Tap Vol 6 Issue 15 by Harborside Press LLC

EGFR-Mutant Lung Cancer 11 | Managing Cancer Pain at the End of Life

| Metastatic Breast Cancer

VOLUME 6, ISSUE 15

AUGUST 25, 2015

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

Immune Checkpoint Inhibitors: The Dawn of a New Era for Lung Cancer Therapy

Best of ASCO

Studies Explore New Avenues to Pursue in Metastatic Triple-Negative Breast Cancer By Alice Goodman

By Suresh S. Ramalingam, MD

wo agents targeting novel pathways show promise in metastatic triple-negative breast cancer, according to separate studies presented at the 2015 ASCO Annual Meeting and reviewed at the Best of ASCO® meeting by Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital, Boston. The first study suggested that an irinotecan cousin, etirinotecan pegol (NKTR-102), may provide clinically meaningful benefit to patients with late-stage triple-negative breast cancer, especially those with brain metastases, which represents an unmet need.1 The second study revealed that the androgen receptor—a major target in prostate cancer—is also a valid therapeutic target in androgen receptor–positive triple-negative breast cancer,2 which accounts for 10% to 50% of all triple-negative breast cancers. Enzalutamide (Xtandi) achieved clinical benefit in patients who expressed the androgen receptor and would otherwise have been slated for more toxic chemotherapy.

Etirinotecan Pegol The phase III BEACON study, authored by Edith A. Perez, MD, of the Mayo Clinic, Jacksonville, and colleagues, showed promising results for etirinotecan pegol in a cohort of patients with triple-negative breast cancer. Steven J. Isakoff, MD, PhD BEACON was designed to compare etirinotecan pegol vs physician’s choice (any of the following agents: eribulin, vinorelbine, gemcitabine, taxane, or ixabepilone) in 852 patients with disease progression following anthracycline, taxane, and capecitabine. About 25% of patients had triplenegative breast cancer. At baseline, about 8% of patients in both groups had stable brain metastases, and 53% had liver mecontinued on page 10

Issues in Oncology

‘Right to Try’ Laws: Helpful or Harmful? By Jo Cavallo

he therapeutic paradigm for lung cancer has changed rapidly over the past few years toward individualized therapy. For certain subsets of patients, molecularly targeted agents have resulted in robust gains in overall survival and quality of life. However, for the majority of patients with nonsquamous non–small cell lung cancer (NSCLC), and for all patients with squamous NSCLC, chemotherapy remains the cornerstone of treatment. Chemotherapy provides modest therapeutic benefits in patients with advanced-stage disease. This longstanding paradigm is now going through a major shift with the advent of immunotherapy. continued on page 90

Dr. Ramalingam is Professor of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

ince 2014, “Right to Try” legislation has been sweeping the nation. Created to enable terminally ill patients to gain access to experimental drugs, biologics, and devices by sidestepping the approval process of the U.S. Food and Drug Administration (FDA), at press time, 22 states have enacted Right to Try laws, and 19 states have legislation pending. Although provisions in the law vary from state to state, they generally permit terminally ill patients access to an investigational treatment if a physician rec-

ommends use of the treatment; the patient gives informed consent; and the treatment has completed a phase I clinical trial. In some states, the laws exempt drug manufacturers and physicians from liability against claims arising from adverse side effects of the treatment. However, Right to Try legislation does not mandate that pharmaceutical companies provide their drugs or devices to patients, nor are health insurance companies required to pay for the treatment. Critics say these laws have created a false expectation that desperate patients will be able to gain quick Not only don’t these laws access to potentially lifeaccomplish anything as a legal saving treatments because they can bypass the FDA’s matter, as a policy matter, to the expanded-access applicaextent that they confuse patients or tion process and go directly manufacturers about the process, they to the manufacturer for the drug. However, accordcould actually be quite harmful. ing to Patricia J. Zettler, —Patricia J. Zettler, JD JD, Associate Professor at

Oncology Meetings Coverage Best of ASCO �� 1, 3, 4, 10 MASCC/ISOO Symposium �� 14–16 FDA Update �� 12–13, 22–23 Regorafenib in Colorectal Cancer ��24 Peter B. Bach, MD, MAPP, on Calculating the Value of Cancer Drugs ��30 Mark R. Gilbert, MD, on Classification of Gliomas �� 44 Geriatrics for the Oncologist ��50 Compassionate Drug Use Requests ��54 Direct From ASCO �� 60–63

continued on page 57

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The ASCO Post | AUGUST 25, 2015

PAGE 2

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Conor Lynch, Executive Editor Conor@harborsidepress.com James O. Armitage, MD Editor-in-Chief

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Associate Editors

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Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Syed A. Abutalib, MD Cancer Treatment Centers of America

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Manmeet Ahluwalia, MD, FACP Cleveland Clinic

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Joseph S. Bailes, MD Texas Oncology

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Laurence H. Baker, DO University of Michigan Health System

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center

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

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

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Nagi El-Saghir, MD American University of Beirut, Lebanon

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John Cox, DO Texas Oncology

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Michael P. Link, MD Stanford University Medical Center

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Richard Boxer, MD University of Wisconsin School of Medicine

Robert W. Carlson, MD National Comprehensive Cancer Network

Jamie Von Roenn, MD American Society of Clinical Oncology

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland

Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com Randi Londer Gould and Susan Reckling, Senior Editors Randi@harborsidepress.com Susan@harborsidepress.com Sarah McGullam, Web Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Regine M. Lombardo, Senior Graphic Designer Regine@harborsidepress.com Terri Caivano, Layout Artist Terri@harborsidepress.com Gail van Koot, Editorial Coordinator Gail@harborsidepress.com Elizabeth Janetschek, Editorial Assistant Elizabeth@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Jeannine Coronna, Vice President, Director of Operations Jeannine@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

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ASCOPost.com | AUGUST 25, 2015

PAGE 3

Best of ASCO® Thoracic Oncology

Moving Forward in Non–Small Cell Lung Cancer: Targeted Combinations and Immunotherapy By Alice Goodman

he newer targeted therapies and immunotherapies have proven to be a boon to the treatment of lung and other cancers, but how best to deploy those therapies remains a burning question. Another important focus of current research is the identification and validation of biomarkers for these therapies. At the recent Best of ASCO® meeting in Boston, Leena Gandhi, MD, PhD, of Dana-Farber Cancer Institute, Boston, discussed non–small cell lung cancer (NSCLC) studies addressing these issues. The studies were originally presented at the 2015 ASCO Annual Meeting.

response doubled the response rate to 63% and increased the disease control rate to 88%. “We see the added benefit of trametinib in both lung cancer and melanoma, with a more marked improvement in response rate for lung cancer compared with melanoma,” Dr. G andhi told listeners. “Currently, this same study in BRAF-mutated lung cancer is evaluating dabrafenib and trametinib as first-line therapy.”

vival are significant,” Dr. Gandhi commented. “In addition, all three studies have shown that there is a striking difference in toxicity favoring checkpoint inhibitors over standard therapy. This pushes us toward using these drugs. With the addition of nivolumab as a second-line option in updated National Comprehensive Cancer Network (NCCN) guidelines, PD-1 inhibition has become a new standard of care,” she noted.

Biomarker Results in POPLAR

Immunotherapies are moving into first-line studies and combination studies. These drugs are changing how we treat lung cancer.

Combination Targeted Therapy Interim results of the combination arm of an ongoing phase II study suggest that combining the BRAF inhibitor dabrafenib (Tafinlar) with the MEK inhibitor trametinib (Mekinist) improves results obtained with dabrefenib alone in patients with BRAF V600E–mutated NSCLC, making this combination of interest to pursue in this setting.1 Bruce Johnson, MD, of Dana-Farber Cancer Institute, originally presented these data at the Annual Meeting. Speaking at the Best of ASCO meeting in Boston, Dr. Gandhi noted that previously presented data from the dabrafenib monotherapy arm of this trial focused on 84 patients with BRAF-mutated NSCLC. With dabrafenib alone, the response rate of 32% was not as high as with other epidermal growth factor receptor (EGFR) therapies, Dr. Gandhi pointed out. The rate of stable disease was 24% with dabrefenib monotherapy, for an overall disease control rate of 56%. In the combination arm, the addition of trametinib to dabrafenib in a small group of 24 patients evaluable for

Several studies suggest that anti– PD-1 and anti–PD-L1 strategies are effective in lung cancer. The randomized, open-label, global CheckMate 017 trial found that nivolumab (Opdivo) was superior to docetaxel in 272 patients with advanced squamous cell NSCLC in whom platinum-containing doublet chemotherapy had failed, increasing median overall survival from 6 months to 9.2 months (P = .00025).3 This study, which was presented at the Annual

—Leena Gandhi, MD, PhD

PD-1 and PD-L1 Inhibitors Turning to immunotherapy with inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in NSCLC, another abstract looked at the efficacy, safety, and predictive biomarker results from the POPLAR study—a randomized phase II trial of atezolizumab (formerly known as MPDL3280A, an anti–PD-L1 agent) vs docetaxel as second- or third-line therapy of advanced NSCLC.2 The POPLAR results were presented by Alexander I. Spira, MD, PhD, of Virginia Cancer Specialists Research Institute, Fairfax, at the Annual Meeting. “A high mutational load, as is frequently seen in NSCLC, may contribute to increased immunogenicity, so targeting PD-1 and PD-L1 may be beneficial,” Dr. Gandhi explained.

Novel Therapies for Lung Cancer ■■ Interim results suggest that combining a BRAF inhibitor with a MEK inhibitor boosts response rates and disease control in BRAF V600E–mutated non–small cell lung cancer (NSCLC); the magnitude of response to this combination is greater in NSCLC than in melanoma. ■■ Immunotherapy is more effective and less toxic than docetaxel in advanced lung cancer, but identifying a valid biomarker remains elusive. ■■ Expression of PD-L1 is being studied as a biomarker for anti–PD-1 and anti–PD-L1 therapies but faces a number of hurdles. A better biomarker is needed.

Meeting by David R. Spigel, MD, of Sarah Cannon Research Institute/Tennessee Oncology, Nashville, led to U.S. Food and Drug Administration approval of nivolumab in NSCLC. The authors of CheckMate 017 collected tumor biopsies to quantify PDL1 expression in hopes of identifying a biomarker for response. More than 40% of patients had > 1% PD-L1 expression with the assay used in this study. “Analysis of PD-L1 expression as a biomarker had murky results in CheckMate 017. No significant differences in response to nivolumab vs docetaxel were observed at 1%, 5%, and 10% levels of PD-L1 expression,” she noted, but the study was underpowered to detect differences between different levels of expression. An identically designed trial, CheckMate 057, presented at the Annual Meeting by Luis Paz-Ares, MD, PhD, of Hospital Universitario 12 de Octubre in Madrid, showed the same encouraging trend toward improved survival for nivolumab over docetaxel in nonsquamous NSCLC.4 In CheckMate 057, PD-L1 expression was correlated with benefit from nivolumab, with nivolumab showing improved efficacy at all cutoff points for expression (ie, 1%, 5%, and 10%). “The follow-up of all three trials is short, but the differences to date in sur-

The saga of validating PD-L1 expression as a biomarker of benefit from anti–PD-1 and anti–PD-L1 therapies continues, with some studies suggesting that this is a useful biomarker and others being equivocal. Complicating this issue is the observation that PDL1–negative patients also derive benefit from immunotherapy. In the POPLAR study, analysis of biomarkers from tumor specimens in both tumor-infiltrating cells and tumor cells showed that patients with no PDL1 expression have the lowest overall response rates.2 Patients with the highest levels of tumor cell expression had the best response rate of 38%, compared with 13% for other levels of expression. Dr. Gandhi said high levels of PD-L1 expression also appear to separate out patients who will respond to treatment with another anti–PD-L1 agent, pembrolizumab (Keytruda).5 “The real difference in response [with atezolizumab and pembrolizumab] is seen only at high levels of PD-L1 expression. High levels of expression were not evaluated with nivolumab,” she noted. “PD-L1 is not a perfect biomarker, but it does differentiate patients who will and won’t respond to some degree. PD-L1 expression is a better predictor than histology and smoking status, and it correlates with differences in outcome,” Dr. Gandhi continued. The problems with measuring PDL1 status are partly related to the use of different assays, different antibodies, different cutoff points, fresh vs archival tissue, heterogeneity between multiple tumors and multiple sampling within a tumor, interval between biopsy and treatment, and specimens from primary vs metastatic disease. continued on page 4

The ASCO Post | AUGUST 25, 2015

PAGE 4

Best of ASCO® Thoracic Oncology

Immunotherapy Makes Inroads in Small Cell Lung Cancer By Alice Goodman

arly data on immunotherapy for small cell lung cancer (SCLC) have been encouraging. SCLC may catch up to non–small cell lung cancer (NSCLC), where immunotherapy is now standard of care, if these early data are borne out in phase III trials. Phase Ib and II studies of immunotherapy in SCLC were presented for the first time at the 2015 ASCO Annual Meeting and selected for the recent Best of ASCO® meeting in Boston, where Sarah B. Goldberg, MD, MPH, of Yale Cancer Center, New Haven, Connecticut, discussed the findings.1,2

KEYNOTE-028 Pembrolizumab was generally well tolerated and has promising antitumor activity in patients with programmed cell death ligand 1 (PD-L1)–positive extensive-stage SCLC who have had disease progression on prior platinum-based chemotherapy, according to the preliminary results of KEYNOTE-028, a phase Ib study with multiple cohorts and multiple diseases.1 The study was presented at the Annual Meeting by Patrick Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston. Of 157 patients with SCLC screened, 42 had PD-L1 expression of at least 1%.

Immunotherapy is not standard of care for SCLC, as it is for NSCLC. I will be actively seeking trials of immunotherapy for my SCLC patients, so these data change my practice in that regard. —Sarah B. Goldberg, MD, MPH

“Chemotherapy is the mainstay of treatment for small cell lung cancer. Selected patients are treated with prophylactic cranial irradiation. Topotecan is the standard second-line treatment and is approved by the [U.S. Food and Drug Administration],” she noted. “There have been no practicechanging advances in a long time. Now it seems that immunotherapy may change that, with studies of pembrolizumab [Keytruda] and nivolu mab [Opdivo] with or without ipilimumab [Yervoy],” Dr. Goldberg told listeners.

All patients in the SCLC cohort either had treatment failure on, or were not candidates for, standard chemotherapy. Autoimmune disease was an exclusion criterion. If at least a partial response was achieved, patients were slated for pembrolizumab therapy for 2 years or until disease progression. Only 20 patients went on to treatment with pembrolizumab. “Patients with SCLC tend to be sicker than patients with NSCLC, often with brain metastases and declining performance status,” Dr. Goldberg said. “Waiting for PD-L1 status test results can take several weeks, and waiting can be challenging for these patients,” she added.

Non–Small Cell Lung Cancer

to refine how to use that biomarker,” Dr. Gandhi continued. She said that the NCCN has included nivolumab for the treatment of squamous cell and non–squamous cell NSCLC but states that PD-L1 expression should not be used to select patients. “I think it’s premature for the NCCN to state that. We need more data,” she said. “Immunotherapies are moving into first-line studies and combination studies. These drugs are changing how we treat lung cancer,” she concluded. n

continued from page 3

“These differences make it difficult to predict using PD-L1 status. Levels of expression do not predict which patients will not benefit from therapy, but don’t throw out the baby with the bathwater. That is, don’t discount using a biomarker in decision-making for anti– PD-1 therapy,” she told the audience. “PD-L1 expression is a dynamic biomarker, it can change over time with exposure to therapy, and it is harder to pin down to a rigid range of sensitivity. We need to identify the best assay and the best immune biomarker. Then we need

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

New Directions in SCLC ■■ Immunotherapy appears to achieve durable responses in some patients with advanced, previously treated small cell lung cancer (SCLC); they have been early studies with small numbers of patients. ■■ Further study is needed to determine which drugs and which combinations will prove most effective in SCLC and to identify a biomarker for response.

Overall, pembrolizumab was well tolerated at 21 weeks. One treatment-related death due to colitis was reported, and no cases of pneumonitis occurred. Of the 20 patients, 7 responded, for a response rate of 35%; all were partial responses. Several patients had stable disease, and 45% had progressive disease. Median time to response to pembrolizumab was 8.6 weeks. Many responses are ongoing, with 6 out of 7 responding out to 40 weeks. “This is encouraging for SCLC after relapse,” Dr. Goldberg noted. No survival data are available. Enrollment in the SCLC cohort of KEYNOTE-028 is continuing, and further results are awaited.

Nivolumab With or Without Ipilimumab Deep and durable responses achieved in melanoma have led to study of nivolumab with or without ipilimumab in SCLC. A phase I/II study of recurrent SCLC after one line or more of prior therapy has shown encouraging preliminary results.2 The data were originally presented at the Annual Meeting by Scott J. Antonia, MD, PhD, of Moffitt Cancer Center, Tampa, Florida. The study enrolled patients with progressive disease regardless of PD-L1 status or the number of prior chemotherapy regimens. Patients were treated with nivolu References 1. Planchard D, Groen HJM, Kim TM, et al: Interim results of a phase II study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in patients with BRAF V600E mutated metastatic non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8006. Presented May 31, 2015. 2. Spira AI, Park K, Mazieres J, et al: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing atezolizumab (MPDL3280A) vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting. Abstract 8010. Presented May 31, 2015. 3. Spigel D, Reckamp K, Rizvi NA, et

mab at two different doses (n = 40), and combination nivolumab/ipilimumab was given at various dose levels (n = 35). “Many of these patients were heavily pretreated. They had to have had at least one prior regimen, but about 60% had two or three prior lines of therapy,” Dr. Goldberg said. The rates of grade 3 and 4 toxicity were higher with the combination than with nivolumab monotherapy. “Looking at the fine print, limbic encephalitis was reported in two patients and resolved in one; grade 5 myasthenia gravis was reported in one patient and was fatal,” she said. Among 40 evaluable nivolumab recipients, the overall response rate was 18%. There were no complete responses, and the partial response rate was 18%. The rate of stable disease was 20%, and the disease control rate was 38%. In 46 evaluable patients on the combination arm, the overall response rate was 17%, complete response rate was 2.2%, partial response rate was 15%, stable disease rate was 37%, and disease control rate was 54%. Duration of response has not yet been reached for nivolumab at this early time point. “The changes in tumor burden are exciting for patients who do respond,” Dr. Goldberg commented. continued on page 10

al: A phase III study (CheckMate 017) of nivolumab (anti-programmed death-1) vs docetaxel in previously treated advanced or metastatic squamous cell non–small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 31, 2015. 4. Paz-Ares L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced nonsquamous non–small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. Presented May 30, 2015. 5. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC).1 FDA-approved for treatment of advanced RCC since 2009

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1* *Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efﬁcacy and safety of VOTRIENT in ﬁrst-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT® (pazopanib) tablets WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages. Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

EFFICACY LIGHTS THE WAY

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

2.8

MONTHS

4.2

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. CHF occurred in 0.5% of patients on each arm. Monitor blood pressure (BP), and manage promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and reinitiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of CHF. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal (GI) hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events. Do not use VOTRIENT in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events (VTEs): VTEs have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • GI Perforation and Fistula: In RCC trials, GI perforation or fistula was reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events, and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension (HTN): HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9, and 90% of cases occurred in the first 18 weeks). BP should be well controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased BP promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT, as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if HTN is severe and persistent despite antihypertensive therapy and dose

reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein at baseline and periodically as clinically indicated. Interrupt treatment for 24-hour urine protein ≥3 grams, and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation

Once-daily oral dosing1

VOTRIENT: Summary of serious and common adverse reactions1

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

• Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm

• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced

• Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting

• No dose adjustment is required in patients with mild hepatic impairment • In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modiﬁcations based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

Pazopanib (VOTRIENT®) has a Category 1 recommendation as a ﬁrst-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology. NCCN Guidelines® also include therapies other than pazopanib (VOTRIENT®) as ﬁrst-line options.3

Important Safety Information for VOTRIENT (cont’d) during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases

concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of P-glycoprotein (PgP) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

• Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients. The most common adverse reactions (≥20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GSK; 2015. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer v3.2015. ©National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed April 13, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

VOTRIENT.com/HCP/aRCC

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

5/15

VRT-1114203

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)]. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the groups receiving VOTRIENT and placebo, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction

(LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other

Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.15.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC Who Received VOTRIENT VOTRIENT Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Adverse % % % % % % Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmarplantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

B:14.25”

T:13”

S:12.5”

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT Versus Placebo VOTRIENT Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Parameters % % % % % % Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose increased 41 <1 0 33 1 0 Total bilirubin increased 36 3 <1 10 1 <1 Phosphorus decreased 34 4 0 11 0 0 Sodium decreased 31 4 1 24 4 0 Magnesium decreased 26 <1 1 14 0 0 Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a singlearm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Eye Disorders: Retinal detachment/tear. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs that Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or BCRP should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant Use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs that Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 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 of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from Day 9 through Day 14 postpartum (preweaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In pooled clinical trials with VOTRIENT, 30% (618/2080) of patients were aged >65 years. Patients aged >65 years had an increase in ALT elevations of >3 X ULN compared to patients aged <65 years (23% versus 18%) [see Warnings and Precautions (5.1)]. In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Postimplantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved. Revised: 4/2015 VTR:14BRS Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

The ASCO Post | AUGUST 25, 2015

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Best of ASCO® Triple-Negative Breast Cancer continued from page 1

tastases. Lung metastases were present in 36% of the etirinotecan pegol group and 40% of the physician’s choice group. Unfortunately, the study did not meet its primary endpoint. There was about a 2-month improvement in overall survival with etirinotecan pegol, but it was not statistically significant. However, in a prespecified subset of 67 patients with brain metastases, etirinotecan pegol improved median overall survival by 5.1 months compared with physician’s choice: 10 vs 4.8 months (P < .01). The 1-year survival rate in patients with brain metastasis was 44.4% for etirinotecan pegol vs 19.4% for physician’s choice. Similarly, in 456 patients with liver metastases, median overall survival was significantly improved with etirinotecan pegol: 10.9 vs 8.3 months, respectively (P = .002).

cal activity and good tolerability in heavily pretreated patients, but survival is not statistically significantly improved in advanced breast cancer. The significant improvements in outcome in the groups with brain metastases and liver metastases deserve further study,” he said. Dr. Isakoff pointed out that there are at least three molecules with an irinotecan molecule backbone being studied in breast cancer: etirinotecan pegol, an antibody drug conjugate called IMMU132, and MM-398.

Enzalutamide A phase II study, presented at the 2015 ASCO Annual Meeting by Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center, New York, suggested that enzalutamide—a drug currently approved for treatment of metastatic castration-resistant prostate cancer—may hold

Where this drug [etirinotecan pegol] gets interesting is a provocative finding of doubling of survival in the subset of patients with brain metastases. Improved survival in patients with liver metastases is also of interest. —Steven J. Isakoff, MD, PhD

Etirinotecan pegol had lower rates of toxicity compared with physician’s choice, with very few grade 3 or higher toxicities. Biomarker studies to identify predictors of response and outcomes are underway. “Where this drug gets interesting is a provocative finding of doubling of survival in the subset of patients with brain metastases, which represents only 67 patients in this study. Improved survival in patients with liver metastases is also of interest. Etirinotecan pegol also significantly improved global health on the EORTC [European Organisation for Research and Treatment of Cancer] Quality of Life [questionnaire],” Dr. Isakoff said. “Overall, etirinotecan pegol has clini-

promise for the treatment of androgen receptor–positive triple-negative breast cancer. This is the first report to show clinical responses in breast cancer. The androgen receptor is expressed in 10% to 50% of patients with triple-negative breast cancer, Dr. Isakoff said. For enrollment in this study, androgen-receptor positivity was considered to be any expression greater than 0% by immunohistochemistry. Of 165 patients screened, 118 had some degree of androgen-receptor expression. Evaluable patients were those with androgen-receptor expression > 10% on immunohistochemistry, which represented 55% of the study population. The primary endpoint was clinical

Small Cell Lung Cancer

SCLC. Response rates were 35% for pembrolizumab in PD-L1–positive patients, 17% for nivolumab monotherapy, and 18% for nivolumab plus ipilimumab in all comers. Several responses appear to be durable. These are all phase I studies, and it is still too early to determine if the combination is better than singleagent therapy,” Dr. Goldberg said. “Toxicity may be related to paraneoplastic syndromes in some cases, which require close monitoring and aggressive treatment if they occur. The biomarker issue is up in the air. It is challenging to identify a biomarker, especially in

continued from page 4

For this study, PD-L1 expression was not a requirement. However, patients who were PD-L1–positive did respond, as did PD-L1–negative patients. “These are still early days for immunotherapy in SCLC. It appears that PD-L1 expression may be useful but is not necessary for response,” Dr. Goldberg said.

Encouraging but Not Definitive Data “These data are extremely encouraging for heavily pretreated patients with

New Therapies in Triple-Negative Breast Cancer ■■ Two studies identified new approaches that show promise in advanced triple-negative breast cancer: the irinotecan derivative etirinotecan pegol, and enzalutamide, a drug targeting the androgen receptor. ■■ Etirinotecan pegol appears to be particularly effective in patients with brain metastases, a subset of patients that represents an unmet need. ■■ A genomic signature called PREDICT-AR appears to identify patients who will derive the most benefit from enzalutamide.

benefit (defined as complete or partial response or stable disease) at 16 weeks. Among evaluable patients, the clinical benefit ratio was 35% at 16 weeks. In the intent-to-treat population, the clinical benefit rate was 25% at 16 weeks. Among evaluable patients, there were two complete responses and five partial responses. “This is fascinating. There are RECIST [Response Evaluation Criteria in Solid Tumors] responses to androgen blockade, which has never been reported before,” Dr. Isakoff stated. Median progression-free survival was 14 weeks. In the intent-to-treat population, higher androgen-receptor expression was associated with longer progressionfree survival: Progression-free survival for androgen-receptor expression > 10% vs < 10% was 14 vs 8 weeks, respectively. Dr. Traina and colleagues analyzed 404 tissue samples with gene profiling and came up with an androgen receptor–related gene signature for androgenreceptor positivity called PREDICTAR. This signature was found to predict clinical benefit and may be useful for future studies of androgen blockade in breast cancer, Dr. Isakoff said. Patients whose tumors expressed the signature had a 16-week clinical benefit rate of 40% vs 11% for those whose tumors did not express the signature. PREDICT-AR also predicted improvement in progression-free survival: Those who tested positive for PREDICT-AR had a median progression-free survival of 16 weeks vs 8 weeks in those who

tested negative for PREDICT-AR. Among evaluable patients who were PREDICT-AR–positive and treated in the first or second line, median progression-free survival was 40+ weeks, Dr. Traina told The ASCO Post. “That’s remarkable in triple-negative breast cancer,” she commented. “It is clear that enzalutamide has clinical activity in androgen receptor– positive triple-negative breast cancer, with consistent safety. The novel diagnostic assay, PREDICT-AR, will be studied further,” Dr. Isakoff said. “It is important to note that triplenegative breast cancer is heterogeneous—it is an immunohistochemical basket with at least five different subtypes amenable to different treatments. Androgen receptor is clearly expressed in a substantial proportion of patients—at least 50% in this study.” “The PREDICT-AR signature is also common, found in about 50% of advanced triple-negative breast cancers, and is worthy of further development. It is encouraging that we are learning how to predict response,” Dr. Isakoff said. n

SCLC, in part because the biopsy samples we are able to obtain are often very small. It is sometimes difficult for sick patients to wait for their PD-L1 status,” she continued. “Immunotherapy is not standard of care for SCLC, as it is for NSCLC. I will be actively seeking trials of immunotherapy for my SCLC patients, so these data change my practice in that regard. Ongoing trials are conducted to study pembrolizumab, nivolumab, and ipilimumab in SCLC,” Dr. Goldberg said. n

References 1. Ott PA, Fernandez MEE, Hiret S, et al: Pembrolizumab (MK-3475) in patients with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. 2015 ASCO Annual Meeting. Abstract 7502. Presented May 30, 2015. 2. Antonia SJ, Bendell JC, Taylor, MH, et al: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. 2015 ASCO Annual Meeting. Abstract 7503. Presented May 30, 2015.

Disclosure: Dr. Goldberg has received research funding from AstraZeneca.

Disclosure: Drs. Isakoff, Perez, and Traina reported no potential conflicts of interest.

References 1. Perez EA, Awada A, O’Shaughnessy J, et al: ASCO Annual Meeting. Abstract 1001. Presented June 1, 2015. 2. Traina TA, Miller K, Yardley DA, et al: ASCO Annual Meeting. Abstract 1003. Presented June 1, 2015.

ASCOPost.com | AUGUST 25, 2015

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In the Clinic Thoracic Oncology

Gefitinib in EGFR-Mutant Metastatic NSCLC 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 July 13, 2015, gefitinib (Iressa) was approved for first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a U.S. Food and Drug Administration–approved test.1,2 The approval of gefitinib occurred concomitantly with a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen), a companion diagnostic test for patient selection.

OF NOTE Gefitinib is a reversible inhibitor of the kinase activity of wild-type and activating mutations of EGFR.

Supporting Efficacy Data Approval was based on the objective response rate in a multicenter singlearm trial in which 106 treatment-naive patients with metastatic EGFR-mutant NSCLC received gefitinib at 250 mg daily. Patients had a median age of 65 years (25% ≥ 75 years, 49% < 65 years), 100% were white, 71% were female, 64% were never-smokers, 93% had a World Health Organization performance status of 0 or 1, and 97% had adenocarcinoma histology (97%). On blinded independent central review, the response rate was 50% (95% confidence interval [CI] = 41%–59%) with a median duration of response of 6.0 months. The investigator-determined response rate was 70% (95% CI = 61%–78%), with a median duration of response of 8.3 months. The efficacy results are supported by an exploratory analysis of outcome in a subset of 186 of 1,217 patients in a randomized open-label trial of first-line gefitinib at 250 mg vs up to six cycles of carboplatin/paclitaxel in EGFR-mutant metastatic NSCLC. Patients in this subset had a median age of 59 years (7% ≥ 75 years, 70% < 65 years), 100% were Asian, 83% were female, 96% were

never-smokers, 94% had a WHO performance status of 0 or 1, and 100% had adenocarcinoma histology. As assessed by blinded independent central review, median progression-free survival in this subset analysis was 10.9 months in 88 gefitinib recipients vs 7.4 months in 98 carboplatin/paclitaxel recipients (hazard ratio = 0.54, 95% CI = 0.38–0.79). The objective response rate was 67% in gefitinib patients, with a median duration of response of 9.6 months, vs 41% in carboplatin/paclitaxel patients, with a median duration of response of 5.5 months.

