TAP Vol 6 Issue 3 by Harborside Press LLC

Pancreatic Cancer 11-13 | Geriatrics for the Oncologist

| Hematology Q&A

45, 50

| Triple-Negative Breast Cancer

VOLUME 6, ISSUE 3

FEBRUARY 25, 2015

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

Gastrointestinal Cancers Symposium

Ramucirumab Added to FOLFIRI Yields Results Similar to Bevacizumab or Aflibercept in Second-Line Colorectal Cancer Higher Price a Concern By Caroline Helwick

he phase III international RAISE trial found that ramucirumab (Cyramza) extends survival when given with chemotherapy to metastatic colorectal cancer patients who progress on treatment,1 but some experts commented that “financial toxicity” might be an issue, given the modest benefit. “The RAISE trial met its primary endpoint. The addition of ramucirumab induced an increase in overall survival, with a hazard ratio [HR] of 0.84. The addition of ramucirumab also significantly increased progression-free survival,” said Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall d’Hebron University Hospital and Director of the Vall d’Hebron Institute of Oncology in Barcelona.

By Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

Ramucirumab Background Ramucirumab is a fully humanized monoclonal antibody that inhibits angiogenesis by targeting the vascular endothelial growth factor (VEGF) receptor 2 and prevents binding of Josep Tabernero, MD, PhD VEGF. It was approved by the U.S. Food and Drug Administration in 2014 to treat gastric or gastroesophageal junction cancer and non– small cell lung cancer following progression. The RAISE study randomly assigned 1,072 patients to second-line treatment with FOLFIRI (leucovorin, continued on page 4

Issues in Oncology

ABIM President Richard J. Baron, MD, Announces Immediate Changes to Maintenance of Certification Program

Translational Research: Under Assault From the Bottom Line

ne of the disheartening aspects of becoming a senior medical administrator is that you have the opportunity to view the health-care system from two sides. From the Presidential suite, it is clear that there is increasing chaos in health care in the United States, characterized by blowouts of expenditures, falling patterns of reimbursement, a government that doesn’t have a solution to paying the bills, an inflated pharmaceutical bottom line, a profession faced with increasing uncertainty (and potentially inadequate staffing numbers in cancer care), and a public that fears the increasing costs of health insurance and copays while continuing to demand every innovation continued on page 90

Dr. Raghavan is President, Levine Cancer Institute, Charlotte, North Carolina. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

he American Board of Internal Medicine (ABIM) announced substantial changes to its Maintenance of Certification (MOC) program and indicated a desire to work more closely with the internal medicine community. ABIM President and CEO Richard J. Baron, MD, MACP, reached out to diplomates via e-mail to open a conversation on how to improve MOC with the following statement: ABIM clearly got it wrong. We launched programs

that weren’t ready and we didn’t deliver an MOC program that physicians found meaningful. We want to change that. Nearly 80 years ago, the American Medical Association and the American College of Physicians founded the ABIM, which was charged with distinguishing the discipline of internal medicine from other forms of practice by creating uniform standards for internists. Those standards have evolved over the years, reflecting the dynamic nature of internal mediI have heard you, and ABIM’s Board cine and its more than 20 subspecialties. has heard you. We will continue to One year ago, ABIM listen to your concerns and evolve our changed its decennial MOC program to a more program to ensure it embodies our continuous one. This shared values as internists. change generated legiti—Richard J. Baron, MD, MACP mate criticism among in-

Oncology Meetings Coverage GI Cancers Symposium �� 1-5, 11-14 ASH �� 15-17, 21 SIOG ��23 SABCS �� 28-30 Stuart Lichtman, MD, on Geriatric Oncology ��23 ASCO Endorses ESMO Guidelines ��32-35 Direct From ASCO �� 41-44 New! Hematology Review ��45 Inside the Black Box �� 48 Amy C. Degnim, MD, on Atypical Hyperplasia �� 84 Letters to the Editor �� 88

continued on page 63

CMS to Cover Lung Cancer Screening, see page 66

A Harborside Press® Publication

The ASCO Post | FEBRUARY 25, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

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Joseph S. Bailes, MD Texas Oncology

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

Laurence H. Baker, DO University of Michigan Health System

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

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Hagop M. Kantarjian, MD MD Anderson Cancer Center

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

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

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

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

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Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

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David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Jay S. Cooper, MD Maimonides Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

John Cox, DO Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

E. David Crawford, MD University of Colorado

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

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

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ASCOPost.com | FEBRUARY 25, 2015

PAGE 3

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Surgery Plus Immunotherapy Improves Survival in Melanoma Patients With Gastrointestinal Metastases By Caroline Helwick

hen melanoma patients develop metastases to the gastrointestinal (GI) tract or pancreas, resection of these lesions may improve survival, according to two single-institution studies presented at the 2015 Gastrointestinal Cancers Symposium. In a study that earned a Merit Award, researchers reported that resection of GI metastatic lesions combined with systemic immunotherapy improved overall survival over either approach alone.1 “Treatment of GI melanoma metastases should include a combination of metastasectomy and immunotherapy,” said Gary Deutsch, MD, MPH, of the John Wayne Cancer Institute at Providence–St. John’s Health Center, Santa Monica, California. “And the ability to achieve a surgical cure results in a superior melanoma-specific survival, compared to palliative surgery.” The study reported by Dr. Deutsch, involving 457 patients, appears to be the largest series of GI tract melanoma metastases reported to date. The aim of the study was to clarify the role of surgical resection in the setting of systemic immunotherapy. “Our question was how to best manage melanoma patients who develop GI metastases, which are quite common. Traditionally, systemic treatment options were not very good for metastatic disease, and we were very aggressive with resecting isolated lesions,” he said. “That used to be the best we could offer these patients, but we actually achieved long-term survival in up to 15% of patients.” The availability of better systemic therapy—specifically ipilimumab (Yervoy) and anti–[programmed cell death 1 (PD-1)] agents—might enhance the effect of surgery when used in combination, the researchers postulated. Dr. Deutsch said he often sees patients who have disease progression on treatment with ipilimumab, which renders them ineligible to continue on a clinical trial of that agent. “They come to us, and we look at it from a systemic perspective,” he said. “They may have one small metastasis that is growing, which we can take out. Maybe it’s a resistant clone that is not responding to ipilimumab, and we can render them NED [no evidence of disease]…. We wanted to evaluate the subset of such patients with GI tract metastases.”

We are trying to change the treatment paradigm for metastatic disease. I think the combination approach is where we are headed, which will be even more exciting in the future, when we have both ipilimumab and the PD-1 inhibitors available, and potentially even newer, more effective agents. —Gary Deutsch, MD, MPH

Study Details The study was a review of 457 melanoma patients who developed GI tract metastases between 1971 and 2013. Median time from initial diagnosis to the identification of GI metastasis was 49.5 months. Of the 457 patients, 270 (59%) had undergone surgical resection of GI metastases; 308 (67%) had been treated with immunotherapy. The primary endpoint of the analysis was melanoma-specific survival after diagnosis of the GI metastases. The Kaplan-Meier analysis compared immunotherapy alone (ipilimumab, vaccine, interleukin-2 [Proleukin], interferon), surgery alone, combination therapy, and neither approach in a multivariable analysis. Patients who underwent surgery were further stratified by surgical intent.

Survival Advantage A statistically significant survival advantage was observed for patients who were treated with both surgery and immunotherapy. Median overall survival was 20 months for this group, compared to 13 months with surgery alone, 8 months with immunotherapy alone, and only 5 months when neither treatment was delivered (P < .01). When surgery was performed with curative intent, the outcomes were even better, with median survival being 30 months, vs 12 months when surgery was palliative (P = .02). The group receiving surgery plus immunotherapy did not significantly differ in terms of patient and tumor characteristics from the group undergoing surgery alone, so patient selec-

tion did not appear to strongly influence these findings, he said. On the multivariable analysis, factors significantly associated with survival included metastasectomy (hazard ratio [HR] = 0.54, P < .01), immunotherapy (HR = 0.68, P = .03), age at GI metastasis diagnosis (HR = 1.01, P < .01), and primary tumor location on the trunk vs head and neck; (HR = 1.66, P = .02). “Younger patients with longer median time from their primary diagnosis to GI metastasis were more often selected for surgical treatment,” he noted. Dr. Deutsch predicted that with increasing use of anti–PD-1 agents, “the survival differences may be even more pronounced.” In an interview with The ASCO Post, Dr. Deutsch indicated, “We are trying to change the treatment paradigm for metastatic disease. I think the combination approach is where we are headed, which will be even more exciting in the future, when we have both ipilimumab and the PD-1 inhibitors available, and potentially even newer, more effective agents.” “I think surgery will have a role in two ways,” he continued. “One is where patients treated with immunotherapy do not have a good response. I think there may be a role for aggressive surgical resection in selected patients.

Secondly, and more interestingly, is in situations where patients respond to immunotherapy except for one or two isolated sites. If we address these surgically, the two approaches can potentially be synergistic.”

Pancreatic Metastasectomy Improves Survival Similarly, in a study considered the largest series of its kind, researchers from Moffitt Cancer Center, Tampa, Florida, reported outcomes for melanoma patients who underwent resection of lesions isolated to the pancreas.2 This situation rarely occurs; therefore, this “large” series included only 24 patients, who underwent potentially curative resection between 1998 and 2013. The 5-year overall survival rate was 67% and 5-year disease-specific survival rate was 67%. Of the 24 patients, 10 died of their disease. These outcomes for disease-free interval and overall survival were comparable to those observed after resection of the more common metastases from renal cell carcinoma. The overall survival rate was higher than the previously reported 5-year survival of 27%, according to lead author Matthew P. Doepker, MD, of Moffitt Cancer Center, who suggested, “Pancreatic metastasectomy for melanoma should be considered in select patients with isolated metastases,” he said. n

Disclosure: Drs. Deutsch and Doepker reported no potential conflicts of interest.

References 1. Deutsch GB, Kirchoff D, Bailey M, et al: Gastrointestinal metastases from melanoma. 2015 Gastrointestinal Cancers Symposium. Abstract 340. Presented January 16, 2015. 2. Doepker MP, Juan TH, Chen DT, et al: Association of pancreatic metastasectomy for melanoma with long-term overall survival. 2015 Gastrointestinal Cancers Symposium. Abstract 264. Presented January 16, 2015.

Treating Metastatic Melanoma ■■ Melanoma patients who develop isolated metastatic lesions to the GI tract can often undergo resection. ■■ Resection of GI metastatic lesions combined with systemic immunotherapy improved overall survival over either approach alone. ■■ Resection of isolated pancreatic lesions may also improve survival.

The ASCO Post | FEBRUARY 25, 2015

PAGE 4

Gastrointestinal Cancers Symposium Ramucirumab Plus FOLFIRI continued from page 1

fluorouracil, irinotecan) plus ramucirumab or placebo. Patients had shown disease progression during or following first-line combination therapy with bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine. The response rates were similar between the two arms—13.4% with ramucirumab; 12.5% with placebo— but ramucirumab significantly improved both progression-free and overall survival.

