the brain and spine and was the principal investigator of the largest brain tumor vaccine trial funded by the National Cancer Institute. The study’s phase II (ClinicalTrials.gov Identifier: NCT01814813) results showed the experimental vaccine

helped extend the lives of glioblastoma multiforme patients. The study is now in its third phase. “Dr. Parsa’s dedication to his patients made him a role model not just among physicians, but for all of us who were privileged to have worked with him,” said Dean M. Harrison, President and CEO of Northwestern Memorial HealthCare. “Though his legacy will continue to inspire us for many years, his passing has been felt deeply across Northwestern Medicine.” Before coming to Northwestern in 2013, Dr. Parsa was Professor and Vice Chair of the Department of Neurological Surgery at the University of California, San Francisco. He received his bachelor’s degree in molecular biophys-

ics and biochemistry from Yale University and his doctorate and medical degrees from SUNY Downstate Medical Center. He completed his surgical internship and residency at Columbia University. He served on the board of several organizations, including the American Association of Neurological Surgeons and the Society for NeuroOncology. He performed about 300 surgeries per year, in addition to continuing his research, as well as teaching. Dr. Parsa is survived by his wife, Charlotte Shum, MD, Associate Professor of Orthopaedic Surgery at Feinberg School of Medicine, and their three children: Julia, Micheline, and Ismail. n

Oncologic Surgeon Kristin R. Corgan, MD, Dies at 46 By Ronald Piana

ancer is largely a disease of the elderly, with the average age at diagnosis of about 70 years old. Cancer, in that it is a slow-motion fading away before loved ones, is an especially traumatic disease, even more so when it strikes children and adults in their prime. Such was the case with Kristin Ruth Corgan, MD, an oncologic surgeon who lost her own battle with breast cancer, dying on April 23. Dr. Corgan was 46.

A Life’s Mission Dr. Corgan was born on October 3, 1968. According to her family, Dr. Corgan knew from an early age that she wanted to pursue a career caring for others and making a difference in whatever community she settled in. A hardworking and bright young woman, after graduating from high school, Dr. Corgan entered Vanderbilt University in Nashville. She continued her scholastic excellence at Vanderbilt, and midway through her junior year, she decided to become a doctor. Following her undergraduate degree, she enrolled at Wake Forest University School of Medicine in Winston-Salem, North Carolina. Early on in medical

Kristin Ruth Corgan, MD

school, Dr. Corgan discovered a passion for surgery and decided on that as her specialty. After obtaining her MD degree from Wake Forest, Dr. Corgan entered Waterbury Hospital/Yale University in New Haven, Connecticut, where she did her internship and surgical residency. It was during her residency that she met Thaddeus Fabian, MD, whom she would marry. After completing her surgical residency, Dr. Corgan and her husband settled in Marietta, Georgia, a suburb on the outskirts of Atlanta.

A Dream Fulfilled In 2005, Dr. Corgan fulfilled her dream and opened a private practice called Georgia Breast Care, where she worked tirelessly caring for breast cancer patients. Lisa Brown, who worked

with Dr. Corgan as her nurse practitioner for the past 8 years, reflected, “She’s somebody you wanted to work harder for and be better for. You wanted to give her everything you had because that’s what she gave everybody else.” Another associate and friend, medical oncologist Gena Volas-Redd, MD, of Marietta, said she met Dr. Corgan 15 years ago, when she first joined Georgia Cancer Specialists, a large multidisciplinary practice affiliated with Dr. Corgan’s practice. “It’s been 15 wonderful years, … and it’s just been all good memories,” Dr. Volas-Redd said, adding, “As a physician, Dr. Corgan’s reputation and magnetism attracted people from all over the state, saving the lives of many women.” Dr. Corgan was active in educating surgeons across the country in advanced, minimally invasive techniques in breast surgery. She also was deeply engaged in the local medical community and served as a board member of the Cobb County Medical Society. Dr. Corgan served as Secretary of the Medical Executive Committee for the medical staff of WellStar Kennestone Hospital and was President in 2008. She also

served on the Medical Care Evaluation Committee and the Cancer Committee at Kennestone Hospital. Dr. Corgan’s other professional accomplishments included serving as a diplomat of the American Board of Surgeons and as a fellow of the American College of Surgeons. She was on the National Teaching Faculty of both the American College of Surgeons and the American Society of Breast Surgeons. Dr. Corgan is survived by her husband, their cherished poodle, Harrison, her mom, Vivian Corgan of Tallahassee, Florida, and a host of loving family. After Dr. Corgan’s passing, an online message board filled with heartfelt tributes to her life as a doctor and caregiver. One of many patients who captured the essence of this fine doctor, who left far too soon, had this to say: “I am deeply saddened, shocked, and in tears after receiving a letter from the clinic today informing me of Dr. Corgan’s passing. She was a God-sent Angel who guided me through my breast cancer diagnosis in 2006. Dr. Corgan advised me as a friend would on what path I should take in treating my cancer, and I deeply admired and respected her for that.” n

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In Memoriam

Remembering Mark R. Green, MD, a Leader in Lung Cancer Research and Treatment By Ronald Piana

“F

ew people have impacted cancer clinical research in the past quarter century as much as Mark Green. His expertise in lung cancer and clinical trial design led to the successful completion of seminal studies combining radiation and chemotherapy that forever changed

14 years, during which time he held many leadership roles including Head of the Division of Hematology/Oncology and Director of UCSD Cancer Center, which he successfully led to its first 5-year core grant. While at UCSD, Dr. Green also held the Edwin and Evelyn Tasch Professorship in Cancer Research, which was established in his honor.

A Lasting Influence in Lung Cancer

Mark R. Green, MD

the management of patients with earlystage lung cancer,” said past ASCO president Richard Schilsky, MD, in memory of his friend and colleague Mark R. Green, MD, who died on February 23. He was 70 years old. Dr. Green was born on January 13, 1945, in Norwalk, Connecticut. The son of a physician, Dr. Green decided early in life that he also wanted to pursue a career in medicine. After graduating from high school, Dr. Green entered Harvard University, where he received his BA and MD degrees. He then went to Beth Israel Hospital for his residency and ended up doing the latter part at the National Cancer Institute, which solidified his decision to enter the field of oncology. After completing his residency, Dr. Green went out West, doing his oncology fellowship at Stanford University Medical Center. In 1976, Dr. Green joined the faculty at the University of California, San Diego (UCSD), where he remained for

Dr. Green is widely recognized for his early investigations of induction chemotherapy and treatment of lung cancer as a systemic disease. These investigations led to the identification of induction chemotherapy followed by radiation as superior to radiotherapy alone for patients with locoregionally advanced unresectable non–small cell lung cancer (NSCLC). “Dr. Mark Green was one of the most influential lung cancer medical oncologists in the past 50 years. He had a command of the oncologic literature that was second to none. He was one of the few doctors I have known who was not only able to quote chapter and verse about the latest cancer research, but he was also able to synthesize it for your particular patient—a marvelous combination and one that is rare in medicine,” commented long-time colleague Gerard A. Silvestri, MD, MS, FCCP, Hillenbrand Professor of Thoracic Oncology at the Medical University of South Carolina. He is best known for his engaged leadership and intellectual contributions in the Alliance in Clinical Trials for Oncology (formerly Cancer and

Leukemia Group B [CALGB]). He was the longest-serving Chair of the Respiratory Committee of CALGB, a position he held for more than 20 years, and also served as Vice Chairman of CALGB from 1995 to 2007, while Dr. Richard Schilsky was Chairman. Under his leadership, CALGB also investigat-

premature departure leaves a vacuum in the hearts of everyone he has touched. He will be remembered as one of the greats—a true mentor and a mensch.” In 1996, Dr. Green was appointed the Mary M. Gilbreth Chair of Clinical Oncology and Director of the Hollings Cancer Center at the Medical Universi-

Those of us who had the honor and privilege of knowing and working with Dr. Green will fondly remember his intellectual brilliance, his vast knowledge of clinical oncology, his fiery passion for a good debate, and, above all, his genuine compassion for others. ed the role of adjuvant chemotherapy for stage 1B NSCLC, the timing of concurrent radiotherapy for limited-stage small cell lung cancer, and the role of new drugs (including the taxanes, gemcitabine, and topotecan).