How It Works Activating EGFR mutations—eg, exon 19 deletion and exon 21 point mutation L858R—in NSCLC cells have been found to promote tumor cell growth, inhibit apoptosis, upregulate angiogenic factors, and promote metastasis. Gefitinib is a reversible inhibitor of the kinase activity of wild-type and activating mutations of EGFR, with prevention of autophosphorylation of tyrosine residues associated with the receptor resulting in inhibition of downstream signaling and EGFR-dependent proliferation. The binding affinity of gefitinib for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than that for wild-type EGFR. Gefitinib also inhibits insulin-like growth factor– and platelet-derived growth factor–mediated signaling at clinically relevant concentrations.

How It Is Given The recommended dose of gefitinib is 250 mg once daily with or without food until disease progression or unacceptable toxicity. Gefitinib should be withheld for up to 14 days for acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), grade ≥ 2 alanine transaminase (ALT) or aspartate transaminase (AST) elevation, grade ≥ 3 diarrhea, signs or symptoms of severe or worsening ocular disorders including keratitis, and grade ≥ 3 skin reactions. Treatment can be resumed when the adverse reaction fully resolves or improves to grade 1. Gefitinib should be permanently discontinued for confirmed interstitial lung disease, severe hepatic impairment, gastrointestinal perforation, and persistent ulcerative keratitis. The gefitinib dose can be increased to 500 mg daily in the absence of severe adverse drug reactions when used

concomitantly with strong CYP3A4 inducers (eg, rifampicin, phenytoin, tricyclic antidepressants), with treatment being resumed at 250 mg 7 days after discontinuation of the strong CYP3A4 inducer. Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole) increase gefitinib concentrations, warranting heightened monitoring for adverse reactions with concomitant use. Drugs that elevate gastric pH can reduce gefitinib levels. Gefitinib should be given 12 hours after the last dose or 12 hours before the next dose of a proton pump inhibitor and 6 hours before or after an H2-receptor antagonist or antacid. International normalized ratio (INR) elevations and hemorrhage have been reported in patients taking warfarin during gefitinib treatment. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.

Safety Profile Safety data for gefitinib are from 2,462 patients with NSCLC who received monotherapy at 250 mg daily in three randomized clinical trials. Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease were ex-

OF NOTE Gefitinib carries warnings/precautions for interstitial lung disease, hepatotoxicity, gastrointestinal perforation, ocular disorders, skin disorders, and embryofetal toxicity.

cluded from these trials. Data on common adverse events are from one randomized clinical trial in which 1,126 patients received gefitinib at 250 mg daily and 562 patients received placebo as second- or third-line treatment for metastatic NSCLC. The most common adverse events of any grade occurring more frequently in the gefitinib group were skin reactions (47% vs 17%), diarrhea (29% vs 10%), decreased appetite (17% vs 14%), and vomiting (14% vs 10%); the most common grade 3 or 4 adverse events were diarrhea (3% vs 1%), decreased appetite (2.3% vs 2.0%), and skin reactions (2.0% vs 0.4%). The most common laboratory abnormalities of any grade occurring

New Approval for Gefitinib in NSCLC ■■ Gefitinib (Iressa) was recently approved for first-line treatment of patients with metastatic non– small cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an approved companion diagnostic test. ■■ The recommended dose of gefitinib is 250 mg once daily with or without food until disease progression or unacceptable toxicity.

more frequently in gefitinib recipients were increased ALT (38% vs 23%, grade 3 or 4 in 2.4% vs 1.4%), increased AST (40% vs 25%, grade 3 or 4 in 2.0% vs 1.3%), and proteinuria (35% vs 31%, grade 3 or 4 in 4.7% vs 3.3%). Approximately 5% of gefitinib patients and 2.3% of placebo patients discontinued treatment due to adverse events, with the most common reasons in gefitinib patients being nausea (0.5%), vomiting (0.5%), and diarrhea (0.4%). The most frequent fatal adverse events in gefitinib patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). Serious and uncommon adverse drug reactions observed in the pooled population of NSCLC patients receiving gefitinib monotherapy included interstitial lung disease (1.3%), fatal hepatotoxicity (0.04%), and grade 3 ocular disorders (0.1%). Gefitinib carries warnings/precautions for interstitial lung disease, hepatotoxicity, gastrointestinal perforation, ocular disorders including keratitis, bullous and exfoliative skin disorders, and embryofetal toxicity. Patients receiving gefitinib should undergo periodic liver function testing. Women should not breast-feed during treatment. n References 1. U.S. Food and Drug Administration: Gefitinib (Iressa). Available at http://www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm454692.htm. Accessed July 28, 2015. 2. Iressa (gefitinib) tablets prescribing information, AstraZeneca, July 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206995s000lbl.pdf. Accessed July 28, 2015.

The ASCO Post | AUGUST 25, 2015

PAGE 12

FDA Update

FDA Approves Carfilzomib Combination for Patients With Relapsed Multiple Myeloma

he U.S. Food and Drug Administration (FDA) approved carfilzomib (Kyprolis) in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

In the United States, there are nearly 96,000 people living with, or in remission from, multiple myeloma. The estimated number of new cases of multiple myeloma in 2014 was more than 24,000, and the estimated number of deaths was 11,090. The approval was based on a demonstration of improved progressionfree survival in the multicenter, open-label ASPIRE trial. In this international, randomized phase III trial, 792 patients with relapsed or refractory multiple myeloma after one to three lines of prior therapies were randomly assigned (1:1) to receive lenalidomide and dexamethasone with or without carfilzomib for 18 cycles. Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned crossover from the control arm to treatment with carfilzomib.

fied boundary for statistical significance. A partial response or better was achieved by 87% of patients on the three-drug arm and 67% on the two-drug arm.

The safety profile of carfilzomib in the three-drug combination was similar to that described in the current label. Serious adverse events were reported in 60%

of patients in the three-drug arm and 54% in the two-drug arm. Cardiovascular events, venous thromboembolic events, and thrombocytopenia occurred more frequently in patients on carfilzomib. n

Inactivated T Cell

PD-1 Receptor

Activated T Cell

Study Details The study demonstrated a statistically significant prolongation of progression-free survival, as determined by an independent review committee (hazard ratio [HR] = 0.69; 95% confidence interval [CI] = 0.57–0.83; P = .0001, stratified log-rank test). Median progression-free survival was 26.3 months in patients receiving carfilzomib plus lenalidomide and dexamethasone and 17.6 months in those receiving lenalidomide and dexamethasone alone. A treatment effect was observed across all subgroups tested, but the magnitude of the treatment effect was reduced in patients with a higher tumor burden at study baseline. An interim analysis of overall survival, the key secondary endpoint, was conducted at the same time and found that the difference in overall survival did not reach the prespeci-

Safety Profile

PD-L2 PD-1 Receptor

Tumor

PD-L1

Artist’s interpretation based on scanning electron microscopy.

ASCOPost.com | AUGUST 25, 2015

PAGE 13

FDA Update

FDA Grants Breakthrough Therapy Designation to Lenvatinib for Metastatic Renal Cell Carcinoma

he U.S. Food and Drug Administration (FDA) granted lenvatinib (Lenvima) Breakthrough Therapy designation for investigational use in patients with advanced or metastatic

renal cell carcinoma who were previously treated with a vascular endothelial growth factor (VEGF)-targeted therapy. Lenvatinib is a multiple receptor ty-

rosine kinase inhibitor currently indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.

Discover PD-1: an immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands, PD-L1 and PD-L2.1,2,4—6 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,7

PD-L1, an immune checkpoint ligand, is a potential predictive biomarker expressed on tumor cells in many different types of cancer8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway and PD-L1 as a potential predictive biomarker.

To discover more about the PD-1 pathway and to register for updates, visit discoverthePD1pathway.com.

PD-1=programmed death receptor-1; PD-L1=programmed death receptor-1 ligand 1; PD-L2=programmed death receptor-1 ligand 2. References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. 2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. 3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477. 5. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 6. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 7. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268. 8. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):OF1–OF10.

Clinical Trial Results Lenvatinib was designated as a Breakthrough Therapy based on results of a phase II open-label, multicenter study involving 153 patients who were previously treated with a VEGF-targeted therapy and randomly assigned 1:1:1 to receive lenvatinib and everolimus (Afinitor), lenvatinib, or everolimus. Nearly all patients (99%) had received one prior VEGF-targeted therapy, 1% had received two prior VEGF-targeted therapies, and 18% had received prior immunotherapy. The results of this study were presented in an oral presentation at the 2015 ASCO Annual Meeting. Patients receiving lenvatinib plus everolimus had a median progression-free survival of 14.6 months, a 9.1-month improvement over everolimus alone (hazard ratio = 0.40, P < .001). In addition, the highest overall response rates were observed in the combination arm (43%, compared with 27% with lenvatinib alone and 6% with everolimus alone), with a median duration of response of 13.1 months. n

Dactinomycin Formulation Gets Orphan Drug Designation

he U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to NanoSmart Pharmaceuticals’ novel formulation of dactinomycin for the treatment of Ewing sarcoma, a rare type of childhood bone cancer. The designation was granted on the basis of a plausible hypothesis that the novel formulation, which uses NanoSmart’s proprietary drug delivery platform, may be clinically superior to the original drug. The new formulation consists of dactinomycin, a well-understood cancer drug, incorporated into a proprietary ANA-conjugated nanoemulsion. Cytotoxic agents like dactinomycin are known to be effective for Ewing sarcoma and other cancers but are limited by toxicity and often cause lifelong complications. The novel formulation is expected to localize drug delivery to the tumor site, thereby increasing effectiveness at the tumor while simultaneously improving safety by reducing collateral damage to healthy tissues. n

The ASCO Post | AUGUST 25, 2015

PAGE 14

MASCC/ISOO International Symposium Neuro-oncology

Short Course of Radiotherapy May Be Adequate for Elderly and Frail Patients With Glioblastoma Multiforme By Meg Barbor

o difference in overall survival or progression-free survival was observed between elderly and/or frail patients undergoing short and standard courses of radiotherapy for glioblastoma multiforme, according to data presented by Elena Fidarova, MD, at the 2015 Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) Annual Meeting on Supportive Care in Cancer in Copenhagen.1 “The short radiotherapy regimen may be recommended as a treatment option for elderly and/or frail patients given the similar overall survival, progression-free survival, and quality-of-life results,” said Dr. Fidarova, a radiation oncologist at the International Atomic Energy Agency (IAEA) in Vienna. “For patients in poor condition, such as the elderly or frail, a short course of radiotherapy is very beneficial, especially in some countries where there are problems with transporting patients to receive their radiotherapy,” said Sebastiano Mercadante, MD, moderator of the session and Director of the Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Clinic for Cancer, Palermo, Italy. “So having information about the similarity of efficacy of a short course in comparison with a traditional course is very important.”

Study Population and Methods Dr. Fidarova and her colleagues at the IAEA conducted a phase III, international multicenter, prospective, noninferiority study on 98 patients randomized to receive radiotherapy as either 25 Gy delivered in five fractions (n = 48) or 40 Gy delivered in 15 fractions (n = 50). The study aimed to evaluate overall survival, progression-free survival, and

health-related quality of life. Patients were stratified by age (< 65 or ≥ 65), Karnofsky Performance Score, and extent of surgical resection. Of the 98 patients randomized, 96 were eligible for health-related quality-of-life analysis: 47 in the short-course and 49 in the standard-course radiotherapy groups. Patients aged ≥ 50 years with a Karnofsky Performance Score of between 50% and 70% were classified as “frail,” patients aged ≥ 65 years with a Karnofsky Performance Score of between 50% and 70% were classified as “elderly and frail,” and those aged ≥ 65 years with a Karnofsky Performance Score of between 80% and 100% were classified as “elderly.” The study population presented with newly diagnosed glioblastoma multiforme (World Health Organization

Short-Course Radiotherapy for Elderly Patients With Brain Cancer ■■ There was no difference in health-related quality of life between patients with glioblastoma multiforme receiving short-course radiotherapy (25 Gy in 5 fractions) or standard-course radiotherapy (40 Gy in 15 fractions). ■■ Short-course radiotherapy was found to be noninferior to commonly used radiotherapy regimens. ■■ Investigators concluded that short-course radiotherapy may be recommended for elderly/frail patients with glioblastoma multiforme, given the similar overall survival, progression-free survival, and quality-of-life results.

Health-Related Quality of Life “The response rate was quite high and comparable in the two groups,” said Dr. Fidarova. In the short-course [radiotherapy] group, the response rate was 96% at baseline, 86% at 1-month follow-up, and 85% at 4-month follow-up; in the standard-course cohort, it was 98% at

The short radiotherapy regimen may be recommended as a treatment option for elderly and/or frail patients given the similar overall survival, progression-free survival, and quality-of-life results. —Elena Fidarova, MD

grade IV) and had undergone no previous chemotherapy or radiotherapy. Their initial surgery/biopsy at diagnosis had to be performed within 6 weeks prior to randomization, and initiation of treatment radiotherapy began within 2 weeks of randomization. The European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQC30), in combination with the brain module QLQ-BN20 and the Mini Mental Status Examination (MMSE), was administered to patients at baseline, 4 weeks after completion of radiotherapy, and every 3 months thereafter until disease progression.

baseline, 63% at 1-month follow-up, and 62% at 4-month follow-up. The median overall survival was 7.9 months in the short-course radiotherapy group and 6.4 months in the standard-course radiotherapy group (P = .988). The median progressionfree survival was 4.2 months in both arms. “The response rate dropped significantly by the fourth follow-up, which is understandable given the median [progression-free survival] and [overall survival],” Dr. Fidarova added. By the fourth follow-up, response rates fell to 29% and 22% in the short- and standard-course cohorts, respectively.

Dr. Fidarova and her colleagues observed no difference between study arms in global quality of life/main function scales/symptoms, except in the category of insomnia. An improvement was observed in both arms at 4 months of follow-up in the categories of global quality of life, social and physical function, fatigue, and insomnia but was only significant for insomnia in the short-course radiotherapy group. At study end, investigators found no difference in health-related quality of life between the two arms. They concluded that short-course radiotherapy was noninferior to commonly used radiotherapy for elderly and/ or frail patients with glioblastoma multiforme. n Disclosure: This study was coordinated and funded by the IAEA under the IAEA Coordinated Research Activities.

Reference 1. Fidarova E, Ghosh S, Kepka L, et al: Quality of life in elderly/frail patients with glioblastoma multiforme: Results of the IAEA randomized phase III study comparing short and standard course of radiotherapy. 2015 Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology Annual Meeting on Supportive Care in Cancer. Abstract 22-1-O. Presented June 26, 2015.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | AUGUST 25, 2015

PAGE 15

MASCC/ISOO International Symposium Symptom Management

Dispelling the Myths Associated With Osteonecrosis of the Jaw By Meg Barbor

steonecrosis of the jaw associated with cancer treatment is frequently misunderstood, according to Cesar Augusto Migliorati, DDS, MS, PhD, who delivered an update on its proper recognition and management at the 2015 Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer in Copenhagen.1 Dr. Migliorati dispelled some common myths about osteonecrosis of the jaw and presented information that may be new to many clinicians.

Bisphosphonates and Beyond Currently, several agents are recognized as being associated with osteonecrosis of the jaw, including bisphosphonates, denosumab (Prolia, Xgeva), and antiangiogenics. “A lot of people still call it bisphosphonate-associated osteonecrosis of the jaw, but it’s no longer a bisphosphonate problem only,” said Dr. Migliorati, Professor and Chair, Department of Diagnostic Sciences and Oral Medicine, University of Tennessee Health Science Center, Memphis. “Further, we know now that if you combine bisphosphonates with antiangiogenics in advanced renal tumors, there is an increased risk for this condition to occur. So that’s another new recognized risk factor for this condition,” he added.

Recognizing Symptoms According to a 2014 update from the American Academy of Oral and Maxillofacial Surgeons (AAOMS),2 patients may be considered to have osteonecrosis of the jaw if the following characteristics are present: current or previous treatment with antiresorptive or antiangiogenic agents; exposed bone or bone

that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for more than 8 weeks; and no history of radiation therapy to the jaw or obvious metastatic disease to the jaw. Dr. Migliorati recommended first thoroughly evaluating a patient’s history, including history of medications; oral complaints (pain, discomfort, tingling/paresthesia, bad breath, pus, swelling); dental history; and past treatment of an oral problem, including any history of surgery, trauma, and/or use of local and systemic antibiotics. Next, the patient should be examined for exposed bone and/or infection, purulent secretion, abscess formation, and fistula. Finally, a radiographic evaluation should be conducted.

Risk Factors The presence of certain factors may place patients at higher risk for osteonecrosis of the jaw, warned Dr. Migliorati. They include the use of medications for osteoporosis or cancer that have been associated with osteonecrosis of the jaw, the presence of active dental/periodontal disease, and individual predisposition. The latter “should be considered since the majority of patients on these medications do not develop osteonecrosis,” he said. Situations that may affect a person’s risk of osteonecrosis of the jaw include the duration on any drug associated with osteonecrosis of the jaw (the longer the duration, the higher the risk), a switch from a bisphosphonate to denosumab, and concomitant use of a bisphosphonate plus an antiangiogenic agent. “In our experience adjudicating thousands of cases, we think there

Osteonecrosis of the Jaw ■■ Currently, several agents are recognized as being associated with osteonecrosis of the jaw, including bisphosphonates, denosumab, and antiangiogenics. ■■ Early diagnosis of osteonecrosis of the jaw leads to easier management. ■■ Medical treatment is often recommended for early-stage osteonecrosis of the jaw, with surgery often indicated for more advanced-stage disease. ■■ Dental extractions do not cause osteonecrosis of the jaw but expose the alveolar bone, which may already be necrotic.

may be an additional risk, and patients can develop osteonecrosis of the jaw in a short period (sometimes 1 month) after the first injection of denosumab,” he stated. “So this is something we still have to learn more about.”

Dental Extractions In patients taking antiresorptives, dental extractions have been blamed as the cause for osteonecrosis of the jaw. “We have always questioned this possibility because there was never an ex-

tient quality-of-life evaluation, and the patient’s initial response to cancer therapy. “The earlier the diagnosis, the easier the management,” said Dr. Migliorati. When osteonecrosis of the jaw is classified as AAOMS stages 0 to II, he recommended frequent follow-ups, encouraging the use of antimicrobial rinses, prescribing systemic antibiotics when there is active infection or signs of paresthesia, and performing minor local debridement to eliminate sharp bone edges that

A lot of people still call it bisphosphonate-associated osteonecrosis of the jaw, but it’s no longer a bisphosphonate problem only. —Cesar Augusto Migliorati, DDS, MS, PhD

planation of the diagnosis that led to the extraction,” Dr. Migliorati explained. “Every time a dental extraction is performed, there is a diagnosis for it—most commonly an infection that has destroyed the bone support of the tooth or a fracture of the tooth that can’t be restored,” he said. “So we need to know why the teeth are being extracted, rather than blaming the extraction.” Patients heal from dental extractions when the wound is well handled, antibiotics are used, and patients are monitored, he reported. “So we can treat patients rather than sending them home with an active infection and saying ‘I can’t treat you because of the risk of osteonecrosis of the jaw.’ So that concept is changing completely.” Dr. Migliorati and his colleagues are currently collaborating with a group in Greece on this topic. “We want to publish proof that dental extractions do not cause osteonecrosis of the jaw but expose the alveolar bone, which may already be necrotic,” he said.

Surgical or Medical Treatment Once osteonecrosis of the jaw has been recognized, a decision must be made regarding treatment—medical or surgical. This decision can be influenced by the general health and cancer prognosis of the patient, a pa-

could aggravate the oral mucosa. For patients in a more advanced stage of osteonecrosis of the jaw (AAOMS stage III) who have not responded to treatment, Dr. Migliorati recommended surgical intervention with resection, bone and soft-tissue grafting, and primary closure of the defect. Reconstruction of the surgically resected bone with titanium bars may be necessary in more advanced cases, when the defect is too large, he stated. “The use of antiresorptives is not going to go away, but rather continue to increase, so the chances are good that we’re going to be seeing more of these cases,” said Dr. Migliorati. “We have to learn to recognize them quickly, make a correct diagnosis, and then manage them as soon as possible.” n Disclosure: Dr. Migliorati is a consulant for Amgen and Colgate Palmolive.

References 1. Migliorati C: Recognition and management of osteonecrosis of the jaw. 2015 MASCC/ISOO International Symposium. Parallel Session PS11. Presented June 26, 2015. 2. Ruggiero SL, Dodson TB, Fantasia J, et al: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 72:1938-1956, 2014.

The ASCO Post | AUGUST 25, 2015

PAGE 16

MASCC/ISOO International Symposium Symptom Management

Managing Cancer Pain at the End of Life By Meg Barbor

ancer-related pain does not exist in a vacuum. To effectively treat it, clinicians should understand the contributing factors. Proper assessment and management of cancer pain at the end of life can significantly alleviate patient suffering, according to Eduardo Bruera, MD, FAAHPM, Department Chair of Palliative Care and Rehabilitation Medicine in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston. “One of the challenges of pain in cancer patients close to the end of life is that it doesn’t come alone,” said Dr. Bruera at the 2015 Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held recently in Copenhagen.1 “It comes accompanied by fatigue, emotional distress, and the beginning of cognitive change, and it is in that context that we must assess and manage pain.” He added, “Some patients have circumstances tougher than others, especially in countries where the likelihood of getting a painkiller is close to zero. The vast majority of patients who will die of cancer will never get a single dose of an opioid analgesic.”

Assessment of Pain Dr. Bruera advised that clinicians first assess the pain mechanism (eg, cancer, infection, procedure), the intensity of pain and other symptoms, and previous use of opioids. “You might spend 25 minutes figuring out exactly what the pathophysiology is, and then you propose an opioid that made the patient very sick a few weeks ago, and your credibility is down the drain,” he said.

End-of-Life Cancer Pain ■■ Patients with cancer should be carefully assessed for the level of pain, including previous use of opioids. ■■ Pain intensity can be influenced by a number of outside factors. ■■ Screening for nicotine/alcohol dependency can help identify patients at higher risk for chemical coping.

He recommended use of the Edmonton Symptom Assessment System, which is completed by the patient and can measure multiple symptoms in less than 2 minutes.

the insurance company refuses to pay for it, and I need to change their painkiller,” he said. “Be aware that that can be a problem. However, they are more convenient, as the patient takes them less often.”

One of the challenges of pain in cancer patients close to the end of life is that it doesn’t come alone. It comes accompanied by fatigue, emotional distress, and the beginning of cognitive change, and it is in that context that we must assess and manage pain. —Eduardo Bruera, MD, FAAHPM

When cancer patients are screened regularly, more symptoms are identified. “[With screening], you can discover eight symptoms in a visit vs two if [you rely on] the patient to volunteer the information,” he said. Screening also allows for comparison over time and quality assurance, which helps clinicians to understand how they are doing and what they can do better.

Pain Intensity: Only One Component Pain intensity can be a useful numerical expression … but is “just a component of information for us,” said Dr. Bruera. Myriad factors can influence the number a patient uses to describe his or her pain (eg, the actual cancer, targeted therapy, divorce, emotional burden, loss of a job). “These are all part of the experience of suffering that affects patients, and that’s what they express.” According to Dr. Bruera, the “ideal management of pain” includes a painkiller that is effective 24 hours a day; use of routine laxatives; and consideration of nonsteroidal anti-inflammatory drugs, adjuvant drugs, physical techniques, and anticancer therapy. He recommended the use of any strong opioid (morphine, hydromorphone, oxycodone, fentanyl, methadone, oxymorphone) and stated that they all have similar effects and toxicity. Slow-release opioids are not better painkillers and have no reduced side effects, he told the audience. They are also five times more expensive than shortacting opioids. “For 35% of patients to whom I prescribe a slow-release opioid,

Dr. Bruera encouraged the use of adjuvant drugs, including corticosteroids, bisphosphonates, acetaminophen, and methylphenidate. “Certainly corticosteroids are fantastic, and methylphenidate can have a wonderful effect if the patient gets sleepy,” he said. “For neuropathy, we frequently end up having to make a litany of regimen changes (for example, trying opioids plus gabapentin, triycyclics, baclofen, lamotrigine, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors)—the question is which one works better for your patient.”

Practical Approach to Assessment If a patient is not responding well to an opioid, Dr. Bruera recommends an enhanced assessment in which three amplifiers of expression should be identified: delirium, somatization (“total pain”), and addictive history. Delirium can be caused by cancer, but it can also be caused by opiates. “Opiates can lead the patient to opiate-induced neurotoxicity, but it is important that we don’t universally blame the opioid, because there are other factors,” he said. “A patient can get disinhibited because of the delirium, and they may perceive that their pain is worse,” he explained. “Patients with delirium will ‘hyperexpress.’” If opioid-induced neurotoxicity occurs, begin opioid rotation and increase hydration, he advised. “Stop all of the offending drugs that you can, and it really doesn’t matter to which opioid you go,” said Dr. Bruera. “What mat-

ters is that you make the diagnosis that there’s opioid toxicity and you start the rotation, which is reasonably easy when methadone is not involved.” Dramatic improvement in refractory pain symptoms has been demonstrated in most rotation studies. “One of the results when you rotate is that people feel better; their pain gets better,” he added.

Other Tools The CAGE-AID questionnaire, which screens for alcohol and drug problems, can help to screen patients at high risk for using drugs, nicotine, or alcohol as a means of coping. “Patients with nicotine or alcohol dependence might convey a higher risk for chemical coping with opiates,” said Dr. Bruera. “But absence of a history of chemical coping is no security at all,” he warned. “The booze doesn’t matter. It’s a marker for the way your patient will cope chemically with an opioid,” he said. “Screening does not diagnose chemical coping, but the apparent behaviors are the ones that make the diagnosis.” If a patient demonstrates chemical coping, educate the patient and family, create a supportive environment, prevent dose escalation, and rule out psychiatric disorders, he advised. Finally, Dr. Bruera focused on the prevention of constipation, calling it a “huge issue.” “There is an underestimation of the suffering component of constipation in our cancer patients,” he said. “There’s no tolerance, and it’s completely underdiagnosed.” Appropriate diagnosis of constipation, education of the patient, and aggressive use of laxatives are crucial to alleviating this bothersome side effect. “Ultimately, when a patient comes to me with increased pain, it might be cancer-related, but it could have nothing to do with the cancer,” said Dr. Bruera. “Close to the end of life, we address human suffering. And people have the right to call it whatever they want to call it.” n

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

Reference 1. Bruera E: Cancer pain at the end of life: Rational and realistic management choices. 2015 MASCC/ISOO Annual Meeting. Parallel Session PS22. Presented June 27, 2015.

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 | AUGUST 25, 2015

PAGE 22

FDA Update

FDA Approves Sonidegib for Locally Advanced Basal Cell Carcinoma

he U.S. Food and Drug Administration (FDA) approved sonidegib (Odomzo) for the treatment of patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or those who are not candidates for sur-

gery or radiation therapy. The approval was based on demonstration of a durable objective response rate in an international, multicenter, double-blind, randomized, two-arm, noncomparative trial in patients with locally advanced basal cell carcinoma

not amenable to local therapy or metastatic basal cell carcinoma.

Trial Details The clinical trial enrolled 230 patients who were randomly assigned (2:1) to receive sonidegib 800 mg (n

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]

= 151) or 200 mg (n = 79) daily until disease progression or unacceptable toxicity. Randomization was stratified by disease stage (locally advanced or metastatic), histologic subtype (aggressive or nonaggressive), and geographic region.

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 | AUGUST 25, 2015

PAGE 23

FDA Update

The majority (84%) of those enrolled had locally advanced disease. Among patients with locally advanced basal cell carcinoma randomly assigned to receive sonidegib 200 mg daily, the median age was 67 years; 58% were male, 89% were white, 67% had an Eastern Cooperative Oncology Group performance status of 0, and

three patients had nevoid basal cell carcinoma syndrome. Most (76%) had received prior therapy for basal cell carcinoma, and approximately half of these patients (56%) had an aggressive histology. Approval was based on demonstration of durable objective responses in patients with locally advanced basal

Trim: 7.625 x 10.5

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

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

cell carcinoma, as determined by central independent review according to a modification of Response Evaluation Criteria in Solid Tumors (RECIST). The objective response rate for the 66 patients in the sonidegib 200-mg arm was 58% (95% confidence interval [CI] = 45%–70%], consisting of 3 (5%) complete responses and 35 (53%) par-

tial responses. A prespecified sensitivity analysis using an alternative definition for complete response, defined as at least a partial response according to magnetic resonance imaging and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a complete response rate of 20%. A similar response rate was noted in the 128 patients in the sonidegib 800-mg arm (44% [95% CI = 35%–53%]).

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

Among the 38 responding patients in the 200-mg arm, 7 patients (18%) experienced subsequent disease progression, and 4 of these 7 patients had maintained a response of 6 months or longer. The remaining 31 patients (82%) continue to respond, with ongoing responses ranging from 1.9+ to 18.6+ months; 16 patients have ongoing responses of 6 months or longer, and the median duration of response has not been reached.