All Subgroups Benefited Median time to disease progression in patients receiving ramucirumab plus FOLFIRI was 5.7 months compared with 4.5 months in the placebo arm (HR = 0.79, P = .0005). Median overall survival was 13.3 months and

11.7 months (HR = 0.84, P = .0219), respectively. “All different subgroups benefited in terms of overall survival, and there was even more consistent benefit in progression-free survival,” he said. The

fatigue, diarrhea, and hypertension. “Though the rate of neutropenia was higher, the rate of febrile neutropenia, the clinically significant toxicity, was similar—3.6% vs 2.7% in the placebo arm,” said Dr. Tabernero, “and the ad-

The RAISE trial met its primary endpoint. The addition of ramucirumab induced an increase in overall survival, with a hazard ratio of 0.84. —Josep Tabernero, MD, PhD

arms were balanced for the proportion of patients (> 50%) receiving posttreatment regimens and the particular agents they received, he added. Treatment with ramucirumab plus FOLFIRI was well tolerated, though the addition of ramucirumab increased the incidence of grade 3/4 neutropenia,

verse events were manageable.” The study validates angiogenesis as an important target in colorectal cancer, he said. Other antiangiogenic agents approved in this malignancy include bevacizumab, ziv-aflibercept (Zaltrap), and regorafenib (Stivarga). Dr. Tabernero pointed out that the

study population was representative of patients seen in everyday practice. He cautioned, however, that the findings should not be extrapolated to other regimens used in colorectal cancer. n Disclosure: Dr. Tabernero reported a consulting or advisory role with Amgen, Celgene, Chugai Pharma, ImClone Systems, Lilly, Merck KGaA, Millennium Takeda, Novartis, Roche/ Genentech, Sanofi, and Taiho Pharmaceutical.

Reference 1. Tabernero J, Cohn AL, Obermannova R, et al: RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progressive during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 2015 Gastrointestinal Cancers Symposium. Abstract 512. Presented January 17, 2015.

EXPERT POINT OF VIEW

ommenting on the RAISE study at a press briefing held during the 2015 Gastrointestinal Cancers Symposium, moderator Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, acknowledged that improvements of 1 to 2 months in progression-free and overall survival appear modest. However, she said, “We want to offer patients all we can, because these agents [biologics] tend to be well tolerated, and they can be combined with chemotherapy.” Study discussant Wafik S. El-Deiry, MD, PhD, FACP, an American Cancer Society Professor and Deputy Director and Program Leader at Fox Chase Cancer Center, Philadelphia, indicated that RAISE is the third major study to show an overall survival benefit for antiangio-

(leucovorin, fluorouracil [5-FU], irinotecan) or FOLFOX (leucovorin, 5-FU, oxaliplatin) in the second line and VELOUR evaluated ziv-aflibercept (Zaltrap) plus FOLFIRI.

We want to offer patients all we can, because these agents [biologics] tend to be well tolerated and they can be combined with chemotherapy. —Smitha S. Krishnamurthi, MD

“Though the study designs were not the same, the outcomes appear similar,” he said. Overall survival was improved by approximately 1.5 months in each trial, with the addition of an antiangiogenic agent.

Future Study

Wafik S. El-Deiry, MD, PhD, FACP

genic therapy in the second line, after first-line chemotherapy plus bevacizumab (Avastin). The TML trial evaluated bevacizumab plus FOLFIRI

• Ramucirumab plus FOLFIRI vs anti–epidermal growth factor receptor (EGFR) plus FOLFIRI in the second line in the wild-type KRAS population

Randomized comparisons and studies of antiangiogenic combinations would be the next step, and the following were Dr. El-Deiry’s suggestions for future study: • Ramucirumab (Cyramza) plus FOLFIRI vs bevacizumab plus FOLFIRI in the second-line setting after FOLFOX plus bevacizumab • Ramucirumab plus FOLFIRI in patients who have received prior FOLFOX therapy without bevacizumab

• Single-agent ramucirumab in patients who cannot tolerate chemotherapy • Ramucirumab or ramucirumabplus-capecitabine maintenance • Ramucirumab plus FOLFIRI vs ziv-aflibercept plus FOLFIRI in the second line after prior F OLFOX or FOLFOX plus bevacizumb “We also need biomarkers to predict

response, and in 2015, we also need to assess and compare financial toxicities of these regimens,” he concluded.

Cost Considerations Colorectal cancer specialist eonard B. Saltz, MD, of Memorial L Sloan Kettering Cancer Center, commented to the speakers that ramucirumab and ziv-aflibercept in the second-line setting are “equivalent,” yet “ramucirumab [in gastric cancer and non–small cell lung cancer, where it is approved] is more than double the cost” of ziv-aflibercept and bevacizumab. He estimated that comparison at $12,000 vs $5,000. “I cannot think of a patient in whom the use of second-line ramucirumab would be appropriate, given the other alternatives,” Dr. Saltz said. He added that the trial showed a survival benefit over the control arm, but not over current standard care. Dr. El-Deiry responded that clinical trials in colorectal cancer will offer

I cannot think of a human being in whom I might consider secondline ramucirumab in colorectal cancer, because I don’t have any reason to believe it is meaningfully different from either bevacizumab or aflibercept. —Leonard B. Saltz, MD

ASCOPost.com | FEBRUARY 25, 2015

PAGE 5

Gastrointestinal Cancers Symposium Pancreatic Cancer: Latest Drug Development Hits and Misses By Caroline Helwick

argeting one of the deadliest cancers and seeking to fill an unmet need, drug development in pancreatic cancer is an area of high interest. This was certainly the case at the 2015 Gastrointestinal Cancers Symposium, where results were impressive for some novel agents but disappointing for several others.

This proof-of-concept study has exceeded its objectives, providing clear direction for the further development of IMM-101, in combination with chemotherapy, as a first-line treatment option for metastatic pancreatic cancer.

Hit: IMM-101 Given in combination with gemcitabine, the novel agent IMM-101 nearly doubled median overall survival time, vs gemcitabine alone, in an international randomized phase II study of 110 previously untreated patients with advanced pancreatic cancer.1 IMM-101 is a bacterially derived systemic immunomodulator given intradermally. In the IMAGE 1 trial, patients

Perspective continued from page 4

the opportunity to “determine what the niche will be for this drug, should there be one,” adding that “outside of a clinical trial, it is not appropriate to use this drug.”

Open Discussion Dr. Tabernero defended the “clean design” of the study “in a very homogeneous population” and its ability to demonstrate an effect in this population. “Whether the price for this effect [is fair] is an open discussion,” he said. In an interview with The ASCO

—Angus G. Dalgleish, MD

received up to 15 injections of IMM-101 over a maximum period of 12 cycles alongside gemcitabine. The combination was associated with consistent and significant improvements in overall survival and progression-free survival, in both the intent-to-treat and

per-protocol analyses. Improvements were most notable in the predefined subgroup of patients with metastatic disease (84% of the total). In the per-protocol analysis of this subgroup, median overall survival was 7.5 months, vs 4.4 months with gemcitabine alone (hazard ratio

Post, Dr. Saltz elaborated on his concerns about the potential cost of ramucirumab for second-line colorectal cancer treatment. “I cannot think of a human being in whom I might consider second-line ramucirumab in colorectal cancer, because I don’t have any reason to believe it is meaningfully different from either bevacizumab or aflibercept,” he said. When ziv-aflibercept debuted, Dr. Saltz advocated against using this drug, due to its modest benefit at a high cost, but he indicated that the cost has since been lowered to bring it almost on a par with bevacizumab. “Ramucirumab

is more than double the price of those two,” he emphasized.

A ‘Different Story’ Another expensive drug in colorectal cancer—regorafenib (Stivarga)— is “a different story,” he said, “because as limited as it may be, it’s used third line after other regimens fail.” Neither ramucirumab nor ziv-aflibercept offers a new line of therapy, he emphasized. He noted Dr. El-Deiry’s proposal for additional trials but predicted these will not happen, since they lack financial incentives.

= 0.46, P = .002), and median progression-free survival was 4.4 months, vs 2.3 months (hazard ratio = 0.40, P < .001), reported Angus G. Dalgleish, MD, St. George’s University of London. These differences represent increases of 70% in overall survival and 91% in progression-free survival. Differences in the intent-to-treat analyses were also statistically significant in the metastatic subgroup, he said. “This randomized, controlled, proofof-concept study has exceeded its objectives, providing clear direction for the further development of IMM-101, in combination with chemotherapy, as a first-line treatment option for metastatic pancreatic cancer,” Prof. Dalgleish said. “No additional burden of adverse events continued on page 11

“The interesting question is whether the data from RAISE will justify a compendium listing for ramucirumab, which does not consider the cost of drugs,” he said. “Probably, yes. But there is no reason to think that it will be anything other than an expensive regimen with no benefit. It may become an option for American oncologists, but personally I believe it is irresponsible to use it.” n

Disclosure: Drs. Krishnamurthi, El-Deiry, and Saltz reported no potential conflicts of interest.

See letter from Dr. El-Deiry on page 88

Don’t Miss These Important Reports in This Issue of The ASCO Post Stuart M. Lichtman, MD, on the International Society of Geriatric Oncology see page 23

Jill Gilbert, MD, on ACGME Accreditation Standards see page 36

Fatima Cardoso, MD, on Male Breast Cancer see page 30

Joyce O’Shaughnessy, MD, on Iniparib in Metastatic Triple-Negative Breast Cancer see page 54

Visit The ASCO Post online at ASCOPost.com

Elena M. Stoffel, MD, and Paul J. Limburg, MD, on ESMO Guidelines for Familial-Risk Colorectal Cancer see page 32

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Please see additional Important Safety Information on adjacent page.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO® (nivolumab) treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immunemediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immunemediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Other Immune-Mediated Adverse Reactions In Trial 1, the following clinically significant, immunemediated adverse reactions occurred in less than 1% of OPDIVO-treated patients: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillian-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO. Lactation It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment. Serious Adverse Reactions Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Common Adverse Reactions The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). Please see brief summary of Full Prescribing Information on the following pages. Reference: 1 OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor [see Clinical Studies (14) in full Prescribing Information]. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days-3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as improved to Grade 0 with completion of corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immunemediated colitis from initiation of OPDIVO was 2.5 months (range: 1-6 months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days-2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information].

Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO (nivolumab)-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving OPDIVO: two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. In two patients, OPDIVO was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4-15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO and, in one patient, Grade 3 immunemediated hepatitis recurred resulting in permanent discontinuation of OPDIVO. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVOtreated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction (defined as ≥ Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and 6 months after OPDIVO initiation, respectively. OPDIVO was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days-11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while continuing to receive levothyroxine. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. The median time to onset in OPDIVO-treated patients was 1.6 months (range: 0-3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immunemediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of OPDIVO-treated patients in Trial 1: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome.