‘A True Mentor and a Mensch’ Dr. Green served as a mentor for several investigators who are active in lung cancer research today. Colleague Ramaswamy Govindan, MD, recalled Dr. Green. “He was truly a great role model for me. To this day, I am inspired by his encyclopedic knowledge, sharp wit, vision, passion for excellence, and kindness toward others. The oncology community has lost an invaluable leader.” Another colleague, Rogerio Lilenbaum, MD, remarked, “Mark Green was the consummate researcher—passionate, inquisitive, analytic, and unrelenting in the pursuit of excellence. Mark inspired an entire generation of clinical researchers, and his

ty of South Carolina (MUSC), serving in these posts through 2000. He retired from the full-time faculty as a Professor Emeritus in 2004, took on the roles of Medical Director for the Network for Medical Communication and Research and Clinical Professor of Medicine at MUSC. Recently, Dr. Green served as Chief Medical Officer of Xcenda, a position he held since 2007. A representative from Xcenda remarked on Dr. Green’s death, “Those of us who had the honor and privilege of knowing and working with Dr. Green will fondly remember his intellectual brilliance, his vast knowledge of clinical oncology, his fiery passion for a good debate, and, above all, his genuine compassion for others.” Dr. Green has more than 300 scientific publications to his credit and coauthored The Comprehensive Textbook of Thoracic Oncology. He is survived by his wife, two daughters, and two brothers. n

 In Memoriam Michael Katz, MBA

Andrew Parsa, MD, PhD

Kristin Ruth Corgan, MD

Mark R. Green, MD

1967–2015

1953–2015

1968–2015



1945–2015

The ASCO Post | MAY 25, 2015

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Letters to the Editor

Article on Rare Cancer Generates Enthusiastic Response

he article “Shining a Spotlight on Epithelioid Hemangioendothelioma,” written by Jane Gutkovich and published in the April 10, 2015, issue of The ASCO Post, generated an enthusiastic response from the patient and advocate community of individuals with this rare cancer. Here, we are pleased to share a snapshot of some of the letters we received from readers, including the author herself.

path for doctors to take if my diagnosis changes. Fortunately, my condition is currently “stable,” but of course with this rare cancer anything is possible and a change in my condition will mean a scramble for the next form of therapy.

Thank you for bringing awareness to this disease. n —Ingrid E. Coddington

Concerted Effort Needed As the mother of a patient diagnosed with the rare EHE cancer in 1998 at the

age of 20, I want to thank you for publishing “Shining a Spotlight on Epithelioid Hemangioendothelioma,” by Jane Gutkovich. Your assistance in communicating to oncologists information about this rare cancer is so very important for a con-

A Storm of Hope Thank you so, so much for giving me space in The ASCO Post. It is hard to overestimate the importance of this publication, not only because many physicians will become aware of our group of patients with epithelioid hemangioendothelioma (EHE) and their families, and the work we are doing on this rare cancer, but also because it provided a huge boost in morale to hundreds of patients living with EHE and their families. These are individuals who have gotten used to the fact that EHE is on a far-away periphery when it comes to professional knowledge and attention. As such, having my article published within The ASCO Post, a prestigious oncology publication that is well read by health professionals, has resulted in a storm of hope and motivation among our support group for EHE patients and their families. n —Jane Gutkovich jgutkovich@gmail.com

Rarity of Disease Means Lack of Information When I was diagnosed with EHE in December, my world fell apart. The path has been even more difficult due to the rarity of the disease and lack of information available. Therefore, I am extremely grateful that [The ASCO Post] published Ms. Gutkovich’s paper on this rare cancer. I am sure that such a comprehensive article will give the relevant information to the increasing number of people diagnosed. n —Beverley Williams

Fortunately, I Am ‘Stable’ I would like to take this opportunity to thank you for the wonderful article you published on EHE. I am a patient with EHE and I find it very difficult to understand how there can be no clear

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

ASCOPost.com | MAY 25, 2015

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Letters to the Editor

certed effort worldwide to treat those with this diagnosis. This help is greatly appreciated! n —Lois Scott

Diagnosed Too Late My son, Michael Tuttle, was diagnosed much too late to be treated for EHE. He was, young, vibrant,

athletic, and a fighter. Because this cancer was so rare, however, my son was referred from doctor to doctor, in an effort to understand his symptoms and determine a diagnosis. One physician even thought he was a drug addict and just seeking a means to obtain pills; he was so emotionally hurt by that accusation.

When, finally, he was diagnosed at the Mayo Clinic in Phoenix, he had stage IV EHE, and the cancer had metastasized to both lungs, all of his ribs, his ankles, wrists, leg (where it had originated years before), and liver. My son died within a month of his diagnosis. Thank you so much for publishing

We want to change the face of EGFR-targeted therapy Cutaneous toxicities are caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 Inhibition of wild-type and mutant EGFR in non–small cell lung cancer (NSCLC)

Cutaneous toxicities can be dose-limiting

Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

The symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 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.7,8

90% of patients treated with approved EGFR TKIs experience rash7,8

The future of EGFR inhibition

The skin is dependent on wild-type EGFR signaling for normal growth and differentiation.1,9,10 Druginduced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Strategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 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. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org /ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. 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 February 2, 2015.

information on this rare and horrific disease. The death of anyone is painful and particularly when that individual is young and should have years of life left to live. I am attaching a picture of my son, Michael Tuttle, taken 1 year ago, with me. Again, thank you so much. n —Karen Tuttle

Karen Tuttle and her son, Michael, in a photo shortly before his death in 2014 following a diagnosis of epithelioid hemangioedema (EHE).

Autopsy Reveals EHE Thank you for publishing the article by Jane Gutkovich on EHE. My son passed away in September 2014 from this cancer. At the time of his death, doctors still had not been able to diagnose his condition. We had an autopsy performed and learned that my son’s death was due to this very rare cancer. Thank you again for publicizing information about EHE. n —Darlene Frank

I Am A Person With EHE Thank you for publishing the article “Shining a Spotlight on Epithelioid Hemangioendothelioma” by Jane Gutkovich. Like Ms. Gutkovich’s son, I am a person with EHE. It is encouraging that The ASCO Post has allowed Jane to share information on this rare cancer with your readers. Jane has worked tirelessly to learn about and connect with EHE experts around the world and to communicate information to others with this disease. I commend you for recognizing her work and allowing others to learn about this disease through your publication. I do hope that you will continue to follow up on EHE and report on any data presented at the 2015 ASCO Annual Meeting. n —Christine A. Gaudreau