Adverse Events Serious and common adverse reactions and discontinuation of sonidegib for adverse reactions occurred more frequently in the 800-mg treatment arm. Adverse reactions occurring in more than 10% of patients treated in the 200-mg arm were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients in the 200-mg arm were serum lipase and creatine kinase elevations. The most serious risks of sonidegib are rhabdomyolysis and embryofetal toxicity. Sonidegib carries a boxed warning alerting health-care professionals that the drug may cause death or severe birth defects in a developing fetus when administered to a pregnant woman. Health-care professionals should verify pregnancy status prior to the initiation of sonidegib, counsel pregnant women on the potential risks of sonidegib to the embryo and fetus, and advise nonpregnant women to use effective contraception during treatment with sonidegib and for at least 20 months after the last dose based on the 28-day half-life of sonidegib. n

The ASCO Post | AUGUST 25, 2015

PAGE 24

Lab Notes Journal Spotlight Gastrointestinal Cancer

Regorafenib Improves Overall Survival in Asian Patients With Previously Treated Metastatic Colorectal Cancer By Matthew Stenger

n a phase III trial (CONCUR) reported in The Lancet Oncology, Jin Li, MD, and colleagues found that the multikinase inhibitor regorafenib (Stivarga) improved overall survival vs placebo in Asian patients with previously treated metastatic colorectal cancer.1 Regorafenib is approved in the United States for treatment of patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF (vascular endothelial growth factor) therapy, and, if KRAS wild type, an anti-EGFR (epidermal growth factor receptor) therapy. In the phase III CORRECT trial that supported regorafenib’s approval, 111 of 760 patients were Asian, with most being Japanese.

bevacizumab (Avastin), cetuximab (Erbitux), or panitumumab (Vectibix) was allowed but not mandatory. The primary endpoint was overall survival. The regorafenib and placebo groups were generally balanced for age (median 58 and 56 years), region (China for 82% and 88%), Eastern Cooperative Oncology Group performance status, main site of disease, presence of KRAS mutation (yes in 34% and 26%, no in 37% and 43%, unknown in 29% and 31%), presence of BRAF mutation (yes in 0% and 1%, no in 21% in both, unknown in 79% and 78%), time from metastatic diagnosis (median 20 months in both), multiple metastatic sites, and previous systemic treatments. Previous targeted treatment included none in 41% and 38% of pa-

This phase III trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatmentrefractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. —Jin Li, MD, and colleagues

Study Details In this double-blind trial, 204 patients with progressive disease from 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam were randomized 2:1 between April 2012 and February 2013 to receive oral regorafenib 160 mg/d (n = 136) or placebo (n = 68) on days 1 to 21 of 28-day cycles. Both groups received best supportive care. Patients had to have received at least two previous treatment lines, including a fluoropyrimidine plus oxaliplatin or irinotecan. Previous treatment with

tients, anti-VEGF or anti-EGFR therapy in 59% and 62%, anti-VEGF but not anti-EGFR therapy in 24% and 19%, anti-EGFR but not anti-VEGF therapy in 18% and 25%, and both in 18%.

Improved Overall Survival After a median follow-up of 7.4 months, median overall survival was 8.8 months (95% confidence interval [CI] = 7.3–9.8 months) in the regorafenib group vs 6.3 months (95% CI = 4.8–7.6 months) in the placebo group (hazard ratio [HR] = 0.55, P = .00016). Median progression-free survival was 3.2

Survival Benefit With Regorafenib in Metastatic Colorectal Cancer ■■ Regorafenib treatment significantly prolonged overall survival in Asian patients with previously treated metastatic colorectal cancer. ■■ Exploratory analysis suggested better outcomes in patients with no prior targeted therapy.

months (95% CI = 2.0–3.7 months) vs 1.7 months (95% CI = 1.6–1.8 months (HR = 0.31, P < .0001). Subgroup analysis showed a consistent effect of regorafenib in almost all subgroups. In an exploratory analysis of the effect of previous targeted biologic treatment, the hazard ratio for overall survival was 0.31 (95% CI = 0.19–0.53) among 82 patients with no prior treatment and 0.78 (95% CI = 0.51–1.19) among 122 who had received at least one targeted agent. An additional exploratory analysis of overall survival with censoring at the start of post-study treatment showed hazard ratios of 0.57 (95% CI = 0.32–1.02) in patients with prior targeted treatment and 0.27 (95% CI = 0.15–0.49) in those with no prior treatment. After disease progression, 31% of patients in the regorafenib group and 43% of the placebo group received additional systemic treatment. Objective response rates were 4% in the regorafenib group and 0% in the placebo group (P = .045), and disease control rates were 51% vs 7% (P < .0001).

Adverse Events Drug-related adverse events of any grade occurred in 97% of the regorafenib group and 46% of the placebo group, with the most common in the regorafenib group being hand-foot skin reaction (73% vs 4%) and hyperbilirubinemia (36% vs 7%). Grade ≥ 3 drug-related adverse events occurred in 55% vs 14%, with the most common being hand-foot skin reaction (16% vs 0%), hypertension (11% vs 3%), hyperbilirubinemia (7% vs 1%),

hypophosphatemia (7% vs 0%), and increased alanine transaminase (7% vs 0%) and aspartate transaminase levels (6% vs 0%). Drug-related serious adverse events occurred in 9% vs 4%. Adverse events led to treatment interruption or dose reduction in 71% vs 16%, most commonly due to hand-foot syndrome and laboratory events in the regorafenib group, and to treatment discontinuation in 14% vs 6%, most commonly due to laboratory events in the regorafenib group (hand-foot skin reaction in 1%). The investigators concluded: “This phase III trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting.” n

Disclosure: The study was funded by Bayer HealthCare Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Li J, Qin S, Xu R, et al: Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. May 13, 2015 (early release online).

Learning to Refine the Use of Regorafenib to Best Advantage in Advanced Colorectal Cancer Richard Goldberg, MD, of The Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute, Columbus, offers his perspective on the CONCUR trial discussed above. See page 25.

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Perspective

Learning to Refine the Use of Regorafenib to Best Advantage in Advanced Colorectal Cancer By Richard Goldberg, MD

n patients with advanced colorectal cancer who have been heavily treated with a sequence of chemotherapy regimens and/or targeted therapies, the goals of treatment on or off a clinical trial are readily definable. These patients and their managing teams are striving to extend the length of lives, maintain quality of life, provide hope in a palliative care setting, identify new active agents, and refine the optimal use of those agents either alone or as part of combination therapies. When enrolling in these trials, patients have accepted randomization to a new treatment compared with best supportive care, highlighting both the individual patient’s and the population’s needs for better outcomes. And this strategy has been successful. Such studies have recently identified monoclonal antibodies targeting the epidermal growth factor receptor cetuximab (Erbitux) and panitumumab (Vectibix), the cytotoxic agent TAS-102, and the multitargeted tyrosine kinase inhibitor regorafenib (Stivarga) as agents that extend survival in this heavily pretreated group of people. Once these tools are identified as effective, we need to refine their use to best advantage. The CONCUR trial—reported by Li and colleagues1 and reviewed in this issue of The ASCO Post—helped to do this by extending the findings from the Dr. Goldberg is Physician-in-Chief, The Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute, Columbus.

CORRECT trial,2 a study that led to the U.S. Food and Drug Administration approval of regorafenib in the setting of advanced colorectal cancer that is refractory to chemotherapy.

improve during treatment in any of the four cohorts. The agent appeared active in cohorts with both KRAS wild-type and KRAS-mutated tumors.

This study suggests the potential for earlier deployment of regorafenib and its use in combination therapy. These strategies are being tested with both FOLFIRI and FOLFOX in the second-line setting.

CORRECT vs CONCUR Trials How does the CONCUR study extend our knowledge about the use of this new agent? The CONCUR study was conducted in patients of Asian and non-Japanese ancestry, a population that had not been enrolled in the prior phase III CORRECT trial; the CORRECT trial did enroll patients of Japanese ancestry but not individuals from other Asian countries. In the regorafenib-treated cohort in the CORRECT vs CONCUR studies, 49% vs 38% had at least three prior treatments; 52% vs 26% had an Eastern Cooperative Oncology Group performance status of 0; 54% vs 34% of the patients’ tumors had KRAS mutations; and none vs 41% had prior exposure to biologic agents. Despite these differences in the characteristics of the treated cohorts, the toxicity profiles were nearly identical. The relative benefits for CONCUR’s less heavily pretreated group were marginally better than for the patients treated in the CORRECT trial: median progression-free survival of 2.2 vs 1.9 months and median overall survival of 8.8 vs 6.4 months. Similar to what was seen in the CORRECT trial, the exposure to regorafenib did not lead to an earlier deterioration of quality of life compared with the cohorts randomized to placebo treatment, nor did quality of life

examining the experiences of patients treated outside a prospective phase III trial) that regorafenib has activity and utility in treating pa-

—Richard Goldberg, MD

The Next Steps What are the next steps for regorafenib now that we have this additional information? This study suggests the potential for earlier deployment of regorafenib and its use in combination therapy. These strategies are being tested with both FOLFIRI (folinic acid, fluoroura cil [5-FU], and irinotecan) and FOLFOX (folinic acid, 5-FU, oxaliplatin) in the second-line setting. Clinical experience has also suggested the need for refining the dose and schedule of regorafenib, looking at lower doses and schedules using alternating weeks of treatment and treatment-free intervals. This is related to the need for dose adjustment and dose delays in patients treated with 160 mg daily for 3 of 4 weeks. It is clear from these two trials (as well as from the Bayer-funded CONSIGN registry retrospectively

tients with advanced colorectal cancer. As we learn to use this agent better, we hope to exploit its value even more effectively. n

Disclosure: Dr. Goldberg has been an advisor to Taiho, served on the data monitoring committee for Eli Lilly, and his institution has received research funding from Bayer.

References 1. Li J, Qin S, Xu R, et al: Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebocontrolled, phase 3 trial. Lancet Oncol 16:619-629, 2015. 2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.

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In the Clinic Hematology

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

n July 24, 2015, carfilzomib (Kyprolis) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone in the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.1,2 Carfilzomib was previously approved as a single agent for treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib (Velcade) and an immunomodulatory agent and had disease progression within 60 days of completion of their last therapy. The revised labeling for carfilzomib includes a revised dose schedule and safety information for monotherapy in this setting, and new warnings/precautions have been added to the labeling.

OF NOTE Carfilzomib exhibits antiproliferative and proapoptotic activities in solid and hematologic tumor cells, inhibits proteasome activity in blood and tissue, and delays tumor growth in animal models of various cancers.

Efficacy Data The new approval was based on improved progression-free survival in a phase III open-label trial in which 792 patients with relapsed or refractory multiple myeloma after one to three lines of prior therapy were randomly assigned to receive lenalidomide plus low-dose dexamethasone with (n = 396) or without carfilzomib (n = 396) for 18 cycles.3 Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned crossover from the control group to treatment with carfilzomib. In the carfilzomib and control groups, median age was 64 and 65 years, 54% and 59% of patients were male, 95% in both groups were white,

the number of prior regimens was one in 46% and 40% and two in 30% and 35%, 55% and 58% had undergone prior transplantation, and International Staging System disease stage was I in 42% and 39% and II in 37% and 38%. Testing for genetic mutations was performed in 53% of patients, with highrisk mutations identified in 12% and 13% of patients. On independent review, median progression-free survival was 26.3 months

The drug exhibits antiproliferative and proapoptotic activities in solid and hematologic tumor cells. It inhibits proteasome activity in blood and tissue and delays tumor growth in animal models of multiple myeloma, hematologic, and solid tumors.

How It Is Given Carfilzomib is given as a 10-minute intravenous infusion on 2 consecutive days each week for 3 weeks followed

Expanded Indication for Carfilzomib ■■ Carfilzomib (Kyprolis) was recently approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed multiple myeloma who have received one to three prior lines of therapy. ■■ Carfilzomib is given as a 10-minute intravenous infusion on 2 consecutive days each week for 3 weeks followed by a 12-day rest period in each 28-day cycle; treatment is continued for up to 18 cycles or until disease progression or unacceptable toxicity.

(95% confidence interval [CI] = 23.3– 30.5 months) in the carfilzomib group vs 17.6 months (95% CI = 15.0–20.6 months) in the control group (hazard ratio [HR] = 0.69, P = .0001). A treatment effect favoring carfilzomib was observed across all subgroups, but the magnitude of benefit was reduced in patients with higher tumor burden (improvement of 11 months for stage I, 8 months for stage II, and 2 months for stage III). An interim analysis of overall survival performed at the time of progressionfree survival analysis showed that the difference between groups did not reach the protocol-specified early stopping boundary. A partial response or better was observed in 87% vs 67% of patients.

How It Works Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome.

OF NOTE Carfilzomib carries warnings/ precautions for cardiac toxicities, acute renal failure, tumor lysis syndrome, pulmonary toxicity, pulmonary hypertension, dyspnea, and hypertension.

by a 12-day rest period in each 28-day cycle. The recommended starting dose is 20 mg/m2 in cycle 1 on days 1 and 2. If tolerated, the dose can be escalated to a target dose of 27 mg/m2 on day 8 of cycle 1. From cycle 13, the doses on days 8 and 9 are omitted. Treatment is continued for up to 18 cycles or until disease progression or unacceptable toxicity. Oral lenalidomide is given at 25 mg on days 1 to 21, and oral or intravenous dexamethasone at 40 mg on days 1, 8, 15, and 22 of each cycle. In patients on dialysis, carfilzomib should be administered after the procedure. All patients should receive hydration prior to administration and, as needed, following administration. Patients should be premedicated with dexamethasone at the recommended dose prior to all cycle 1 doses and if infusion reactions occur or recur. Thromboprophylaxis is recommended, with the regimen based on assessment of the patient’s underlying risks. Antiviral prophylaxis should be considered to reduce risk of herpes zoster reactivation. Treatment should be withheld or dose-reduced for absolute neutrophil count < 0.5 × 109/L; platelets < 10 × 109/L or evidence of bleeding with thrombocytopenia; serum creatinine ≥ 2 × baseline or creatinine clearance < 15 mL/min, creatinine clearance reduction to ≤ 50% of baseline, or need for

dialysis; or any severe or life-threatening nonhematologic toxicity. One dose level reduction is from 27 to 20 mg/m2 or from 20 to 15 mg/m2.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring during the first 12 cycles of therapy in the carfilzomib group were anemia (35% vs 33% in the control group), neutropenia (32% vs 30%), diarrhea (29% vs 27%), fatigue (28% vs 27%), and thrombocytopenia (26% vs 19%). Grade ≥ 3 adverse events that occurred with an incidence > 2% higher in the carfilzomib group included neutropenia (27% vs 23%), thrombocytopenia (15% vs 10%), and hypokalemia (6% vs 3%). Despite protocol-mandated use of thromboprophylaxis, venous thromboembolic events occurred in 13% of carfilzomib recipients vs 6% of the control group. The most common grade 3 or 4 laboratory abnormalities in the carfilzomib group were lymphopenia (46% vs 31%), neutropenia (39% vs 36%), hypophosphatemia (31% vs 27%), and thrombocytopenia (26% vs 15%). Serious adverse events occurred in 60% vs 54% of patients, with the most common in the carfilzomib group being pneumonia (14% vs 11%), respiratory tract infection (4% vs 1.5%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%). Adverse events led to treatment discontinuation in 26% vs 25% of patients and to discontinuation of carfilzomib in 12%, with the most common reasons being pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). Deaths due to adverse events within

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 www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

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In the Clinic

30 days of the last dose of any therapy occurred in 7% vs 7% of patients, with the most common causes being cardiac events (3% vs 2%), infection (2% vs 3%), renal events (0% vs < 1%), and other events (2% vs 3%). Among patients receiving carfilzomib, the incidence of serious adverse events was 50% in patients aged

≤ 65 years, 70% in those aged 65 to 74 years, and 74% in those aged ≥ 75 years. Carfilzomib carries warnings/precautions for cardiac toxicities, including cardiac failure and myocardial infarction with fatal outcome, and myocardial ischemia; acute renal failure; tumor lysis syndrome; pulmonary toxicity, includ-

ing acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease; pulmonary hypertension; dyspnea; hypertension, including hypertensive crisis; venous thrombosis; infusion reactions; thrombocytopenia; hepatic toxicity and hepatic failure; thrombotic thrombocytopenic purpura/hemolytic

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

uremic syndrome; posterior reversible encephalopathy syndrome; and embryofetal toxicity. Patients should be monitored regularly for serum creatinine, blood pressure, platelet counts, and liver enzymes. If hypertension cannot be controlled, a risk-benefit decision on continued on page 28

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

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

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In the Clinic Carfilzomib continued from page 27

continued carfilzomib treatment is necessary. Patients should be monitored for tumor lysis syndrome, including uric acid levels, and treated promptly. Patients should be monitored for signs and symptoms of thrombotic thrombo-

cytopenic purpura/hemolytic uremic syndrome. If posterior reversible encephalopathy syndrome is suspected, neuro-radiologic imaging for onset of visual or neurologic symptoms should be considered. Females of reproductive potential should avoid becoming pregnant during treatment. n

References 1. U.S. Food and Drug Administration: Carfilzomib. Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455873. htm. Accessed July 28, 2015. 2. Kyprolis (carfilzomib) for injection prescribing information, Onyx Pharmaceuticals, Inc, an Amgen Inc. sub-

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

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

Erb0813PBS_693US13PBS02201_7x9wip3.indd 2

sidiary, July 2015. Available at http:// www.accessdata.fda.gov/d rugsatfda_ docs/label/2015/202714s009lbl.pdf. Accessed July 28, 2015. 3. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142-152, 2015.

table 3: (Continued)

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

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

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Announcements

Children’s Hospital of Philadelphia Appoints Madeline Bell, MS, as CEO

he Children’s Hospital of Philadelphia (CHOP) announced that Madeline Bell, MS, formerly President and Chief Operating Officer, has been appointed President and Chief Executive Officer and will succeed Steven M. Altschuler, MD, as CEO. The transi-

tion of leadership was completed on July 1, 2015. “I am very pleased that Madeline will succeed me as CEO of CHOP,” said Dr. Altschuler. “Her years of experience made her the ideal choice to lead this wonderful organization.… I wish Mad-

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

eline every success in the years to come and stand ready to assist her in any way I can,” he said. “The opportunity to lead this organization during such a dynamic and changing time in health care is exciting. I will do all I can, with the help of a skilled and

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

Rev August 2013 693US13PBS02201

dedicated team, to ensure that The Children’s Hospital of Philadelphia’s reputation for preeminence in pediatric health care and commitment to the mission endures long into the future,” Ms. Bell said. The appointment of Ms. Bell as CEO was the result of a multiyear succession planning process, conducted in anticipation of Dr. Altschuler’s retirement. Appointed in April 2000, Dr. Altschuler completed 15 years of service as CEO upon his retirement.

Madeline Bell, MS

Early Career Ms. Bell began her career as a pediatric nurse at CHOP in 1983, later leaving the organization to move into hospital administration. She returned to CHOP in 1995 to head Home Care and Case Management and since that time has held a number of leadership positions, eventually advancing to Executive Vice President and Chief Operating Officer in 2007. In 2010, she assumed the title of President and Chief Operating Officer. A mission-driven leader recognized for hospital operational excellence, Ms. Bell has made numerous contributions to CHOP, including the development of the largest pediatric ambulatory network in the country, the implementation of a single-platform electronic health record, the expansion of a 4 million–square foot campus, and the development of numerous nationally recognized clinical and family-centered care programs. n

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

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Expert’s Corner Issues in Oncology

Calculating the Value of Cancer Drugs A Conversation With Peter B. Bach, MD, MAPP By Jo Cavallo

Peter B. Bach, MD, MAPP

or nearly a decade, Peter B. Bach, MD, MAPP, Director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center in New York, has been a leading voice in sounding the alarm over the escalating cost of cancer drugs and in seeking a solution to the problem. In 2012, Dr. Bach and his colleagues at Memorial, Leonard B. Saltz, MD, Chief, Gastrointestinal Oncology Service and Head, Colorectal Oncology Section, and Robert E. Wittes, MD, then Physician-in-Chief, made headlines when they announced in an op-ed1 in The New York Times that Memorial Sloan Kettering would no longer prescribe ziv-aflibercept (Zaltrap) to its patients with advanced colorectal cancer because the drug cost more than twice as much—$11,063 for a month of treatment—as bevacizumab (Avastin) but provided the same survival benefit, pro-

longing patients’ lives for a median of 1.4 months. (A few weeks later, Sanofi, the manufacturer of ziv-aflibercept, reduced the cost of the drug by 50%.) The following year, the chorus of protests over the high cost of cancer drugs grew louder after an international group of 120 experts in chronic myeloid leukemia authored an article in Blood,2 arguing that it was important to lower the prices of cancer drugs so more patients could afford them. In an article published earlier this year,3 Dr. Bach and his colleagues examined the history of cancer drug pricing in the United States and found that the “average price of anticancer drugs, adjusted for inflation and health benefits, increased by 10% annually—or an average of $8,500 per year—from 1995 to 2013.”

tween the cost of drugs and benefit or how novel the compound is. Pricing is just based on what the market will bear.”

Calculating Drug Value ASCO has been investigating how to define and ensure the delivery of high-value oncology care for more than 10 years, and in June, the Society released details of its findings in a conceptual framework for assessing value in cancer care in the Journal of Clinical Oncology,4 a move praised by Dr. Bach. He is incorporating some of the core principles used in ASCO’s value framework in an interactive calculator he has developed called DrugAbacus. DrugAbacus (drugabacus.org) is a research tool that Dr. Bach has cre-

How can we quantify the key issues in value, and what about the value of hope and other constructs that seem hopelessly abstract? —Peter B. Bach, MD, MAPP

“The notion that drug prices are linked to anything coherent like value or benefits has been debunked,” said Dr. Bach. “Drug pricing is illogical because as drugs gained competitors, their prices went up; as drugs gained market share, their prices went up; and as they gained new indications, their prices went up. There is no relationship be-

ated to compare the cost of 54 oncology drugs approved by the U.S. Food and Drug Administration (FDA) since 2001 with what their prices would be if factors such as drug side effects, survival benefit, and whether the treatment was expensive to develop were added to the equation to determine actual valuebased pricing.

The ASCO Post talked with Dr. Bach about the development of the DrugAbacus and his pursuit of valuebased oncology drug pricing.

Calculating Value Why did you create the DrugAbacus, and what is its purpose? The Drug Abacus is essentially a proof-of-principle research tool. I developed it because it seemed like the appropriate next step in trying to determine value in drug pricing. The issue that prices are rising very rapidly has been pretty clearly documented by our group at Memorial Sloan Kettering and by folks at other institutions. And I’ve published a few articles, as have a number of other people, raising questions about how drug prices might be determined more coherently. Drug pricing should have some relation to benefit, but it doesn’t. It should have some relation to how novel the compound is, but it doesn’t. In some articles I’ve written, I’ve done head-to-head comparisons to determine a rationale for price disparity. How can it be that ceritinib (Zykadia) for late-stage lung cancer costs about $1,700 more than crizotinib (Xalkori)—$13,200 per month vs $11,500 per month, respectively? The notion that we should be thinking about value when it comes to drug pricing is becoming entrenched, but there is the concern of how to define value or apply it in the real world of caring

Don’t Miss These Important Reports in This Issue of The ASCO Post Patricia J. Zettler, JD, on ‘Right to Try’ Legislation see page 1

Richard Goldberg, MD, on Using Regorafenib in Advanced Colorectal Cancer see page 25

Ruth O’Regan, MD, on Estrogen-Receptor Signaling in HER2-Positive Breast Cancer see page 38

Beatriz Korc-Grodzicki, MD, PhD, on Being a Geriatrician in the World of Oncology see page 50

Arthur L. Caplan, PhD, on the Creation of Johnson & Johnson’s Independent Bioethics Panel see page 54

Marianne Berwick, PhD, MPH, on Public Overreaction to Link Between Citrus Fruit Consumption and Melanoma see page 83

Visit The ASCO Post online at ASCOPost.com

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Expert’s Corner

for our patients. Everybody’s stake in this effort is different. How can we quantify the key issues in value, and what about the value of hope and other constructs that seem hopelessly abstract? In the course of listening to concerns about what to take into consideration when determining value, I thought that if we could wrangle these notions into empiric structures, maybe we could come up with a value equation. Since there was no disagreement on which components go into the equation but, rather, how much they matter, I converted the information into a mathematical way of thinking about value in drug pricing.

they couldn’t afford the insurance copayments. Please talk about that experience. I still harbor the belief that the reason we are all in the business of biomedical innovation is to benefit patients. I think the reality of that marketplace, however, is that it largely benefits a number of parties involved in the process between the scientists and the point of care but

that the end users—the patients—are regularly left behind. The goal of my research and the reason others are attempting to clarify drug value and pricing is to reduce human suffering. Undoubtedly, you can blame insurance cost-sharing structures for making it difficult for patients to afford these drugs, and I do. But insur-

ance cost-sharing structures are a consequence of high drug prices, and if you tack on cost-sharing charges for a drug like blinatumomab (Blincyto), which costs $180,000 and has to be administered in the hospital, you ensure that some patients with acute lymphoblastic leukemia will not get the drug. continued on page 32

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2

Interactive Tool How does the DrugAbacus work? The home page of the DrugAbacus shows an image and price of pembrolizumab (Keytruda, $2,500) and one of imatinib (Gleevec, $9,000) and asks: Are these the right prices; should they cost more or less? Inside the DrugAbacus is all the information that might be relevant to the value of the drug, including efficacy, toxicity, novelty, cost of development, disease rarity, and population burden of disease. The user can then decide how much each of these factors should matter in a drug’s value; the abacus calculates the user’s “abacus” price and compares it to the drug’s actual price. The users of the DrugAbacus are people who are concerned that we need a better model for drug pricing. This version of the DrugAbacus offers a very rough draft of how we could put a value on drug pricing. I think of it as a sort of version 0.1, but going from 0 to 0.1 matters because it takes us from asking how could we do this to this is how we do it—now let’s work out the details. There is hard work ahead, but there is coherence with this model, and it gives us a start. I am not making a judgment about what is the right way to go about this. The DrugAbacus is a proof of concept that helps users create a value equation and actually map drugs to it to come up with a value-based price, but I don’t expect it to be used at the point of care. It is a policy tool aimed at addressing the concern that the drug-pricing system is completely broken right now and endeavors to help find what a better pricing system might look like.

Patients Left Behind I read that you were inspired to develop the DrugAbacus after hearing from patients who didn’t fill their prescriptions because

Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with ﬁrst-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

13% (95% CI, 3%–32%)

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com. References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 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. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. 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;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

The ASCO Post | AUGUST 25, 2015

PAGE 32

Expert’s Corner

That scenario is also true of imatinib, the most important drug to be developed in my professional lifetime. Novartis has raised the price of the drug nearly threefold since it was approved by the FDA in 2001 for chronic myeloid leukemia—and more recently in the treatment of childhood acute lymphoblastic leukemia— and some patients aren’t getting their prescription filled because of insurance copayments. I can’t look at that situation and say our system is working. In 2014, the FDA approved 10 drugs for cancer treatment and that many or more will be approved this year, which is great news. But if these new treatments don’t get to the patients we are developing them for because they can’t afford them, something is broken, and what’s broken is drug pricing. So the focus has to be on solving this problem.

Total Price Flexibility

course in the first place? And the answers, respectively, are, we can’t, and because they can. n Disclosure: Dr. Bach reported no potential conflicts of interest.

References 1. Bach PB, Saltz LB, Wittes RE: In cancer care, cost matters. The New York Times. October 14, 2012. Available at www.nytimes.com. Accessed July 27, 2015. 2. Experts in Chronic Myeloid Leukemia: The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: From the perspective of a large group of CML experts. Blood 121:4439-4442, 2013. 3. Howard DH, Bach PB, Berndt ER, et al: Pricing in the market for anticancer drugs. J Econ Perspect 29:139-162, 2015. 4. Schnipper LE, Davidson NE, Wollins DS, et al: American Society of Clinical Oncology statement: A conceptual framework to assess the value of cancer treatment options. J Clin Oncol 33:2563-2577, 2015. B:14.25 in

What has been the reaction from drug manufacturers to your concerns about drug pricing?

market leverage to jack up the price as much as possible without adding any value, and use tools to wall off competition and the entry of generics into the marketplace. Their goal is to maximize their near-term profits, and they have very little interest in any other approach to pricing. The question I keep asking, and I’ve been asking it ever since Sanofi lowered its price for [ziv-aflibercept] by 50% after we wrote one op-ed in The New York Times, is why are we acting like these drug prices are real? The prices are products of markets, so we have indulged pricing flexibility, and our marketplace tolerates unlimited pricing indiscretion by the pharmaceutical industry. Point to another industry where an op-ed can lead to a 50% price reduction. That response proved total price flexibility. The questions we should be asking are how do we plan to pay for all the drugs that will come out over the next 20 years, and how can drugs like sofosbuvir (Sovaldi) for the treatment of hepatitis C cost $84,000 per 12-week

Visit ASCOPost.com for Interviews Filmed During the 2015 ASCO Annual Meeting The ASCO Post presents these and other important discussions: ■■

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Whole-Brain Radiation and Radiosurgery in Patients With Brain Metastases Issues of Value in Melanoma Treatment PALOMA3 Study on Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer Global Oncology: Cancer Care in Resource-Challenged Areas Ibrutinib, Bendamustine, and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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S:13 in

continued from page 30

The reality is that many of these companies are full of people who believe in the same mission that I just articulated and believe that they are “cannibalizing their young” in the pursuit of near-term profits. Some companies are structured around capitalization of the current broken health-care system, and other companies are in business for the long haul, and they have very different reactions to the goal of trying to rationalize the pricing system into a sustainable model that benefits patients. The companies that are in business for the long haul and have been around for a long time are believers in their model of innovation and are fully on board with the notion that we need indication- and performance-specific drug pricing. That is a model that I developed and one that Express Scripts Holding Company is now using to set pricing for some cancer drugs based on how well they work. But there are other companies that are in the arbitrage business. They buy up an asset, try to get it cheap, use

T:14 in

Peter B. Bach, MD, MAPP

DID YOU KNOW? FOR NEARLY 15 YEARS (1999-2014), NO FDAAPPROVED, SECOND-LINE REGIMEN EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF PATIENTS WITH METASTATIC NSCLC1-4

NSCLC=non-small cell lung cancer.

Visit www.CYRAMZAHCP.com for more information 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 SECOND-LINE TREATMENT OF METASTATIC NSCLC5 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.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

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 (ATEs)

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac

arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. 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 (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, 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

• Impaired wound healing can occur with antibodies inhibiting the VEGF

pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has 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 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 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.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio

for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(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

527

415

329

231

156

103

501

386

306

197

129

• 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 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • 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=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 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.5 Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

• Based on its mechanism of action, CYRAMZA can cause fetal harm

when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

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 colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, 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 of age, 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.

• 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%).