For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO (nivolumab), administer high-dose corticosteroids, and if appropriate, initiate hormonereplacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14) in full Prescribing Information]. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) with a median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range: 1 day-9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year. Clinically significant adverse reactions were also evaluated in 574 patients with solid tumors enrolled in two clinical trials receiving OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks, supplemented by immune-mediated adverse reaction reports across ongoing clinical trials [see Warnings and Precautions]. In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumabrelated Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%). OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Table 1 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients. The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 1:

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

All Grades

Grades 3-4

Percentage (%) of Patients

Adverse Reaction Skin and Subcutaneous Tissue Disorders Rasha Pruritus Respiratory, Thoracic, and Mediastinal Disorders Cough Infections and Infestations Upper respiratory tract infectionb General Disorders and Administration Site Conditions Peripheral edema a

Grades 3-4

Chemotherapy (n=102)

21 19

0.4 0

7 3.9

0 0

2.0

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

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

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

Test Increased AST Increased alkaline phosphatase Hyponatremia Increased ALT Hyperkalemia a

Chemotherapy

All Grades

Grades 3-4

All Grades

Grades 3-4

28 22

2.4 2.4

12 13

1.0 1.1

25 16 15

5 1.6 2.0

18 5 6

1.1 0 0

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

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

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

Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations]. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A0

Issued December 2014 1506US14BR02624-01-01

ASCOPost.com | FEBRUARY 25, 2015

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Gastrointestinal Cancers Symposium Pancreatic Cancer

Pancreatic Cancer continued from page 5

above those related to chemotherapy or the underlying disease was observed,” he said. The study is ongoing.

Hit: PF-04136309 In combination with FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin), the novel chemokine receptor antagonist PF-04136309 resulted in an impressive treatment response and validated CCR2 inhibi-

resents an exciting new option for further development in pancreatic cancer.”

Hit: MM-398 The addition of MM-398, a nanoliposomal encapsulation of irinotecan, to 5-FU/leucovorin was shown to improve overall survival in patients with metastatic Aaron J. Scott, MD

Laura Goff, MD

Andrea Wang-Gillam, MD

tion in pancreatic cancer, said Andrea Wang-Gillam, MD, PhD, of Washington University, St. Louis.2 The dense microenvironment of pancreatic tumors is thought to contribute to chemotherapy resistance. Inflammatory monocytes are frequently found in these tumors and are associated with poor outcomes. PF-04136309 inhibits the chemokine receptor CCR2 on inflammatory monocytes in the tumor microenvironment, the investigators explained. The study enrolled patients with borderline resectable or locally advanced pancreatic cancer who received FOLFIRINOX alone or with PF-04136309 for six cycles. Of 29 evaluable patients receiving the combination, 14 (48.3%) had tumor shrinkage of at least 30%. Sequential biopsies showed that protumoral cytokines in the microenvironment were upregulated with F OLFIRINOX alone but were suppressed with the combination. Study discussant Laura Goff, MD, of Vanderbilt University Medical Center, Nashville, commented, “This is a remarkable tumor response without substantial additional toxicity.… PF-04136309 rep-

pancreatic cancer previously treated with gemcitabine in an expanded prespecified per-protocol analysis of the NAPOLI-1 trial.3 In the per-protocol population, MM-398 plus 5-FU/leucovorin achieved a median overall survival of 8.9 months, vs 5.1 months with 5-FU/leucovorin alone (hazard ratio = 0.47, P = .018).

Miss: Dual Non-ATP Inhibitor Rigosertib The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival or response, compared with gemcitabine alone, in an international randomized study.4 Rigosertib is a first-in-class non-ATP inhibitor of the Ras binding site on downstream effector proteins, including Raf and PI3K, and has shown efficacy in preclinical models. The randomized, open-label study included 160 patients with untreated metastatic pancreatic cancer, enrolled from 50 sites internationally. Patients received rigosertib (1,800 mg/m2 on days 1, 4, 8, 11, 15, and 18) plus gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 4-week cycle) or gemcitabine alone (same schedule). Median overall survival was 6.1 months for rigosertib/gemcitabine, vs 6.4 months for gemcitabine alone. Median progression-free survival was 3.4

Drugs in Development for Pancreatic Cancer ■■ IMM-101, a novel immunomodulator, improved both progression-free and overall survival when combined with gemcitabine, vs gemcitabine alone, in the IMAGE 1 trial. ■■ The chemokine receptor antagonist PF-04136309, given with FOLFIRINOX, resulted in an impressive treatment response and validated CCR2 inhibition as a target in pancreatic cancer. ■■ The addition of MM-398, a nanoliposomal encapsulation of irinotecan, to 5-FU plus leucovorin improved overall survival in the NAPOLI-1 trial. ■■ Failing to achieve objectives were the first-in-class non-ATP inhibitor rigosertib (given with gemcitabine) and the MEK inhibitor pimasertib.

months for both groups, according to Aaron J. Scott, MD, of the University of Colorado, Denver. Partial responses were observed in 19% on the combination and 13% receiving gemcitabine alone. Mutational analysis was performed on 47 samples, of which 41 were positive for mutations (KRAS, PI3K, p53), but no differences in outcomes emerged by mutational status.

Miss: MEK Inhibitor Pimasertib An international phase II trial of a MEK inhibitor in patients with previously untreated metastatic pancreatic cancer was also negative.5 The study, led by Eric Van Cutsem, MD, of University Hospitals Gasthuisberg and KU Leuven in Belgium, randomized 88 patients to receive pimasertib plus gemcitabine or gemcitabine alone. There was no difference in median progression-free survival between the arms, and in a preliminary analysis, overall survival was also similar. Disease

PRMA Consulting, Roche, and TNI BioTech; is on the speakers bureau of Bristol-Myers Squibb; has received research funding from Celgene, GW Pharma, Immodulon Therapeutics; and has received patents and royalties from Binor Pharma, Celgene, GW Pharma, TNI BioTech, and Vulsana. Dr. Wang-Gillam has served as a consultant or advisor for Merrimack and Pfizer; has received research funding from Aduro Biotech, EMD Serono, Halozyme Therapeutics, Merrimack, Millennium, OncoMed, Pfizer, and Prometheus. Dr. Scott reported no potential conflicts of interest. Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Novartis, Merck Serono, Roche, and Sanofi.

References 1. Dalgleish AG, IMAGE 1 trial investigators: IMAGE 1: A multicenter randomized, open-label, proof-of-concept, phase II trial comparing gemcitabine with and without IMM-101 in advanced pancreatic cancer. 2015 Gastrointestinal Cancers Symposium. Abstract 336. Presented January 16, 2015. 2. Wang-Gillam A, Nywening TM, Sanford DE, et al: Phase 1B study of FOLFIRINOX plus PF-04136309 in patients with borderline resectable and locally advanced pancreatic adenocarcinoma. 2015 Gastrointestinal Cancers Symposium. Abstract 338. Presented January 16, 2015. 3. Chen L-T, Von Hoff DD, Li C-P, et al: Expanded analyses of NAPOLI-1: Phase 3 study of MM-398 with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovo-

Pimasertib plus gemcitabine did not improve outcomes for patients with pancreatic cancer, compared with gemcitabine alone, which is consistent with findings for other MEK inhibitors. —Eric Van Cutsem, MD

control was numerically higher with the combination (61.4% vs 45.5%), but the response rates were similar. “Pimasertib plus gemcitabine did not improve outcomes for patients with pancreatic cancer, compared with gemcitabine alone, which is consistent with findings for other MEK inhibitors,” Dr. Van Cutsem said. “The primary endpoint was not met, and assessment of secondary endpoints suggests that there is no clinically meaningful difference between the treatment arms.” n Disclosure: Prof. Dalgleish owns stock or has other ownership interests in Celgene; has received honoraria from Bristol-Myers Squibb, Celgene, and TNI BioTech; has served as a consultant or advisor for Binor Pharma, Celgene, CureVac, Immodulon Therapeutics, Ipsen, Novartis,

rin, in metastatic pancreatic cancer previously treated with gemcitabine-based therapy. 2015 Gastrointestinal Cancers Symposium. Abstract 234. Presented January 15, 2015. 4. Scott AJ, O’Neil BH, Gomes C, et al: A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. 2015 Gastrointestinal Cancers Symposium. Abstract 342. Presented January 16, 2015. 5. Van Cutsem E, Hidalgo M, Bazin I, et al: Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer. 2015 Gastrointestinal Cancers Symposium. Abstract 344. Presented January 16, 2015.

The ASCO Post | FEBRUARY 25, 2015

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Gastrointestinal Cancers Symposium Pancreatic Cancer

FOLFIRINOX Plus Radiation Renders Some Locally Advanced Pancreatic Cancer Patients Resectable By Caroline Helwick

nvestigators from H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, have reported an approach to pancreatic cancer that downstages some locally advanced patients to borderline resectable status and achieves a negative surgical margin rate exceeding 96%. The study earned a Merit Award at the 2015 Gastrointestinal Cancers Symposium, where Eric A. Mellon, MD, PhD, a radiation oncology resident at Moffitt, presented the findings.1

Eric A. Mellon, MD, PhD

“Locally advanced pancreatic cancer is considered unresectable; however, we have observed that some of these patients respond sufficiently for resection to be possible,” he told The ASCO Post. “Five of our locally advanced patients were able to have complete resections after neoadjuvant therapy. Out of 49 patients, 5 is not a lot, but normally, this number would be 0, and none of the 5 has recurred.” The key seemed to be the use of FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin). “I looked for a common thread among these five patients we could take to surgery and saw that they all received FOLFIRINOX,” he said. The other neoadjuvant regimens were gemcitabine-based, including gemcitabine/docetaxel/capecitabine (GTX), gemcitabine/nab-paclitaxel (Abraxane), and gemcitabine alone.

Chemoradiotherapy Strategy The optimal approach to borderline resectable disease has been controversial, as randomized trial data are lacking. One option, taken at Moffitt, is to give highdose multiagent chemotherapy, followed by stereotactic body radiation therapy, which can deliver a high radiation dose, shrink gross disease, and enhance the possibility of achieving a margin-negative resection, “the only hope of cure,” he noted. Even if the tumor does not become amenable to resection, “local disease control from radiation therapy may also improve quality of life,” he added.

This neoadjuvant approach resulted in downstaging 10% of patients with locally advanced disease and altogether

rendered about 50% of borderline resectable patients amenable to surgery, where surgeons achieved negative margins in

97%. “For borderline resectable disease, this is an extremely high negative margin rate,” Dr. Mellon indicated.