The ASCO Post | MAY 25, 2015

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Just Engaging in ‘Some’ Leisure Time Physical Activity Reduces Overall and Cancer-Specific Mortality By Charlotte Bath

here’s good news for those who recognize the benefits of exercise but feel they have neither the time nor energy for frequent workouts: A recent study reported in JAMA Internal Medicine1 has found that just performing “some” leisure time physical activity, even below the recommended minimum level, reduces overall mortality, including mortality due to cancer and cardiovascular disease. There’s good news, too, for exercise zealots: The study found no excess mortality risk at 10 or more times the minimum recommended by the 2008 Physical Activity Guidelines for Americans.2 Those guidelines recommend a minimum of 75 minutes of vigorousintensity activity or 150 minutes of moderate-intensity aerobic activity per week (7.5 metabolic equivalent hours per week) for adults. The current study found that individuals who performed some physical activity, but below the recommended 7.5 metabolic hours per

week, had a 20% lower mortality than those reporting no leisure time physical activity. “For cancer deaths, we saw the same pattern as for overall mortality,” the study’s lead author Hannah Arem, MHS, PhD, a postdoctoral fellow in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI), said in an interview with The ASCO Post. For individuals performing physical activity at one to two times the recommended minimum level, “the reduction in cancer-specific mortality risk was 21%, which is a significant amount,” Dr. Arem continued. “Beyond that there were incremental increases in benefit, up to the 31% reduced risk” in cancerspecific mortality among individuals performing 10 or more times the recommended minimum, she added. For cancer mortality, there seems to be a pattern of more activity still having benefit, “even though it is marginal benefit at ex-

ercise levels beyond one to two times the recommended level.” For overall mortality, there was a 31% lower risk at one to two times the minimum recommended leisure time physical activity, a 37% reduced risk at two to three times the minimum, and a 39% reduced risk at three to five times the minimum. “An upper threshold for mortality benefit occurred at three to five times the physical activity recommendation,” according to the study report, “however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%).” For cardiovascular mortality, the upper threshold was also three to five times the recommended minimum.

Comorbidity Data The study used pooled data from six studies within the NCI Cohort Consortium. Among the 661,137 participants (291,485 men and 369,652 women),

46,358 had a history of cancer and 61,158 had a history of heart disease. The median age was 62. At a median follow-up of 14.2 years, 116,686 deaths were observed. There were no statistically significant differences in mortality between those who had a previous history of cancer and those who did not,” Dr. Arem said. The overall number of cancer deaths was 29,294. The study did not include data on the site or types of cancer. Hazard ratios for mortality differed among never, former, and current smokers. As expected, current smokers had a greater risk, but former smokers had a lower risk than never smokers. For example, among those performing physical activity at three to five times the recommended minimum (the upper threshold for overall mortality benefit), the hazard ratios were 0.69 for current smokers, 0.64 for never smokers, and 0.56 for former smokers. However, these differences could be due to imperfect adjustment for smoking intensity.

Expect Questions About Physical Activity and Reduced Mortality Risks By Charlotte Bath

study finding that just doing some leisure time physical activity reduces overall and cancer-specific mortality by 20% and that more activity can provide even greater survival benefits concludes that health-care professionals should encourage inactive patients to perform more leisure time physical activity.1 Answers to patients’ questions about the types and

miology and Genetics, said in an interview with The ASCO Post. Those guidelines recommend a minimum of 75 minutes of vigorousintensity activity or 150 minutes of moderate-intensity aerobic activity per week or an equivalent combination of moderate and vigorous activity. “Aerobic activity should be performed in episodes of at least 10

For cancer deaths, we saw the same pattern as for overall mortality…. For individuals performing physical activity up to the recommended minimum level, the reduction in risk was 20%, which is a significant amount. —Hannah Arem, MHS, PhD

amounts of physical activity that provide substantial benefit can be found in the 2008 Physical Activity Guidelines for Americans,2 the study’s lead author, Hannah Arem, MHS, PhD, a postdoctoral fellow at the National Cancer Institute’s Division of Cancer Epide-

minutes, and preferably, it should be spread throughout the week,” according to the guidelines. The study by Dr. Arem and colleagues in JAMA Internal Medicine found a 31% lower risk of mortality among individuals who met the mini-

mum recommended physical activity or performed twice the recommended minimum leisure time physical activity, a 37% reduced risk at two to three times the minimum, and a 39% reduced risk at three to five times the minimum. “For cancer deaths, we saw the same pattern as for overall mortality,” Dr. Arem said. For individuals performing physical activity up to the recommended minimum level, “the reduction in risk was 20%, which is a significant amount,” Dr. Arem continued. “Beyond that there were incremental increases in benefit—up to the 31% reduced risk” in cancer-specific mortality among individuals performing 10 or more times the recommended minimum.

Walk, Run, Bike, Swim Consistent with other studies, walking was the most reported physical activity in the study by Arem et al. The study supplement lists examples of the approximate amounts of four activities needed to meet the minimum recommendations and multiples of that. For example, meeting the mini-

mum level of physical activity recommended by the 2008 Physical Activity Guidelines for Americans would require walking a 20-minute mile every day, swimming for 35 minutes twice a week, biking for 45 minutes twice a week, or running 10-minute miles for 45 minutes once a week. Reaching 10 times the recommended minimum would mean walking for 3 hours every day, swimming for 1½ hours every day, biking for 2½ hours every day, or running for 1 hour every day. n

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

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“There is interest in looking at the relationship with physical activity among smokers,” Dr. Arem said, “but that is not something we were able to look at here because we didn’t have the highest level of detail on smoking— how much they smoked, how many years, across all six cohorts.”

Evidence Gap The study addressed the upper limit of benefit from leisure time physical activity “because that is really where the evidence gap was,” Dr. Arem said. “We

shown lower risks of mortality among long-term long-distance runners as well as Tour de France cyclists. Thus, current trends in increasing marathon or triathlon participation should not cause alarm, at least with regard to mortality.”

Walking Most Popular Physical activity was self-reported by the participants, and the largest contributor of overall metabolic equivalent hours per week was leisure time walking. Brisk walking “is past the moderate threshold,” Dr. Arem noted.

The take-home message is that individuals who met the recommended minimum did derive a substantial benefit, as is described in the guidelines, and that the additional benefit existed but was marginal. —Hannah Arem, MHS, PhD

went into this with the question of what is happening at these higher levels. We thought it is possible that there is going to be a continued decrease in mortality risk with more and more exercise. Or it is possible, conversely, that we could see increases with extremely high levels. And we really didn’t see either. We were interested to find that the Physical Activity Guidelines for Americans really do capture the majority of the mortality benefit. And beyond that, there were really very small changes in mortality risk.” Some previous studies had shown possible harms from high levels of leisure time physical activity, such as the risk of cardiac events being transiently increased during vigorous-intensity physical activity, particularly among individuals who had been inactive. “Although our study is not poised to examine the risk during or immediately after exercise or comorbid cardiac conditions, such as atrial fibrillation, our findings do not support the hypothesis for increased mortality risk at [leisure time physical activity] levels of 10 or more times the federal guidelines,” the study authors wrote. “The present findings align with other studies that have

“So it is a moderate-intensity aerobic activity.” The six different cohort studies had different survey formats to assess time spent in different activities, with some questionnaires listing activities including walking, jogging/running, swimming, or strenuous activities. “For all six studies, we calculated energy expended per activity by multiplying the estimated metabolic equivalent (a multiple of the resting metabolic rate) value by the number of hours per week and summed across activities to estimate overall [leisure time physical activity] energy expenditure in [metabolic equivalent] hours per week,” the investigators explained in the study report.