• For patients with nonsquamous 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. • 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.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can 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 available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in

nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page. RB-L HCP ISI 24APR2015 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, randomised 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, randomised 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. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. 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. RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved. CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. 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. CONTRAINDICATIONS None. 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 nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated 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 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. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. 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%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). 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. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has 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. Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. 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. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

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 docetaxeltreated 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%). 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. Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 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 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 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. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can 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 available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk 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. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. 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 pharmacokinetic analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild (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) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 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 3 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 3 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 • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients 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. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients 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. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

RB-L HCP BS 04MAY2015

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JournalLab Spotlight Notes Breast Cancer

Adding Everolimus to First-Line Trastuzumab/Paclitaxel Does Not Increase Progression-Free Survival in HER2-Positive Metastatic Breast Cancer But Benefit Is Seen in Hormone Receptor–Negative Disease By Matthew Stenger

n the phase III BOLERO-1 trial, reported in The Lancet Oncology, Sara A. Hurvitz, MD, of the University of California, Los Angeles, and colleagues found that the addition of the mTOR inhibitor everolimus (Afinitor) to trastuzumab (Herceptin)/paclitaxel did not significantly increase progressionfree survival among patients with HER2-positive metastatic breast cancer. 1 A 7-month prolongation in progression-free survival was observed with everolimus among hormone receptor–negative patients.

Study Details In this double-blind trial, 719 patients from 28 countries were randomly assigned 2:1 between September 2009 and December 2012 to receive first-line everolimus (n = 480) or placebo (n = 239) plus trastuzumab and paclitaxel. Everolimus was given orally at 10 mg once daily, trastuzumab was given intravenously at a 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg in each 4-week cycle, and paclitaxel was given intravenously at 80 mg/ m² on days 1, 8, and 15 of each cycle. To be eligible for the trial, patients could not have received previous systemic therapy for advanced disease, except endocrine therapy that was discontinued due to disease progression before randomization. Neoadjuvant or adjuvant trastuzumab or chemotherapy had to have been stopped ≥ 12 months before randomization. Randomization was stratified by previous trastuzumab administration and visceral metastasis. The two primary objectives were investigator-assessed progressionfree survival in the full study population and in the subset of patients with hormone receptor–negative disease, with the latter objective being added during the course of the study based on new clinical and biologic findings. Efficacy analyses were in the intentto-treat population.

Patient Characteristics In the everolimus and placebo groups, 208 patients (43%) and 103 patients (43%) had hormone receptor–negative disease. The everolimus and placebo groups were generally balanced for age (median, 54 and 52 years [56 and 53 years in hormone receptor– negative population]), ethnicity (45% and 41% Caucasian, 41% and 44% Asian [46% and 38% Caucasian, 41% and 46% Asian]), Eastern Cooperative Oncology Group performance status (0 for 58% and 62% [0 for 61% and 63%]), metastatic disease (93% in both [92% in both]), visceral involvement (70% and 71% [65% and 70%]), and bone involvement (44% and 49% [33% and 45%]), The two groups were also balanced in terms of previous therapy (neo/adjuvant trastuzumab in 11% in both, neo/ adjuvant chemotherapy in 45% and 51%, taxane in 24% and 27%, anthracycline in 39% and 47%, other chemotherapy in 40% and 46% [neo/adjuvant trastuzumab in 11% and 13%, neo/adjuvant chemotherapy in 39% and 52%, taxane in 25% in both, anthracycline in 34% and 50%, other chemotherapy in 36% and 50%]), hormonal therapy for hormone receptor–positive disease (neo/adjuvant in 19% and 20%, metastatic in < 1% in both, neoadjuvant or adjuvant and metastatic in 5% and 3%), and radiotherapy (36% and 41% [26% and 39%]). All patients had undergone surgery.

Key Outcomes Median follow-up was 41.3 months. In the full population, median progression-free survival was 14.95 months (95% confidence interval [CI] = 14.55–17.91 months) in the everolimus group vs 14.49 months (95% CI = 12.29–17.08 months) in the placebo group (hazard ratio [HR] = 0.89, P = .1166). In the hormone receptor–negative subpopulation, median progression-free survival was 20.27 months (95% CI continued on page 38

The ASCO Post | AUGUST 25, 2015

PAGE 38

Lab Notes Journal Spotlight Role of Everolimus continued from page 37

= 14.95–24.08 months) in the everolimus group vs 13.08 months (95% CI = 10.05–16.56 months) in the placebo group (HR = 0.66, P = .0049); however, the protocol-specified significance threshold of P = .0044 was not crossed. Objective response rates were 67.1% vs 69.0% in the full population and 73.1% vs 70.9% in the hormone receptor–negative population.

Dose Intensity Median relative dose intensity was 0.54 for everolimus (compared with 0.96 for placebo) among all patents and 0.53 (compared with 0.95) in the hormone receptor–negative population. Dose interruption or reduction was performed in 86% of everolimus recipients vs 74% of placebo recipients in the full population and 85% vs

74% in the hormone receptor–negative population.

Adverse Events The most common adverse events of any grade in the everolimus group were stomatitis (67% vs 32% in the placebo group), diarrhea (57% vs 47%), and alopecia (47% vs 53%). The most common grade 3 or 4 adverse events in the everolimus group were neutropenia (25% vs 15%), stomatitis (13% vs 1%), anemia (10% vs 3%), and diarrhea (9% vs 4%). Serious adverse events occurred in 36% vs 15% of patients, with the most common in the everolimus group being pneumonitis (4%), pneumonia (4%), and pyrexia (3%). Adverse events led to treatment discontinuation in 55% of the everolimus group vs 40% of the placebo group, with the most common causes being peripheral neuropathy (8% vs 8%), neurotoxicity (6% vs 8%), and pneumonitis (6% vs < 1%).

Treating HER2-Positive Breast Cancer ■■ The addition of everolimus to trastuzumab/paclitaxel did not increase progression-free survival. ■■ A clinically important 7-month prolongation was observed with everolimus in hormone receptor–negative disease. ■■ Deaths related to adverse events occurred in 17 patients (4%) in the everolimus group vs 0 in the trastuzumab/paclitaxel–alone group.

Although progression-free survival was not significantly different between groups in the full analysis population, the 7.2 months prolongation we noted with the addition of everolimus in the [hormone receptor]-negative, HER2positive population warrants further investigation…. —Sara A. Hurvitz, MD, and colleagues

On-treatment deaths related to adverse events occurred in 17 patients (4%) in the everolimus group and in no patients in the placebo group. Causes of death in the everolimus group included respiratory and thoracic disorders in eight patients; infections (including respiratory) in five; and cardiac disorder, cerebrovascular accident, injury, and metabolic acidosis in one patient each. The investigators concluded: “Although progression-free survival was not significantly different between groups in the full analysis population, the 7.2 months prolongation we noted with the addition of everolimus in the [hormone receptor]-negative, HER2positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The

safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial.” n Disclosure: The BOLERO-1 study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www. thelancet.com.

Reference 1. Hurvitz SA, Andre F, Jiang Z, et al: Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. June 16, 2015.

The Conundrum of Estrogen-Receptor Signaling in HER2-Positive Breast Cancer By Ruth O’Regan, MD

OLERO-1—reviewed in this issue of The ASCO Post—is the next installment in a series of randomized trials evaluating the addition of everolimus (Afinitor) to standard therapy in metastatic breast cancer.1 The initial evaluation of everolimus in the HER2-positive metastatic setting looked extremely promising, with data suggesting that the mTOR inhibitor could perhaps reverse resistance to trastuzumab (Herceptin).2 Unfortunately, larger randomized trials1,3 have failed to confirm the initial hopes that everolimus would be a significant addition to the evolving armamentarium for HER2-positive metastatic disDr. O’Regan is Chief, Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, and Carbone Comprehensive Cancer Center, Madison.

ease. BOLERO-3, which evaluated the addition of everolimus to trastuzumab and vinorelbine in the trastuzumab-resistant setting, showed a

setting, showed no improvement for patients in the investigational arm.1 Progression-free survival in the control arms in both BOLERO tri-

Given the toxicity of everolimus… as well as the availability of multiple other agents…, it seems unlikely that the mTOR inhibitor will be developed further for metastatic HER2-positive breast cancer. —Ruth O’Regan, MD

modest improvement in progression-free survival of just over 1 month at initial analysis, which was not confirmed by central analysis.3 BOLERO-1, which evaluated the addition of everolimus to trastuzumab and paclitaxel in the first-line

als was more or less consistent with similar trials in this setting.4-7

Differences in Benefit However, the intriguing finding of different outcomes based on hormonereceptor status initially noted in BO-

LERO-3 was additionally shown in BOLERO-1. In BOLERO-3, subgroup analysis demonstrated an improvement in progression-free survival, with a hazard ratio of 0.65 in patients with HER2positive, hormone receptor–negative cancers, compared with a hazard ratio of 0.93 in HER2-positive, hormone receptor–positive cancers.3 Progression-free survival stratified by hormone-receptor status was even more striking in BOLERO-1, where patients with HER2-positive, hormone receptor–negative cancers had an increase in progression-free survival from 14 months in the control group to 20 months in the investigational arm, although this did not meet significance per the criteria of the trial. As with BOLERO-3, there was no benefit to the addition of everolimus in patients with HER2-positive, hormone receptor– positive cancers.1 In the other randomized trials4-7 that accrued patients with HER2-positive metastatic breast cancer,

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PAGE 39

Perspective

such impressive differences based on hormone receptor were not noted. The key question regarding this difference in benefit from the addition of everolimus based on hormone receptor is whether cancers that are HER2-positive but hormone receptor–negative specifically benefit from the addition of mTOR inhibition to trastuzumab and chemotherapy or whether HER2positive, hormone receptor–positive cancers fail to benefit, or perhaps even have a worse outcome, when the HER2 pathway is inhibited in the absence of estrogen-receptor blockade. In support of the former possibility, patients on the investigational arm of BOLERO-1 had a median progression-free survival of 20 months, which is consistent with (though somewhat longer than) the overall progressionfree survival in other first-line trials, such as CLEOPATRA.4 Overall, however, it would appear more likely that the combination of HER2 and mTOR inhibition enhances estrogen-receptor signaling, resulting in relative resistance to HER2-directed therapies. Considerable cross-talk exists between the HER2 and estrogenreceptor pathways, and preclinical studies have shown that inhibition of HER2 in breast cancer models that are additionally estrogen receptor– positive results in the induction of estrogen-receptor signaling.8,9 From a clinical standpoint, the addition of estrogen-receptor inhibition to dual HER2 inhibition increased the response rate in patients with HER2positive, estrogen receptor–positive cancers treated in the preoperative setting.10,11 Therefore, it is possible, as suggested by Hurvitz et al,1 that the addition of hormone-receptor inhibition to mTOR and HER2 inhibition in these BOLERO trials might have improved outcomes for patients with HER2-positive, hormone receptor– positive breast cancers.

Distinct Subtypes, Different Biology The natural biology of HER2positive, hormone receptor–positive cancer remains incompletely understood. Emerging data suggest that these cancers are heterogeneous, with at least two distinct subtypes.9 Using intrinsic subtyping,12 a majority of these cancers are either luminal A or luminal B, which would be expected to have very different biologic courses and response to available therapies.

The finding that almost one-third of these HER2-positive, hormone receptor–positive cancers are luminal A,12 known to have a poor response to chemotherapy, may contribute to the universal finding that HER2-positive cancers that are hormone receptor– positive have a lower complete re-

sponse rate to preoperative chemotherapy than hormone receptor–negative cancers.9 In support of this differential response to preoperative chemotherapy in HER2-positive, hormone receptor–positive cancers, another study showed a low complete response rate to preoperative trastuzumab-based

chemotherapy in cancers with high expression of hormone receptors, with a higher response rate in those with moderate to low expression levels.13 However, trials to date that have evaluated the omission of chemotherapy in patients with HER2-positive, continued on page 40

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The ASCO Post | AUGUST 25, 2015

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Perspective

Ruth O’Regan, MD continued from page 39

hormone receptor–positive breast cancers demonstrate higher response rates with trastuzumab-based chemotherapy compared with dual HER2 and estrogen-receptor inhibition in the absence of chemotherapy—although none of these trials stratified patients based on subtype of HER2-positive, estrogen receptor–positive cancer.11,14

cancers.15 This finding supports the existence of key differences between HER2-positive breast cancers according to hormone-receptor status.

Further Development? Results from these BOLERO trials beg the question of whether everolimus should be further developed in the HER2-positive setting for patients with hormone receptor–negative can-

The differential effects based on hormone receptor expression warrant further investigation, particularly in the hormone receptor–positive setting…. —Ruth O’Regan, MD

Molecular Analysis of HER2-Positive Cancers There have been elegant molecular studies performed on tumor specimens from the BOLERO-1 and BOLERO-3 trials in an attempt to identify a biomarker that could justify the further development of everolimus in the HER2-positive setting.15 Lack of PTEN and mutation of PI3 kinase are both associated with a benefit from the addition of everolimus to trastuzumab-based chemotherapy. Patients with tumors lacking PTEN had a 23-month progression-free survival with the addition of everolimus to trastuzumab-based chemotherapy in BOLERO-1. Some key differences between hormone receptor–negative and hormone receptor–positive breast cancers were identified using next-generation sequencing, with a higher rate of mutations in TP53 and a lower rate of mutations in CCND1, FGFR, and GATA3 noted in hormone receptor–positive

cers, as well as perhaps for cancers that lack PTEN. There was significant toxicity noted in BOLERO-1, which resulted in dose reductions, suggesting that the optimal dose of everolimus when given with chemotherapy is 5 mg.1 Given the toxicity of everolimus, although this can be managed proactively, as well as the availability of multiple other agents, either approved or in development, it seems unlikely that the mTOR inhibitor will be developed further for metastatic HER2-positive breast cancer. However, the differential effects based on hormone-receptor expression warrant further investigation, particularly in the hormone receptor–positive setting, where it seems possible that some cancers could be treated with targeted agents alone without the use of chemotherapy. n Disclosure: Dr. O’Regan is an advisor to and has received research support from Novartis and Genentech.

References 1. Hurvitz SA, Andre F, Jiang Z, et al: Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind trial. Lancet Oncol 16:816-829, 2015. 2. Andre F, Campone M, O’Regan R, et al: Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110-5115, 2010. 3. Andre F, O’Regan R, Ozguroglu M, et al: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3). Lancet Oncol 15:580-591, 2014. 4. 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. 5. Gelmon KA, Boyle FM, Kaufman B, et al: Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results of NCIC CTG MA.31. J Clin Oncol 33:1574-1583, 2015. 6. Ellis PA, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2positive metastatic breast cancer: Primary results from the MARIANNE study. 2015 ASCO Annual Meeting. Abstract 507. 7. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012. 8. Xia W, Bacus S, Hegde P, et al: A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset

in breast cancer. Proc Natl Acad Sci U S A 103:7795-7800, 2006. 9. Paplomata E, Nahta R, O’Regan RM: Systemic therapy for early stage HER2-positive breast cancers: Time for a less-is-more approach? Cancer 121:517-526, 2015. 10. Rimawi MF, Mayer IA, Forero A, et al: Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726-1731, 2013. 11. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere). Lancet Oncol 13:25-32, 2012. 12. Carey LA, Barry WT, Pitcher B, et al: Gene expression signatures in pre- and posttherapy specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. 2014 ASCO Annual Meeting. Abstract 506. 13. Bhargava R, Dabbs DJ, Beriwal S, et al: Semiquantitative hormone receptor level influences response to trastuzumabcontaining neoadjuvant chemotherapy in HER2-positive breast cancer. Mod Pathol 24:367-374, 2011. 14. Harbeck N, Gluz O, Christgen M, et al: Efficacy of 12 weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. 2015 ASCO Annual Meeting. Abstract 506. 15. Slamon DJ, Hurvitz SA, Chen D, et al: Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3. 2015 ASCO Annual Meeting. Abstract 512.

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The ASCO Post | AUGUST 25, 2015

PAGE 42

Lab Notes Journal Spotlight Neuro-oncology

New Molecular Classifications of Gliomas Established By Matthew Stenger

wo studies reported in The New England Journal of Medicine identified new molecular classifications of glioma that capture biologic and prognostic differences. The Cancer Genome Atlas Research Network identified three prognostically significant subtypes of lower-grade glioma that were identified by IDH mutation and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) status.1 Jeanette E. EckelPassow, PhD, of the Mayo Clinic, Rochester, Minnesota, and colleagues identified five subtypes of glioma based on IDH mutation, 1p/19q codeletion, and TERT promoter mutation status.2

IDH Mutation and 1p/19q Codeletion The Cancer Genome Atlas Research Network study1 involved genome-wide analysis of 293 diffuse grade II or III gliomas from adults, including analysis of exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. The in-

ATRX inactivation (86%). Patients with wild-type IDH had significantly shorter overall survival vs those with IDH mutation (age-adjusted hazard ratio [HR] = 7.4, 95% confidence interval [CI] = 4.0–13.8). Median overall survival in these patients was 1.7 years, compared with 6.3 years in patients with IDH mutation and no 1p/19q codeletion and 8.0 years in patients with IDH mutation and 1p/19q codeletion (P < .001 for trend). Survival in the lower-grade glioma patients with wild-type IDH was intermediate between that of patients with glioblastoma with wild-type IDH (median, 1.1 years) and glioblastoma patients with IDH mutation (median, 2.1 years). In multiple-predictor models adjusting for age and extent of resection, wild-type IDH, IDH mutation with no 1p/19q codeletion, or IDH mutation with 1p/19q codeletion accurately stratified patient outcomes. Grade, but not histologic class, was a significant predictor of outcome in multivariate analysis including IDH and 1p/19q status.

The integration of genome-wide data from multiple platforms delineated three molecular classes of lowergrade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. —The Cancer Genome Atlas Research Network

vestigators found that three primary lower-grade glioma classes were best represented by IDH and 1p/19q status, that lower-grade gliomas with IDH mutation had either 1p/19q codeletion or TP53 mutation in a mutually exclusive manner, and that the majority of lowergrade gliomas with wild-type IDH were genomically and clinically similar to primary glioblastoma.

Associations With Survival Patients who had lower-grade gliomas with IDH mutation and 1p/19q codeletion had the best clinical outcomes; these patients had mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Almost all gliomas with IDH mutation and no 1p/19q codeletion had mutations in TP53 (94%) and

The investigators concluded: “The integration of genome-wide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma.”

IDH or TERT Mutation and 1p/19q Codeletion The study reported by Eckel-Passow and colleagues2 involved 615 patients with grade 2 or 3 gliomas and 472 with grade 4 gliomas. Among those with grade 2 or 3 gliomas, 29% had IDH mutation,

1p/19q codeletion, and TERT mutation (triple-positive), 5% had TERT and IDH mutations only, 45% had IDH mutation only, 7% were triple-negative, and 10% had TERT mutation only. Among patients with grade 4 gliomas, < 1% were triple-positive, 2% had TERT and IDH mutations only, 7% had IDH mutation only, 17% were triple-negative, and 74% had TERT mutation only. Mean age at diagnosis was lowest (37 years) among patients with only IDH mutations and highest (59 years) among those with only TERT mutations.

Associations With Survival The molecular groups were independently associated with overall survival among patients with grade 2 or 3 gliomas, with poorest survival among patients with TERT mutation only. On multivariate analysis, compared with triple-positive patients, hazard ratios (HRs) for death were 1.31 (95% confidence interval [CI] = 0.55–3.12) among those with TERT and IDH mutations only, 2.08 (95% CI = 1.22–3.57) among those with IDH mutation only, 3.74 (95% CI = 1.91–7.36) among triplenegative patients, and 11.74 (95% CI = 6.15–22.41) among those with TERT mutation only. In grade 4 gliomas, molecular group is associated with overall survival. However, in the multivariable model, molecular group is no longer associated with overall survival; in the multivariable model, only age is statistically significant.

Acquired Mutations and Germline Variants Common acquired mutations were: CIC, FUBP1, NOTCH1, and PIK3CA or PIK3R1 in triple-positive patients; TP53 and ATRX in those with TERT and IDH mutations only and IDH mutation only; EGFR, PTEN, and NF1 in triple-negative patients; and EGFR, EGFRvIII, PTEN, NF1, RB1, and PIK3CA or PIK3R1 in those with TERT mutation only. Associations with molecular groups and known glioma germline variants were assessed using a group of 11,950 controls. Germline variants included: 8q24 in triple-positive patients; 8q24 and TP53 3´ untranslated region in those with TERT and IDH mutations

Improved Understanding of Glioma Tumor Biology See discussion by Mark R. Gilbert, MD on page 44.

Molecular Profiling of Glioma

n the Cancer Genome Atlas Research Network study, median overall survival was 1.7 years in patients with wild-type IDH, 6.3 years in those with IDH mutation and no 1p/19q codeletion, and 8.0 years in those with IDH mutation and 1p/19q codeletion. Lowergrade gliomas with IDH mutation had either 1p/19q codeletion or TP53 mutation in a mutually exclusive manner. Molecular groups identified by Eckel-Passow et al were associated with overall survival among patients with grades II and III but not grade IV gliomas. The five molecular groups were associated with specific germline variants. n only; 8q24 and PHLDB1 in those with IDH mutation only; CDKN2A/B, RTEL1, and TERT in triple-negative patients; and CDKN2A/B, RTEL1, TERT, and TERC in those with TERT mutation only. The investigators concluded: “Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis.” n Disclosure: The Cancer Genome Atlas Research Network study was funded by the National Institutes of Health. The study reported by Eckel-Passow and colleagues was supported by the National Institutes of Health and others. For full disclosures of the study authors, visit www.nejm.org.

References 1. The Cancer Genome Atlas Research Network: Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015. 2. Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:24992508, 2015.

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The ASCO Post | AUGUST 25, 2015

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Perspective

Improved Understanding of Glioma Tumor Biology By Mark R. Gilbert, MD

he management of patients with lower-grade gliomas is evolving. As evidenced by two recent publications in The New England Journal of Medicine,1,2 reviewed in this issue of The ASCO Post, there has been a substantial increase in our knowledge of the molecular characteristics of these neoplasms. This clearer understanding allows us to better subclassify these diseases, leading to a marked improvement in the prediction of biologic behavior and prognosis. The importance of these molecular findings and the ability to accurately classify these subtypes of what have been classically deemed “lower-grade gliomas” cannot be overemphasized. Prior to these findings, intense discussions regarding the nuances of cellular morphology ensued to provide more accurate and reproducible classification of the lower-grade glioma subtypes: oligodendroglioma, oligoastrocytoma, and astrocytoma. However, despite these efforts, there was variable concordance among even the most established neuropathologists, especially with regard to the designation of oligoastrocytoma.

leted” or “not co-deleted,” these two trials demonstrated that the combination of radiation and chemotherapy nearly doubled the overall survival duration of the patient population classified as co-deleted compared with radiation alone.5,6 Conversely, a survival benefit was not found in the patient population without the co-deletion. Therefore, these analyses definitively demonstrated the predictive value of the 1p 19q co-deletion, as it helps to determine optimal patient treatment based on its presence or absence. The next seminal finding, published in 2008, was the discovery of mutations in the isocitrate dehy-

cal trials could either stratify patients accurately or be designed to study new treatments in a more homogeneous patient population.

The Importance of IDH Mutations The studies reported by The Cancer Genome Atlas Research Network and Eckel-Passow et al1,2 have clearly accomplished this mission. Both have determined that IDH mutation status is of primary importance and, not coincidentally, that IDH mutation is probably a very early event, given the uniform finding in tumor cells when present. What is also clear from both stud-

IDH wild-type lower-grade glioma should be considered as a biologically aggressive glioma, with clinical properties similar to those of glioblastoma.

drogenase 1 (IDH1) or IDH2 genes in a high percentage of lower-grade Pivotal Discoveries gliomas.7 The initial publications and Fortunately, there have been sev- subsequent retrospective studies of eral pivotal discoveries over the past 20 large patient cohorts confirmed that years. First, there was the recognition the finding of either an IDH1 or IDH2 that a subset of lower-grade gliomas, mutation confers a much better proghistologically classified as oligoden- nosis within the WHO grade.8 Furthermore, IDH mutations condroglioma (either grade 2 or 3 by the World Health Organization [WHO] fer an alteration in tumor cell metabocriteria) had both a better prognosis lism that results in accumulation of an and a much higher rate of response to abnormal metabolite, 2-hydroxyglutaeither chemotherapy or radiation treat- rate (2-HG), which causes epigenetic ment than their astrocytoma counter- changes that lead to a hypermethylparts.3 Molecular analyses of these oli- ated state.9 These findings are linked godendroglial tumors revealed unique to improved response and patient chromosomal findings: the allelic loss prognosis (relative to IDH wild-type of the short arm of chromosome 1(1p gliomas of similar histology); the poloss of heterozygosity) and the long tential for an imaging biomarker, as arm of chromosome 19 (19q loss of 2-HG can be detected by magnetic heterozygosity).4 This molecular desig- resonance spectroscopy; and, most nation proved to be highly prognostic important, a possible selective target when evaluated in both retrospective for specific inhibitors or IDH-mutant and prospective series. targeted immunotherapy.10 Given these important findings, it When patients on two randomized trials of anaplastic gliomas (WHO was critically important that they be grade 3) were subclassified as “co-de- codified into a molecular classification system that would allow accurate clasDr. Gilbert is Senior Investigator and sification of individual tumors. With Chief, Neuro-Oncology Branch, National such a classification, an accurate progInstitutes of Health, Bethesda, Maryland. nosis could be determined and clini-

—Mark R. Gilbert, MD

ies, but particularly highlighted in the work by The Cancer Genome Atlas Research Network, is that IDH wildtype lower-grade glioma should be considered as a biologically aggressive glioma, with clinical properties similar to those of glioblastoma. In this context, many in neuro-oncology are treating these patients with the same regimens as are used for patients with histologically classified glioblastoma. From the perspective of clinical trials, failure either to stratify (balance) or exclude IDH wild-type tumors in a randomized trial may lead to misinformation, given the profound difference in prognosis with IDH-mutated tumors. Obviously, clinical trials evaluating treatments targeting the IDH mutation or its metabolic effects should exclude the IDH wild-type tumors. It is not yet clear whether future studies of glioblastoma should include the grade 3 IDH wildtype or conversely exclude the IDHmutated glioblastoma, as these patients have an overall far better prognosis.

Beyond IDH Mutations These studies go beyond the importance of IDH mutations, further classifying tumors by evaluating the 1p 19q

status, mutations in the TERT promoter, mutations in ATRX, and mutations in p53. Eckel-Passow and colleagues combined the IDH, 1p 19q, and TERT status into a classification system akin to that popularized in breast cancer. They have proposed that tumors could range from “triple negative” to “triple positive” and that the prognosis could be predicted on this basis. Interestingly, however, the finding of a TERT mutation alone was associated with a prognosis that was even worse than triple-negative tumors, whereas TERT mutation in the presence of IDH or IDH and 1p19q loss was associated with the best prognosis. Investigation of the underlying biology for the paradoxical effect of TERT mutation will likely provide important insights.

Clinical Implications These collective findings have tremendous implications in the clinical care of patients with gliomas. The lower-grade tumors (WHO grade 2 or 3) can now be much more accurately classified. In the setting of IDH mutation, 1p 19q loss indicates an oligodendroglioma, whereas ATRX and/ or p53 mutation signifies an astrocytic neoplasm. This would suggest that the designation of oligoastrocytoma should be considered only rarely and ideally be eliminated when biomarker data are available to resolve classification of the tumor. Given that tumor biology is likely quite different between the astrocytic and oligodendroglial tumors, specific treatments and clinical trials will likely be needed to exploit tumor-specific biology. As described here, this is clearly the case for the IDH wild-type tumors, where the tumor cells lack the characteristic metabolic changes, molecular changes (ie, hypermethylation), or prognosis associated with the mutation. The future is promising, as these investigations and others have resulted in a marked improvement in our understanding of glioma tumor biology. However, these findings will change the clinical research landscape, as now a previously uncommon tumor type will need to be further subclassified for trials targeting the unique biology of these cancers. This approach will

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Perspective

mandate that large collaborative and cooperative efforts are undertaken and that the investigator and patient communities work together to speed implementation and accrual to these pivotal trials. In this way, critical laboratory findings will not only be translated into improved classification, but also into marked improvements in individualized patient treatments. n Disclosure: Dr. Gilbert reported no potential conflicts of interest.

References 1. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al: Comprehensive, integrative genomic

analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015. 2. Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499-2508, 2015. 3. Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12:2013-2021, 1994. 4. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendro-

gliomas. J Natl Cancer Inst 90:1473-1479, 1998. 5. Cairncross G, Wang M, Shaw E, et al: Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Longterm results of RTOG 9402. J Clin Oncol 31:337-343, 2013. 6. van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: Long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 31:344-350, 2013. 7. Parsons DW, Jones S, Zhang X, et al: An integrated genomic analysis of human glioblastoma multiforme. Sci-

ence 321:1807-1812, 2008. 8. Weller M, Felsberg J, Hartmann C, et al: Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: A prospective translational study of the German Glioma Network. J Clin Oncol 27:5743-5750, 2009. 9. Lu C, Ward PS, Kapoor GS, et al: IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474-478, 2012. 10. Choi C, Ganji SK, DeBerardinis RJ, et al: 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:624-629, 2012.

Announcements

Penn’s Basser Center for BRCA Names David Livingston, MD, Winner of 2015 Annual Basser Global Prize

he Basser Center for BRCA at Penn’s Abramson Cancer Center has announced the recipient of its third annual Basser Global Prize: molecular cancer expert David L ivingston, MD, Emil Frei Professor of Genetics and Medicine at Harvard Medical School and Deputy Director of the Dana-Farber/Harvard Cancer Center. Dr. Livingston has made significant contributions toward understanding how DNA mutations damage the repair genes BRCA1 and BRCA2 to promote cancer development.

Susan Domchek, MD

A marquee component of the center, the Basser Global Prize includes $200,000 in unrestricted support of the winner’s innovative BRCA1/2-related research efforts. “Nominees for the Basser Global Prize represent the pioneers in our field

The Basser Center and the Basser Global Prize provide extraordinary opportunities for scientists to pursue research directed at reducing the heavy burden of BRCA disease. —David Livingston, MD

has the potential to significantly reduce the likelihood of BRCA1 cancer developing in mutation-bearing women.” Dr. Livingston added, “The Basser Center and the Basser Global Prize provide extraordinary opportunities for scientists to pursue research directed at reducing the heavy burden of BRCA disease.”

The Basser Center conducting the most innovative research aimed at developing new strategies for the prevention and treatment of BRCArelated cancers,” said Susan Domchek, MD, Executive Director of the Basser Center for BRCA and the Basser Professor of Medicine in Penn’s Abramson Cancer Center. “One of the primary missions of the Basser Center is to fund the projects that will make a difference for patients with BRCA1/2 mutations, giving them better options for targeted therapies and improved quality of life.”