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PAGE 13

Gastrointestinal Cancers Symposium Study Details The institutional review included all nonmetastatic borderline resectable (n = 110) or locally advanced (n = 49) pancreatic cancer patients treated with stereotactic body radiation therapy between 2009 and 2013 at Moffitt Cancer Center. Borderline resectable patients typically received induction chemotherapy

with GTX, while locally advanced patients received FOLFIRINOX or a gemcitabine-based regimen. Definitions for resectability were based on the National Comprehensive Cancer Network guidelines for pancreatic adenocarcinoma. Patients received stereotactic body radiation therapy in five equal fractions. Dosepainting techniques were used to increase

the dose to areas of tumor vessel abutment (30–50 Gy, median 40 Gy). Gross disease received a minimum of 28 Gy. Fifty-one percent of borderline resectable patients underwent resection, with a 3% positive margin rate. The other 49% did not go to surgery, because they progressed to unresectable or metastatic status on imaging (21%), proved to be unresectable at

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014. Copyright © 2014 Clovis Oncology. DARO-101 8/14

surgery (7%), demonstrated metastases at surgery (14%), or proved to be medically inoperable due to performance decline during neoadjuvant therapy (7%). Ten percent of locally advanced patients underwent complete resection, and 4% were unresectable at the time of surgery. The other patients (86%) did not have imaging response sufficient for possible resection. “In our experience, borderline resectable or locally advanced pancreatic cancer status entering the treatment protocol is unimportant, compared with whether patients undergo complete resection,” Dr. Mellon said. In patients who were not surgically resected, the 1-year local tumor control rate was 78%. Among the locally advanced patients, 21 received FOLFIRINOX and 25 re-

Neoadjuvant Therapy in Pancreatic Cancer ■■ A Moffitt Cancer Center review showed that 10% of pancreatic cancer patients with locally advanced disease could be downstaged to borderline resectable after neoadjuvant radiation and chemotherapy, primarily FOLFIRINOX.

ceived a gemcitabine-based regimen. Of them, five patients on FOLFIRINOX were downstaged to borderline resectable status, but no patient on a gemcitabine-based regimen was downstaged (P = .015). “The median follow-up for the five resected locally advanced patients is only 6 months, but none has yet died (P = .09 for survival of resected vs unresected locally advanced patients). We observed that FOLFIRINOX was associated more often with complete resection,” he said. Mild (grade 1/2) acute radiationinduced toxicities, such as fatigue, pain, nausea, and diarrhea, were common, but chronic radiation-induced toxicities were rare. “No toxicity prevented surgical resection,” Dr. Mellon said. He noted that F OLFIRINOX is difficult for some patients to tolerate, so patient selection is important. At Moffitt, FOLFIRINOX is reserved for fit, younger patients with locally advanced disease, who require a more aggressive neoadjuvant approach. Borderline resectable patients, he added, are usually well served with a faster, less toxic course of GTX. n

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

Reference 1. Mellon EA, et al: 2015 Gastrointestinal Cancers Symposium. Abstract 360. Presented January 16, 2015.

The ASCO Post | FEBRUARY 25, 2015

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Gastrointestinal Cancers Symposium Esophageal Cancer

Radiotherapy Alone as Effective as Chemoradiation Therapy in Palliation of Dysphagia in Patients With Advanced Esophageal Cancer By Caroline Helwick

alliation of dysphagia associated with advanced esophageal cancer can be effectively accomplished with radiotherapy alone, without the addition of chemotherapy, according to a multinational phase III study presented at the 2015 Gastrointestinal Cancers Symposium.1 “There was no significant improvement in dysphagia when chemotherapy was added to radiotherapy. The trial was not powered to show equivalence and thus is a negative trial,” said Michael Gordon Penniment, MD, of Royal Adelaide Hospital in Australia. “Radiotherapy alone remains an excellent tool for palliation of [dysphagia in] patients with advanced esophageal cancer and should remain the standard of care.” The conclusion, however, was ques-

and performance status, were similar. The study’s primary endpoint was relief of dysphagia, defined as an improvement of at least one point on the Mellow scale at 9 weeks and at 4 weeks thereafter. The researchers hypothesized that chemotherapy would add 15% to the dysphagia response to radiotherapy alone. “A response required improved swallowing 9 weeks after starting radiotherapy, maintained until week 13,” he explained.

No Differences Observed There were no significant differences between the two treatment arms for dysphagia, progression-free survival, or overall survival, Dr. Penniment reported. Patients receiving radiotherapy alone

Radiotherapy alone remains an excellent tool for palliation of [dysphagia in] patients with advanced esophageal cancer. —Michael Gordon Penniment, MD

tioned by some specialists, including David Ilson, MD, of Memorial Sloan Kettering Cancer Center, New York (see sidebar).

Study Details TROG 03.01 NCIC CTG ES2 was conducted in the United Kingdom, Canada, Australia, and New Zealand and therefore reflects practice in several countries, Dr. Penniment said. The study included 220 patients, who were randomized to receive either palliative radiotherapy (35 Gy in 15 fractions or 30 Gy in 10 fractions) or the same with chemotherapy (cisplatin 80 mg/m2 on day 1 or 20 mg/m2 on days 1–4 plus fluorouracil 800 mg/m2/day on days 1–4). Baseline parameters, including proportion with metastatic disease (approximately 73%)

had a dysphagia response rate of 68%, which was maintained in 42% of patients. The response to chemoradiotherapy was 74%, which was not a significant difference (P = .34) vs radiotherapy alone, and this was maintained in 47% (P = .43). The 15% difference in the primary endpoint was not met, he noted. Median overall survival was 203 days for the radiotherapy arm and 210 days for the chemoradiotherapy arm. “There was no difference and no trend for chemoradiotherapy vs radiotherapy alone. These overall survival curves are the same,” he indicated. “Although the results of the trial showed equally poor survival prognosis in both arms, 21 patients were still alive 2 years post treatment, and a large percentage of these patients had

Radiotherapy vs Chemoradiation Therapy for Dysphagia ■■ A phase III multinational trial showed that radiotherapy was as effective as chemotherapy plus radiation as palliative treatment of dysphagia in patients with esophageal cancer. ■■ Response rates to treatment were 68% to radiation alone and 74% to chemoradiation therapy. This difference was not significant.

EXPERT POINT OF VIEW

avid Ilson, MD, of Memorial Sloan Kettering Cancer Center in New York, criticized the trial presented by Dr. Penniment at the 2015 Gastrointestinal Cancers Symposium for lacking a chemotherapy-alone arm. “Chemotherapy alone, in phase III trials, has achieved dysphagia relief in 70%

[Outside of strict palliation], it’s not clinically appropriate to give radiotherapy alone and follow the patients. —David Ilson, MD

of patients,” he said. “To me, it would be a logical consideration to include a chemotherapy-alone arm in the trial.” He acknowledged that for palliation, radiotherapy alone “is reasonable,” but “to claim that 3 weeks of radiotherapy is keeping patients alive for 1 or 2 years is preposterous. I am surprised that patients would live with radiation alone for 9 to 10 months. This is an aggressive cancer, and on supportive care alone, patients die within a few months.” Outside of strict palliation, according to Dr. Ilson, “It’s not clinically appropriate to give radiotherapy alone and follow the patients…. I disagree completely that this is a first choice.” Dr. Ilson said he initiates chemotherapy in patients with metastatic esophageal cancer. “If they respond, and their dysphagia gets better, you are also treating them for metastatic disease. Often, I will put a stent in later. If the tumor overgrows the stent, I will give radiation.” n Disclosure: Dr. Ilson reported no potential conflicts of interest.

metastatic disease,” he said. He commented, “Survival beyond 1 year was something of a surprise…. There’s a group of patients who, though palliative, with active oncologic care might actually be surviving beyond 1 year.” Although survival outcomes were similar, patients receiving chemoradiotherapy experienced more toxicity, especially more nausea (P < .01) and vomiting (P < .01). In a quality-of-life analysis, no significant differences were observed. In the dysphagia domain, improvements were noted for 50% of the chemoradiotherapy arm and 64% of the radiotherapy arm; the median time to improvement was 2.6 and 2.3 months, respectively. Dr. Penniment indicated that 33 patients in the radiotherapy arm did receive chemotherapy as well “somewhere in their journey,” usually not because they became symptomatic. “But two-thirds of the radiotherapy arm

never got chemotherapy and had good symptom control,” he noted. “Two of my patients getting radiotherapy alone were among those still alive and well at 2 years,” he continued. “We are looking at data to see if we can predict that group. We are confident there will be a group of patients who can get by with less treatment than 3 weeks of radiotherapy plus or minus chemotherapy and a group needing more or something different.” n

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

Reference 1. Penniment MG: A full report of the TROG 03.01 NCIC CTG ES2 multinational phase III study in advanced esophageal cancer comparing palliation of dysphagia and quality of life in patients treated with radiotherapy or chemoradiotherapy. 2015 Gastrointestinal Cancers Symposium. Abstract 06.

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ASH Annual Meeting Hematology

First Randomized Trial to Show Benefit of Tyrosine Kinase Inhibitor in Newly Diagnosed Acute Myeloid Leukemia By Alice Goodman

orafenib (Nexavar) added to chemotherapy improved event-free survival and relapse-free survival in younger patients with acute myeloid leukemia, according to results of the randomized, controlled phase II SORAML trial.1 However, no significant improvement in

Christoph Röllig, MD

overall survival has been seen to date. “Sorafenib plus chemotherapy is feasible in younger patients with acute myeloid leukemia. The drug achieved significant and relevant event-free survival and relapse-free survival but, interestingly, not overall survival,” said lead author C hristoph Röllig, MD, University Hospital Dresden, Germany, at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition. “This is the first randomized trial evidence for clinical benefit for a tyrosine kinase inhibitor in previously untreated acute myeloid leukemia. A confirmatory trial is needed

to establish this as a new standard for acute myeloid leukemia,” he added. The addition of sorafenib was associated with more frequent toxicities, including fever, diarrhea, bleeding events, liver toxicity, hand-foot syndrome, and rash. Prior to the SORAML trial, evidence from case reports and early-phase, nonrandomized trials suggested a benefit for sorafenib in acute myeloid leukemia. Hubert Serve, MD, and colleagues from Dr. Röllig’s German SAL study group conducted a trial comparing sorafenib vs placebo in addition to chemotherapy in the first-line setting in elderly patients and found no benefit.2 SORAML was designed to study sorafenib in younger patients with acute myeloid leukemia. Following the diagnosis of acute myeloid leukemia, 267 patients (aged 18 to 60 years) were randomly assigned to receive two cycles of induction chemotherapy (daunorubicin and cytarabine) plus sorafenib vs placebo. Patients with intermediate or high cytogenetic risk who achieved remission on induction and had suitable donors went on to transplant; the others went on to three cycles of consolidation with high-dose chemotherapy plus or minus sorafenib followed by 1 year of maintenance with sorafenib vs placebo. Sorafenib was not given concomitantly with chemotherapy.

Sorafenib in Acute Myeloid Leukemia ■■ Sorafenib, a tyrosine kinase inhibitor, improved event-free survival and relapsefree survival when added to chemotherapy in younger patients with newly diagnosed acute myeloid leukemia but did not improve overall survival. ■■ Side effects were increased with the addition of sorafenib to chemotherapy. ■■ Further study is needed to confirm the benefits of adding sorafenib to chemotherapy. At present, it is being used off-label at some centers.

The median age of the study patients was 50 years. About 87% had de novo acute myeloid leukemia, and about 17% had FLT3-ITD–positive disease; about one-third had NPM1 mutations.