Applicability to a Wider Population A commentary by Todd M. Manini, PhD, Associate Professor of Medicine at the University of Florida, Gainesville, noted that the results of the study are “consistent with the plethora of existing evidence” and “clearly demonstrate that leisure time physical activity is associated with a reduced mortality

risk with similar effects seen in cancer- and cardiovascular disease–related mortality.”3 In addition, he wrote, there is “some important new knowledge” related to the findings on levels of physical activity and risk reduction. But he also noted that the results “are not applicable to the U.S. population as a whole because the cohorts were largely white (approximately 95%).” Asked to comment on that statement, Dr. Arem replied, “I think the best application of our findings is for a similar population. So, unfortunately, it is hard to say if we could generalize to very different populations. But that is a very important question. There are efforts to try to enroll more diverse populations in future studies to be able to definitively answer that question.” The median age of the study participants was 62, and the mean age for those younger than 60 was 52. The results “are going to be most applicable for a similar population,” Dr. Arem stated. “So they may not apply to someone who is in a very different age range. That said, looking at an outcome like mortality, one needs to look at a population toward older age to be able to accrue enough deaths. If one were to run a study in 30 or 40 year olds, you would have a very long study.” Other recent studies have also explored the relationship between physical activity and cancer. A study in JAMA Oncology found that men rated as having high cardiorespiratory fitness in midlife had reduced risks of colorectal and lung cancers, and those who were diagnosed with cancer had a 32% reduced risk of cancer-related death.4 A study in the Journal of Clinical Oncology found that a supervised moderate-intensity to high-intensity combined resistance and aerobic exercise program was effective in reducing pain, nausea, and vomiting, as well as maintaining better physical functioning among breast cancer patients undergoing adjuvant chemotherapy.5

‘Unique and Important Contributions’ Dr. Arem and her coauthors noted that their findings on the shape of the physical activity–mortality dose-

response curve offer three “unique and important contributions to inform health-care professionals and future guidelines.” They listed these contributions as: “(1) the currently recommended amounts of [leisure time physical activity] provide most of the longevity benefits, (2) the longevity benefit threshold appears to be approximately three to five times the recommended physical activity minimum, and (3) there does not appear to be an elevated mortality risk with [leisure time physical activity] levels as high as 10 or more times the recommended minimum.” Dr. Arem added, “The take-home message is that individuals who met the recommended minimum did derive a substantial benefit, as is described in the guidelines, and that the additional benefit existed but was marginal.” n

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

References 1. Arem H, Moore SC, Patel A, et al: Leisure time physical activity and mortality: A detailed pooled analysis of the doseresponse relationship. JAMA Intern Med. April 6, 2015 (early release online). 2. Physical Activity Guidelines Advisory Committee: 2008 Physical Activity Guidelines for Americans. Washington, DC; U.S. Dept. of Health and Human Services; 2008. Available at www.health.gov/ PAGuidelines. Accessed May 8, 2015. 3. Manini TM: Using physical activity to gain the most public health bang for the buck. JAMA Intern Med. April 6, 2015 (early release online). 4. Lakoski SG, Willis BL, Barlow CE, et al: Midlife cardiorespiratory fitness, incident cancer, and survival after cancer in men: The Cooper Center longitudinal study. JAMA Oncol. March 26, 2015 (early release online). 5. van Wart H, Stulver MM, van Harten WH, et al: Effect of low-intensity physical activity and moderate- to highintensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: Results of the PACES randomized clinical trial. J Clin Oncol. April 27, 2015 (early release online).

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IN MULTIPLE MYELOMA

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a significant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3 Do residual disease and immune dysfunction form a cycle that complicates our strategies?

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, 100 MILLION MYELOMA CELLS MAY REMAIN.4

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNE SYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14 Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16

References: 1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick reflection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-onthe-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:30733079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:18601873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print]. 15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

The ASCO Post | MAY 25, 2015

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Emerging Clinical Data on Cancer Management BREAST CANCER Emergency Room Visits and Hospitalizations Are Common Among Women With Early Breast Cancer Receiving Chemotherapy Emergency room visits and hospitalizations are common among patients with early breast cancer receiving chemotherapy, particularly among those receiving a regimen containing docetaxel, according to a study supported by the Ontario Institute of Cancer Research, Toronto. “In this population-based cohort study, emergency room visits and hospitalizations were significantly higher among women with early breast cancer undergoing adjuvant chemotherapy compared with agematched noncancer controls and compared with themselves 2 years before their cancer diagnosis,” the researchers wrote in the Journal of Oncology Practice. Patients diagnosed between January 2007 and December 2009 were identified using the Ontario Cancer Registry. “Patient records were linked deterministically to provincial health-care databases to provide comprehensive medical follow-up,” the investigators noted. All patients received one or more cycles of adjuvant chemotherapy. A total of 8,359 patients with early breast cancer were matched to the same number of noncancer controls on age, comorbidity, and geographic location. The mean age of the study participants was 53.67 years. “Emergency room visits and hospitalizations within 30 days of chemotherapy were identified. If the primary reason for the visit was a common chemotherapy toxicity, the visit was considered chemotherapy associated. All-cause and chemotherapy-associated visits were compared between patient cases and controls,” the authors explained. Overall, most visits were for emergency room alone, 68.9% of visits by patients receiving chemotherapy and 82.4% of visits by noncancer controls. “The proportion of patients with at least one emergency room visit and hospitalization was significantly higher in patients with early breast cancer undergoing chemotherapy compared with noncancer controls (43.4% vs 9.4%, P < .001),” the researchers reported. Patients receiving adjuvant chemotherapy for early breast cancer were also more likely to have multiple emergency room visits and hospitalization visits (17.9% vs 2.4%, P <􏰂.001).

The most common chemotherapy regimens contained docetaxel (65.8%). Paclitaxel-containing regimens were taken by 13.9% of patients; 20% took anthracyclines alone; and 20.8% used trastuzumab (Herceptin) in combination with chemotherapy. “Patient characteristics varied significantly by chemotherapy regimen,” the researchers reported. “Compared with both the docetaxel and paclitaxel cohorts, patients in the anthracyclineonly cohort were significantly older (P ≤ .001), had a higher comorbidity burden (P = .01), and were more likely to have stage I breast cancer (P ≤ .001).” Among those receiving chemotherapy for early breast cancer, 62.4% of all their visits were considered chemotherapy related. The primary reasons for emergency room visits by patients receiving chemotherapy were fever or neutropenia, infection, and gastrointestinal complaints. These toxicities were observed in 24% of patients receiving chemotherapy and “were more common with the use of docetaxel (29%) than with paclitaxel (13%) or anthracyclines alone (16%, P < .001),” the investigators reported. “Comorbidities in patients receiving chemotherapy were associated with an increased risk of all-cause emergency room visits and hospitalizations (P < .001) but were not associated with an increased risk of chemotherapy-associated emergency room visits and hospitalizations (P = .13),” the researchers observed. The rate of emergency room visits and hospitalizations was “significantly higher than in randomized clinical trials of adjuvant chemotherapy, where rates of emergency room visits and hospitalizations are rarely or never reported,” the investigators noted. “The use of adjuvant chemotherapy in patients with early breast cancer outside clinical trials may result in increased toxicities for several reasons. Compared with the general population, patients in clinical trials are younger, have fewer comorbidities, and have more social supports,” the researchers wrote. “Patients enrolled onto clinical trials undergo increased clinical monitoring compared with patients treated off trials, which may result in earlier detection and treatment of chemotherapy-associated toxicities.” The authors concluded, “Interventions aimed at early detection and intervention for chemotherapy-associated toxicities, particularly in the highest-risk women, have the potential to decrease

emergency room visits and hospitalizations in patients with early breast cancer and improve quality of care.” Enright K, et al: J Oncol Pract. January 20, 2015 (early release online).