High-Impact Research The primary focus of Dr. Livingston’s laboratory is to understand the fundamental mechanisms and steps by which inherited mutations in BRCA1/2 lead to

breast and ovarian cancers. His group is pursuing an approach that focuses on understanding, in detail, the cellular processes that are rendered defective by BRCA1 mutation. In this regard, he and his group have recently unearthed a potentially promising target function that may be important for preventing BRCA1-related cancers, as well as for the treatment of non-BRCA1 cancers that have spread. Dr. Livingston’s goal is to reduce the number of cells in the breast and ovaries of BRCA1 mutation–bearing women that manifest a high potential for becoming malignant. “Our objective is to eliminate them by a relatively nontoxic approach and to ensure that they do not accumulate thereafter,” Dr. Livingston explained. “If successful, such an approach

In 2012, the Basser Center was established through a $25 million gift from Penn alumni Mindy and Jon Gray in memory of Mindy Gray’s sister Faith Basser, who died of ovarian cancer at age 44. In 2013, the Grays made an additional $5 million gift to launch the Basser External Research Grant Program, a unique funding program for high-impact, translational cancer research projects aimed at advancing the care of people living with BRCA1 and BRCA2 mutations. The Basser Global Prize was established by Shari Basser Potter and Leonard Potter to honor a visionary scientist who has conceptually advanced BRCA1/2-related research that has led to improvements in clinical care. Applications for the 2016 Basser Prize will be open in February 2016. n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | AUGUST 25, 2015

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Announcements

APOS Announces 2015 Award Winners at the World Congress of Psycho-Oncology

he American Psychosocial Oncology Society (APOS) honored five award winners at the 2015 World Congress of Psycho-Oncology, held from July 28–August 1 in Washington, DC.

Holland Distinguished Leadership Award: Matthew J. Loscalzo, LCSW Professor Loscalzo is the Liliane Elkins Professor in Supportive Care Programs in the Department of Supportive Care Medicine, Professor in Department of Population Sciences, Executive Director of the Department of Supportive Care Medicine, and the Administrative Director of the Sheri & Les Biller Patient and Family Resource Center at the City of Hope-National Medical Center.

Matthew J. Loscalzo, LCSW

Professor Loscalzo has previously held leadership positions at Memorial Sloan Kettering Cancer Center, the Johns Hopkins Oncology Center, and the Rebecca and John Moores Cancer Center at the University of California at San Diego. He is recognized as a pioneer in the clinical, educational, and research domains of psychosocial aspects of cancer.

Distinguished Public Service Award: Rebecca Kirch, JD Ms. Kirch is the American Cancer Society’s Director of Quality of Life & Survivorship. She provides strategic direction and coordination for

Rebecca Kirch, JD

the Society’s national agenda addressing quality care and quality-of-life issues for all adults and children facing cancer and its aftermath. Through research, programs, and advocacy, these

initiatives include a suite of policies and practices that integrate palliative care for managing pain, symptoms and stress, psychosocial care for emotional support, impairment-driven re-

habilitation for addressing disability, and enhancing person-centered and goal-directed clinical communication skills. Ms. Kirch previously served on the

senior leadership team of the American Cancer Society Cancer Action Network (ACS CAN) as Associate Director of Policy and earlier, as Deputy Director of its federal lobbying team.

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PAGE 47

Announcements Outstanding Clinical Care Award: Donna Greenberg, MD At Massachusetts General Hospital (MGH) Cancer Center, Dr. Greenberg has been a psychiatric consultant to oncology patients and their oncologists over the past several decades, teaching and consulting on the orthopedic oncology service, pain service, and pallia-

Donna Greenberg, MD

tive care service, as well as the consultation psychiatry service. In addition to acting as Program Director of Psychiatric Oncology at MGH, she is Associate Professor of Psychiatry at Harvard Medical School and has directed medical student teaching in psychiatry at MGH over these years. She is a founding member and fellow

of APOS and served as president from 2008–2009. She is also Past President of the Association of Medicine and Psychiatry and serves on the Council of Academy of Psychosomatic Medicine. She is co-editor of the 2015 textbook Psychiatric Care of the Medical Patient, psychosocial oncology section editor of the continued on page 48

The ASCO Post | AUGUST 25, 2015

PAGE 48

Announcements APOS 2015 Award Winners continued from page 47

journal Cancer, and an editor of APOS’s Psycho-Oncology: A Quick Reference.

New Investigator Award: Allison Applebaum, PhD Dr. Applebaum is an Assistant Attending Psychologist in the Depart-

Allison Applebaum, PhD

ment of Psychiatry and Behavioral Sciences at Memorial Sloan Kettering Cancer Center and an Assistant Professor of Psychology at W eill-Cornell Medical College. Dr. Applebaum is the Director of the Caregivers Clinic at Memorial. The Caregivers Clinic at Memorial is the first of its kind in the nation and

provides comprehensive psychosocial care to family members and friends of patients who experience significant distress and burden as a result of their caregiving role. Dr. Applebaum’s program of research focuses on the development and dissemination of psychosocial interventions for patients with cancer and their caregivers. Her work is internationally recognized, and she is currently funded by the American Cancer Society to develop and evaluate a Web-based, meaning-centered psychotherapeutic intervention that addresses existential distress and decreased quality of life experienced by cancer caregivers. Dr. Applebaum is also working on the adaptation of emotion regulation therapy for cancer caregivers.

Outstanding Education and Training Award: Gwendolyn Quinn, PhD Dr. Quinn is a Senior Member in the Health Outcomes and Behavior Program of the H.L. Moffitt Cancer Center and Director of the Survey Methods Core. She is Professor in the Department of Oncologic Sciences at the Morsani College of Medicine and the Department of Community and Family Health in the College of Public Health at the University of South Florida.

Gwendolyn Quinn, PhD

Her research and training efforts focus on understanding the determinants of health behavior to improve oncology health communication initiatives. She has developed a line of research focused on improving patient/physician communication, through understanding the barriers and benefits of health-care service use from the perspective of both the patient/ consumer and health-care providers. Her current research and training efforts have been in the context of reproductive health; sexuality; fertility preservation; cancer genetics services; quality-of-life issues in pediatric, adolescent, and young adult cancer populations; smoking relapse prevention; clinical trials (including minority barriers to participation); and training researchers to conduct research with high-risk populations. n

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Genitourinary Cancers Compiled by Liz Janetschek

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with genitourinary cancers—prostate, bladder, uterine, and testicular. The trials are investigating genetic biomarkers of cancer; proton beam therapy; allogeneic bone marrow therapy; combination chemotherapy; stereotactic radiotherapy; and surgical interventions.

OBSERVATIONAL Study Type: Observational Study Title: Molecular Epidemiology of Pediatric Germ Cell Tumors Study Sponsor and Collaborators: Children’s Oncology Group, National Cancer Institute (NCI) Purpose: To study DNA samples from younger patients with germ cell tumor and their parents or siblings. Studying samples of tumor tissue and saliva from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer. Primary Outcome Measures: Pediatric germ cell tumor associated with genetic susceptibility [time frame: up to 5 years] Principal Investigator: Jenny Poynter, PhD, Children’s Oncology Group; poynt006@umn.edu, 612-625-4232 ClinicalTrials.gov Identifier: NCT01434355

PILOT Study Type: Pilot/interventional/ single-group assignment Study Title: Pilot Study of Adjuvant Proton-Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix With Metastases to Regional Lymph Nodes Study Sponsor and Collaborators: Massachusetts General Hospital, NCI Purpose: To determine if protonbeam radiation is effective in controlling cancer growth. The investigators are also looking to see if proton-beam radiation can reduce side effects when compared to standard radiation treatment (photon radiation). Primary Outcome Measures: Magnitude of radiation dose reductions, radiation side effects and delayed complications [time frame: 5 years]

Principal Investigator: Karen De Amorim Bernstein, MD, Massachusetts General Hospital; kbernstein2@partners.org ClinicalTrials.gov Identifier: NCT01600040

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase I Study of Allogeneic Human Bone Marrow Derived Mesenchymal Stem Cells in Localized Prostate Cancer Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center Purpose: To determine if systemically infused allogeneic bone marrow derived mesenchymal stem cells (MSC) home to sites of prostate cancer in men with localized adenocarcinoma of the prostate that are planning to undergo a prostatectomy Primary Outcome Measures: To quantify the amount of systemically infused MSC DNA relative to recipient DNA at sites of prostate cancer in men with localized adenocarcinoma of the prostate that are scheduled to undergo a prostatectomy [time frame: up to 3 years] Principal Investigator: Samuel Denmeade, MD, Johns Hopkins University; contact Carolyn Chapman, RN; cchapma7@jhmi.edu, 443-287-7841 ClinicalTrials.gov Identifier: NCT01983709

PHASE I/II Study Type: Phase I/II/interventional/single-group assignment Study Title: A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer Study Sponsor and Collaborators: University of Washington, NCI Purpose: To study the side effects and best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and to see how well they work in treating patients with bladder cancer Primary Outcome Measures: Maximum tolerated dose of sirolimus based on the incidence of dose-limiting toxicity graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (phase I) [time frame: up to 28 days]; percent of patients with

pathologic complete response (phase II) [time frame: 12 weeks] Principal Investigator: Robert Montgomery, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206-616-8289 ClinicalTrials.gov Identifier: NCT01938573

PHASE II Study Type: Phase II pilot/interventional/single-group assignment Study Title: A Pilot Phase II Trial of Intravenous Paclitaxel and Intraperitoneal Carboplatin Followed by Radiation in Patients With Advanced Stage Uterine Serous Carcinoma Study Sponsor and Collaborators: Albert Einstein College of Medicine of Yeshiva University, NCI Purpose: To study the side effects and how well paclitaxel given into the vein and carboplatin given directly into the abdominal cavity (intraperitoneally) followed by radiation therapy work in treating patients with stage IIIC-IV serous uterine cancer Primary Outcome Measures: Degree of tolerability, estimated by the proportion of participants who complete six treatment cycles of intraperitoneal carboplatin [time frame: up to 18 weeks] Principal Investigator: Merieme Klobocista, MD, Albert Einstein College of Medicine of Yeshiva University; mkloboci@montefiore.org, 718-405-8082 ClinicalTrials.gov Identifier: NCT02112552 Study Type: Phase II/interventional/ parallel assignment Study Title: Phase II Stereotactic Body Radiotherapy and Stereotactic Hypofractioned Radiotherapy for Oligometastatic Prostate Cancer Study Sponsor and Collaborators: University of Florida Purpose: To evaluate the outcomes of patients treated with an investigational radiation regimen using stereotactic radiotherapy for oligometastatic prostate cancer and to establish efficacy and safety in this setting Primary Outcome Measures: Improvement in median progression-free survival in patients with metastatic prostate cancer over historic control rates in hormone-receptive and castration-resistant subgroups [time frame: 78 months after radiation treatment] Principal Investigator: Roi Dagan, MD, MS, University of Florida; contact

Intake Coordinator at 877-686-6009 ClinicalTrials.gov Identifier: NCT01859221

PHASE III Study Type: Phase III/interventional/parallel assignment Study Title: A Phase III Surgical Trial to Evaluate the Benefit of a Standard vs an Extended Pelvic Lymphadenectomy Performed at Time of Radical Cystectomy for Muscle Invasive Urothelial Cancer Study Sponsor and Collaborators: Southwest Oncology Group, NCI Purpose: To study standard pelvic lymphadenectomy to see how well it works compared to extended pelvic lymphadenectomy in treating patients undergoing surgery for invasive bladder cancer Primary Outcome Measures: Disease-free survival [time frame: up to 6 years from date of step 2 registration] Principal Investigator: Seth P. Lerner, MD, Baylor College of Medicine; contact Jennifer I. Scott, jscott@ swog.org, 210-614-8808 ext 1007 ClinicalTrials.gov Identifier: NCT01224665 Study Type: Phase III/interventional/parallel assignment Study Title: A Randomized Study of Radiation Hypofractionation Via Extended vs Accelerated Therapy for Prostate Cancer Study Sponsor and Collaborators: University of Miami Purpose: To study if accelerated hypofractionation radiotherapy for prostate cancer of 36.25 Gy delivered in 5 fractions will not be inferior to the standard treatment of 70.2 Gy given in 26 fractions with respect to 2-year failure defined as a positive biopsy 2 years post treatment completion or earlier evidence of biochemical or clinical failure. Primary Outcome Measures: Compare the 2-year failure rates between the treatment arms using a noninferiority margin of 12% [time frame: 2 years] Principal Investigator: Matthew Abramowitz, MD, University of Miami; mabramowitz@med.miami.edu, 305243-4200 ClinicalTrials.gov Identifier: NCT01794403 n Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov.

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Geriatrics for the Oncologist

Geriatric Oncology: A Geriatrician’s Perspective By Beatriz Korc-Grodzicki, MD, PhD “The management of older individuals, including older cancer patients, involves a wisdom developed over a lifetime, thanks to time-consuming listening and painstaking collection and interpretation of clinical details.” —Lodovico Balducci, MD

t is not simple to be a geriatrician in a world of oncologists. When I arrived at the cancer center where I have been working for the past 6 years, I had to significantly fine-tune the principles that had been the backbone of my profession. As a geriatrician in a primary care practice or working as a geriatric hospitalist, I had strived to provide high-quality care for older adults, minimizing unnecessary interventions, avoiding polypharmacy, and always keeping in mind the patient’s independence and quality of life as critical factors of the equation. Coming into a cancer center, I was confronted with a different principle: These older adults came with one purpose only: to treat and beat their cancer. They did not want to hear about “less is more.” They wanted to live, and in order to do that, their cancer needed to be treated. My role shifted. I was there Dr. Korc-Grodzicki is Chief of the Geriatrics Service at Memorial Sloan Kettering Cancer Center and Professor of Clinical Medicine at Weill Cornell Medical College, New York.

to help the frail patient walk a difficult path of suffering the fewest possible adverse events while preventing complications related to geriatric syndromes such as delirium, falls, incontinence, or failure to thrive, which would have placed him or her at higher risk not only of death but also of suffering treatment failure, institutionalization, and a very poor quality of remaining life.

treating patients in their 50s or 60s. The clinical behavior of some tumors changes with age. Some become more aggressive due to a prevalence of unfavorable genomic changes or resistance to chemotherapy. Others, like breast cancer, become more indolent due to an increased prevalence of hormone-receptor rich tumors and endocrine senescence. The aging process itself brings physio-

Chronologic age differs from functional age, and this difference— the uniqueness of each patient— needs to be captured and integrated in the decision-making process of cancer treatment. —Beatriz Korc-Grodzicki, MD, PhD

Treating Older Patients With the increase in the aging population and life expectancy, oncologists are aggressively treating patients into their 80s and even 90s, patients who a few decades ago would have received only symptomatic treatment without hesitation. With a paucity of data to make evidence-based decisions in this population, clinicians need to extrapolate from studies done with a much younger cohort. However, treating patients in their 80s is not the same as

logic changes leading to decline in the function of organs. For example, kidney function decreases with age and pulmonary compliance declines, as does bone marrow cellularity and reserve. The remodeling of physiologic reserve or “homeostenosis” is influenced not only by genetic factors but also by environmental factors, dietary habits, and interactions with comorbidity as well as social conditions. Chronologic age differs from functional age, and this difference—the

GUEST EDITOR

Stuart M. Lichtman, MD

eriatrics for the Oncologist is guest edited by Stuart M. Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Dr. 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 SIOG. Visit www.siog.org for more on geriatric oncology. uniqueness of each patient—needs to be captured and integrated in the decisionmaking process of cancer treatment. It is essential to identify patients with a longer life expectancy or those who are fitter, potentially more resilient, and continued on page 52

15th Annual Conference of the International Society of Geriatric Oncology (SIOG) Join the best minds in Geriatric Oncology during the 15th SIOG Annual Conference taking place in Prague, Czech Republic, on November 12–14, 2015.

he 3-day scientific program of SIOG 2015 will have the theme: “Geriatric Oncology and Supportive Care: A Global Approach to Advance the Science.” Highlights of This Year’s Conference • Special partnership session with the Multinational Association of Supportive Care in Cancer (MASCC): Nutrition issues and challenges in older patients with cancer • Multidisciplinary management of older patients with cancer: the vi-

tal role of supportive care • Toward a new age: innovative approaches in diagnosis and treatment • Hematologic malignancies: challenges are in the oldest old • Geriatric assessment: now what? • and many more… Keynote speakers are major international figures in Geriatric Oncology: Arti Hurria (United States), Etienne Brain (France), Hans Wildiers (Belgium), Matti Aapro (Switzerland), Matthew Seymour (United Kingdom), Barbara Eichhorst (Germany), Michael Jaklitsch (United States), and Jane Phillips (Australia). View the full scientific program by visiting http://www.siog.org/. We are pleased to announce that a

series of special SIOG activities are organized during the conference such as: • A Nursing and allied health meeting will be held on Wednesday, November 11. • A Young SIOG: Peer-to-Peer Mentorship session will be organized on Thursday, November 12. • The SIOG Young Investigators Award Session will once again be held and will recognize three Young Investigators for their outstanding work. Preselected awardees are: Martine Puts (Canada); Doris Lijsbeth van Abbema (Netherlands), and Peggy Sue Burhenn (United States). • Selected for the outstanding quality of their work, three Nursing & Allied Professional Investigators will be competing for this SIOG Award. Preselected

awardees are: Regina Girones (Spain); Cindy Kenis (Belgium) and Muhammad Adnan Khattak (Australia). • Both these awards will be handed out during the SIOG Presidential session, on Saturday, November 14. • Not to miss: our SIOG special guidelines session on Saturday, November 14. Updates on the following guidelines will be presented: radiopharmaceuticals, HER2, CLL, bone, and genomic tools. Register now and save! Discounted rates are available for SIOG and ESMO members. Deadline: October 29, 2015. We are looking forward to welcoming you in Prague! For more information, visit http:// www.siog.org/.

DEEPER RESPONSES? LONGER DURATION OF THERAPY? It’s time to take a deeper look at the critical debates in multiple myeloma today. SEE WHAT YOUR PEERS SAY AND SHARE YOUR OPINION AT DEBATINGMYELOMA.COM

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Geriatrics for the Oncologist A Geriatrician’s Perspective

Geriatric Assessment

continued from page 50

Decline in functional status is associated with frailty and worse cancer treatment outcomes. Basic and instrumental activities of daily living and other performance measures such as walking speed and muscle strength tests have been shown to have a greater predictive value on physical function compared to

therefore more likely to benefit from aggressive treatment vs those who are more vulnerable to adverse outcomes.

Increased Comorbidities The incidence of pathology increases as we age. The presence of multiple chronic diseases or comorbidities represents a major difference between the younger and the older cancer patient. Frequent comorbidities in the elderly such as cardiovascular disease, hypertension, diabetes, or dementia influence the management of the cancer. Comorbidities may increase the risk of complications, modify cancer behavior, or mask symptoms, with subsequent delays in cancer diagnosis. On the other hand, cancer treatment may worsen cormorbidities or increase the frequency of drug interactions. Comorbidities influence the patient’s life expectancy independently of the cancer. In the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Older Adult Oncology, version 2.2015, the approach to decision-making in the older adult starts with the question: “Is the patient at moderate or high risk of dying or suffering from cancer considering his or her overall life expectancy?” If the answer is no, symptom management and supportive care are recommended.1

traditional oncology measures of performance. Therefore, comorbidity, disability, and frailty need to be clearly recognized as markers of risk in the elderly. The comprehensive geriatric assessment is a multidimensional, multidisciplinary patient evaluation that leads to the identification of patient problems in all these domains and the development

of a plan for resolving these problems. This tool has been validated in geriatric oncology and was shown to predict morbidity and mortality in older patients with cancer as well as to uncover problems relevant to cancer care that would otherwise go unrecognized. It provides important information about the health status of the older patient

Cognitive Dysfunction Cancer patients with cognitive dysfunction represent a new challenge for oncologists. After age 65, the risk of developing Alzheimer’s disease doubles about every 5 years. By age 85, nearly half of all people will have some signs of the disease. The increased rate of dementia in the elderly converges with the higher likelihood of developing cancer. Patients with cancer/dementia overlap are often diagnosed later in the disease process, screening is less standardized, and adherence with treatment is often difficult. The ability of patients to decide on a course of therapy in concert with the oncologist is critically important. Many oncologists are conflicted as to whether true informed consent for treatment can be obtained from older cancer patients when their cognitive abilities are impaired or unclear. It is imperative that health-care providers who care for older adults with cancer be able to assess cognitive function, understand the implications of cognitive impairment when patients need to make decisions, address the potential for treatment-related further cognitive decline, and be able to facilitate shared, patient-centered cancer decision-making.

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Geriatrics for the Oncologist

prior to cancer treatment and ascertains a patient’s need for psychosocial support, care giving, transportation, and so forth, which may be critical for adequate cancer treatment. Hurria et al2 and Extermann et al3 used elements of the comprehensive geriatric assessment in addition to other factors for the development of the CARG (Cancer

and Aging Research Group) and CRASH (Chemotherapy Risk Assessment Scale for High age patients) scores, respectively, which may predict hematologic and nonhematologic chemotherapy toxicity. The CARG score was shown to be more effective than the Karnofsky performance status for the prediction of grade 3 to 5 hematologic toxicities.

The NCCN and the International Society of Geriatric Oncology (SIOG) have recommended that some form of geriatric assessment be conducted to help cancer specialists determine the best treatment for their older patients. However, comprehensive geriatric assessment is time-consuming and requires close cooperation between

oncologists and geriatricians. An important practical aspect of the comprehensive geriatric assessment is the feasibility of incorporating it into an already busy clinical oncology practice. One approach is the development of screening tools that would sort out who is an “older adult” with intact physiology and psychosocial conditions and who is in need of further multidisciplinary evaluation. Puts et al4 showed that the effectiveness of such an approach—a screening tool for all older patients followed by an in-depth assessment of those deemed to be at risk—is not established yet and needs to be validated in randomized controlled trials. Randomized controlled trials are also needed to clearly demonstrate that a resource-intensive comprehensive geriatric assessment is effective in improving outcomes compared with usual care in the oncology setting.

Closing Thoughts

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How are we going to apply geriatric principles to oncology patients? Innovative models of care need to be developed and disseminated in order to transform these principles into an integral part of routine oncology practice. In addition, the development of longitudinal sharedcare models that optimize the contribution of each discipline offers a tremendous opportunity for partnerships between oncologists and geriatricians. As Harvey Jay Cohen, MD, wrote in the Journal of the American Geriatrics Society, “Hopefully, through such a shared approach, the burden of dealing with the complexities of care for the older cancer patient can be eased for the patient as well as family and professional care provider.”5 n Disclosure: Dr. Korc-Grodzicki reported no potential conflicts of interest.

References 1. National Comprehensive Cancer Network: NCCN Guidelines Version 2.2015: Senior Adult Oncology. Available at www. nccn.org/professionals/physician_gls/ pdf/senior.pdf. Accessed July 31, 2015. 2. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:3457-3465, 2011. 3. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients. Cancer 118:3377-3386, 2012. 4. Puts MT, Hardt J, Monette J, et al: Use of geriatric assessment for older adults in the oncology setting: A systematic review. J Natl Cancer Inst 104:1133-1163, 2012. 5. Cohen HJ: A model for the shared care of elderly patients with cancer. J Am Geriatr Soc 57(suppl 2):S300-S302, 2009.

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Issues in Oncology Bioethics

Johnson & Johnson Creates Independent Bioethics Panel to Evaluate Compassionate Drug Use Requests If successful, the new model could create a more equitable and consistent system for seeking investigational drugs. By Jo Cavallo

n May 2015, Johnson & Johnson announced its partnership with New York University (NYU) School of Medicine in New York to create a first-of-its kind independent bioethics panel to review requests made to the company for compassionate use of an investigational drug and determine how the company should respond.

“One is that people who are very sick want to try an untested drug. The second reason is that there is a drug with proven or near-proven efficacy, but it is in scarce supply because it can’t yet be manufactured in a sufficient amount. We are going to be looking at requests for the latter-type drugs to start.”

People say Americans can’t ration or make tough decisions, but I know they can because I saw it with the transplant program. So that gives me hope that we can duplicate that same sense of equity and fairness in the area of compassionate drug use. —Arthur L. Caplan, PhD

The 10-member Compassionate Use Advisory Committee is made up of an international group of doctors, ethicists, and patient advocates and is headed by nationally known bioethicist Arthur L. Caplan, PhD, Drs. William F. and Virginia Connolly Mitty Professor and Founding Director of Medical Ethics in the Department of Population Health at NYU Langone Medical Center. Dr. Caplan is also cofounder of the United Network for Organ Sharing, which matches cadaver organs with patients on the transplant waiting list. Many of the criteria used to develop a fair distribution system for the United Network for Organ Sharing—such as a patient’s age, severity of a patient’s condition, and prognosis—are being considered for the Compassionate Use Advisory Committee, but the exact details for evaluating compassionate drug use requests and granting access to specific patients have not been finalized. The pilot program, which was launched in July 2015 and began with one investigational medicine—Johnson & Johnson has not announced the name of the drug—will be expanded if the program is successful. “Compassionate use occurs for two reasons,” explained Dr. Caplan.

To ensure complete independence and to avoid any conflicts of interest, funding for the Compassionate Use Advisory Committee will be paid directly to NYU School of Medicine. “I report to NYU School of Medicine, not to Johnson & Johnson,” said Dr. C aplan. “Now, it is still Johnson & Johnson’s money, I’m not saying they are not in the background, but I tried to get our committee to be as independent as I could. This is an interesting experiment. If it works, I think this type of program could help in a lot of settings, not just in the pharmaceutical setting, but also in governmental agencies and in nongovernmental organizations, because the issue of how to distribute scarce resources to desperate people is sadly very common.”

Leveling the Playing Field Having this type of independent review panel tasked with weighing specific criteria for granting access to investigational drugs will create a more equitable, objective, and consistent system for desperate patients, said Dr. Caplan, and could help tamp down public outcry if the request is denied. “Right now, it looks like somebody in the drug company makes a decision, and patients don’t know how or why the decision was made. Although we

are not going to make public every detail of how our decisions get made, we are going to announce some of the criteria we thought about and describe the background of the experts on this committee and their level of independence. We don’t care if Johnson & Johnson makes money or loses money, our decisions will have nothing to do with that, so the perception of this group will be perhaps a little more trustworthy. This system has worked in organ transplantation, and I think it can work here,” said Dr. Caplan. And no one, regardless of social or political status, said Dr. Caplan, will be able to jump to the front of the line and get favored treatment. “I think Johnson & Johnson came to us because it wanted to try a different approach to granting requests for investigational drugs. So, rather than having people calling saying, ‘I’m a senator and I need this drug’ or ‘I know the head of the Board of Trustees and I should get the drug,’ the company felt this was a better way to proceed, because all requests will be anonymized. I also believe there was a feeling that there was inequity in responding to the squeakiest wheels.” (Specialists seeking access to the investigational drug for a patient know they must submit their request through Johnson & Johnson’s website at janssenmedinfo@its.jnj.com.) According to Amrit Ray, MD, Chief Medical Officer for Janssen Pharmaceutical Companies of Johnson & Johnson, the company is committed to respecting the Compassionate Use Advisory Committee’s recommendations. “The Compassionate Use Advisory Committee will review requests for compassionate use and then return its recommendation to us. We recognize that these are decisions that are very important to patients and continue to take full responsibility for making the decision after hearing from the Committee. We have also made the commitment that whatever decision we make, we will be absolutely transparent with the Committee. I expect that in the majority of cases, we will follow the Compassionate Use Advisory Committee’s recommendation,” said Dr. Ray.

Streamlining Access to Investigational Drugs Although drug companies and the U.S. Food and Drug Administration (FDA) have had a formal framework in place for granting access to experimental drugs outside of clinical trials since the early days of the AIDS crisis in the late 1980s, requests for expanded access to these drugs has intensified in the megaphone age of social media and as drugs have become more targeted. To meet the demand and provide quicker response, in 2009, the FDA broadened its rules for expanded access to unapproved drugs and recently announced a simplified process for physicians to obtain experimental drugs for their patients with serious or life-threatening illnesses and no other treatment options. The new measure, “Individual Patient Expanded Access Applications: Form FDA 3926,” is currently still in development and is designed to take physicians just 45 minutes to complete. In 2014, the FDA fielded and approved over 1,800 applications for expanded access to investigational drugs, ranging from use in individual patients to larger protocols involving over 100 patients.

‘Right to Try’ Laws In response to growing social media campaigns to make the compassionate drug use approval process even faster and easier, as of this writing, 22 states have passed so-called Right to Try laws, and 19 more states have legislation either pending or ready to be signed into law (see page 1 for a report on “‘Right to Try’ Laws: Helpful or Harmful?”). Although provisions in these statutes vary from state to state, essentially Right to Try laws allow terminally ill patients to bypass the FDA and make a request for drugs that have passed phase I trials directly to the drug manufacturer. But many experts say these laws are fraught with legal and ethical problems. According to Patricia J. Zettler, JD, Associate Professor at Georgia State University College of Law and former Associate Chief Counsel for Drugs at the FDA, companies that wish to supply their drugs to patients still require FDA authorization before they are allowed to proceed. continued on page 56

Trusted to take a bite out * of G-CSF acquisition costs GRANIX® has gained >34% share of the US short-acting G-CSF hospital market in its first 17 months1 » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)2 – 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)2 » 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)2 » Offering a 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 colonystimulating 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. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of March 2015. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices. References: 1. This information is an estimate derived from the use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospital channel March 2015. IMS expressly reserves all rights, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength). 2. 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-40680 May 2015. Printed in USA.

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Issues in Oncology Independent Bioethics Panel continued from page 54

“As a legal matter, these laws don’t do anything,” said Professor Zettler. “The groups pushing these laws have touted them as taking the FDA out of the process or as circumventing the FDA process, but the Constitution essentially says that federal law trumps state law,

meaning that in the context of drug approval, states don’t have the option to circumvent or replace the federal process.” In addition, the law doesn’t mandate that companies must grant a patient’s or physician’s request, nor are insurance companies required to cover any costs the companies may charge for the drug. “These laws are very, very

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.