Study Results The complete response rate was similar between the groups: 60% in the sorafenib group vs 59% in the placebo group. Event-free survival, the primary endpoint, was significantly prolonged in the sorafenib arm. At a median follow-up of 36 months, the median event-free survival was 21 months for sorafenib vs 9 months for placebo (P = .013). A similar pattern was observed for relapse-free survival at 3 years: 56% vs 38%, respectively. The median relapsefree survival has not yet been reached for sorafenib and was 23 months for placebo. Three-year overall survival was 63%

for sorafenib vs 56% for placebo. The median overall survival for sorafenib vs placebo has not yet been reached. In the 46 patients who had FLT3ITD–positive disease, no difference between the treatment arms was observed for event-free survival, but relapse-free survival and overall survival trended in favor of sorafenib. n

Disclosure: Bayer Healthcare Germany provided research funding for this study.

References 1. Röllig C, et al: Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia. 2014 ASH Annual Meeting. Abstract 6. Presented December 7, 2014. 2. Serve H, et al: Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia. J Clin Oncol 31:3110-3118, 2013.

EXPERT POINT OF VIEW

ommenting on this study, David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, said that longer followup is needed, especially in light of the lack of overall survival benefit, which may have been due to salvage therapy. “Sorafenib clearly has activity in acute myeloid leukemia. While there have been small nonrandomized trials and case series reported before, this is the first randomized study to show a benefit in this setting. It is also the first time a tyrosine kinase inhibitor combined with chemotherapy has shown benefit in acute myeloid leukemia. At our center, we are using sorafenib [Nexavar] off-label in relapsed/refractory acute myeloid leukemia with FLT3 mutations, but this study suggests there may be a broader benefit that includes patients without FLT3 mutations,” Dr.

Steensma continued. “With these data, I hope that more payers will approve it [for acute myeloid leukemia].”

served decreased blasts and increased blood counts. When community physicians see these data, I think that up-

Acute myeloid leukemia has a dazzling amount of abnormalities, even in individual patients. Each patient has a unique configuration of genetic abnormalities, and these variations undergo dynamic changes over time. —Bob Löwenberg, MD

“The fact that sorafenib is a ‘messy’ tyrosine kinase inhibitor may not be bad [ie, having several targets],” he said. “I’ve treated acute myeloid leukemia patients with sorafenib and ob-

take of sorafenib will increase, but this is an uncommon disease,” he said. Bob Löwenberg, MD, of Erasmus University Medical Center, Rotterdam, The Netherlands, who introduced this

talk at the plenary session, commented on the “open-minded approach” of enrolling all newly diagnosed patients with acute myeloid leukemia under age 60 and not focusing on one subset. He too suggested that sorafenib’s ability to block so many targets may account for the positive showing in this study, since no other tyrosine kinase inhibitor has shown enough of an effect to move forward in this disease. “Acute myeloid leukemia has a dazzling amount of abnormalities, even in individual patients. Each patient has a unique configuration of genetic abnormalities, and these variations undergo dynamic changes over time. This may explain why a drug specifically targeted to one molecular abnormality won’t work,” Dr. Löwenberg commented. n Disclosure: Drs. Steensma and Löwenberg reported no potential conflicts of interest.

The ASCO Post | FEBRUARY 25, 2015

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ASH Annual Meeting Hematology

High Hopes for AG-221 in Advanced Leukemia By Alice Goodman

lthough the data are preliminary, single-agent AG-221 therapy targeted to the IDH2 (isocitrate dehydrogenase 2) mutation holds great promise as a nonchemotherapy approach to the treatment of advanced hematologic malignancies, including relapsed/refractory acute myelogenous leukemia (AML) and untreated AML. In an updated analysis of a doseecalation phase I trial that now in-

syndromes. What we have learned with additional experience is that responses have been durable. It’s only an interim analysis and it’s very early, but my dream is that this becomes a treatment for IDH2 mutation–positive patients. This treatment has minimal toxicity and could be an alternative to chemotherapy,” Dr. Stein said. About 15% to 20% of AML patients harbor the IDH2 mutation, which leads

AG-221’s unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood disorders. —Eytan Stein, MD

cludes 73 patients with advanced hematologic cancer, AG-221 was well tolerated and achieved more than 90% inhibition of its target (ie, 2-HG [2-hydroxyglutarate]) in patients with an IDH2 mutation.1 In 45 evaluable patients with the IDH2 mutation, the overall response rate was 56%; 15 patients achieved a complete response (9 with incomplete platelet recovery), and 10 had a partial response; 17 patients had stable disease throughout the treatment period. Moreover, responses were durable, lasting as long as 9 months on study. No patient in complete remission has relapsed. An estimated 90% of responses are 3 months or longer, and four responders are beyond 6 months of treatment. “These findings are remarkable and were achieved in patients unlikely to respond to other chemotherapies,” noted lead author Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center, New York. “These data provide continued validation of mutant IDH2 as a therapeutic target in AML and myelodysplastic

to overproduction of 2-HG, thereby preventing immature white blood cells from maturing into normal white blood cells. AG-221 is a first-in-class, potent oral inhibitor of the IDH2 mutant enzyme; this novel agent “takes the brakes off ” of undifferentiated white blood cells and allows them to mature as normal cells, acting in a similar manner as all-trans-retinoic acid and arsenic trioxide (Trisenox) in acute promyelocytic leukemia (APL), he explained.

EXPERT POINT OF VIEW

“T

hese results are fantastic,” said David Steensma, MD, a hematologist-oncologist at Dana-Farber Cancer Institute and Harvard Medical School, Boston. “We have long wanted agents for AML [acute myelogenous leukemia] like we have for APL [acute promyelocytic leukemia],

These results are fantastic. We have long wanted agents for AML like we have for APL, noncytotoxic chemotherapy approaches that release cells stuck in immature stages. —David Steensma, MD

noncytotoxic chemotherapy approaches that release cells stuck in immature stages. Unfortunately, IDH2 is only present in less than 20% of AML.” An implication that can be drawn from these data is that patients with relapsed/refractory AML should undergo molecular testing for the IDH2 mutation, and if the mutation is present, they could be treated with AG-221. “Patients refractory to conventional therapies who might otherwise be enrolled in hospice could achieve an excellent result, just like a patient I saw treated at our institution with AG-221 who almost certainly would have died without this type of therapy. Now this patient has undergone stem cell transplantation,” Dr. Steensma said. Dr. Steensma said that if further studies confirm these encouraging results, AG-221 could be transformative, allowing patients with no other alternatives a chance for curative transplant. He also said AG-221 may be useful in other malignancies that harbor IDH2 mutations, including glioblastoma multiforme. n Disclosure: Dr. Steensma reported no potential conflicts of interest.

Early Responses The updated analysis Dr. Stein presented at the 2014 Annual Meeting of the American Society of Hematology was based on 73 patients and 4 additional dose-expansion cohorts. The cohort of 73 patients included 55 with relapsed/refractory AML, 5 with untreated AML, 6 with myelodysplastic syndrome, and 6 with other hematologic malignancies. The median age of all patients was 67 years (range, 33–90 years). At the time of the 2014 ASH Annual Meeting, 45 patients were evaluable for response. Twelve patients had initiated therapy

Encouraging Preliminary Results With AG-221 ■■ AG-221, a first-in-class therapy targeted to the IGH2 mutation, achieved excellent results in advanced hematologic malignancies. ■■ The overall response rate was 56%, and responses were durable in these patients who exhausted other treatment options.

too recently and were not evaluable for response, and 16 patients discontinued therapy without an evaluable 28day assessment. The maximal tolerated dose had not yet been reached.

Toxicity Update AG-221 was well tolerated. Cancerrelated symptoms, not attributable to this drug, were mild to moderate and included nausea, fever, diarrhea, and fatigue. One case of dose-related grade 5 hypoxia was reported in a patient with unrelated fungal pneumonia and sepsis. The 60-day all cause mortality rate was 13.7%. Most of the serious adverse events were mild to moderate and considered disease-related. Serious adverse events possibly drug-related were reported in 13 patients. Eleven deaths were reported, nine of them unrelated to treatment; two

deaths due to sepsis/hypoxia and atrial flutter, respectively, were possibly treatment-related, he said. “I believe that AG-221’s unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood disorders,” Dr. Stein commented. n

Disclosure: Dr. Stein is a consultant for Janssen Pharmaceuticals and Agios Pharmaceuticals.

Reference 1. Stein EM, Altman JK, Collins R, et al: AG-221, an oral, selective, first-inclass, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. 2014 ASH Annual Meeting. Abstract 115. Presented December 7, 2014.

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ASH Annual Meeting Hematology

Radiotherapy in Good-Prognosis DLBCL By Caroline Helwick

imited-stage nonbulky diffuse large B-cell lymphoma (DLBCL) carries an excellent prognosis, and radiotherapy provides no value in patients who obtain a complete response, according to the phase III 02-03 trial from the Lysa/Goelams group, presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.1 “The benefit of radiotherapy following chemotherapy in limited-stage DLBCL remains controversial. Before the ‘rituximab [Rituxan] era,’ four randomized trials turned in conflicting results. More recently, the German Unfolder study prematurely closed the R-CHOP without radiotherapy arm in bulky limited-stage DLBCL due to an excess of relapse,” said Thierry Lamy, MD, PhD, of the University Hospital of Rennes in France. To further examine the benefit of radiotherapy after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in this population, Dr. Lamy and colleagues initiated a randomized trial in patients with nonbulky (tumor size < 7 cm) limited-stage DLBCL in 2005. They concluded that radiotherapy following R-CHOP is of no value to the vast majority of patients. “With the current follow-up, the addition of radiotherapy is not significantly superior to R-CHOP alone and should be reserved for the minority of patients who do not reach complete response after R-CHOP,” Dr. Lamy said.

Study Details Depending on risk factors, patients received 4 or 6 consecutive cycles of R-CHOP14, followed or not by involved-field radiotherapy at 40 Gy delivered 4 weeks after the last cycle of R-CHOP. All patients were evaluated by fluorodeoxyglucose–positron emission tomography (FDG-PET) at baseline, after 4 cycles of R-CHOP,

and at the end of treatment. The recommendation was that patients in partial response (tumor regression > 50% but a persistent positive FDG-PET) after cycle 4 receive an additional 2 cycles of R-CHOP followed by radiotherapy. The primary objective was event-free survival 1 year after the last randomization. There were 301 evaluable patients (median age, 56 years), of whom 82% had normal LDH levels, 96% had no B symptoms, and the majority had an International Prognostic Index score of 1 to 2. The main tumor site was cervical lymph nodes, and 40% had extranodal sites.

sponses were observed in 82% after RCHOP alone and 85% after R-CHOP plus radiotherapy; partial responses (PET-positive) were observed in 16% and 12%, and stable disease was noted in one and two patients, respectively. At the end of treatment, complete responses were observed in 93% and 95%, respectively. There were partial responses in seven patients treated with R-CHOP alone and one patient

With the current follow-up, the addition of radiotherapy is not significantly superior to R-CHOP alone and should be reserved for the minority of patients who do not reach complete response after R-CHOP.