LUNG CANCER Prior Cancer Does Not Affect Outcomes Among Patients With Advanced Lung Cancer, Suggesting They Be Included in Clinical Trials Analysis of data from 102,929 patients with stage IV lung cancer found that “prior cancer does not convey an adverse effect on clinical outcomes, regardless of prior cancer stage, type, or timing.” Based on these findings, investigators from the Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, concluded that “broader inclusion in clinical trials of advanced lung cancer patients with a history of prior cancer should be considered.” Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked registry, the investigators identified patients older than age 65 years with stage IV lung cancer diagnosed between 1992 and 2009. “Prior cancer was characterized by type, stage, and timing. All-cause and lung cancer–specific survival were compared between patients with and without prior cancer using propensity score–adjusted Cox regression,” Andrew Laccetti, MD, and colleagues wrote in the Journal of the National Cancer Institute. Overall, 14.7% of the patients had a history of cancer, 76% localized or regional stage, “so presumably cured or at least not life-limiting in the context of advanced lung cancer,” the authors noted. Most prior cancers were diagnosed 5 or fewer years before lung cancer was diagnosed. The most common prior cancer types were prostate (27.9%), gastrointestinal (15.1%), other genitourinary (14.4%), and breast (14.2%). In propensity score–adjusted analysis, patients with prior cancer had better all-cause survival (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.91–0.94) and better lung cancer– specific survival (HR = 0.81, 95% CI = 0.79–0.82). “In a simulated clinical trial–eligible population (age < 75 years, no comorbidity, treated with chemotherapy), similar trends were noted. In subset analyses according to stage, type, and timing of prior cancer, no group of

patients with prior cancer had inferior survival compared with patients without prior cancer,” the researchers wrote. “Fewer than 5% of adults with cancer in the United States participate in clinical trials,” the investigators noted. Among the barriers to accrual, “clinical trial eligibility criteria present a major barrier to study enrollment and represent one of the few accrual factors directly controlled by investigators and sponsors,” the authors added. The findings that prior cancer did not adversely impact all-cause or lung cancer–specific survival and patients with prior cancer actually had slightly better survival “suggest that broader inclusion in clinical trials of advanced lung cancer patients with prior cancer could be considered without impacting study outcomes,” the researchers concluded. “Such policy modifications could lead to faster accrual, higher trial completion rates, and more generalizable results, ultimately providing better treatments to more patients sooner.” Laccetti AL, et al: J Natl Cancer Inst 107:djv002, 2015.

EGFR L858R Mutation in Blood Sample May Serve as Surrogate for Biopsy in Determining EGFR-Mutation Status Using a novel polymerase chain reaction assay “to efficiently assess” epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cf DNA) from blood samples of patients with advanced non–small cell lung cancer (NSCLC), the Spanish Lung Cancer Group has “shown that the EGFR L858R mutation in cf DNA is a negative prognostic biomarker.” The group reached this conclusion after conducting a prespecified analysis of a secondary objective of the European Tarceva vs Chemotherapy (EURTAC) trial. That trial demonstrated greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced NSCLC and the L858R mutation in exon 21 or a deletion in exon 19. In the recently reported analysis, published in JAMA Oncology, median overall survival was shorter in patients with the L848R mutation in cfDNA than in patients with the exon 19 deletion. In an accompanying editorial, corresponding author Roy S. Herbst, MD, PhD, of the Yale School of Medicine, New Haven, Connecticut, and coauthors stated, “The updated EURTAC

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study demonstrates that mutations detected in cf DNA are prognostic and consistent with data obtained from tumor biopsies.” The editorialists noted that “the potential benefits of liquid biopsies include a better evaluation of the tumor genome landscape with the identification of a comprehensive set of targetable mutations and the serial noninvasive monitoring, which may allow the detection of additional mutations from emerging subclones, including those involved in the development of acquired resistance. Finally, the presence of specific mutations in cf DNA may help identify populations of patients who are likely to have worse (or better) outcomes and who may require alternative treatments.” Using the peptide nucleic acid–mediated 5ʹ nuclease real-time polymerase chain reaction (TaqMan) assay, the Spanish Lung Cancer Group examined EGFR mutations in cfDNA isolated from 97 baseline blood samples from patients in the EURTAC trial from 2007 to 2011. These patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, no prior chemotherapy for metastatic disease, and were treated in the trial with erlotinib or chemotherapy. The authors noted that the “rate of detection of EGFR mutations in cfDNA varies according to the method used” and that the TaqMan assay they developed “yields 78% sensitivity and 100% specificity.” EGFR mutations in cfDNA were detected in 76 of 97 (78%) patients with usable blood samples. Median overall survival was 13.7 months in patients with the L858R mutation in cfDNA vs 30.0 months in those with the exon 19 deletion (P < .001). “Univariate analyses of patients with EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter overall survival (hazard ratio [HR], 2.70 [95% CI, 1.60–4.56]; P < .001) and progressionfree survival (HR, 2.04 [95% CI, 1.20– 3.48]; P = .008). For patients with the L858R mutation in tissue, median overall survival was 13.7 (95% CI, 7.1–17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1– 46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09–4.52]; P = .03),” the researchers wrote. “In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer progression-free survival (HR, 0.41 [95% CI, 0.23–0.74]; P = .003).” The authors noted, the “finding that

the L858R mutation detected in cfDNA exerts a negative influence on survival indicates that a prospective study is warranted to examine the use of EGFR mutations in cfDNA as a viable surrogate biomarker. The Spanish Lung Cancer Group is participating in two ongoing clinical trials in patients with advanced-stage EGFR-mutant NSCLC, in which plasma and serum

are being collected for EGFR mutation testing in cfDNA at baseline, at response, and at disease progression: the European phase II BELIEF trial (NCT01562028) of erlotinib plus bevacizumab (Avastin) and the Spanish Lung Cancer Group phase II GOAL trial (NCT01513174) comparing gefitinib plus olaparib (Lynparza) vs gefitinib alone. These trials will

shed additional light on EGFR mutation assessment in cfDNA and pave the way for its implementation in clinical care.” Karachaliou N, et al: JAMA Oncol. February 26, 2015 (early release online). Morgensztern D, Politi K, Herbst RS: JAMA Oncol. February 26, 2015 (early release online). continued on page 190

JOP CELEBRATES 10 YEARS OF ADVANCING THE DELIVERY OF QUALITY CARE The May 2015 issue of Journal of Oncology Practice (JOP) marks the 10th Anniversary for JOP. During the last decade, the mission of JOP has been expressed by the original reports and perspectives we have published—focusing on key issues in care delivery. Our readers recognize that the remarkable revolution in our science is matched by the challenges of how we deliver care. JOP provides a unique forum to enlighten readers about the complexities of health care delivery, the definition and measurement of quality, key issues in health policy, discussions of the challenges in performing research, and business acumen required for any practice enterprise.

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In the Literature Emerging Clinical Data continued from page 189

HCV AND HIV INFECTION Therapy for Hepatitis C Virus Infection in Patients With Cancer May Prevent Liver Disease Progression “Hepatitis C virus (HCV) infection is a neglected disease in patients with cancer,” Harrys A. Torres, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston noted in the Journal of the National Comprehensive Cancer Network. To rectify that situation, the researchers reviewed the records of HCV-infected patients with cancer seen at The University of Texas MD Anderson Cancer Center from 2008 to 2011 and analyzed the outcomes of those who were treated for HCV. “This is the largest series to analyze HCV infections in patients with cancer,” the investigators stated.

Study Details Of 1,291 patients who had positive test results for an antibody to HCV (anti-HCV), 744 (58%) were tested for HCV-RNA, and 642 of these patients (86%) were found to have had chronic HCV infections. Among these 642 patients, 68% were men; 65% were nonHispanic white; 66% had genotype-1 (G-1) infections; and 72% had solid tumors, including 26% with hepatocellular carcinoma. “Complete remission of cancer was achieved in 223 patients (35%),” the authors noted. A total of 348 patients received HCV therapy, 250 before and 98 after cancer diagnosis. Most of the 98 underwent combination therapy with peginterferon alfa-2a (PegIntron) and ribavirin. HCV therapy was frequently associated with adverse events (54%), mainly hemato-