724-43396

poor because they create false hope,” said Dr. Caplan. “It is unethical to give people the notion that they are entitled to something when they are not going to get it. And these laws don’t address issues that people who are not terminally ill have, and they make up big numbers of people requesting unapproved drugs or devices.”

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-40580 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Job Number: 21279 Revision No: 0 Date: 05/14/15

RIchard Klein

Although the FDA has not taken a position on Right to Try laws, Richard Klein, Director of the Patient Liaison Program in the FDA’s Office of Health and Constituent Affairs, agrees that these laws have the potential to add confusion to the process of gaining access to unapproved drugs. “The FDA has a mechanism in place, and it’s been a successful mechanism,” said Mr. Klein. “I don’t know what Right to Try has added, and it might also make the process more complicated because there are different laws in different states.” To date, there are no reports of terminally ill patients actually having received a drug through Right to Try laws.

Making a Difference for Patients Since Johnson & Johnson’s announcement of the establishment of the Compassionate Use Advisory Committee, the company has been flooded with requests from scientists, pharmaceutical and biotechnology companies, and patients for more information about the program, according to Dr. Ray. “We have received calls from patients asking how they can help, and they have expressed feedback that they are pleased to see such a positive step forward,” said Dr. Ray. “They are really looking forward to hearing about the outcome of the pilot program, and their encouragement has caused us to redouble our efforts. The real goal here is to make a positive difference for our patients.” “Everyone is watching and hoping that this experiment might provide a better way to go,” adds Dr. Caplan. “I was inspired by the positive experience with the United Network for Organ Sharing. People say Americans can’t ration or make tough decisions, but I know they can because I saw it with the transplant program. People understand how that system works, and they accept that it tries to be fair. So that gives me hope that we can duplicate that same sense of equity and fairness in the area of compassionate drug use.” n Disclosure: Dr. Caplan, Prof. Zettler, and Mr. Klein reported no potential conflicts of interest. Dr. Ray is an employee of Janssen Research & Development, LLC.

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Issues in Oncology ‘Right to Try’ Laws continued from page 1

Georgia State University College of Law and former Associate Chief Counsel for Drugs at the FDA, the U.S. Constitution guarantees that federal law supersedes state law and that state laws cannot permit manufacturers to provide patients with access to unapproved drugs under the Food, Drug, and Cosmetic Act,1 which prohibits the sale or distribution of any drug or device into interstate commerce until it is proven to be safe and effective.

patients, overall, he said, it is good to see greater engagement and dialogue on the issue of compassionate drug use (See page 54 for more on the Johnson & Johnson Independent Bioethics Panel). “One thing that these new laws and other legislation in development show is the level of engagement of lawmakers in representing the public on an issue of importance to patients,” said Dr. Ray. “I think that active engagement has more potential to be productive than leaving things

One thing that the new laws in development show is the level of engagement of lawmakers in representing the public on an issue of importance to patients. It is good for the public to see dialogue that involves all of the stakeholders, including lawmakers, patients, industry, and academic groups. —Amrit Ray, MD

“Not only don’t these laws accomplish anything as a legal matter, as a policy matter to the extent that they confuse patients or manufacturers about the process, they could actually be quite harmful,” said Professor Zettler.

Active Engagement and Dialogue Although Amrit Ray, MD, Chief Medical Officer for Janssen Pharmaceutical Companies of Johnson & Johnson, states that no steps should be taken that would create false hope for

to chance. It is good for the public to see dialogue that involves all of the stakeholders, including lawmakers, patients, industry, and academic groups.” Professor Zettler said that although Right to Try legislation may not accomplish its goals, it is understandable why the statute is being enacted across the country. “People want to help terminally ill patients, and I think that for a lot of politicians, there are probably good motives behind wanting to pass these laws,” said Professor Zettler. “But what terminal-

ly ill patients really need are effective treatments for their particular condition, and these laws don’t do anything to create those treatments. So, to the extent that they are taking away resources from efforts to achieve the result that patients really need and add confusion about the FDA’s approval process, I don’t see them as a positive thing.” To date, there are no reports that patients have actually acquired investigational drugs through Right to Try laws.

Expediting Medical Innovation Nationally On May 21, 2015, the U.S. House of Representatives’ Committee on Energy and Commerce approved the 21st Century Cures Act.2 It proposes to accelerate the development and approval of new drugs and devices on a national level and adds about $1.5 billion per year for 3 years to the National Institutes of Health’s (NIH) current $30.3 billion budget. The law also provides an additional $2 billion per year for 5 years to create the NIH Innovation Fund, which would support precision medicine initiatives and the work of young scientists’, as well as $550 million over 5 years in additional funding for the FDA to implement drug-approval changes called for in the law. Although a number of nonprofit organizations representing patients, family caregivers, health-care providers, and researchers support the bill, in a recent article in The New England Journal of Medicine, 3 Jerry Avorn, MD, Division Chief, Pharmacoepidemiology and Pharmacoeconomics and Professor of Medicine at Harvard Medical School,

and Aaron S. K esselheim, MD, JD, MPH, Associate Professor of Medicine at Harvard Medical School and Associate Physician at Brigham and Women’s Hospital, voiced concern that the Cures Act could actually reduce the effectiveness of the current FDA approval process. “Over the past 80 years, this country’s regulatory approach has embraced steadily improving criteria for accurately assessing therapeutic efficacy and risk. Patients and physicians would not benefit from legislation that instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th century,” wrote the authors. A vote by the full House of Representatives on the 21st Century Cures Act is expected this summer. If it passes, it would then go to the Senate for a vote and could be before President Obama to be signed into law in early 2016. n

Disclosure: Dr. Ray is an employee of Janssen Research & Development, LLC.

References 1. U.S. Food and Drug Administration: Key legal concepts: Interstate commerce, adulterated, and misbranded. Available at http://www.fda.gov/Cosmetics/GuidanceRegulation/LawsRegulations/ucm074248.htm. Accessed July 28, 2015. 2. Johnson JA, Thaul S, Bagalman E: H.R. 6: The 21st Century Cures Act. Available at https://www.fas.org/sgp/ crs/misc/R44071.pdf. Accessed July 28, 2015. 3. Avorn J, Kesselheim AS: The 21st Century Cures Act: Will it take us back in time? N Engl J Med 372:2473-2475, 2015.

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The ASCO Post | AUGUST 25, 2015

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In the Clinic Dermatologic Oncology

Sonidegib in Basal Cell Carcinoma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n July 24, 2015, sonidegib (Odomzo) was approved for treatment of patients with locally advanced basal cell carcinoma recurring after surgery or radiation therapy and patients who are not candidates for surgery or radiation therapy.1,2

Efficacy Data The approval was based on demonstration of durable objective responses in a two-arm phase II trial in which 230 patients with locally advanced basal cell carcinoma not amenable to local therapy or metastatic basal cell carcinoma were randomized 2:1 to receive oral sonidegib at 800 mg (n = 151) or 200 mg (n = 79) daily until disease progression or unacceptable toxicity.2,3 In total, 84% of patients had locally advanced disease. Both 200-mg and 800-mg doses of sonidegib showed antitumour activity in patients with advanced basal cell carcinoma. The 200-mg dose was associated with a more favorable safety profile than the 800-mg dose. The benefit-to-risk profile of 200-mg sonidegib was determined a potentially new treatment option for this difficult-to-treat population of patients with advanced basal cell carcinoma.

OF NOTE Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Among patients with locally advanced disease randomized to receive 200 mg daily of sonidegib (the approved dose), the median age was 67 years, 58% were male, 89% were white, 67% had an Eastern Cooperative Oncology Group performance status of 0, 76% had received prior treatment for basal cell carcinoma, and 56% had an aggressive histology. None had received prior Hedgehog inhibitor treatment. Among 66 patients with locally advanced disease who received 200 mg, the objective response rate was 58% (95%

confidence interval [CI] = 45%–70%). Among the 38 patients with an objective response, 7 (18%) had subsequent disease progression, with 4 having maintained a response of at least 6 months. At last analysis, the remaining 31 patients had ongoing responses of 1.9+ to 18.6+ months, and the median duration of response had not been reached. The objective response rate among 128 patients with locally advanced disease receiving 800 mg was 44% (95% CI = 35%–53%). A prespecified sensitivity analysis defining complete response as at least partial response on magnetic resonance imaging or photography and no evidence of tumor on biopsy of the residual lesion indicated a complete response rate of 20%. However, in the study, the classification of complete response required confirmation in multiple biopsy samples, with these results being assessed by an independent review committee. As a result of these more stringent criteria, the complete response rate in the study was only 5%.

How It Works Sonidegib is an inhibitor of the Hedgehog signaling pathway. It binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. Most sporadic basal cell carcinomas have mutations in the PTCH1 gene or Smoothened, which lead to activation of signaling and expression of the Hedgehog pathway and its targets.

How It Is Given The recommended dose of sonidegib is 200 mg once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Treatment should continue until disease progression or unacceptable toxicity. Sonidegib treatment should be interrupted for severe or intolerable musculoskeletal adverse reactions, first occurrence of serum creatine kinase elevation between 2.5 and 10 times the upper limit of normal (ULN), and recurrent creatine kinase elevation between 2.5 and 5 times ULN; treatment can be resumed at 200 mg upon resolution of clinical signs and symptoms. Treatment should be permanently discontinued for creatine kinase elevation > 2.5 times ULN with worsening renal function, creatine kinase elevation > 10 times ULN, recurrent creatine kinase elevation > 5 times ULN, and recurrent severe or intolerable musculoskeletal adverse reactions. Concomitant administration with strong CYP3A inhibitors (eg, saqui-

Second Hedgehog Inhibitor Approved for Basal Cell Carcinoma ■■ Sonidegib (Odomzo) was approved for treatment of patients with locally advanced basal cell carcinoma recurring after surgery or radiation therapy and patients who are not candidates for surgery or radiation therapy. ■■ Sonidegib is the second Hedgehog inhibitor approved in basal cell carcinoma, with vismodegib (Erivedge) being the first. ■■ The recommended dose of sonidegib is 200 mg once daily on an empty stomach, at least 1 hour before or 2 hours after a meal.

navir, telithromycin, ketoconazole, itraconazole) and concomitant use for more than 14 days with moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole) should be avoided. Concomitant use with strong and moderate CYP3A inducers (eg, carba mazepine, modafinil, phenobarbital, St. John’s wort) should be avoided.

Safety Profile In the phase II trial, the most common clinical adverse events of any grade in patients receiving 200 mg of sonidegib were muscle spasms (54%), alopecia (53%), dysgeusia (46%), fatigue (41%), nausea (39%), musculoskeletal pain (32%), diarrhea (32%), and decreased weight (30%). The most common grade 3 adverse events (no grade 4 events reported) were fatigue (4%), muscle spasms (3%), and decreased weight (3%). Serious ad-

OF NOTE Sonidegib has a boxed warning for embryo-fetal risk, as it can cause embryo-fetal death or severe birth defects when administered to a pregnant woman.

verse events occurred in 18% of patients. Adverse events led to treatment interruption in 20% of patients and treatment discontinuation in 34%, with the most common causes of treatment discontinuation being muscle spasms (5%), dysgeusia (5%), asthenia (4%), increased lipase (4%), and nausea (4%). The most common laboratory abnormalities of any grade were increased serum creatinine (92%), increased serum creatine kinase (61%), hyperglycemia (51%), and increased lipase (43%). The most common grade 3 or 4 abnormalities were increased lipase (13%), increased serum creatine kinase (8%), hyperglycemia (4%), and increased alanine transaminase and aspartate transaminase (both 4%). Thus, serum

creatine kinase levels must be measured and renal function tests performed in all patients prior to starting treatment with sonidegib, periodically during treatment, and as clinically indicated. The frequencies of common adverse events, serious adverse events, and discontinuation of treatment due to adverse events were higher in patients receiving the 800-mg dose. Sonidegib has a boxed warning for embryo-fetal risk, as it can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Thus, the pregnancy status of women of reproductive potential must be verified prior to starting treatment. Women of reproductive potential must be advised to use effective contraception during treatment and for at least 20 months after the last dose. Males must be advised of the potential risk of exposure through semen and encouraged to use condoms with a pregnant partner or a female partner of reproductive potential during treatment and for at least 8 months after the last dose. Sonidegib also carries warnings/precautions for blood donation and musculoskeletal adverse reactions. Patients should be advised not to donate blood or blood products during treatment or for at least 20 months after the last dose. Women should not breast-feed during treatment or for at least 20 months after the last dose. n References 1. U.S. Food and Drug Administration: Sonidegib. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm455865.htm. Accessed July 28, 2015. 2. Odomzo (sonidegib) capsules prescribing information, Novartis Pharmaceuticals, July 2015. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2015/205266s000lbl. pdf. Accessed July 28, 2015. 3. Migden MR, et al: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT). Lancet Oncol 16:716-728, 2015.

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

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Direct From ASCO

New Symposium Brings Together Oncologists and Primary Care Providers to Advance Survivorship Care and Research

ith two-thirds of Americans now living at least 5 years after a cancer diagnosis, there are currently 14.5 million cancer survivors living in the United States. By 2024, that number is expected to increase by nearly 25%.1 Although the growing number of survivors is a welcome sign of progress, this trend also presents challenges, because many of these individuals require significant, ongoing care, such as surveillance for cancer recurrence, screening for new cancers, and care for the long-term effects of their treatment. While ASCO provides a variety of tools and resources for oncologists, a broader workforce is responsible for providing survivorship care, creating communication and coordination among oncology professionals and primary care providers to ensure delivery of the highest quality care. To address these challenges, the American Academy of Family Physicians (AAFP), the American College of Physicians (ACP), and ASCO are cosponsoring the inaugural Cancer Survivorship Symposium: Advancing Care and Research, taking place January 15–16, 2016, in San Francisco, California.

many survivors are transitioned,” said Kevin C. Oeffinger, MD, Symposium Steering Committee Chair and Director of the Cancer Survivorship Center at Memorial Sloan Kettering Cancer Center. “AAFP, ACP, and ASCO are championing an effort to change this paradigm. I anticipate that this monumental effort will serve as a catalyst to bring these two worlds together, and ultimately, to improve the health care of cancer survivors.”

will also include two poster sessions and an oral abstract session featuring abstract categories such as Care Coordination and Financial Implications, Psychosocial Issues, Health Promotion, and Recurrence and Secondary Malignancies.

Head Professor of Medicine and Health Policy at George Washington University, Founding President of the National Coalition for Cancer Survivorship, and a cancer survivor • Anthony L. Back, MD, a medical oncologist, well-known expert in

Truly Interdisciplinary

“The Cancer Survivorship Symposium was created to fill the need for more research to enhance the care of our cancer survivors,” said Ann Partridge, MD, MPH, FASCO, Symposium Program Committee Chair and Director of the Adult Survivorship Program at DanaFarber Cancer Institute. “It will showcase a lot of the work that’s been going on over the last decade, so that patients’ health outcomes can be enhanced.”

physician communication skills, and Director of Palliative Care at the Seattle Cancer Care Alliance • Smita Bhatia, MD, MPH, a cancer survivorship researcher, Director of the Institute for Cancer Outcomes and Survivorship in the University of Alabama at Birmingham (UAB) School of Medicine, and the Vice Chair for Outcomes in the Department of Pediatrics and Associate Director for Cancer Outcomes Research at the UAB Comprehensive Cancer Center. Visit survivorsym.org for more information, to submit an abstract, or to register and reserve a hotel room. n

With representatives from all three cosponsoring organizations contributing to the Symposium planning process, the Cancer Survivorship Symposium program is designed for a broad audience, including primary care providers, oncologists, nurses, advanced practice providers, residents, and oncology fellows interested in taking an interdisciplinary approach to survivorship care, as well as representatives from cancer advocacy organizations. “This Symposium will provide valuable education for primary care providers and oncologists alike as to how best to enhance survivorship care based on data, current best practices, and collaborative discussions across specialties,” said Michelle Quiogue, MD, FAAFP, 2016 Symposium Steering Committee Member and Vice Speaker for the California Academy of Family Physicians.

Kevin C. Oeffinger, MD

A Unique Collaboration As the first collaborative project between these organizations, the Symposium will feature educational sessions, keynote lectures, oral and poster presentations of research, and networking events and will cover topics ranging from risk assessment and care-delivery models to how best to provide multidisciplinary education and training. “In 2005, the Institute of Medicine (IOM) released a hallmark report on cancer survivorship, subtitled ‘Lost in Transition’.2 Critical problems identified by the IOM that have led to fractured care experienced by many cancer survivors are the lack of communication between oncology specialists and primary care providers and the haphazard way in which

Michelle Quiogue, MD, FAAFP

Placing Research Into Clinical Context One of the main goals of the Cancer Survivorship Symposium is to help attendees understand the latest research in this field, and the program reflects this objective. Each session at the Symposium will incorporate multiple perspectives to demonstrate how coordination can help providers overcome barriers to optimal survivorship care. In addition, abstract presentations and discussions will give a more complete picture of current data. The program

Innovative Learning Formats The inaugural Cancer Survivorship Symposium will also feature unique learning and networking opportunities to help attendees get the most out of their experience. Meet the Faculty Networking Roundtables: Attendees can interact with multidisciplinary experts in a small-group setting. Early-career topics, such as finding a mentor and avoiding burnout, will be a focus each day. LIFe Café: The LIFe (Living in the Future) Café gives attendees the opportunity to have frequently asked or casespecific questions about survivorship care answered by experts in the field. In addition, small group discussions will allow for networking across specialties. This is a ticketed event; learn more at survivorsym.org. Keynote Lectures: Multiple keynote lectures will set the stage for individual presentations. Keynote speakers include: • Fitzhugh Mullan, MD, the Murdock

References 1. American Cancer Society: Cancer Treatment & Survivorship Facts & Figures, 2014-2015. Available at http://www.cancer.org/acs/groups/content/@research/ documents/document/acspc-042801.pdf. Accessed July 30, 2015. 2. McCabe MS, Bhatia S, Oeffinger KC, et al: American Society of Clinical Oncology: Achieving high-quality cancer survivorship care. J Clin Oncol 31:631-640, 2013.

Key Dates Abstract Submission Deadline: September 1, 2015, at 11:59 PM (EDT) Early Registration and Hotel Reservation Deadline: Wednesday, December 9, 2015, at 11:59 PM (EST) Cancer Survivorship Symposium: Advancing Care and Research: January 15–16, 2016 Visit survivorsym.org for more.

ASCOPost.com | AUGUST 25, 2015

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Direct From ASCO

Physician Fee Schedule: A Closer Look

he Centers for Medicare & Medicaid Services (CMS) issued the Notice of Proposed Rulemaking for the 2016 Physician Fee Schedule on July 15. Among other changes, CMS proposes new codes and payment levels for Advance Care Planning; requests comments for future implementation of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA); and estimates a 0% aggregate change in reimbursement for medical oncology services and a 3% reduction for radiation oncology services. ASCO is working to examine all of the provisions of the notice and the impact on oncologists. The proposal of Advance Care Planning (ACP) will cover two advance care planning services provided to Medicare beneficiaries by physicians or other practitioners. Previously, these services were only available as part of the “Welcome to Medicare” initial visit, but the proposal would promote access to advance care planning services by providing separate payment and more flexibility in timing. Payment policies that allow patients and oncologists to have conversations and share information needed to make informed choices throughout the course of an illness are essential to promoting high-quality, high-value care. MACRA replaced the Sustainable Growth Rate (SGR) formula for fee adjustments and establishes a MeritBased Incentive Payment System (MIPS) that offers performance improvement incentive payments beginning in 2019. To help with implementation, CMS is seeking input on various provisions of MACRA, including implementation of MIPS and alternative payment models. Additionally, CMS proposes to implement provisions included in MACRA that would allow group reporting of quality measures to a qualified clinical data registry. Finally, while CMS estimates that the overall reimbursement impact for medical oncology and hematology will be 0% in 2016, CMS estimates that the proposed rule will result in a 3% cut for radiation oncology. ASCO is analyzing the various issues that are contributing to the overall reduction, and remains concerned that these cuts could have adverse effects on patient access to medically necessary care. ASCO is examining these and other is-

sues of importance to ASCO members and the oncology community and will be providing comments to CMS by

the September 8, 2015, deadline. Radiation oncology has suffered significant cuts over the past three fee

schedules, so ASCO will pay special attention to better understanding that dynamic. n

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 cases of progression with ﬁrstgeneration EGFR TKIs are related to the T790M mutation1,2

NEARLY 2 OUT OF 3

CASES ARE RELATED TO T790M

T790M is an acquired mutation and has been identified as the most common mechanism of acquired resistance in nearly 2 out of 3 patients with advanced NSCLC.1,2 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 Find out how the T790M mutation could affect the future of NSCLC at: EGFRevolution.com.

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation

as a driver of resistance. References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 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. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

The ASCO Post | AUGUST 25, 2015

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Direct From ASCO

Conquer Cancer Foundation Donor Spotlight: Ludwig Cancer Research

mong the Conquer Cancer Foundation’s newest supporters, Ludwig Cancer Research is an international community of distinguished scientists dedicated to preventing and controlling cancer. Its emphasis on collaboration and long-term support has fostered its role as a leader in immunotherapy and other challenging aspects of cancer research since its founding in 1971. Ludwig has supported the ASCO Annual Meeting through the Conquer Cancer Foundation for the past 2 years, most recently supporting the Cancer Prevention Track at the 2015 ASCO Annual Meeting in Chicago.

Robert L. Strausberg, PhD

The goals of Ludwig and the Conquer Cancer Foundation are closely aligned in that both organizations seek to fund research that advances the diagnosis and treatment of cancers. “Supporting the Conquer Cancer Foundation was a natural fit,” said Robert L. Strausberg, PhD, Ludwig’s Executive Director of Collaborative Sciences. “We don’t doubt that the Conquer Cancer Foundation will know how to put these funds to work in service to what is, after all, a globally shared mission.”

Globally Influential Ludwig supports more than 1,000 researchers and administrative staff working at prestigious institutions and laboratories in the United States, Europe, and Australia. According to Dr.

Strausberg, Ludwig-designated sites “are chosen based on their ability to provide opportunities for collaboration and strong interdisciplinary basic and translational research.”

He continued, “For example, the newly launched Ludwig Lausanne Branch is a multi-institutional, multidisciplinary partnership involving several local Swiss research institutions. Researchers there have the opportunity to work closely with leading hospitals, biotechnology, and pharmaceutical companies to develop novel immunotherapies.” To further promote global collaboration, Ludwig convenes researchers from around the world for an annual meeting.

Advances in Immunotherapy and Genomics A longstanding leader in cancer immunotherapy, Ludwig continues to expand its role in a field that is showing great promise. For example, Jedd Wolchok, MD, PhD, and Stephen Hodi, MD, both ASCO members and Ludwig researchers, presented findings at the 2015 ASCO Annual Meeting and in The New England Journal of Medicine,1 showing that people with advanced melanoma respond better to two immune checkpoint inhibitors, ipilimumab (Yervoy) and nivolumab (Opdivo), than to either alone. Cancer prevention is another important focus area for Ludwig. In partnership with the Conrad N. Hil-

ton Foundation, Ludwig launched a research program to advance dietary interventions and technologies for the prevention of colon cancer. Ludwig is exploring how certain foods might make people either more resistant or vulnerable to this cancer. Specifically, Ludwig researchers are looking at the impact of diet on the gut microbiome and, ultimately, on immune functions, building on their expertise in immune intervention. “We are also very interested in what is often referred to as secondary prevention, or developing screening technologies for the noninvasive detection of early-stage cancer and precancerous growths,” said Dr. Strausberg. “It is during these early stages that treatments are most effective.” In addition to immunotherapy and cancer prevention, Ludwig has leading programs in cellular signaling and genomics. Advancing discoveries for human benefit is at the heart of Ludwig’s research efforts. For instance, “we provide an interface between basic and translational science through our technology development program, led by Jonathan Skipper, PhD,” said Dr. Strausberg. “The program includes small molecule discovery, assay development, preclinical studies, and engineered antibodies. These resources, including scientific teams with specific expertise, help us assess how specific scientific discoveries can be further advanced,” he elaborated.

A Growing Partnership Many Ludwig scientists are already ASCO members, so there is great synergy between the two organizations. At the 2015 ASCO Annual Meeting, there were presentations from U.S.-based researchers at five Ludwig centers, as well as from Ludwig’s international researchers in Europe and Australia. Toward encouraging collaboration both

within Ludwig and the greater cancer research community, Dr. Strausberg offered, “We would love to get to know ASCO members by connecting with them through our new Facebook, Twitter, and LinkedIn pages. ASCO members can share our posts to help raise awareness of research progress, tell us how our research developments may affect their work, or vice versa.” A visionary organization, Ludwig takes a long-term view of scientific development and provides its scientists the freedom to fully pursue and develop their ideas, to take risks, and if they fail, to do so smartly. “This enables our scientists to have more time to do what they do best—ask and answer important scientific questions,” said Dr. Strausberg. “The Conquer Cancer Foundation gratefully acknowledges and sincerely appreciates the support received from Ludwig Cancer Research,” said Nancy Daly, MS, MPH, Executive Director and Chief Philanthropic Officer of the Conquer Cancer Foundation. “It is only due to the generosity of our donors, such as Ludwig Cancer Research, that we are able to pursue our mission of conquering cancer worldwide by funding breakthrough cancer research and sharing cutting-edge knowledge.” To learn more about Ludwig Cancer Research, please visit www.ludwigcancerresearch.org. To learn more about the Conquer Cancer Foundation, please visit www. conquercancerfoundation.org. n Reference 1. Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372: 2006-2017, 2015.

Obesity and Cancer Bundle: Oncology Provider Guides and Patient Booklets

any cancer care providers struggle with addressing the topics of weight loss and weight management with their patients. Obesity and Cancer: A Guide for Oncology Providers is a tool that will help oncology providers integrate strategies for weight loss into their practices by offering practical tips and strategies for weight assessment and weight loss, as well as information about how to be reimbursed for these services. To complement the provider guide,

this bundle also includes ASCO Answers: Managing Your Weight After a Cancer Diagnosis: A Guide for Patients and Families. This booklet provides clear, practical information about different weight loss methods, common challenges to losing and maintaining one’s weight, a discussion of the emotional challenges that accompany making lifestyle changes, and tips for talking with the health care team about weight. With these booklets, both patients

and oncology providers will have the practical tools they need to work together to help patients find a healthy weight. Each bundle includes 10 provider guides and 115 patient booklets. Visit www.cancer.net/estore to order copies for your practice. Enjoy free shipping on all patient education products, and save 20% with ASCO member ID. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | AUGUST 25, 2015

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Direct From ASCO

Strengthening the Doctor-Patient Relationship: An Interview With Lidia Schapira, MD, FASCO

arlier this summer, Lidia Schapira, MD, FASCO, a medical oncologist at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School, was named Editorin-Chief of Cancer.Net, ASCO’s patient information website. Prior to taking on this role, Dr. Schapira was a longtime member of the Cancer.Net Editorial Board, serving as Associate Editor of Psychosocial Oncology for more than a decade.

Lidia Schapira, MD, FASCO

Throughout her career, Dr. Schapira has focused on improving communication between patients and doctors, pioneering workshops and developing educational programs to improve the communication skills of cancer clinicians both nationally and internationally. She has also collaborated with experts in neuroscience and psychology to find new ways to strengthen the therapeutic connection between patients and health-care providers. We spoke with Dr. Schapira about her background and the role she sees Cancer.Net playing in the lives of people with cancer and family caregivers. In your career, in what areas or issues have you chosen to focus your research? I’m interested in the psychological processes that are set in motion in response to a serious illness and in understanding how people respond to these existential threats and turn them into challenges. I also focus on furthering compassionate connections between patients and cancer

clinicians and on understanding the social determinants of health, which include education, socioeconomic status, and resources, as well as cultural and spiritual beliefs. Every single one of these issues never ceases to fascinate me and can be experienced in so many different ways—every encounter with a patient feels fresh and different.

into Spanish, and we are proud to have visitors from every continent (except Antarctica). We continue to embrace new ways of communicating with patients and family caregivers and have built a strong presence on Facebook, Twitter, and YouTube. The number of people visiting the site is increasing at a very fast clip, and this is the best endorsement of our efforts.

active exchange of perspectives and information, and I think we can do even more to help people with cancer become more engaged in their care. This will lead to greater satisfaction and improvements in their quality of life. I also want to address the needs of family caregivers as much as possible, since they are essential partners in cancer care. n

How do you think your research background and clinical experience will help you in your role as Cancer.Net’s Editor-in-Chief? I have always felt it is important to focus on both the patient’s and the physician’s experience. The whole picture can emerge only when we consider the humanity of each participant. As a result, I am constantly looking for new ways of enhancing compassion in clinical care through research and education. This has led me to participate in educational endeavors designed to improve communication skills of cancer clinicians and to work collaboratively with patient advocacy groups to identify better mechanisms for supporting patients throughout the illness experience. So working with Cancer.Net is a natural fit, as it is the best possible platform for the oncology community to provide expert guidance, as well as support and empowerment to patients.

What would you like to accomplish in your time as Editor-in-Chief? I hope to bring some fresh ideas to Cancer.Net about themes that resonate with patients and family caregivers. Communication involves an

Selected portions reprinted from Cancer.Net. © American Society of Clinical Oncology. “Strengthening the Doctor-Patient Relationship: An Interview With Dr. Lidia Schapira” www.cancer.net 11 June 2015. All rights reserved.

How have you seen Cancer.Net change over the past 10+ years? Oh boy—this is a remarkable story of success. Cancer.Net is a trusted source of information [for patients], largely due to the incredible and generous contribution of our expert editors and panelists. Over the past decade, we have expanded the content of the site to include not only rare cancers and novel therapies, but also palliative care, symptom management, communication, cost of care, and all aspects of coping. We have started translating important content

Be a Voice in The Campaign to Conquer Cancer

e’ll provide the resources—you provide the voice. The Campaign to Conquer Cancer is raising $150 million to support a world free from the fear of cancer. Our potential to raise money increases with every new person who learns about our work. We need the most trusted leaders in the oncology community to share the message about our critical movement. That’s you. Most people outside the oncology community are unaware that in just 15 years, the Conquer Cancer Foundation (CCF) has granted more than $150 mil-

lion to fund patient and caregiver education, boost the careers of young oncologists, and support clinical research around the world. Let the people who turn to you for advice on medicine and health know CCF resources are at the core of cancer treatment and discoveries. To learn more, sign up at conquer. org/asco, and we’ll share some ways you can help us connect others to The Campaign to Conquer Cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

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The ASCO Post | AUGUST 25, 2015

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Hematology Expert Review

Microangiopathic Hemolytic Anemia and Thrombocytopenia Part 2: Management

By Syed A. Abutalib, MD, and Jean M. Connors, MD

B:1

T:1

ematology Expert Review is an occasional feature that includes a case report followed by questions, answers, and expert commentary. In the July 25 issue of The ASCO Post, part 1 of a case report was published and focused on diagnosis (see summary below). Here, in part 2, the management of this case is discussed.