No Additional Benefit of Radiotherapy No significant benefit was observed in the cohort receiving radiotherapy after R-CHOP (n = 151) compared with the group receiving R-CHOP alone (n = 150). Complete response rates overall were 84%, and 14% of patients attained partial responses and three patients had stable disease. In the intent-to-treat analysis, after 51 months’ median follow-up, eventfree survival at 5 years was 88%, with 88.4% for the radiotherapy arm and 87.3% for the R-CHOP alone arm (P = .13). Overall survival was 91% for the whole population and 92% for the radiotherapy arm and 90% for the R-CHOP–alone arm (P = .33), Dr. Lamy reported. By assignment group, complete re-

“After 4 cycles of R-CHOP, adding 2 cycles plus radiotherapy for patients in partial response induced similar outcomes as compared to patients who obtained a complete response,” Dr. Lamy pointed out. Relapses occurred in 12 patients (8%) in the R-CHOP–alone arm and 8 patients (5%) of the arm receiving R-CHOP plus radiotherapy, which was not a significant difference. The

—Thierry Lamy, MD, PhD

treated with R-CHOP plus radiotherapy, and stable disease was reported in two patients in the R-CHOP arm, Dr. Lamy added. For the 43 patients who were partial responders after cycle 4, 37 (86%) received 2 additional cycles of RCHOP plus radiotherapy, whereas 6 patients were treated with a different regimen, with or without radiotherapy. Of these 43 patients, 40 ultimately attained a complete response. After complete response, 5-year event-free survival was 89% in the R-CHOP– alone arm, and 91% in the R-CHOP plus radiotherapy arm.

Radiotherapy After R-CHOP in DLBCL ■■ In limited-stage, nonbulky diffuse large B-cell lymphoma, R-CHOP alone, without radiotherapy, induced complete responses in 82% of patients, and routine radiotherapy added little benefit. ■■ In a phase III trial, event-free and overall survival rates at 5 years were not significantly improved with the addition of radiotherapy. ■■ Radiotherapy can be reserved for the minority of patients who fail to achieve a complete response to R-CHOP alone.

median time to relapse was 21 months. In the radiotherapy arm, none of these relapses occurred at the initial tumor site, but in the R-CHOP–alone arm, 5 of 12 relapses occurred at that site. Altogether, nine patients developed progressive disease. “In this prospective study, the results demonstrate that in nonbulky limited-stage DLBCL, R-CHOP alone for 4 to 6 cycles induces very high complete response rates, with a very good overall survival and a very low relapse rate,” he concluded. n Disclosure: Dr. Lamy reported no potential conflicts of interest.

Reference 1. Lamy T, Damaj G, Gyan E, et al: R-CHOP with or without radiotherapy in non-bulky limited-stage diffuse large B cell lymphoma (DLBCL): Preliminary results of the prospective randomized phase III 02-03 trial from the Lysa/ Goelams Group. 2014 ASH Annual Meeting. Abstract 393. Presented December 8, 2014.

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APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” mCRC = metastatic colorectal cancer; OS = overall survival. WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational 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 treatment with Vectibix®. • Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. • In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. • Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS/RAS mCRC • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. • In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/ acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. • Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women. • Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. • Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. • In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inﬂammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aﬂibercept) prescribing information, sanoﬁ-aventis. Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1

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Vectibix (panitumumab) ®

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

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inﬂammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin ﬁssures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive Care Best Supportive Care (N = 234) (N = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

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

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inﬂammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

116 (36) 96 (30) 68 (21) 26 (8)

14 (4) 21 (7) 32 (10) 8 (2)

85 (26) 26 (8) 42 (13) 10 (3)

46 (14)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) SYSTEM ORGAN CLASS Any Grade Grade 3-4 Preferred Term n (%) n (%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 179 (56) 55 (17) 24 (7) 1 (< 1) Acneiform dermatitis 104 (32) 33 (10) Pruritus 75 (23) 3 (< 1) 14 (4) Dry skin 68 (21) 5 (2) 13 (4) Erythema 50 (16) 7 (2) 14 (4) Skin fissures 50 (16) 1 (< 1) 1 (< 1) Alopecia 47 (15) 30 (9) Acne 44 (14) 10 (3) 1 (< 1) Nail disorder 32 (10) 4 (1) 4 (1) Palmar-plantar erythrodysesthesia 30 (9) 4 (1) 9 (3) 2 (< 1) syndrome Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix ®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix ® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix ® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. 80748-R2-V1 – v22 10/14

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INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix ®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix ®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)]. Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational 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 Vectibix®. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix ® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix ®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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PAGE 21

ASH Annual Meeting Hematology

Oral Proteasome Inhibitors Advancing in Multiple Myeloma Trials By Caroline Helwick

wo orally administered proteasome inhibitors—oprozomib and ixazomib—looked encouraging in multiple myeloma studies presented at the 2014 ASH Annual Meeting and Exposition.

Study Details for Oprozomib Oprozomib, given as a single agent in a dose-escalation study of heavily pretreated patients, “showed promising antitumor activity,” which included responses even in patients with carfilzomib (Kyprolis)-refractory disease,1 according to Ravi Vij, MD, of Washington University in St. Louis. Oprozomib binds selectively and irreversibly to its target, resulting in sustained inhibition. Dr. Vij presented data from an ongoing multicenter open-label phase Ib/ II study of 129 patients with hematologic malignancies, including 87 with relapsed and/or refractory disease. “The majority of patients had seen bortezomib [Velcade] and carfilzomib, and quite a few were refractory to both these drugs,” Dr. Vij noted. Patients received oprozomib in various schedules and dose levels in 2-week blocks. The formulation of oprozomib was changed during phase Ib of the study, from

powder-in-capsule to extended-release tablet, and in phase II, step-up dosing was introduced. These amendments appeared to improve the drug’s tolerability. In the phase Ib cohort receiving 150 to 330 mg/d for 2 of every 7 days (2/7 schedule), the objective response rate was 31.3%, and the clinical benefit rate was 50%. In the phase Ib/II patients who received 150 to 270 mg/d for 5 of 14 days (5/14 schedule), the response rate was 23.3%, and the clinical benefit rate was 32.6%. Of note, these response rates were observed before the step-up dosing schedule was initiated. Response data were not presented for the step-up cohorts due to limited treatment exposure (approximately 7 weeks). Interestingly, responses were achieved by 18.2% of carfilzomib-refractory patients in this study, he added.

Our preliminary data suggest that step-up dosing [with oprozomib] is associated with improved tolerability, with fewer gastrointestinal adverse events observed and less hematologic toxicity, though the numbers are small. —Ravi Vij, MD

Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience. —Shaji K. Kumar, MD

Step-Up Dosing The recommended phase II dose and schedules were the 2/7 step-up schedule at 240/300 mg/d and the 5/14 stepup schedule at 150/180 mg/d. In the cohorts evaluated before the benefit of step-up dosing, the most common grade ≥ 3 nonhematologic adverse events were diarrhea, nausea, and

vomiting. With step-up dosing, these events were less common, he said. In the 240/300 mg/d step-up cohorts in phase II, grade ≥ 3 nausea and diarrhea were observed in only 10% each. Similarly, hematologic toxicities grade ≥ 3 were limited to anemia (11%) in the

240/300 mg/d cohort and neutropenia (10%) in the 150/180 mg/d cohort. Treatment-emergent peripheral neuropathy was rare, occurring in five patients (6%), only one being grade 3. Rash was observed in 6 patients (7%), and none continued on page 22

Tailoring Therapy for Diffuse Large B-Cell Lymphoma by Interim PET May Be Problematic By Caroline Helwick

n a study that reflected clinical practice, treatment of diffuse large B-cell lymphoma based on the results of interim positron-emission tomography (PET) was feasible; however, switching PET-positive patients to an alternative treatment still

sity of British Columbia, Vancouver, and colleagues presented the results of their phase II trial at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco.1 “Patients who were PET-negative fol-

PET-positive patients are a group for whom novel treatments should be explored. —Laurie H. Sehn, MD, MPH

resulted in inferior treatment outcomes, and the majority did not achieve a negative PET scan, according to Canadian researchers. Laurie H. Sehn, MD, MPH, Clinical Associate Professor at the British Columbia Cancer Agency and the Univer-

lowing four cycles of R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone] had an excellent outcome, without needing radiotherapy. PET-positive patients had a poorer outcome but did better than expect-

ed compared to historical reports. However, relatively few PET-positive patients converted to a negative PET scan following R-ICE [rituximab, ifosfamide, carboplatin, etoposide], suggesting that simply switching to this alternate non–cross-resistant chemotherapy regimen is insufficient to overcome the inherent resistance in this poor-risk population,” Dr. Sehn said.

Need to Optimize Initial Therapy “While the majority of patients with advanced-stage [diffuse large B-cell lymphoma] will be cured with R-CHOP, those [in whom front-line therapy fails] continue to have a dismal outcome,” she noted. “Optimization of initial therapy remains an important goal.” Interim PET scanning is prognostic in diffuse large B-cell lymphoma and may enable treatment to be tailored, as it could identify patients for whom RCHOP is insufficient. For patients with positive interim PET scans, alternate

non–cross-resistant therapies could be considered prior to the emergence of further drug resistance. With this rationale, a phase II trial was initiated to assess the feasibility and efficacy of PET-tailored therapy for diffuse large B-cell lymphoma in British Columbia. The study enrolled 155 patients (median age, 53) between October 2006 and May 2014 (stage III/IV or stage I/II with B symptoms or bulky mass ≥ 10 cm). Patients were treated with standarddose 3-weekly R-CHOP and could be enrolled at any time prior to cycle 4 without need for a staging PET scan. Interim PET scans were performed at a centralized site following cycle 4. Those with a negative PET scan received two additional cycles of R-CHOP, whereas patients with a positive PET scan were switched to receive four cycles of R-ICE and had a final PET scan after treatment completion. “As per the policy in British Columcontinued on page 22

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PAGE 22

ASH Annual Meeting Oral Proteasome Inhibitors continued from page 21

was ≥ grade 3. There were three deaths in the 5/14 dosing cohort before step-up dosing was instituted: Two were due to upper gastrointestinal bleeding, and one was due to disease progression. “Our preliminary data suggest that step-up dosing is associated with improved tolerability, with fewer gastrointestinal adverse events observed and less hematologic toxicity, though the numbers are small,” Dr. Vij reported. “With the phase II step-up dose of 150/180 mg/d, we have seen no grade 3 gastrointestinal toxicity. There’s also a hint that dose reductions and discontinuations for adverse events are less.” Enrollment on the 2/7 and 5/14 schedules of the extended-release tablet is continuing. Target enrollment for the phase II portion for the myeloma cohort is 94 patients.

Maintenance Ixazomib Data from a phase I/II clinical trial support further evaluation of the investigational, oral, proteasome inhibitor ixazomib in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of newly diagnosed multiple myeloma and alone as maintenance therapy.2 Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, reported the results of

Tailoring Therapy by PET continued from page 21

bia, patients with a positive PET posttreatment received consolidative radiation therapy, if feasible, and this was not considered to be an event with respect to progression-free survival,” Dr. Sehn indicated. Patients with an indeterminate PET were recommended to complete treatment with R-CHOP. Patients with disease progression during cycles 1 to 4 of R-CHOP were taken off study.