logic (74%), the researchers reported. Among the 78 patients with known treatment responses, sustained virologic response occurred in 27 (35%). “Most treated patients were cancer survivors experiencing complete remission,” the authors noted. “No cancer survivors experienced a recurrence of the underlying cancer during HCV therapy. No patient experienced cancer progression within 1 year of HCV therapy, and only one experienced cancer relapse within 2 years after therapy. Selected chemotherapy agents, mainly hormonal, were concomitantly used with HCV treatment.” Patients who did not experience a sustained virologic response were more likely than those who did to be black (29% vs 4%, P = .007), have G-1 infections (72% vs 6%, P < .0001), and higher baseline aspartate aminotransferase (78 vs 47 IU/L. P =.006) and alanine aminotransferase levels (71.1 vs 43.3 IU/L, P = .009). “Overall, progression to cirrhosis (hazard ratio [HR], 0.38; P = .03) and portal hypertension (HR, 0.19; P = .009) was less common in those treated, irrespective of the treatment outcome (sustained virologic response or nonsustained virologic response). Hepatocellular carcinoma developed as a second primary malignancy in 7% of patients with nonhepatocellular carcinoma cancer,” the researchers reported. The authors noted that treatment data for the study were collected until 2011, which was the year when directacting antivirals “such as the first-generation protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) were approved by the U.S. Food and Drug Administration. In our experience,” the authors continued, “a triple combination—one of these two protease inhibitors com-

bined with peginterferon alfa-2a and ribavirin—resulted in substantially higher sustained virologic response rates but also a higher incidence of side effects than dual therapy, as reported in patients without cancer. Peginterferon alfa-2a plus ribavirin are still used in cancer survivors with G-1 infection, especially if combined with recently approved direct-acting antivirals, such as sofosbuvir or simeprevir [Olysio]. In this population of patients, the use of interferon may be encouraged by some oncologists because of its anticancer activity.” The authors concluded, “HCV therapy is feasible and prevents liver disease progression in this forgotten population.” The findings “also suggest that HCV-infected cancer survivors should not be excluded from participating in clinical trials of antiviral therapies while under surveillance for cancer recurrence.” Torres HA, et al: J Natl Compr Canc Netw 13:41-50, 2015.

People Living With HIV in the United States Have a 50% Excess Cancer Risk The nearly 900,000 people in the United States living with diagnosed human immunodeficiency virus (HIV) infection have an excess cancer risk of 50%, according to a joint analysis of data by the National Cancer Institute and the National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. The reasons people with HIV infection have an increased cancer risk include immunosuppression, frequent coinfection with oncogenic viruses, and risk behaviors including smoking. The introduction of highly active antiretroviral therapy in 1996 has led to a decline in mortality related to acquired immunodeficiency syndrome (AIDS), but increased numbers of people living with HIV have resulted in an overall aging of the HIV population. For the analysis, investigators “derived cancer incidence rates for the U.S. HIV-infected and general populations from Poisson models applied to linked HIV and cancer registry data and from Surveillance, Epidemiology, and End Results program data, respectively,” the authors explained in the Journal of the National Cancer Institute. “We applied these rates to estimates of people living with diagnosed HIV at mid-year 2010 to estimate total and expected cancer counts, respectively. We subtracted ex-

pected from total cancers to estimate excess cancers.” At mid-year 2010, an estimated 859,522 people were living with diagnosed HIV infection in the United States, 39.1% for 5 or more years. Most were aged 40 to 59 years, and 74.9% were male, predominantly men who have sex with men. Among the estimated 7,760 cancers occurring among HIV-infected people, 3,920 cancers “were in excess of expected,” the investigators stated. “The most common excess cancers were non-Hodgkin lymphoma (NHL; n = 1,440 excess cancers, occurring in 88% excess), Kaposi’s sarcoma (n = 910, 100% excess), anal cancer (n = 740, 97% excess), and lung cancer (n = 440, 52% excess).” The proportion of excess cancers that were AIDS-defining, such as Kaposi’s sarcoma, NHL, and cervical cancer) declined with age and time since AIDS diagnosis, but the incidence of some non–AIDS-defining cancers, such as lung and anal cancers, has increased.

Key Data “For anal cancer, 83% of excess cases occurred among men who have sex with men, and 71% among those living 5 or more years since the onset of AIDS. Among injection drug users, 22% of excess cancers were lung cancer, and 16% were liver cancer,” the authors noted. Lung and anal cancers “together represent 27% of the total excess, underscoring that the development of strategies for prevention and early detection of these cancers among HIV-infected people is warranted.” Even though the incidence of AIDSdefining cancers declined, “14 years after the introduction of highly active antiretroviral therapy, over half of excess cancers were still AIDS-defining cancers,” the researchers pointed out. “This continuing excess illustrates that improvements in HIV treatment at the population level must remain a priority. Implementing measures to promote access and adherence to highly active antiretroviral therapy, especially targeted to young people and people with HIV only, could prevent many excess AIDSdefining cancers.” The study was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. n Robbins HA, et al: J Natl Cancer Inst 107:dju503, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | MAY 25, 2015

PAGE 191

Announcements

Cancer Survivors: Facts and Figures

he National Cancer Institute’s Office of Cancer Survivorship recently issued the following data: • As of January 2014, it is estimated that there are 14.5 million cancer survivors in the United States. This represents over 4% of the population, according to a report published recently.1 • The number of cancer survivors is projected to increase by 31%, to almost 19 million, by 2024, which represents an increase of more than 4 million survivors in 10 years.1 • Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37%, to 11.9 million.2 • Further, 64% of survivors have sur-

Nicholas J. Petrelli, MD, Receives Service Award

icholas J. Petrelli, MD, Bank of America Endowed Medical Director of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System, received the 2015 Service Award from the Delaware Bio Science Association. Delaware Bio Science is a trade

vived 5 years or more after diagnosis; 41% have survived 10 years or more; and 15% have survived 20 years or more.1 • Overall, 60% of survivors are currently 65 years of age and older.1 • Among today’s survivors, the most

2015

common cancer sites represented include female breast (22%), prostate (21%), colon/rectum (9%), and gynecologic organs (7%).1 For more information, visit the Office of Cancer Survivorship at http:// cancercontrol.cancer.gov/ocs/. n

References 1. DeSantis C, et al: Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252-271, 2014. 2. de Moor JS, et al: Cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev 22:561-570, 2013.

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association focused solely on promoting Delaware’s growing bioscience industry. The Service Award recognizes individuals or organizations who have made significant contributions to improve Delaware’s life-science community. Over the past 13 years, Dr. Petrelli has been a recognized leader in the state of Delaware in the fight against cancer. In addition to his many accomplishments in Delaware, Dr. Petrelli has served on several national advisory panels of the National Cancer Institute, the Society of Surgical Oncology, and ASCO. n

Lung Cancer Skin Cancer Supportive Care Visit education.nccn.org/ac2015 Supported by educational grants from Actelion; AstraZeneca; Bristol-Myers Squibb; BTG International; Celgene Corporation; Genentech BioOncology; Gilead Sciences, Medical Affairs; Lilly; Merck; Novartis Oncology; Pfizer; Prometheus Laboratories Inc.; and Takeda Oncology. This activity is supported by an independent educational grant from sanofi US. This activity was made possible by Pharmacyclics, Inc. and Janssen Biotech, Inc.

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The ASCO Post | MAY 25, 2015

PAGE 192

Book Review

p53 Takes Center Stage By Ronald Piana

ompleted in April 2003, the Human Genome Project was one of the greatest feats of scientific exploration, an inward voyage of discovery to sequence and map all of the genes of our species. Our genome contains an estimated 20,000 to 25,000 human protein coding genes, and each gene, in its own informational way, tells a story about the dizzying complexities of life. From a rose petal to a blue whale, all life on earth shares a commonality: DNA. Life’s unique building block began its publicity tour on February 28, 1953, when Francis Crick and James Watson interrupted the lunch-time crowd at a Cambridge, England, watering hole called The Eagle, announcing that they had “discovered the secret of life” after they had come up with their proposal for the structure of DNA. Several decades later, other researchers would discover that the secret of life was, in many ways, the secret of cancer. With so many genes to choose from, those who wish to write about them must pick out the true stars of our genome, such as The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment, by Jessica Wapner (reviewed in the September 15, 2013, issue of The ASCO Post). Ms. Wapner took a gene very well known to the readers of this journal and gave a meticulous frame-by-frame inspection of its history and the renowned and less-renowned scientists and doctors who played a role in the Philadelphia chromosome’s discovery and ultimate development of a successful drug for leukemia. It was a good book because Ms. Wapner carefully wove together the basic and applied science within the stories of the dedicated researchers as they maneuvered the process of bringing pharmaceuticals to market.