Summary of Part 1

26-year-old woman presented to labor and delivery triage with fatigue, heavy vaginal bleeding, and gastrointestinal upset on postpartum day 8 after vaginal delivery. Prior to presentation, she reported diarrhea and nausea with nonbilious, nonbloody emesis, which since had resolved. She had left upper quadrant pain, which worsened with deep inspiration. On review of systems, she experienced dizziness, with no syncopal episodes. She denied fever or chills, bleeding gums or easy bruising, dysuria, or vaginal discharge other than blood. Her medical history was notable for sickle cell trait, scoliosis, and chronic borderline hypertension. Following physical examination and evaluation of laboratory values, doctors performed peripheral blood smear examination. The most likely diagnosis was determined as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome. ADAMTS13 analysis was performed to aid in making the correct diagnosis (ADAMTS13 is a metalloproteinase present in the blood responsible for cleaving ultralarge von Willebrand factor multimers into smaller-sized multimers. Deficiency results in thrombotic thrombocytopenic purpura. Activity levels less than 10% are considered severely low.) This patient’s ADAMTS13 level was less than 10% of normal, thus confirming the diagnosis of thrombocytopenic purpura. Part 2 of this case report, which continues here, focuses on management of this patient. n

Continued Case Study Plasma exchange was continued until platelets peaked at 170,000/μL, at

which point it was stopped. Two days after stopping therapeutic plasma exchange, the patient developed fever,

epistaxis, and oozing at the plasmapheresis catheter site. On examination, she was sleepy but

BEFORE SURGERY, THERE IS A

HER2+ BREAST CANCER

PRE-OPPORTUNITY

Indication PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated for use in combination with trastuzumab and docetaxel as 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. 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

Important Safety Information Boxed WARNINGS: Left Ventricular Dysfunction 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 — 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 for 7 months after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy or within 7 months following the last dose of PERJETA in combination with trastuzumab to immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555 and to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

References: 1. PERJETA Prescribing Information. Genentech, Inc. 2015. 2. Referenced with permission from NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer V.3.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed July 17, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

PER/052915/0057(1)

Printed in USA.

07/15

17.5”

15.5”

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Hematology Expert Review

arousable and had a high fever of 102˚ F with chills. She became hemodynamically unstable, with a heart rate of 160 beats/min and a blood pressure of 60/40 mm Hg.

Key Laboratory Results Emergency laboratory results revealed sodium 135 mmol/L, potassium

5.5 mmol/L, chloride 111 mmol/L, bicarbonate 18 mmol/L, urea nitrogen 45 mg/dL, creatinine 2.6 mg/dL, and glucose 100 mg/dL. The alanine transaminase was 20 U/L; aspartate transaminase, 45 U/L; total bilirubin, 2.0 mg/dL; direct bilirubin, 0.6 mg/dL; and albumin, 1.4 g/dL.

The white blood cell count was 21,000/μL with predominant neutrophils. The hemoglobin was 11.0 g/dL, hematocrit was 33.0%, and platelets dropped to 65,000/μL. The prothrombin time was 21.1 seconds, activated partial thromboplastin time was 55.7 seconds, and international normalized ratio was 4.

Fibrinogen was 80 mg/dL. D-dimer level was greater than 4,000 times the upper limit of normal. Examination of the peripheral blood smear film revealed schistocytes, anemia, and thrombocytopenia. At this point, fluid resuscitation was started. continued on page 66

CONSIDER REFERRING PATIENTS WITH HER2+ EARLY-STAGE BREAST CANCER (POSITIVE NODAL STATUS OR TUMORS >2 CM) TO A MEDICAL ONCOLOGIST FOR PERJETA-BASED THERAPY PRIOR TO SURGERY 1 • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA®)-based neoadjuvant regimens as an option for the treatment of HER2-positive (HER2+) early-stage breast cancer (category 2A) 2 • The first and only opportunity for eligible patients with HER2+ early-stage breast cancer to receive PERJETA-based therapy is prior to surgery (see indication statement) 1 — PERJETA is not approved as adjuvant therapy

To speak with a Genentech sales representative for information regarding PERJETA, please visit www.perjeta.com/rep.

TREAT HER NOW.

T:10.5”

TREAT HER EARLY.

B:11.5”

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 Grades 3-4 reactions was 2.0% and 2.5%, respectively, according to NCI-CTCAE (version 3) • In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1 • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use 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 Most Common Adverse Reactions Neoadjuvant Treatment of Breast Cancer • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting • The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity 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.

S:9.875”

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, left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • In Study 2, for patients receiving neoadjuvant treatment, the incidence of LVSD was higher in PERJETA-treated groups than in the trastuzumab and docetaxel 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 • In Study 3, for patients receiving neoadjuvant treatment, 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, in 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and in 10.5% of patients treated with PERJETA in combination with TCH • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting and every 6 weeks in the neoadjuvant 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 trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if LVEF has not improved or has declined further Infusion-Associated Reactions • PERJETA has been associated with infusion reactions • In Study 1, 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) Grades 1-2 • 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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PAGE 66

Hematology Expert Review Question 1

Question 2

Question 3

What is the best first step in management of this patient? A. Assay for mutations in comple ment regulatory protein genes B. Check blood ADAMTS13 (also known as von Willebrand factor– cleaving protease) level C. Start plasma exchange

In the current era, the majority of patients with thrombotic thrombocytopenic purpura will receive therapeutic plasma exchange before the development of “ classic pentad”? A. True B. False

What is the next best step in the management of this patient? A. Emergency blood cultures and initiation of broad-spectrum antibiotics B. Emergency plasma exchange C. Eculizumab

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012

WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY Left Ventricular Dysfunction 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, 5.1, 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. (5.2, 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 eventfree 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 doxorubicincontaining 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 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. In 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/m 2 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)]. 5.2 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 or within 7 months following the last dose of PERJETA in combination with trastuzumab, 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 or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, 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. 5.3 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

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See page 67 for answers and expert discussion.

of infusion reactions was 13.0% in the PERJETA-treated 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 placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. 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 docetaxeltreated 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 NCI-CTCAE (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 suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Left Ventricular Dysfunction [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

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Hematology Expert Review

Microangiopathic Hemolytic Anemia and Thrombocytopenia Part 2: Management Answers From Hematology Expert Review Questions on Page 64 Question 1: What is the best first step in management of this patient? Correct Answer: C. Start plasma exchange. 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 2.75 years of follow-up (median total follow-up of 50 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%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 Placebo PERJETA + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades Grades, % 3–4, %

All Grades, %

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

Expert Perspective Although distinguishing among thrombotic thrombocytopenic purpura, typical hemolytic uremic syndrome, Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

0.0 0.3 2.0 1.5 0.0 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 placebo-treated 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 placebotreated 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 placebotreated 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. 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 % % % % Grades All Grades All Grades All Grades All Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue Asthenia Edema peripheral Mucosal inflammation Pyrexia

27.1 0.0 26.2 0.9 12.0 17.8 0.0 20.6 1.9 2.8 10.3 0.0

2.8

0.0 25.5 1.1 0.0 16.0 2.1

0.0

0.9

0.0

21.5 0.0 26.2 1.9 10.3 0.0 16.8 0.0

2.8 8.3

0.0 25.5 0.0 0.0 8.5 0.0

5.3

0.0

66.4 0.0 65.4 0.0 2.8 21.5 1.9 26.2 0.9 11.1

0.0 67.0 0.0 0.0 28.7 1.1

Skin and subcutaneous tissue disorders Alopecia Rash

Cosmos Communications K

and atypical hemolytic uremic syndrome (see Table 1 in the online version of this article at www.ascopost.com) is warranted, it can take several days to obGastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory Neuropathy 12.1 0.9 8.4 0.9 1.9 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 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 NCI-CTCAE (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 patients 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.

tain appropriate test results. When the diagnosis of thrombotic thrombocytopenic purpura is suspected, emergent continued on page 68

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Hematology Expert Review Hemolytic Anemia continued from page 67

therapeutic plasma exchange should be initiated immediately, without waiting for confirmatory test results, due to the substantially high mortality associated with untreated or misdiagnosed thrombotic thrombocytopenic purpura.1,2 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, % Grades All Grades All Grades All 3–4 Grades 3–4 Grades 3–4 Grades % % % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 Asthenia 9.7 0.0 14.7 1.3 13.2 Edema peripheral 11.1 0.0 4.0 0.0 9.2 Mucosal 23.6 0.0 20.0 0.0 17.1 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 Rash 19.4 0.0 10.7 0.0 21.1 Dry skin 5.6 0.0 9.3 0.0 10.5 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 Dyspepsia 25.0 1.4 8 0.0 22.4 Nausea 52.8 0.0 53.3 2.7 44.7 Vomiting 40.3 0.0 36.0 2.7 39.5 Constipation 18.1 0.0 22.7 0.0 15.8 Stomatitis 13.9 0.0 17.3 0.0 11.8 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 Anemia 19.4 1.4 9.3 4.0 38.2 Leukopenia 22.2 19.4 16.0 12.0 17.1 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 peripheral Headache 22.2 0.0 14.7 0.0 17.1 Dysgeusia 11.1 0.0 13.3 0.0 21.1 Dizziness 8.3 0.0 8.0 1.3 15.8 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 Arthralgia 11.1 0.0 12.0 0.0 6.6 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 Dyspnea 12.5 0.0 8.0 2.7 10.5 Epistaxis 11.1 0.0 10.7 0.0 15.8 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5

3.9 1.3 0.0 1.3 0.0 0.0 1.3 0.0 0.0 11.8 0.0 0.0 5.3 0.0 0.0 46.1 17.1 11.8 17.1 11.8 2.6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.3 1.3 0.0 0.0 0.0 0.0 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) 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)

This approach is somewhat analogous to immediate initiation of aspirin or ATRA (all-trans retinoic acid) at the first suspicion of ischemic heart disease or acute promyelocytic leukemia, respectively. Timely (“medical emergency’) intervention with daily plasma exchange substantially reduces the mortality associated with thrombotic

thrombocytopenic purpura from 90% to less than 25%.3-5 Interestingly, as in our patient, pregnancy can trigger development of both acquired and congenital thrombotic thrombocytopenic purpura. The guidelines developed by the British Committee for Standards in Haematology and the British Transplantation Society

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA.

8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients.

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.

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 of PERJETA were observed between these patients and younger patients.

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 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 or within 7 months following the last dose of PERJETA in combination with trastuzumab, 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 or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, 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 (5.2), Clinical Pharmacology (12.3)].

Cosmos Communications K

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 7 months following the last dose of PERJETA in combination with trastuzumab. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, 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)].

endorse that microangiopathic hemolytic anemia and thrombocytopenia due to ADAMTS13 deficiency occurs either due to autoantibodies against ADAMTS13 or ADAMTS13 deficiency secondary to mutations.2 Plasma exchange removes the immunoglobulin G autoantibody against ADAMTS13 and replenishes ADAMTS13 levels.1,2 A recombinant form of ADAMTS13 is currently in the early stages of development and hopefully will make its way into therapeutics.6 Question 2: In the current era, the majority of patients with thrombotic thrombocytopenic purpura will receive therapeutic plasma exchange before the development of “classic pentad”? Correct Answer: A. True.

Expert Perspective Once obvious precipitating causes of microangiopathic hemolytic anemia and thrombocytopenia are excluded, the consensus is to initiate therapeutic plasma exchange.2,3 This approach with “presumptive diagnosis of thrombotic thrombocytopenic purpura” has made the “classic pentad” a rare presentation in an individual patient.

8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

Question 3: What is the next best step in management of this patient? Correct Answer: A. Emergency blood cultures and initiation of broadspectrum antibiotics.

10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

Expert Perspective

17 PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)] • Advise pregnant women and females of reproductive potential that PERJETA exposure can result in fetal harm, including embryo-fetal death or birth defects [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)] • Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab [see Warnings and Precautions (5.2) and Use in Special Populations (8.6)] • Advise nursing mothers treated with PERJETA to discontinue nursing or discontinue PERJETA, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)] • If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who are exposed to PERJETA during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)]

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

In this evolving clinical course, new findings need to be addressed and not assumed to be due to persistent or recurrent thrombotic thrombocytopenic purpura, although it should be considered. The new clinical finding of fever can be associated with recurrent thrombotic thrombocytopenic purpura. The clinical findings of fever, severe hypotension, and bleeding are concerning for sepsis-associated disseminated intravascular coagulation, a known complication of therapeutic plasma exchange.7 The laboratory values, especially the high prothrombin time and the low fibrinogen level, strongly favor acute disseminated intravascular coagulation. Thus, the most appropriate best first step was to draw blood cultures and start broad-spectrum antibiotics to stabilize the patient. Twenty-four hours later, the blood cultures grew methicillin-resistant Staphylococcus aureus, thought to originate from the plasmapheresis catheter, which was removed. Forty-eight hours later, she had recovered, but the platelet count dropped to 18,000/μL. Repeat examination of the peripheral

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Hematology Expert Review

blood smear film revealed schistocytes, anemia, and thrombocytopenia. A new pheresis catheter was placed, plasma exchange was restarted (recurrent thrombotic thrombocytopenic purpura), and antibiotics were continued. Repeat blood cultures were negative. The platelet count rapidly increased to 210,000/μL after 3 days of plasma exchange. Following stabilization, she was discharged and sent home in excellent condition, with follow-up in the hematology clinic. Eculizumab (Soliris) is a monoclonal antibody approved by the U.S Food and Drug Administration for the treatment of pediatric and adult patients diagnosed with atypical hemolytic uremic syndrome.8 Eculizumab binds with high affinity to complement protein C5, blocking the formation of the C5b-9 cell membrane attack complex, leaving proximal functions of opsonization and immune clearance intact. Eculizumab is not indicated for sepsis-associated acute disseminated intravascular coagulation or recurrent thrombotic thrombocytopenic purpura. n

Disclosure: Drs. Abutalib and Connors reported no potential conflicts of interest.

References 1. Schwartz J, Winters JL, Padmanabhan A, et al: Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: The sixth special issue. J Clin Apher 28:145-284, 2013. 2. Scully M, Hunt BJ, Benjamin S, et al: Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 158:323-335, 2012. 3. George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 371:654-666, 2014. 4. Tsai HM: Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14:1072-1081, 2003. 5. Sadler JE: Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112:11-18, 2008. 6. Plaimauer B, Kremer Hovinga JA,

GUEST EDITORS

Syed A. Abutalib, MD

Jean M. Connors, MD

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

Jean M. Connors, MD, Assistant Professor, Harvard Medical School, Hematology Division, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston

Juno C, et al: Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost 9:936-944, 2011. 7. Basic-Jukic N, Kes P, Glavas-Boras S, et al: Complications of therapeutic plasma

exchange: Experience with 4,857 treatments. Ther Apher Dial 9:391-395, 2005. 8. Soliris (eculizumab) prescribing information, Alexion Pharmaceuticals Inc, 2011. Available at http://www.accessdata.fda.gov/ drugsatfda_docs/label/2011/125166s172lbl. pdf. Accessed April 19, 2015.

Announcements

ACCC Launches Immuno-Oncology Program for Community‐Based Cancer Care Providers

he Association of Community Cancer Centers (ACCC) has launched the Institute for Clinical Immuno-Oncology (ICLIO), a first-ofits-kind initiative aimed to facilitate the rapid adoption of immuno-oncology in the community cancer setting.

cal care, deciphering reimbursement, insurance, social work, and supporting patient access to emerging treatment options. “Immuno-oncology is becoming increasingly integral to cancer treatment, and education on its adoption

Immuno-oncology is becoming increasingly integral to cancer treatment, and education on its adoption in clinical practice is a critical need for providers and patients. —Lee S. Schwartzberg, MD, FACP

To help with the rapid uptake of immuno-oncology at the community level, the ACCC developed ICLIO as the premier source for immuno-oncology implementation resources. ICLIO enables medical professionals to offer their patients cutting-edge cancer care by educating them on the best practices for immuno-oncology integration into all aspects of care: clini-

in clinical practice is a critical need for providers and patients,” said Lee S. Schwartzberg, MD, FACP, Division Chief of Hematology/Oncology and Professor of Medicine at the University of Tennessee Health Science Center, Memphis, and Chair of ICLIO. “ICLIO resources will help guide multidisciplinary cancer teams through the practical application of immuno-

therapy to provide the best care possible for cancer patients.”

Five Domains ICLIO educational tools focus on five primary domains: clinical optimization, coverage and reimbursement, management best practices, patient access and advocacy, and training and development. ICLIO is open to all providers through ACCC, whose membership boasts more than 2,000 cancer programs and 20,000 providers nationwide. It is estimated that more than 60% of all cancer patients in the United States are treated by a health-care provider in the ACCC network. “ACCC is committed to being a leader in cancer care education by providing the most up-to-date and innovative cancer treatment resources and information to our members,” said ACCC President Steven L. D’Amato, BSPharm, BCOP. “We recognize the critical need for offering immunotherapy in community cancer centers and established ICLIO to empower cancer care providers to address the dynamic intricacies of

Steven L. D’Amato, BSPharm, BCOP

immuno-oncology real-world treatment and delivery.” The ICLIO website is now live at accciclio.org, offering a wealth of resources. ICLIO will host its First Annual National Conference in Philadelphia, Pennsylvania on October 2, 2015, to explore the challenges and opportunities within the emerging clinical and operational applications of cancer immunotherapy. An Advisory Committee overseeing the planning and development of ICLIO is chaired by Dr. Schwartzberg and will comprise ACCC members and other immuno-oncology leaders. Bristol-Myers Squibb provided ACCC with a charitable contribution to develop the comprehensive ICLIO program. n

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials FOR NEWLY DIAGNOSED MULTIPLE MYELOMA

SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone. Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®. Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages. Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

80 Rd Continuous vs MPT Rd Continuous vs Rd18 Rd18 vs MPT

Logrank P value (2-sided) HR (95% CI) 0.72 (0.61, 0.85) P<0.0001 0.70 (0.60, 0.82) 1.03 (0.89, 1.20)

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

Progression-Free Survival (Years) •535 PFS Rd Continuous Rd18 541 MPT MM-020 547 Study design: The

Events: (52.0%), (64.3%), MPT=334/547 400Rd Continuous=278/535 319 265 218 Rd18=348/541 168 105 55 19 (61.1%)2 391 380 (FIRST)

319 265 167 304 244 compared REVLIMID170+

108 116 low-dose

56 30 58 28 (Rd) dexamethasone

7 2 6 1 Continuous until

0 0 0 progression,

trial fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed Number of Subjects at mg Risk patients who did not receive a stem cell transplant (SCT). REVLIMID was given 25 once daily orally on Days 1 to 21 of 28-day cycles, PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%) ≤75 years and 20 mg for patients and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID REVLIMID REMS® Program Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS®

program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436 Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken Tumor Flare Reaction: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) DRUG INTERACTIONS Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436 Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

The ASCO Post | AUGUST 25, 2015

PAGE 74

Announcements

John M. Cunningham, MD, to Chair Pediatrics at the University of Chicago

ohn M. Cunningham, MD, the Donald N. Pritzker Professor and Interim Chair of the Department of Pediatrics at the University of Chicago, has been formally appointed Chair of the department. An authority on the study and treat-

ment of childhood cancers, as well as the biology and therapy of hemoglobinopathies, Dr. Cunningham is known for his work on understanding the molecular mechanism underpinning red blood cell production. He has developed stem cell transplant techniques for the 70%

of children who do not have a sibling match. These approaches have made transplant an option for any child requiring this therapy. A native of Ireland, Dr. Cunningham earned his medical degree from University College Dublin,T:7”followed by a mas-

ter of science degree in biochemistry from King’s College London. He completed his residency at St. Laurence’s Hospital and a hematology fellowship at the Mater Misericordiae University Hospital, both in Dublin. In addition, he was a Wellcome Re-

REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Platelet counts

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM). 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)]. Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)]. 2.4 Starting Dose for Renal Impairment in MM Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)]. 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

ASCOPost.com | AUGUST 25, 2015

PAGE 75

Announcements

John M. Cunningham, MD

search Fellow in clinical science at the Royal Free Hospital School of Medicine in London, where he also completed his clinical training in bone marrow transplantation. In 1993, he joined the Divisions of Experimental Hematology and Bone Marrow Transplantation at St. Jude T:7” Hospital in MemChildren’s Research

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)]. Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

named Vice Chairman for Research in Pediatrics in 2008. He has served on the editorial board of the Journal of Biological Chemistry and is a reviewer for several journals. He is a member of the American Cancer Society’s Council for Extramural Grants, and Pediatric Series Editor for The Oncologist. n

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)]. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)]. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)]. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)]. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

phis, where he was appointed Director of the Cell and Gene Therapy Laboratories, as well as Chair of the Institutional Review Board. In December 2006, Cunningham moved to the University of Chicago to become Professor of Pediatrics and Section Chief of Hematology/Oncology and Stem-Cell Transplantation. He was

The ASCO Post | AUGUST 25, 2015

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Announcements

Karen Reckamp, MD, MS, Named Medical Director for Clinical Research Operations at City of Hope

edical oncologist and lung cancer researcher Karen Reckamp, MD, MS, has been named Medical Director for Clinical Research Operations at City of Hope. In this newly created position,

Dr. Reckamp will expand her current role as Chair of the Cancer Protocol Review and Monitoring Committee, in which she has been instrumental in supporting and shaping the regulatory, operational, and

scientific directives of the clinical research mission of City of Hope. As Medical Director, she’ll serve as Medical Advisor for Clinical Research Operations, as Medical T:7” Trials Unit, and as Director of the Clinical

5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] • Tumor Flare Reactions [see Warnings and Precautions (5.10)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] 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. 6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0)

36 (6.7)

(continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

Karen Reckamp, MD, MS

ASCOPost.com | AUGUST 25, 2015

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Announcements

Coordinating Liaison for pharmaceutical contracts. She will also share responsibility for the review and selection of clinical trials within City of Hope. “Dr. Reckamp has shown remarkable leadership as City of Hope moves to launch a new era of scientific research and lifesaving clinical trials,” said Larry W. Kwak, MD, PhD, Associate Director for

Developmental Therapeutics and Translational Research at City of Hope and Director of the Toni Stephenson Lymphoma Center. “Her deep knowledge of the complex regulatory and operational aspects of City of Hope’s clinical trials has been, and will continue to be, invaluable as we rapidly turn breakthrough research T:7”and cures.” into new treatments

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

Nationally known for her clinical research expertise, Dr. Reckamp is also Co-Chair of the institution’s Lung Cancer and Thoracic Oncology Program, helping expand options for people diagnosed with lung cancer. She is currently principal investigator for an arm of the National Cancer Institute’s NCIMolecular Analysis for Therapy Choice,

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

Back painc

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

Neck pain

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

Cellulitisc

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

8 (1.5)

0 (0.0)

Diabetes mellitus% e

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1% (continued)

Insomnia

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

46 (8.5)

30 (5.5)

10 (1.9)

4 (0.7)

1 (0.2)

Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Vascular disorders

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

< 1%

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

7 (1.3)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications

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Lower respiratory tract infection

known as the NCI-MATCH trial. Dr. Reckamp joined City of Hope in 2007 as Assistant Professor of Medicine in the Department of Medical Oncology & Therapeutics. In 2012, she became Associate Professor in the Department of Medical Oncology & Therapeutics Research, and Codirector of the Lung Cancer and Thoracic Oncology Program. n

The ASCO Post | AUGUST 25, 2015

PAGE 78

Announcements

James Metz, MD, Named Chair of Penn Medicine Department of Radiation Oncology

ames Metz, MD, has been named the Chair of the Department of Radiation Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The Morton M. Kligerman Professor of Radiation Oncology, Dr. Metz has been serving as Interim Chair since November 2014, and held a series of administrative positions within the

department beginning in 2005, when he was appointed Director of Clinical Operations. In 2009, he was appointed Vice Chair of the Clinical Division in T:7” and in 2010, beRadiation Oncology,

James Metz, MD

without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

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Announcements

came Director of Quality Assurance and Quality Improvement. Subsequently, in 2014, he was appointed Vice Chair of the department. Dr. Metz also led the development of the Roberts Proton Therapy Center, the largest proton center in the world that opened in 2010. His clinical research emphasizes multimodality

therapies for locally advanced gastrointestinal malignancies. “Dr. Metz is a collaborative and inclusive leader who has played an important role in elevating the department’s level of excellence and reputation, both nationally and internationally,” said J. Larry Jameson, MD, PhD, Dean of the T:7”Medicine. Perelman School of

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

Dr. Metz received his medical degree from the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson School of Medicine. He was a resident, and then Chief Resident, at the Hospital of the University of Pennsylvania beginning in 1996, and joined the Penn faculty in 1999. n

adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively). Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. 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 [see Warnings and Precautions Section (5.7 to 5.10)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

Dr. Metz has pioneered the use of online cancer survivorship care plans and Web-based cancer education and information. He is nationally recognized as the longtime Editor-in-Chief, and now Executive Director, of OncoLink, named on numerous occasions as one of the Top 10 medical websites in the world by the National Library of Medicine.

The ASCO Post | AUGUST 25, 2015

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Pankaj Sharda, MD, Joins Fox Chase Cancer Center Department of Medicine

ankaj Sharda, MD, has joined the Department of Medicine, Endocrinology Division at Fox Chase Cancer Center as an Attending Physician, where he will specialize in endocrinology, diabetes, and metabolism. “It is an honor to become part of such a

Pankaj Sharda, MD

prestigious and well-established organization as Fox Chase Cancer Center,” said Dr. Sharda. “Through a comprehensive multidisciplinary and individualized approach that combines groundbreaking research with the latest treatment options, I am able to offer patientsT:7” the care they need to

7.3 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 91 years of age. After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

achieve an optimum quality of life.” Dr. Sharda completed an internal medicine residency at Atlantic Health-Overlook Medical Center, where he served as Chief Resident in his final year. He completed his fellowship at Temple University Health Sciences, serving as Chief Fellow. n

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American University of Beirut Appoints Its 16th President, Fadlo R. Khuri, MD

he American University of Beirut (AUB) recently announced Fadlo R. Khuri, MD, as the 16th President of the University. Dr. Khuri is presently Professor and Chairman of the Department of Hematology and Medical Oncology, Emory University School of Medicine,

and holds the Roberto C. Goizueta Distinguished Chair for Cancer Research. He also serves as Deputy Director for the Winship Cancer Institute of Emory University. Dr. Khuri was recently appointed Executive Associate Dean for Research of T:7” School of Medicine. the Emory University

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)]. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)]. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.8)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.9)]. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)]. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. ©2005-2015 Celgene Corporation, All Rights Reserved. REV_MM_HCP_BS_v020 02_2015

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Fadlo R. Khuri, MD

His published work has been cited over 15,000 times. He serves as Editor-in-Chief of Cancer, and has served on more than a dozen prior editorial boards of major journals. Dr. Khuri has also served as a permanent member of multiple peer review committees for ASCO, the American Cancer Society, and the National Cancer Institute. He is an active member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the American Society for Clinical Investigation, as well as ASCO. Dr. Khuri earned his medical degree from Columbia University’s College of Physicians and Surgeons. He completed his residency in internal medicine at the Boston City Hospital, and his fellowship in hematology and medical oncology at the Tufts-New England Medical Center. He was on faculty at The University of Texas MD Anderson Cancer Center from 1995–2002 prior to joining Emory University and Winship Cancer Institute in 2003. Dr. Khuri said, regarding his new position, “It is a genuine honor and a privilege to have been selected to lead AUB into its 150th year. I will engage the AUB community…fully aware of my responsibility to help steward the mission of this great University and its community toward ever more meaningful accomplishment.” n Watch future issues of

The ASCO Post

Pat. www.celgene.com/therapies

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lung and aerodigestive cancers. Dr. Khuri’s has led the recruitment of over 90 faculty members, including 60 clinical investigators, to Emory University, helping oversee an increase in adult cancer patients placed on trial annually from 143 in 2002 to over 650 in 2014, and paving the way for National Cancer Institute (NCI) Comprehensive Cancer Center designation for Winship. Along with Haian Fu, PhD, Khuri founded Winship’s Cancer Drug Discovery, Development, and Delivery Program.

T:10”

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

An accomplished molecular oncologist and translational thought leader, Dr. Khuri’s clinical expertise and research are focused on the development of molecular, prognostic, therapeutic, and chemopreventive approaches to improve the standard of care for patients with

for an in-depth interview with Dr. Khuri on his new position.