Key Data Of the 150 evaluable patients who underwent interim PET scanning, 88 (59%) were PET-negative, 50 (33%) were PETpositive, and 12 (8%) were PET-indeterminate. PET-positive patients were more likely to have elevated LDH and bulky disease at diagnosis. All PET-negative patients completed treatment with R-CHOP as intended, and none received radiotherapy. Of the 50 PET-positive patients, 2 refused to switch to R-ICE and completed treatment with R-CHOP (both received radiotherapy), whereas 48 proceeded to R-ICE. Of these 48, 9 patients failed to complete all four cycles of R-ICE due to toxicity, and 6 of

a study of 65 newly diagnosed patients. Of them, 25 entered the maintenance phase and were the subject of this analysis. They received a median of 31 total cycles (induction and maintenance) with 19 being maintenance cycles. Maintenance with ixazomib improved the depth of response after induction. The overall response rate in this study was 90%; complete respons-

The estimated percentage of patients surviving without disease progression at 2 years was 57%. Serious adverse events were observed in four patients (19%) during ixazomib maintenance, none of which were considered related to treatment. Ixazomib is the first oral proteasome inhibitor and has physiochemical properties distinct from bortezomib. The triplet

Update on Oral Proteasome Inhibitors in Multiple Myeloma ■■ In a phase Ib/II trial of heavily pretreated patients, oprozomib produced a clinical benefit rate of 50%. ■■ In newly diagnosed patients, ixazomib plus lenalidomide/dexamethasone yielded an overall response rate of 90% in a phase II study, including a 22% rate of complete responses, which increased to 52% after single-agent ixazomib was given as maintenance.

es were observed in 22% after induction but increased to 52% by the end of maintenance, Dr. Kumar reported. “With maintenance, we saw a deepening of response in 48% of patients,” he noted. The rate of complete responses plus near complete responses increased from 24% after induction to 62%, with 71% rated very good partial responses or better. Ixazomib maintenance contributed to durable responses. Half the patients were still on maintenance therapy at the time of the report. the 9 switched back to R-CHOP; 3 had disease progression during R-ICE and did not have a final PET scan. The remaining 36 of the 50 PET-positive patients completed four cycles of R‑ICE and underwent a final PET scan. This revealed that 11 had a negative PET post R-ICE (2 received radiotherapy, regardless), whereas 25 had a positive PET post R-ICE (12 received radiotherapy). Of the 12 PET-indeterminate patients, 10 completed treatment with R-CHOP (one received radiotherapy), and 2 were switched to R-ICE (without radiotherapy).

Survival Outcomes With a median follow-up of 45 months, the 4-year progression-free survival of the entire evaluable cohort was 79% and the overall survival was

of bortezomib/lenalidomide/dexamethasone has produced high response rates, and it has become increasingly clear that extended treatment (ie, maintenance therapy) may add benefit to conventional induction strategies, he indicated. “Agents for continuous therapy, however, need to be convenient and well tolerated,” Dr. Kumar suggested. “Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience.” “Single-agent ixazomib maintenance

for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem cell transplant,” he said. Newonset toxicity during single-agent ixazomib maintenance was rare. Only 2 of 21 patients required dose reductions during maintenance, and there were no treatment discontinuations due to adverse events and no on-study deaths. Phase III trials of ixazomib are underway in both newly diagnosed and relapsed cohorts. n

Disclosure: Dr. Vij has received honoraria from Celgene, Onyx Pharmaceuticals, Sanofi, Janssen Pharmaceuticals, Novartis, Millennium, and Array BioPharma and research funding from Celgene and Onyx Pharmaceuticals. Dr. Kumar has served as a consultant to and received research funding from Celgene, Millennium, Onyx Pharmaceuticals, Sanofi-Aventis, Array BioPharma, and Janssen Pharmaceuticals and is on the Board of Directors or advisory committees of Skyline Diagnostics.

References 1. Vij R, et al: Clinical profile of singleagent oprozomib in patients with multiple myeloma. 2014 ASH Annual Meeting. Abstract 34. Presented December 6, 2014. 2. Kumar S, et al: Long-term ixazomib maintenance is tolerable and improves depth of response following ixazomiblenalidomide-dexamethasone induction in patients with previously untreated multiple myeloma. 2014 ASH Annual Meeting. Abstract 82. Presented December 7, 2014.

Role of PET in Diffuse Large B-Cell Lymphoma ■■ In a study of patients from British Columbia, PET scanning after four cycles of R-CHOP identified patients at risk for failure and worse survival. ■■ Switching to an alternate therapy did not overcome treatment resistance.

87%, Dr. Sehn reported. “Overall survival was extremely favorable for PETnegative patients. PET-positive patients had a less favorable outcome but did better than expected compared to historical controls. PET-indeterminate patients had an intermediate outcome,” she noted (Table 1). While PET-tailored therapy in patients with advanced-stage diffuse large B-cell lymphoma was feasible in this population, switching to R-ICE was fairly toxic, Dr. Sehn indicated. Nine of 48 pa-

Table 1: Four-Year Outcomes by PET Status in Diffuse Large B-Cell Lymphoma PET group

4-Year Time to Progression

4-Year Overall Survival

PET-negative

91%

96%

PET-positive

59%

73%

PET-indeterminate

83%

82%

These differences were statistically significant (P = .0001 for time to progression and P = .001 for overall survival). PET = positron-emission tomography. Courtesy of Sehn et al.1

tients (19%) were unable to complete the planned four cycles due to toxicity, which included poor tolerance (n = 5), cytopenias/infection (n = 2), allergy (n = 1), and neurotoxicity (n = 1). Intolerability did not correlate with older age; the average age of these 9 patients was 43 years. “PET-positive patients are a group for whom novel treatments should be explored,” Dr. Sehn suggested. n

Disclosure: Dr. Sehn has received honoraria for consultancy from Roche/Genentech, Gilead, Lundbeck, Janssen, Amgen, Celgene, and Seattle Genetics and research funding from Roche/ Genentech. For complete disclosures of all study authors, see the abstract at www.hematology.org.

Reference 1. Sehn LH, et al: Phase 2 trial of interim PET scan-tailored therapy in patients with advanced stage diffuse large B-cell lymphoma in British Columbia. 2014 ASH Annual Meeting. Abstract 392. Presented December 8, 2014.

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PAGE 23

Geriatrics for the Oncologist

International Society of Geriatric Oncology: At the Forefront of Physician Education and Research Dissemination in Geriatric Oncology By Stuart M. Lichtman, MD

The ASCO Post announces a new department on geriatric oncology to be published on an occasional basis. Geriatrics for the Oncologist is guest edited by Stuart Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Visit SIOG.org for more on geriatric oncology.

t is a great privilege to introduce the first article in this recurring series on Geriatrics for the Oncologist. Each article will highlight a specific topic to bring readers up to date on current research and activities in the field. The aging of the population makes the initiation of the series particularly timely. Most patients seen in the subspecialties of oncology are older individuals. The majority of cancer deaths occur in patients older than 70 years of age. Despite this, older patients are still underrepresented on clinical trials, making it difficult to reach evidence-based decisions. Clinicians still need to extrapolate data derived from studies of younger, fit patients. This lack of information from older patients may be contributing to the increased risk of toxicity and poor outcomes seen in this vulnerable group. Most oncologists are geriatric oncologists in that they are already seeing older patients, or they will be as the expected lifespan increases and the population ages. They need the tools to evaluate and treat this expanding population. Researchers in geriatric oncology are developing objective and validated instruments to help evaluate patients and aid in decision-making. ASCO has been particularly supportive in these efforts. The Society has a geriatric oncology track and a Clinical Science Symposium at the Annual Meeting, an ongoing Special Interest Group, and resources including ASCO University and The ASCO Post providing helpful information on geriatric oncology. The Alliance for Clinical Trials in Oncology, the Gynecologic Oncology Group, and the European Society for Medical Oncology (ESMO) also contribute to the research effort. The Cancer and Aging Research Group has developed a predictive tool for toxicity, and this tool is now being prospectively

validated in various clinical situations. In this first installment of the series, I would like to highlight the International Society of Geriatric Oncology (SIOG; www.siog.org) as well, for its work in educating physicians and providing a forum for the dissemination of research and promotion of new ideas.

International Society of Geriatric Oncology Founded in 2000, SIOG has a worldwide membership and has had yearly meetings to bring together clinical and nonclinical researchers. The organization has its own journal, the Journal of Geriatric Oncology, which is in its sixth volume and indexed in PubMed. Arti Hurria, MD, Director of the Cancer and Aging Program at the City of Hope Comprehensive Cancer Center in Duarte, California, is a founding member of the Cancer and Aging Research Group and the founding and current editor of the journal. SIOG has various task forces, which have published a series of recommendations and guidelines and a “top 10” priorities list to focus research. The 2014 meeting held this past fall in Lisbon had 400 attendees from over 40 countries and covered five major tracts: (1) solid tumors, (2) hematologic malignancies, (3) new therapies and basic science, (4) nursing, supportive care, and geriatric assessment, and (5) advocacy and socioeconomic issues. Presentations covered a broad range of topics, from basic science, addressing the interaction of

sity of Nottingham, United Kingdom), psycho-oncology (Jimmie C. Holland, MD, Memorial Sloan Kettering Cancer Center, New York), and hematology (Reinhard Stauder, MD, MSc, Innsbruck Medical University, Austria).

Screening Recommendations for Elderly Individuals In the session on cancer screening, the challenges of optimal strategies for early identification of four common tumor types in older adults were discussed: colorectal, lung, breast, and prostate cancer. Overall, there is agreement that age is not appropriate as a primary basis of screening recommendations and that there is significant overscreening in low-risk cancers like breast and prostate cancers. For each tumor type, there are multiple challenges to screening in older adults, due to the difficulty of showing survival benefits in patients with lower life expectancy; the risks from screening, follow-up testing, and treatments; the differential testing performance of screening tests in older patients; patient preferences for care; and the paucity of high-quality data to guide r ecommendations.

Treatment in the Adjuvant Setting In a session dedicated to the role of adjuvant chemotherapy in elderly patients, common themes were noted in adjuvant decision-making in breast, lung, and colon cancers. With

Older cancer patients constitute a majority of the patients we evaluate and treat. They need to become the focus of our endeavors. —Stuart M. Lichtman, MD

cancer and aging, to the impact of cancer on the caregiver. There was an emphasis on clinical care in varying cancer types, geriatric assessment, cancer screening, nutrition, sarcopenia and cachexia, and clinical trials. The Plenary Session was dedicated to advances in the field of geriatric oncology, including progress in medical oncology (Vesa Kataja, MD, Kuopio University Hospital, Finland), geriatrics (Muriel Rainfray, MD, Bordeaux Segalen University, Finland), surgery (Kwok-Leung Cheung, MD, Univer-

GUEST EDITOR

improvements in perioperative care, surgical resection with curative intent is more common in older adults. However, there is a dearth of prospective trials addressing the role of adjuvant chemotherapy, with the knowledge gap being especially wide in those over age 75 years. Much of the information is gleaned from outcomes of older participants in age-unspecified trials or analyses of large population databases. Older adults do achieve benefit from adjuvant chemotherapy but are at higher risk for chemotherapy-associated toxicity.