Putting the Puzzle Pieces Together Science writer Sue Armstrong tackles the story of another famous gene in her new book p53: The Gene That Cracked the Cancer Code, a highly informative narrative about the quest for scientific understanding and the promise that recent advances in molecularly targeted pathways hold for the oncology community. She begins by giving the reader a nuts and bolts description of cancer biology, nothing new here for the readers of The ASCO Post.

In Chapter 2, Ms. Armstrong lays the book’s foundation, telling the compelling story of how Drs. Michael Bishop and Harold Varmus were putting the pieces of an exquisite puzzle together: describing the cause of cancer. For oncology fellows rushing about in clinics from Memorial Sloan Kettering to Dana-Farber, this line in the book should serve as a stark reminder of how far we’ve come in just a few decades, thanks to the giants on whose shoulders they now stand. The author writes, “When Drs. Michael Bishop and Harold Varmus started their work together the two scientists were somewhat out on a limb, for in 1970 many of their peers in the scientific community were skeptical, even frankly disbelieving, of the theory that cancer is a disease of the genes, since there was no direct evidence for it.”

A Host of Personalities From there, Ms. Armstrong races headlong into the scientific process that led several groups of scientists, most notably one led by Professor Sir David Lane, to the discovery of the p53 protein. It is an interesting section because the esteemed scientists were barking up the wrong genetic tree, thinking that p53 was an oncogene. In telling of the quest to identify the “real p53” and what

Bookmark Title: p53: The Gene That Cracked the Cancer Code Author: Sue Armstrong Publisher: Bloomsbury Publishing Publication date: November 20, 2014 Price: $19.98; hardcover, 288 pages

nator of human tumors, mutated in the majority of them. Wisely, the author uses mini biographies and amusing anecdotes to break up the dry scientific narrative. “On a stunningly hot afternoon in July 2012, I travelled to Baltimore to meet Dr. Vogelstein, climbing the stairs overlooking the original old hospital of Johns Hopkins…. His lab is famed almost as much for its fun as its hard work. For years, Dr. Vogelstein headed a rock band, a bunch of musicians from his lab who called themselves Wild Type and played at sci-

When Drs. Michael Bishop and Harold Varmus started their work together the two scientists were somewhat out on a limb, for in 1970 many of their peers were skeptical of the theory that cancer is a disease of the genes, since there was no direct evidence for it. —Sue Armstrong

it means to the carcinogenic process, the reader gets treated to a deep understanding of the complexities in laboratory research, the somewhat mysterious place where the startling advances in cancer discovery begin. Not surprisingly, Ms. Armstrong has a host of big personalities to sort out, and at times it’s difficult to keep them and their particular contributions to the p53 story in order. Readers of The ASCO Post will enjoy when she finally arrives at the office of one of those big personalities, Bert Vogelstein, who along with his students discovered that p53 not only played a role in tumorigenesis, but it was a common denomi-

entific venues. The band broke up when the drummer’s wife died of leukemia, and he dropped out to take care of the kids.” That’s good stuff, and Ms. Armstrong is skilled enough to spice the narrative with human portraits without ever feeling like its filler.

Heavy on the Science Ms. Armstrong’s book is informative and entertaining for those with a medical or scientific background or for readers who have a dedicated interest in scientific breakthroughs, but it may be less appealing for more general readers. For example, in the chapter The Smoking Gun, she illustrates the

intriguing role of p53 in the effort to link smoking to lung cancer. This was an epic battle in the history of cancer, pitting courageous doctors against Big Tobacco, and the victory has saved countless millions of lives. While describing this legendary struggle against the tobacco industry, the author writes, “Crucially, while codons 248 and 273 are mutation hot spots in many types of cancer, the database revealed that codon 157 is found exclusively in lung tumors…. The fingerprint of BPDE was all over the p53 database.” Here, as in other sections, Ms. Armstrong’s dedication to getting the science right, proves too jargon-laden and bogs the pace down to a crawl. Make no mistake: This is an important subject, one that oncology fellows should read about, because it will inform them about the processes that propelled oncology forward. Moreover, the field needs a constant supply of fiercely curious minds such as those who discovered p53 and learned how to use it as a tool in the fight against cancer. Unfortunately, the dramatic punch and inspirational messaging of this highly informative book often get lost in acronyms and dry scientific explanations, which could have been streamlined for a better read. Ms. Armstrong is an accomplished science writer, and perhaps writing a book about p53 was a good idea, but sometimes a good idea for a book is a better idea for a magazine article. Such is the case with p53: The Gene That Cracked the Cancer Code. n

ASCOPost.com | MAY 25, 2015

PAGE 193

Announcements

HOPA Announces New President and 2015 Membership Award Winners

he Hematology/Oncology Pharmacy Association (HOPA) has elected Scott Soefje, PharmD, MBA, BCOP, FCCP, to serve as President for the 2015–2016 term. His term began at the 11th HOPA Annual Conference, held March 25–28. Dr. Soefje has served as President-Elect since March 2014.

2015 Basic Science and Clinical Research Literature Award. Dr. Reeves is Clinical Pharmacy Specialist at Butler University and St. Vincent Hospital in Indianapolis. • Joseph S. Bubalo, PharmD, BCPS, BCOP: 2015 Oncology Pharmacy

Practice Literature Award. Dr. Bubalo is Oncology Clinical Pharmacist at Oregon Health and Science University Hospital & Clinics. • Patrick Kiel, PharmD, BCPS, BCOP: 2015 New Practitioner Award. Dr. Kiel is a Clinical Pharmacy

Specialist at Indiana University Health. • Rowena N. Schwartz, PharmD, BCOP, FASHP: 2015 Patient Advocacy Award. Dr. Schwartz is Vice President of Clinical Content and Pharmacy Operations at McKesson Specialty Health. n

SAVE THE DATE Scott Soefje, PharmD, MBA, BCOP, FCCP

Dr. Soefje is a founding member of HOPA, with volunteer contributions that have extended to nearly every facet of the association’s governance. Most recently, he has been an adviser to the Professional Development Committee and member of the Leadership Task Force—responsible for setting the direction of members within the organization, as well as in their professional settings. He has also been Chair of the Health Policy and Advocacy Committee from 2008–2011. Currently, Dr. Soefje serves as the Director of Pharmacy at the University Medical Center Brackenridge in Austin, Texas.

2015 Award Winners At its 11th Annual Conference, HOPA also announced the recipients of the 2015 HOPA Membership Awards. HOPA Membership Awards recognize members who have shown outstanding achievement in their field. HOPA award winners include: • David W. Henry, MS, BCOP, FASHP: 2015 Award of Excellence. Dr. Henry is Chair of the Department of Pharmacy Practice, University of Kansas School of Pharmacy. • Terri Davidson, PharmD, BCOP, FASHP, FCCP, and Ross Davidson: 2015 Special Recognition Award. Dr. Terri Davidson is formerly of Emory University Hospital, where she created one of the first hematology/oncology pharmacy programs in the country; she is now the CEO of Syntaxx Communications. Ross Davidson worked collaboratively with Terri and other HOPA founders. • David J. Reeves, PharmD, BCOP:

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The ASCO Post | MAY 25, 2015

PAGE 194

Women in Oncology Profile: Julie M. Vose, MD, MBA, FASCO, Making a Difference in Both Clinical Medicine and Research By Ronald Piana

Julie M. Vose, MD, MBA, FASCO

t this year’s ASCO Annual Meeting, Julie M. Vose, MD, MBA, FASCO, will begin her term as the Society’s 51st President. It is fitting that the meeting will be held in Chicago, the city where the first seven visionaries met over lunch in 1964 to formulate a medical organization centered on cancer care. From its humble inception, ASCO has grown into the world’s leading oncology organization, but size has not diminished its primary mission: to improve the lives of people with cancer. The incoming ASCO President makes that point clear: “I try to get to know each patient, the patient’s family, and [his or her] modus operandi, so I can understand what works best in dealing with each unique situation. In short: Know your patient as a person,” said Dr. Vose. Dr. Vose was reared in Mitchell, South Dakota, quintessential small-town America, situated in a vast section of the Midwest known as Tornado Alley and The Corn Belt. She grew up in an environment of science and medicine; her father was a pathologist who helped her with her science projects, and her mother was a nurse. “During high school, I’d work summers in my father’s laboratory. That was my first introduction to medicine, looking at cancer cells under the microscope,” said Dr. Vose.