The ASCO Post | AUGUST 25, 2015

PAGE 82

2015

2015 Oncology Meetings September 2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/ The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org 16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org Perspectives in Melanoma XIX September 11-12 • Cleveland, Ohio For more information: http://imedex.com/perspectivesmelanoma-conference/index.asp 24th Annual Symposium on Molecular Pathology: Clinical Applications of Genomic Medicine September 16-17 • Troy, Michigan For more information: http://cmetracker.net/BEAUMONT/

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 The Annapolis Breast Cancer Genomics Conference September 18 • Annapolis, Maryland For more information: http://www.eventbrite.com/e/theannapolis-breast-cancer-genomicsconference-cme-7-cme-creditsregistration-16864239394 2nd International Symposium of the Cancer Research Center of Lyon September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr 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

International Cancer Immunotherapy Conference: Translating Science Into Survival September 16-19 • New York, NY For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=54 &DetailItemID=309#.VXcJKVXtmko 18th Annual Meeting of the Chinese Society of Clinical Oncology September 16-20 • Xiamen, China For more information: www.csco.ac.cn

5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer. global-summit.com/americ

October Advances in Cancer ImmunotherapyTM October 2 • Nashville, Tennessee For more information: www.sitcancer.org/sitc-meetings/ aci2015/tn

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

Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

November 3rd International Conference on Hematology & Blood Disorders November 2-4 • Atlanta, Georgia For more information: http:// hematology.conferenceseries.com

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 13th Annual West Coast Colorectal Cancer Symposium October 23 • Seattle, Washington For more information: http://www.swedish.org/for-healthprofessionals/cme/conferences/ colorectal-cancer-symposium ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org Modern Management of Urologic Cancers: A Multidisciplinary Approach (Memorial Sloan Kettering) October 29-31 • New York, New York For more information: http://www.themerzgroup.com/ mskcc/mskcc-urologic-conference/

33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/ Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015 13th Annual School of Breast Oncology November 5-7 • Atlanta, Georgia For more information: http://www.gotoper.com/ conferences/sobo/meetings/13thAnnual-School-of-Breast-Oncology JADPRO Live at APSHO for Advanced Practitioners in O ncology November 5-8, 2015 • Phoenix, Arizona For more information: jadprolive.com City of Hope Presents: Multidisciplinary Approaches to Cancer Symposium November 5-8 • Las Vegas, Nevada For more information: https://cme.cityofhope.org/ eventinfo_5980.html

ASCOPost.com | AUGUST 25, 2015

PAGE 83

In the News Dermatologic Oncology

Public Urged Not to Overreact to Study Finding Link Between Citrus Fruits and Melanoma Risk By Charlotte Bath

study finding a link between citrus consumption and increased risk of melanoma1 may provide food for thought about the findings and implications as well as whet the appetite for more evidence, but according to several experts commenting on the study, it does not mean you should stop eating citrus fruits. “At this point in time, a public overreaction leading to avoidance of citrus products is to be avoided,” Marianne Berwick, PhD, MPH, wrote in an editorial accompanying the article in the Journal of Clinical Oncology.2 Yet in an interview with The ASCO Post, Dr. Berwick, Distinguished Professor, Department of Internal Medicine and Dermatology at the University of New Mexico, Albuquerque, said that was already happening. “Almost everywhere I go, I’ve had people asking about this,” she said, and whether they should stop eating citrus fruits. “It is a high-profile issue.” That high profile can be attributed to the prevalence of citrus fruits in the diet and their previously acknowledged health benefits, as well as coverage of the study in the national media. That cover-

age quotes study authors and others cautioning against abandoning citrus fruits. For example, in the NBC News coverage, study author Walter Willet, MD, of the Harvard School of Public Health, Boston, stated, “At this point in time, it is not a good idea to avoid citrus fruits.”3 In another article, the study’s corre-

Grapefruits and Orange Juice Analyzing data on 63,810 women in the Nurses Health Study and 41,622 men in the Health Professionals, the study found a 36% higher risk of melanoma among those who consumed overall citrus items 1.6 times or more a day vs less than twice a week.

Among individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors. —Marianne Berwick, PhD, MPH, and colleagues

sponding author, Abrar A. Qureshi, MD, MPH, of the Warren Alpert Medical School at Brown University, Providence, Rhode Island, declared: “We are not recommending changing fruit consumption, as these fruits and vegetables are important for overall health.”4 These and other articles also cited Dr. Berwick’s editorial and noted, as she did, the importance of using sun protection to reduce the risk of melanoma.

“Dietary intake was assessed using a validated food frequency questionnaire at least every 4 years,” according to the study report. “In all food frequency questionnaires, participants were asked how often on average (never to more than six servings per day) during the previous year they had consumed grapefruit (half), oranges (one), and grapefruit and orange juices (one small glass [6 oz]). Overall citrus consump-

tion was calculated as the sum of these individual products.” With up to 26 years of follow-up, 1,840 incident melanomas were documented. “Among individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors,” the authors reported. This apparent association between grapefruits and melanoma “may be explained by its higher levels of psoralens and furocoumarins when compared with oranges,” the researchers wrote in the study report. Psoralens and furocoumarins are “naturally occurring compounds with potential photocarcinogenic properties,” the researchers noted. “Psoralens had been used as tanning accelerators until 1996,” the investigators added, and individuals who had used psoralen tanning activators or sunscreens with psoralen had a higher risk of melanoma. “Orange juice consumption also showed a significant but less apparent association with melanoma risk,” the researchers reported. This “may be partly explained by its much higher continued on page 84

Don’t Miss These Important Reports in This Issue of The ASCO Post Steven J. Isakoff, MD, PhD, on Two Novel Agents in Metastatic Triple-Negative Breast Cancer Treatment see page 1

Leena Gandhi, MD, PhD, on Targeted Combinations and Immunotherapy in Non–Small Cell Lung Cancer see page 3

Sarah B. Goldberg, MD, MPH, on Immunotherapy in Small Cell Lung Cancer see page 8

Cesar Augusto Migliorati, DDS, MS, PhD, on Osteonecrosis of the Jaw in Cancer Treatment see page 15

Eduardo Bruera, MD, FAAHPM, on Cancer Pain Management at the End of Life see page 16

Jin Li, MD, on Regorafenib in Asian Patients With Previously Treated Metastatic Colorectal Cancer see page 24

Peter B. Bach, MD, MAPP, on the Value of Cancer Drugs see page 30

Sara A. Hurvitz, MD, on Everolimus Addition to FirstLine Trastuzumab/Paclitaxel in HER2-Positive Metastatic Breast Cancer see page 37

Mark R. Gilbert, MD, on Glioma Tumor Biology see page 44

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | AUGUST 25, 2015

PAGE 84

In the News Citrus Fruits and Melanoma continued from page 83

consumption levels, which contributed to more than 50% of overall citrus consumption,” the investigators stated. “Consumption of grapefruit juice and oranges was generally not associated with melanoma risk.” The findings were independent

of other lifestyle and dietary factors assessed. These factors included chronic diseases, family history of melanoma, exposure to sunlight, number of moles on arms, cigarette smoking, physical activity, vitamin C supplements, menopausal status, and postmenopausal hormone use among women. “Participants with higher cit-

rus intake were less likely to smoke cigarettes and drink coffee, more likely to exercise, and had higher intake of individual citrus products and vitamin C,” the researchers reported. “In contrast, there was no appreciable difference in sun exposure–related variables and other host risk factors over the intake categories.”

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Factors Limiting Study Enthusiasm “The study has much strength. The rationale is clear, the study was large, and data were collected prospectively,” Dr. Berwick wrote in her editorial. She went on, however, to elucidate a “number of factors” that “limit enthusiasm for this study.” “The first and most important factor is that the study population is not representative of the general population,” Dr. Berwick asserted. The mean Breslow thickness, “the major prognostic factor for melanoma,” was 0.63 mm, far lower than that in the general population studies, including two studies cited by Dr. Berwick, with mean Breslow thicknesses of 1.28 mm and 1.49 mm. “Such a large difference could be accounted for by the fact that these were health professionals who developed melanoma and might be expected to pay more attention to unusual lesions. Such differences underline the lack of representativeness of the population studied,” she wrote. Among the 1,840 documented cases of melanoma in the study, 891, or nearly 50%, were in situ melanomas. “These are very, very thin melanomas,” Dr. Berwick added in the interview with The ASCO Post, and “are often indolent. Very rarely do they cause problems.” The study excluded people with a history of nonmelanoma skin cancer. “Such a history confers a twofold increased risk for developing melanoma. Thus, an artificial bias may have been introduced by eliminating a group who were at significant risk for developing melanoma and who might not have the same risk associated with citrus consumption,” Dr. Berwick pointed out. “Why exclude them? That made no sense to me,” Dr. Berwick said. “You don’t know which direction that will bias the results. It might make them less significant, or it might make them more significant. We don’t know.”

Intermittent vs Continuous Sun Exposure The study found “intermittent ultraviolet exposure, such as that obtained on weekends and holidays, was not associated with melanoma among this group. Instead, continuous exposure was associated, which is at odds with the current literature; continuous exposure does not demonstrate an increased risk for developing melanoma,” Dr. Berwick also noted. In a previous article from the University of New Mexico, Dr. Berwick pointed out that the common lifestyle pattern of being indoors most of the week and then trying to make up for that by staying outdoors as much as possible during the weekend “puts us

ASCOPost.com | AUGUST 25, 2015

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In the News

at higher risk for skin cancer because of our skin’s intermittent exposure to the sun. This irregular exposure prevents our skin from adapting to the sun’s damaging ultraviolet rays.”5

‘Clearly a Need for Replication’ “This is a potentially important study, given that citrus consumption is widely promulgated as an important dietary constituent and has demonstrated benefit for coronary heart disease, cancer prevention, and overall health effects,” Dr. Berwick concluded. In addition to warning against overreaction that could cause people to avoid eating citrus products, Dr. Berwick called for further epidemiologic studies. “There is clearly a need for replication of the

study findings in a different population before modifying current dietary advice to the public,” she stated. n Disclosure: Dr. Berwick reported no potential conflicts of interest.

References 1. Wu S, Han J, Feskanich D, et al: Citrus consumption and risk of cutaneous ma-

lignant melanoma. J Clin Oncol. June 29, 2015 (early release online). 2. Berwick M: Dietary advice for melanoma: Not ready for prime time. J Clin Oncol. June 29, 2015 (early release online). 3. Fox M: Could too much citrus cause skin cancer? NBC News, June 29, 2015. Available at nbcnews.com. Accessed July 23, 2015.

4. Doyle K: Citrus fruit linked with melanoma in preliminary study. WHBL News, June 29, 2015. Available at whbl.com. Accessed July 23, 2015. 5. Frank L: Three questions for skin cancer investigator Dr. Marianne Berwick. University of New Mexico Health Sciences Center news release, May 1, 2014. Available at hscnews.unm.edu. Accessed July 23, 2015.

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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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PAGE 86

In the News

Expect Questions About Increased Risk of Melanoma From Consuming Grapefruits and Orange Juice

“C

ould too much citrus cause skin cancer?” was the lead-in of an NBC News item about a study linking consumption of grapefruits and oranges to an increased risk of melanoma.1 “Citrus consumption and skin cancer: How real is the link?” was the question posed by a headline in The Washington Post.2 With such media coverage, patients may be questioning whether they should stop eating and/or drinking citrus products. A study in the Journal of Clinical Oncology found a 36% higher risk of melanoma among those who consumed overall citrus items 1.6 times or more a day vs less than twice a week, but the study authors cautioned that “further investigation is needed to confirm our findings and explore related health implications.”3 Other researchers and clinicians have pointed out that the study results do no warrant abandoning grapefruit, oranges, or other citrus fruits and their juices. “I love grapefruits and grapefruit juice and oranges and orange juice and am continuing to eat them,” Marianne Berwick, PhD, MPH, Distinguished Professor, Department of Internal Medicine and Dermatology at the University of New Mexico,

Albuquerque, told The ASCO Post. In an editorial accompanying the study report in the Journal of Clinical Oncology, Dr. Berwick, wrote: “For people who would be considered at high risk, the best course might be to advise individuals to use multiple sources of fruit and juice in the diet and to use sun protection, particularly if one is sun sensitive.”4

Getting Full Benefit of Sunscreen In a previous article from the University of New Mexico, Dr. Berwick acknowledged that being outdoors has beneficial mood and health effects, and “it’s very natural to want to be in the sun. What’s unnatural is when we’re indoors all week and then stay outdoors all weekend. This increasingly common lifestyle puts us at higher risk for skin cancer because of our skin’s intermittent exposure to the sun.”5 Protection from the sun should include seeking shade, wearing hats and protective clothing, and properly and adequately using sunscreen. “We don’t use enough sunscreen,” Dr. B erwick stated. “To get the full benefit, apply sunscreen half an hour before going out and then half an hour after being out. It’s very

important that you reapply sunscreen every 2 hours or so while outside.”

Dangers of Indoor Tanning Dr. Berwick implored people not to use tanning salons. “In some cases, tanning salons may be providing 10 times as much ultraviolet radiation as the sun,” Dr. Berwick told The ASCO Post, so those using such salons “are really dosing themselves.” On a positive note, a recent research letter in JAMA Dermatology noted that use of indoor tanning among U.S. adults

the decrease in indoor tanning.” Another research letter, however, noted that indoor tanning is common at places other than tanning salons, such as private homes and gyms. “Some indoor tanning users might seek out gyms to circumvent the federal tanning excise tax, which gyms are not required to collect. Nonsalon tanning locations also seem to attract more high-risk tanners (ie, those who are depressed or have a dependence on tanning),” the authors noted.7 The writers of both letters stressed

It’s very natural to want to be in the sun. What’s unnatural is when we’re indoors all week and then stay outdoors all weekend. This increasingly common lifestyle puts us at higher risk for skin cancer…. —Marianne Berwick, PhD, MPH

had dropped, with 1.6 million fewer women and 0.4 million fewer men using indoor tanning in 2013 than in 2010.6 This decrease “may be partly attributed to the increased awareness of its harms,” the authors wrote. “In addition, a 10% excise tax on indoor tanning was implemented in 2010, which may have contributed to

King Penguins, South Georgia Island, Antarctic

King penguins form colonies that can number several hundred thousand. Once the young hatch, they remain on land for about a year, forming large aggregations while they await the return of their parents with food. How each individual parent identifies its own young amidst the mob is a mystery to me! Photo courtesy of Michael E. Ross, MD, copyright 2015. Send your photo and caption to editor@ASCOPost.com.

the importance of physician counseling to reduce indoor tanning. n Disclosure: Dr. Berwick reported no potential conflicts of interest.

References 1. Fox M: Could too much citrus cause skin cancer? NBC News, June 29, 2015. Available at nbcnews.com. Accessed July 23, 2015. 2. Cha AE: Citrus consumption and skin cancer: How real is the link? The Washington Post, June 29, 2015. 3. Wu S, et al: Citrus consumption and risk of cutaneous malignant melanoma. J Clin Oncol 33:25002508, 2015. 4. Berwick M: Dietary advice for melanoma: Not ready for prime time. J Clin Oncol 33:2487-2488, 2015. 5. Frank L: Three questions for skin cancer investigator Dr. Marianne Berwick. University of New Mexico Health Sciences Center news release, May 1, 2014. Available at hscnews. unm.edu. Accessed July 23, 2015. 6. Guy GP Jr, et al: Recent changes in the prevalence of and factors associated with frequency of indoor tanning among US adults. JAMA Dermatol. July 1, 2015 (early release online). 7. Hillhouse J, et al: Prevalence and correlates of indoor tanning in nonsalon locations among a national sample of young women. JAMA Dermatol. June 24, 2015 (early release online).

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PAGE 88

In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Collaboration Between Surgeons and Medical Oncologists Improves Outcomes for Patients With Stage III Colon Cancer Collaboration between surgeons and medical oncologists “is associated with lower mortality without increased cost among patients with stage III colon cancer,” according to a study by Tanvir H ussain, MD, MSc, and colleagues from Johns Hopkins University School of Medicine, Baltimore, and the University of Michigan Health System, Ann Arbor. “We operationalized collaboration between surgeons and oncologists as the number of patients they shared (ie, when both providers bill for medical services for the same patient), because this has been shown to reflect advice seeking and referral relationships between physicians,” the authors explained.

Survival Benefit An increase from one to five in the number of patients receiving shared care from a surgeon and medical oncologist “translated into an approximately 20% improved survival benefit from all-cause and colon cancer–specific mortalities,” the researchers reported the Journal of Oncology Practice. Coordination of cancer care has been identified as a “priority area for improvement” by the National Institutes of Medicine, the investiga-

tors noted. Explaining their focus on stage III colon cancer, they wrote: “Stage III colon cancer requires timely surgery and adjuvant chemotherapy to improve survival. Because this involves coordination between specialists, patients with stage III colon cancer are vulnerable to poor coordination; many patients do not receive guideline-concordant care, and disparities exist.”

Study Details The retrospective cohort study looked at patients with stage III colon cancer identified using Surveillance, Epidemiology, and End Results (SEER)-Medicare data and diagnosed between 2000 and 2009. All patients were over age 65, slightly more than 57% were female, and close to 86% were white. Overall, 5,160 patients (55.3%) died during the 12-year observation period, which extended until December 31, 2011. The median survival time was 5.3 years. “A total of 9,329 patients received care from 3,623 different surgeons and 2,319 medical oncologists, representing 6,827 unique surgeon–medical oncologist pairs,” the investigators found. The median number of shared patients was three. “As the number of patients shared between specialists increased from one to five (25th to 75th percentile), patients experienced an approximately 20% improved survival benefit from all-cause and colon cancer–specific mortalities. Spe-

cifically, for each additional patient shared between oncologist and surgeon, all-cause mortality improved by 5% (hazard ratio = 0.95; 95% confidence interval [CI], 0.92–0.97), and colon cancer–specific mortality improved by 5% (subhazard ratio = 0.95; 95% CI, 0.91–0.97),” the researchers reported. They found no association between collaboration and cost of care. “Even after accounting for whether specialists worked in the same or different hospitals, patient sharing remained associated with lower mortality, which may suggest that additional informal mechanisms are important,” the investigators pointed out. “Facilitating formal and informal collaboration between specialists may be an important strategy for improving the care of patients with complex cancers,” they concluded Hussain T, et al: J Oncol Pract 11:e388e397, 2015.

Statin Use Not Associated With Reduced Mortality Among Patients With Primary Colorectal Cancer Statin use was not associated with reduced mortality among patients diagnosed with primary colorectal cancer between 2003 and 2009 and followed for a median of 3.4 years in the Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study, an ongoing population-based study of colorectal cancer in southwest Germany. Writing in the Journal of the National Cancer Institute, Michael Hoffmeister, PhD, of the German Cancer Research Center in Heidelberg, and colleagues acknowledged that statins had been associated with moderate reductions in mortality among patients with colorectal cancer in previous studies but noted that “these studies lacked adjustment for some potentially relevant factors associated with statin use.” The reported effects of statins in these previous studies “might reflect incomplete control for stage at diagnosis and other factors associated with the use of statins.” In the current study, “the use of statins and other risk or protective factors were assessed in standardized interviews with 2,697 patients,” the researchers reported. The average age of the patients was 68 years, 40%

were women, and 412 patients (15%) had used statins. The use of statins was associated with being older, male, having a higher body mass index, greater number of pack years of smoking, more frequent use of nonsteroidal anti-inflammatory drugs, and a lower cancer stage. Among the 412 statin users, 59% had stage I or stage II disease, compared with 51% of the 2,285 patients who had not used statins. Along with higher rates of hypercholesterolemia, 88% for statin users vs 21% for nonusers, statin users were more likely to have a history of diabetes, myocardial infarction, stroke, and heart failure and to have general health checkups. “Follow-up included assessment of therapy details, recurrence, vital status, and cause of death. Information about molecular pathological subtypes of colorectal cancer was available for 1,209 patients,” the authors added. A total of 769 patients (29%) died during follow-up. “After a median follow-up of 3.4 years, use of statins was not associated with overall (hazard ratio [HR] = 1.10, 95% CI = 0.85–1.41), colorectal cancer–specific (HR = 1.11, 95% CI = 0.82–1.50), or recurrencefree survival (HR = 0.90, 95% CI = 0.63–1.27),” the authors reported. However, in a subgroup of patients with stage I and II disease who used statins better recurrence-free survival was reported but not better colorectal cancer–specific survival.

Subgroup Analyses “Subgroup analyses according to duration of use, active ingredient, and by age, sex, colorectal cancer stage and location, and by conduct of chemotherapy also suggested no improvement of overall or colorectal cancer–specific survival with the use of statins,” the authors continued. “Furthermore, analyses by the more common forms of major molecular pathological subtypes of colorectal cancer (MSI, CIMP, KRAS, and estrogen receptor–beta expression) did not indicate an association of statin use with improved survival,” they added. n Hoffmeister M, et al: J Natl Cancer Inst 107:djv045, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | AUGUST 25, 2015

PAGE 89

Erratum

recent installment of Inside the Black Box, published in the July 25 issue of The ASCO Post (“FDA’s Pregnancy Category Labeling,” by Todd Palmby, MD, and Eias Zahalka, PhD, MBA), described a risk evaluation and mitigation strategy (REMS) for vismodegib (Erivedge). This product actually does not have an associated REMS for embryo-fetal toxicity (although the risk information is included in the label and medication guide). We regret the error. The corrected text, including the complete question and answer that contained the misinformation, appears below. Does the indicated patient population matter when determining the level of FDA’s concern about a product that can cause embryo-fetal harm? Dr. Palmby: Yes, the patient population is a large part of how FDA determines the level of risk management that is necessary for a product. Many components are considered, including animal data (eg, severity of effects, relative exposure) and mechanism of action, age range and reproductive potential of the population to be treated, the intended prescribers, whether patients have been previously treated, and the stage of the disease. For example, the active ingredient in vismodegib (Erivedge) is a hedgehog pathway inhibitor, which caused severe malformations in offspring of pregnant rats at exposures significantly lower than those observed in patients treated with the recommended dose. Similar findings were first

observed with cyclopamine, a plant alkaloid that also inhibits the hedgehog pathway and causes craniofacial deformities in the offspring of sheep grazing in fields with weeds containing this chemical. In addition, there is a large body of literature describing the critical role of the hedgehog

pathway in embryonic development. Following an extensive discussion among FDA reviewers and the applicant, it was decided that certain elements should not be included in a risk management plan for embryo-fetal toxicity due to the specific indicated population and the impact those ele-

ments may have on patient access to the product. The package insert and the medication guide put into place when vismodegib was approved were deemed sufficient for that indication, but a risk management plan would have to be reevaluated for any subsequent indications considered for approval. n

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The ASCO Post | AUGUST 25, 2015

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Perspective Suresh S. Ramalingam, MD continued from page 1

Updated Clinical Data Monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) receptors have demonstrated superiority over chemotherapy in three randomized clinical trials reported at the 2015 ASCO Annual Meeting. Nivolumab (Opdivo), which targets the PD-1 receptor, was recently approved by the U.S. Food and Drug Administration for the treatment of patients with advanced-stage squamous NSCLC following disease progression on prior platinum-based chemotherapy. This approval was based on a phase III study demonstrating superior overall survival for nivolumab over docetaxel (9.4 months vs 6.0 months, hazard ratio = 0.59).1 The response rate and progression-free survival were also more favorable with nivolumab. Another study that compared nivolumab with docetaxel in patients with advanced nonsquamous histology also met its primary endpoint of improving overall survival (12.2 months vs 9.4 months, hazard ratio = 0.73).2 In both of these studies, the overall toxicity profile was more favorable with nivolumab. Treatment-related grade 3/4 adverse events were observed in 54% of patients treated with docetaxel, compared with 10% of patients treated with nivolumab. Atezolizumab, a monoclonal antibody against PD-L1, was associated with improved outcomes when compared with docetaxel in a randomized phase II study reported by Spira and colleagues at the 2015 ASCO Annual Meeting.3 Pembrolizumab (Keytruda), another antibody against PD-1, and a number of other agents of this class have also demonstrated single-agent activity in lung cancer.4

Similar Scenario to EGFR Inhibitors A consistent observation across these studies is the durability of benefits with immune checkpoint inhibitors. For patients who experience an objective response, the duration of response is significantly longer with immunotherapy than with chemotherapy. This finding makes immunotherapy a particularly appealing option for the treatment of lung cancer. However, the response rates for all of these agents are approximately 15% to 20% in unselected patients, which implies that the therapeutic benefits are limited to a subset of patients who receive

immune checkpoint inhibitors. This situation is not unlike the early years of development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors; they were associated with objective responses in approximately 15% of patients, which was attributed later to the presence of an activating EGFR mutation. It is therefore imperative to identify biomarkers to select patients to maximize the impact of these novel therapies in patients with lung cancer.

results. This might necessitate fresh tumor biopsy for patients who are under consideration for immune checkpoint inhibitor therapy. The antibody utilized for immunohistochemistry is unique for the companion diagnostic test developed for each checkpoint inhibitor. Furthermore, for each of the agents under development, the threshold for PD-L1 positivity is defined differently. This will undoubtedly pose challenges to the pathologist and treating physician, since tissue availability is limited

These exciting results open tremendous possibilities for future research studies and keep our hope alive that cures can be achieved for at least a subset of patients with advanced NSCLC. —Suresh S. Ramalingam, MD

Expression of PD-L1 in the tumor tissue has emerged as a putative biomarker in the studies reported recently. With atezolizumab, the outcomes were significantly superior for patients with expression of PD-L1 in either the tumor cells or immune-infiltrating cells. The efficacy of pembrolizumab was also higher in patients who had PD-L1–positive tumors, which was defined as positive staining by immunohistochemistry in more than 50% of cells. In the studies with nivolumab, the predictive potential of PD-L1 expression was variable. In the trial for squamous cell carcinoma, PD-L1 expression was not a predictive marker for efficacy. However, the nonsquamous cell study demonstrated improved efficacy for nivolumab in patients with PD-L1–positive tumors. In PD-L1– negative cancers, the efficacy did not appear to be superior for nivolumab over docetaxel. Based on these observations, it is likely that the approval of certain immune checkpoint inhibitors will be restricted to patients with PDL1–positive tumors.

PD-L1 Biomarker Limitations Assessment of PD-L1 expression is subject to several potential limitations. Tumor heterogeneity is well known in NSCLC. This could influence PD-L1 expression, since the majority of biopsies are obtained by a fine-needle approach in patients with advanced lung cancer. Dynamic changes in PD-L1 expression with time and intervening therapy can also limit interpretation of

in patients with NSCLC. In addition, scoring for the biomarker is subject to interobserver variability. For all these reasons, assessment of PD-L1 expression is likely to be challenging in some patients. The International Association for Study of Lung Cancer (IASLC) plans to compare the antibodies used for iummunohistochemistry for various checkpoint inhibitors against one another to arrive at a common test that could be used to select treatment. This effort is critical to make biomarker assessment possible in “real-world” settings.

Potential Predictors Under Study Although PD-L1 testing has been the centerpiece of biomarker evaluation in NSCLC, it is important to continue efforts to identify other potential markers. A recent study reported a strong correlation between mutational load and potential for benefit with checkpoint inhibitors.5 Smoking status is another potential predictor for benefit, with a higher response rate noted in current or former smokers.6 In addition, changes in circulating T-cell subpopulations are under study as potential predictive markers.

Clinical Questions Remain In the clinical setting, a number of important questions follow the recent success with checkpoint inhibitors. Studies are already underway to compare PD-1 inhibitors with combination chemotherapy in the front-line setting for advanced NSCLC. Combination strategies to evaluate checkpoint in-

hibitors with chemotherapy are being evaluated. The optimal duration of therapy is unknown, and the present approach involves treatment until disease progression. It is conceivable that continued treatment might not be necessary in at least certain patient subsets, and hence randomized clinical trials should be conducted to address this issue. In addition, efforts are underway to integrate immune checkpoint inhibitors in earlier stages of NSCLC. A phase III study is comparing treatment with a checkpoint inhibitor following concurrent chemoradiotherapy for stage III disease that is not amenable to surgical resection. In patients with resected NSCLC, the ALCHEMIST study will compare nivolumab with observation following adjuvant chemotherapy. The role of checkpoint inhibitors in combination with CTLA-4 (cytotoxic T-lymphocyte–associated antigen) inhibitors and certain molecularly targeted agents is also under evaluation. In summary, recent studies have established immune checkpoint inhibition as an effective treatment strategy for advanced NSCLC. These exciting results open tremendous possibilities for future research studies and keep our hope alive that cures can be achieved for at least a subset of patients with advanced NSCLC. n

Disclosure: Dr. Ramalingam has served on ad hoc advisory board meetings for and has received honoraria from AstraZeneca, Genentech, Merck, and Bristol-Myers Squibb.

References 1. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015. 2. Paz-Ares L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. 3. Spira AI, Park K, Mazières J, et al: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). 2015 ASCO Annual Meeting. Abstract 8010. 4. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015. 5. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Science 348:124-128, 2015. 6. Soria JC, Cruz C, Bahleda R, et al: Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer. 2013 European Cancer Congress. Abstract 3408. Presented September 29, 2013.

Daniel F. Hayes, MD President-Elect

Allen S. Lichter, MD

ASCO Chief Executive Officer

ASCO MEMBER SINCE 1986

ASCO MEMBER SINCE 1980

Julie M. Vose, MD ASCO President

ASCO MEMBER SINCE 1991

Join ASCO’s Leadership Development Program

SHAPE YOUR FUTURE & OURS Participants in this year-long leadership program will learn valuable leadership skills as well as gain extensive exposure to the mission of ASCO. This program requires a time commitment for travel and training. Applicants must have completed their final subspecialty training between 2006 and 2011.

THROUGH THE LEADERSHIP DEVELOPMENT PROGRAM, PARTICIPANTS WILL: • Participate in a diverse class of oncologists from different practice settings • Enhance your leadership skills through interactive sessions • Network and receive mentorship from ASCO leadership

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Atezolizumab (MPDL3280A)*: an investigational, engineered anti-PDL1 antibody

NOW ENROLLING IN LUNG CANCER Genentech is committed to exploring the potential of cancer immunotherapy by investigating the safety and efficacy of atezolizumab (MPDL3280A) in non-small cell lung cancer (NSCLC). Seven clinical trials† are now recruiting patients.

NON-SQUAMOUS Atezolizumab + chemotherapy ± bevacizumab compared with bevacizumab + chemotherapy NCT02366143—“IMpower 150”

Ph III

Atezolizumab + chemotherapy compared with chemotherapy

Ph III

NCT02367781—“IMpower 130” Atezolizumab compared with chemotherapy

Ph III

NCT02409342—“IMpower 110”

PD-L1+

SQUAMOUS Atezolizumab + chemotherapy compared with chemotherapy

Ph III 1L

NCT02367794—“IMpower 131” Atezolizumab compared with chemotherapy

Ph III

NCT02409355—“IMpower 111”

PD-L1+

NON-SQUAMOUS/SQUAMOUS

NSCLC

Atezolizumab compared with best supportive care following chemotherapy NCT02486718—“IMpower 010”

Atezolizumab (MPDL3280A)

Ph III 2L PD-L1+ Ph Ib

Atezolizumab + erlotinib‡

1L/2L

NCT02013219

EGFR+

Find out if your lung cancer patients are eligible for enrollment. For more information Visit:

Locate.AntiPDL1trials.com or ClinicalTrials.gov

Call:

Genentech Trial Information Support Line: 1-888-662-6728 (US only)

Email:

global.rochegenentechtrials@roche.com

*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 trials and should not be construed as a recommendation for use of any product for unapproved purposes. † All trials consistent with information on ClinicalTrials.gov as of July 2, 2015. ‡No limit to the number of prior therapies except for epidermal growth factor receptor tyrosine kinase inhibitors.