Early Career Path After graduating from high school, Dr. Vose entered South Dakota State University. “I majored in medical technology, which is preparation to work in a medical laboratory, but toward the end of my training, I realized that I wanted to become a doctor,” she explained. Upon receiving her undergraduate degree from South Dakota State, Dr. Vose moved slightly south to Nebraska, where she enrolled at the University of Nebraska Medical School. The young medical student had not yet been at-

tracted to a medical specialty until she encountered a mentor. During her junior and senior years, she began doing chart reviews with James O. Armitage, MD. She continued, “I did my fellowship and internship in internal medicine at the University of Nebraska Medical Center, where I continued doing research and clinical trial work with Dr. Armitage, who had become a wonderful mentor. It was during this period that I became fascinated by lymphoma, hematologic malignancies, and stem cell transplantation.”

A Multifaceted Workload Having found her passion for hematologic malignancies, Dr. Vose pursued her work at the University of Nebraska, where she currently is the Neumann M. and Mildred E. Harris Professorial Chair and Chief of the Oncology/Hematology Division in the Department of Internal Medicine at the University of Nebraska Medical Center and the Associate Director of Clinical Research at the Fred and Pamela Buffet Cancer Center. Given the scope of her responsibilities, a large part of Dr. Vose’s energy is fo-

minister cutting-edge treatments and take care of patients and also conduct research to find new ways to treat them. An added benefit is to be able to teach the next generation of cancer providers, which is incredibly rewarding,” she noted. She lauded the University of Nebraska as one of the nation’s leading centers for treatment and transplant for patients with lymphoma and other blood cancers, stressing that as an oncologist deeply engaged in innovative research, it is a dream come true to be part of an institution with such a progressive, forward-looking philosophy. “But oncology is about caring for patients with cancer, and our institution is peopleoriented, which is hugely important in that it creates a warm and supportive environment for our patients,” Dr. Vose stated. Dr. Vose has a wide range of current research pursuits. “I’m interested in multiple research areas such as new therapies for Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; and chronic lymphocytic leukemia, including stem cell transplantation, immunotherapy, pathwaydirected agents, and other novel agents.” Asked whether diminishing federal resources in our current economic environ-

One of ASCO’s initiatives I’m most enthusiastic about is CancerLinQ. It brings real-world data on the treatment of thousands of patients through different practices across the country to our desktop for quality-of-care and data analysis. —Julie M. Vose, MD, MBA, FASCO

cused on administrative needs; she is in charge of 18 faculty members and a large clinical trials infrastructure. Asked if her hefty administrative workload allows time for her research interests, Dr. Vose replied, “Managing a group of this size takes up about 40% of my time. I’m still very active in the clinic, spending about 30% of my time caring for my patients with lymphoma and multiple myeloma. And the rest of my time is spent on clinical research. It’s a very rewarding mix.” She added, “Research is always a delicate balance with funding, so we do a mix of investigator-initiated trials, cooperative group trials, and clinical trials from pharmaceutical companies.” Dr. Vose revealed that she choose a career in academic medicine because it offered the best of both worlds. “I get to ad-

ment would stall much-needed research, Dr. Vose, who also has an MBA in Health Administration from the University of Colorado Business School, responded, “As far as basic and translational research is concerned, it really is an ever-increasing problem, and ASCO needs to support the enhancement of current and future programs by working with the National Cancer Institute to use research dollars in high-priority oncology research.” However, she was quick to point out, it’s not just about money. “As for younger college or medical students interested in oncology, we should support internships and summer programs with oncologists and cancer centers to help students learn early in their careers about the fields of cancer care and oncology research,” said Dr. Vose. Mentorship of the future gen-

eration of oncology specialists is a top priority, as the oncology workforce will be challenged over the next several years due to the aging of the population.

Challenges Ahead As her ASCO presidency approaches, Dr. Vose said she is honored and excited to face the challenges ahead, stressing that coming from a rural part of the country, where some patients have to travel hundreds of miles to see their oncologist, access to quality care throughout the country is a central issue for her. Dr. Vose is also very interested in another important access issue: information. “One of ASCO’s initiatives I’m most enthusiastic about—and the one that has the potential for the most improvement in quality care—is CancerLinQ. It brings real-world data on the 97% of patients not currently treated in clinical trials on thousands of patients through different practices across the country to our desktop for quality-of-care and data analysis,” she explained. As incoming President of ASCO, Dr. Vose sees one of ASCO’s biggest challenges is to assist the oncology health-care team in providing quality cancer care and in keeping up with the rapidly expanding volume of new information coming out daily—and to do so in a cost-effective environment that meets the needs of patients. “I think the way to overcome that challenge is to continue to develop and update oncology-specific guidelines and pathways that can be used as the basis for quality-care management, such as through the Quality Oncology Practice Initiative (QOPI) system. Armed with this information, we can improve the affordability of cancer care by leveraging existing efforts to reform payment and eliminate duplication and waste in oncology care,” she added. Over the past decades, the oncology community has seen significant advances in research and knowledge, which have been translated into vastly improved clinical outcomes. It’s an exciting time of rapid change in cancer care, but the incoming ASCO President reminds us that one thing should always remain constant: “The art of oncology encompasses how to successfully put all of these aspects of oncology care together to benefit an individual patient and support the family through a stressful time,” concluded Dr. Vose. n Disclosure: Dr. Vose reported no potential conflicts of interest.

New from ASCO Journal of Global Oncology

CALL FOR PAPERS The American Society of Clinical Oncology (ASCO), and David Kerr, MD, DSc, founding Editor-in-Chief of the Society’s new Journal of Global Oncology (JGO), invite you to submit your next article to JGO. This new online-only, open access journal fulfills a growing need for content describing the array of challenges health care professionals in resource constrained settings face in conducting research and caring for patients with cancer. First articles will publish third quarter 2015. Currently, it is estimated that nearly 66% of all cancer deaths occur in low- and middle-income countries (LMICs), and this is forecast to increase to 70% by 2030.1

JGO will offer authors an opportunity to make an impact and have their research widely read through ASCO’s extensive content promotion network; ASCO Journals are accessed by nearly 10,000 institutions, and received by more than 25,000 oncologists in over 120 countries. In addition, JGO will apply for early indexing in MEDLINE™, and once indexing is granted, all articles published in JGO will be discoverable on the National Library of Medicine PubMed site. All submissions of original research will adhere to ASCO Journals’ usual rigorous standards of external clinical and statistical peer review, and will be edited by experienced copy editors to reflect the highest standards before publication. 1. International Agency for Research on Cancer, GLOBOCAN, 2012

For more information on submitting to Journal of Global Oncology, please visit GlobalOncologyJournal.org. Journal of Global Oncology is funded through the Conquer Cancer Foundation of the American Society of Clinical Oncology with the support of the Doris Duke Charitable Foundation and Novartis Oncology.

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