Stuart M. Lichtman, MD

r. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org). It may be important to modify regimens that exclude agents with demonstrable poor tolerance in older adults (eg, cisplatin for lung cancer and oxaliplatin in colon cancer). The decision for adjuvant chemotherapy should balance the risk of cancer recurrence against toxicity and competing causes for mortality. Ongoing and future research should focus on the use of geriatric assessment and other predictive tools in decision-making. A session on treatment updates for solid tumors highlighted studies showing that, for the most part, newer therapies are associated with similar benefits and toxicities in younger and older patients included in these clinical trials. Further research should include tools such as geriatric assessment, which can help clinicians identify fit older patients who are candidates for standard treatments.

Interdisciplinary Models of Care To emphasize the universality of the field, there was a session on interdisciplinary geriatric oncology models of care— the international perspective. There were talks by experts from the United States, United Kingdom, and Brazil. It was noted that geriatric oncology is organized differently across the continents. In general, geriatric oncology is gaining increased international interest, and there are efforts to implement geriatric assessment into the standard care of continued on page 26

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

Indication KyprolisÂŽ (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis, and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ÂŠ2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100826J November 2014 Printed in USA

for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results* n

22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

7.8-MONTH MEDIAN DURATION OF RESPONSE (95% CI: 5.6, 9.2)1

Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event1,2 - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each)1

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved. Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of full Prescribing Information on adjacent pages. References: 1. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012. 2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761.

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Geriatrics for the Oncologist International Society of Geriatric Oncology continued from page 23

older cancer patients, with modifications for the uniqueness of the individual regions. The session highlighted the recognition and evaluation of frailty, which included weight loss, polypharmacy, and poor performance status. In

his presidential a ddress, E tienne Brain, MD, PhD (Institut Curie, Saint-Cloud, France) presented the idea of expanding international outreach and dimension as a key strategic goal of SIOG for the next 2 years.

Collaborations and Awards In conjunction with the International

Psycho-Oncology Society (IPOS), SIOG had a session on social and cultural determinants of health in elderly cancer patients. The current concept of coping, coping styles, and special data on elderly patients were presented. At the same time, incoming President Dr. Brain gave a lecture at the 16th Annual Meeting of IPOS on “Geriatric Oncology and Psy-

cho-Oncology, Why Does It Matter?” SIOG established a Young Investigators Interest Group to provide a forum for young researchers in geriatric oncology to collaborate, help identify topics of interest, provide exposure of young researchers to SIOG, improve active participation, and help advocate for geriatric oncology. Awards were presented to outstand-

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a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor during Toxicity KYPROLIS duringTreatment KYPROLIS(continued) Treatment (continued) Renal Toxicity Renal Toxicity • Withhold until renal function has • Withhold until renal function has recovered to recovered Grade 1 to Grade 1 to baseline and monitor monitor renal function.renal function. • Serum creatinine • Serum creatinine equal to or equal toororto baselineorand • Iftoattributable KYPROLIS, at the next scheduled • If attributable KYPROLIS,to restart at the restart next scheduled than 2 × baseline greater than 2greater × baseline 2 at a reduced (from treatment at atreatment reduced dose (from 27dose mg/m to 27 mg/m2 to Adverse Reactions] [see Adverse [see Reactions] 2 202,mg/m OR from to 15 20 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m KYPROLIS™KYPROLIS™ (carfilzomib) (carfilzomib) for Injectionfor Injection Brief Summary BriefofSummary Prescribing of Prescribing Information.Information. Please see Please the KYPROLIS see the package KYPROLISinsert package insert • If not attributable • If nottoattributable KYPROLIS,torestart KYPROLIS, at the restart dose used at the dose used for full prescribing for full prescribing information.information. prior to the event. prior to the event. INDICATIONS INDICATIONS AND USAGE: AND KYPROLIS USAGE:is KYPROLIS indicated for is indicated the treatment for theof treatment patients with of patients multiplewith multiple • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the myeloma who myeloma have received who haveat received least twoat prior least therapies two prior including therapiesbortezomib including and bortezomib an and an previous doseprevious at the discretion dose at the of the discretion physician. of the physician. immunomodulatory immunomodulatory agent and have agentdemonstrated and have demonstrated disease progression disease on progression or within on 60 ordays within of 60 Peripheral days of Neuropathy Peripheral Neuropathy • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. completion ofcompletion the last therapy. of the Approval last therapy. is based Approval on response is based rate on response [see Clinical rate Studies [see Clinical section Studies of fullsection of full • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced • Grade 3 or• 4 Grade 3 or 4 PI]. Clinical benefit, PI]. Clinical such benefit, as improvement such as improvement in survival or in symptoms, survival orhas symptoms, not beenhas verified. not been verified. 2 2 dose (from 27dose mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20 mg/m2 [see Adverse [see Reactions] Adverse Reactions] DOSAGE AND DOSAGE ADMINISTRATION: AND ADMINISTRATION: Dosing Guidelines. Dosing Guidelines. KYPROLIS is KYPROLIS administered is administered intravenously intravenously 2 2 to 15 mg/m ),toat15themg/m discretion ), at the of the discretion physician. of the physician. over 2 to 10 over minutes, 2 to on 10two minutes, consecutive on twodays, consecutive each week days,foreach threeweek weeks for (Days three weeks 1, 2, 8,(Days 9, 15,1,and 2, 8, 9, 15, and • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the 16), followed 16), by a followed 12‑day rest by aperiod 12‑day (Days rest 17 period to 28). (Days Each 1728‑day to 28). Each period28‑day is considered period isone considered treatmentone treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician. 2 cycle (Table 1). cycle In Cycle (Table1,1). KYPROLIS In Cycle is 1, administered KYPROLIS is administered at a dose of 20 at mg/m a dose2.ofIf tolerated 20 mg/min . IfCycle tolerated 1, thein Cycle 1, the Other Other • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. dose should be dose escalated should to be27 escalated mg/m2 beginning to 27 mg/m in2 Cycle beginning 2 andincontinued Cycle 2 and at 27 continued mg/m2 in at subsequent 27 mg/m2 in subsequent • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade non‑hematological 3 or 4 non‑hematological cycles. Treatment cycles. may Treatment be continued may be untilcontinued disease progression until diseaseorprogression until unacceptable or until unacceptable toxicity occurstoxicity [see occurs [see 3 or• 4 Grade 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to toxicities toxicities Dosage and Administration]. Dosage and Administration]. The dose is calculated The dose isusing calculated the patient’s using the actual patient’s body surface actual body area surface at area at 2 2 2 2 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m2). 20 mg/m , OR20from mg/m baseline. Patients baseline. with Patients a body surface with a body area surface greater than area 2.2 greater m2 should than 2.2 m2 should receive a dosereceive basedaupon doseabased upon a 2 • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the body surface body area of surface 2.2 marea of 2.2 m2. Dosedo . Dose adjustments adjustments not need todobenot made needfortoweight be made changes for weight of less changes than of less than previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or equal to 20%. or equal to 20%. a Table 1: KYPROLIS Table 1:Dosage KYPROLIS Regimen Dosage forRegimen Patients for with Patients Multiple with Myeloma Multiple Myeloma National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. Administration Administration Precautions.Precautions. The quantity The of KYPROLIS quantity ofcontained KYPROLIS in contained one single‑use in onevial single‑use (60 mg vial (60 mg Cycle 1 Cycle 1 carfilzomib) may carfilzomib) exceed may the required exceed the dose. required Cautiondose. should Caution be used should in calculating be used inthe calculating quantity the quantity Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 delivered to prevent delivered overdosing. to prevent Do overdosing. not mix KYPROLIS Do not mix with KYPROLIS or administer with or as administer an infusion as with an infusion other with other DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days Days Day Day Day medicinal Theproducts. intravenous Theadministration intravenous administration line should beline flushed shouldwith be normal flushed saline with normal or 5% saline or 5% 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 medicinal 22–28 products. 1 Dextrose Injection, Dextrose USPInjection, immediately USP before immediately and after before KYPROLIS and after administration. KYPROLIS administration. KYPROLIS should KYPROLIS not should not KYPROLIS KYPROLIS 20 20 No 20 20 No20 20No 20 20 No 20 20 No 20 No No No 20 administered be administered as a bolus. KYPROLIS as a bolus. should KYPROLIS be administered should be administered over 2 to 10 minutes. over 2 toReconstitution 10 minutes. Reconstitution (20 mg/m2):(20 mg/m2): Dosing Dosing Dosing Dosing Dosing Dosing Dosing be Dosing and Preparation and Preparation for Intravenous for Intravenous Administration. Administration. KYPROLIS vials KYPROLIS containvials no antimicrobial contain no antimicrobial a Cycles 2 andCycles Beyond 2 and Beyonda preservativespreservatives and are intended and are onlyintended for singleonly use.forUnopened single use. vials Unopened of KYPROLIS vials of areKYPROLIS stable until arethe stable until the Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 date indicated date on the indicated package on when the package stored in when the original stored inpackage the original at 2°C package to 8°Cat(36°F 2°C to to 8°C 46°F). (36°F Theto 46°F). The DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days reconstituted Days Day Day Day reconstituted solution contains solution carfilzomib contains atcarfilzomib a concentration at a concentration of 2 mg/mL.ofRead 2 mg/mL. the complete Read the complete 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 preparation 22–28 1 instructions preparationprior instructions to reconstitution. prior to reconstitution. Reconstitution/Preparation Reconstitution/Preparation Steps: 1. Remove Steps:vial 1. Remove vial KYPROLIS KYPROLIS 27 27 No 27 27 No27 27No 27 27 No 27 27 No 27 No No No refrigerator 27 from fromjust refrigerator prior to use. just prior 2. Aseptically to use. 2.reconstitute Aseptically each reconstitute vial by each slowlyvial injecting by slowly 29 injecting mL 29 mL Dosing Dosing Dosing Dosing Dosing Dosing Sterile DosingWater Sterile (27 mg/m2):(27 mg/m2): Dosing Water USP, for Injection, the solution ontoWALL the INSIDE OFminimize THE VIAL to minimize for Injection, directingUSP, the directing solution onto the INSIDE OF THEWALL VIAL to a If previous cycle a If dosage foaming. Gently invert swirl and/or slowly for about 1 minute, or until complete dissolution foaming. 3. Gently swirl3.and/or the vialinvert slowlythe forvial about 1 minute, or until complete dissolution previousiscycle tolerated. dosage is tolerated. of powder any cakeoccurs. or powder occurs. DO to NOT SHAKE avoid foamIfgeneration. If foaming cake or DO NOT SHAKE avoid foamtogeneration. foaming occurs, allowoccurs, allow Hydration and Hydration Fluid Monitoring. and Fluid Monitoring. Hydrate patients Hydrate to reduce patients thetorisk reduce of renal the toxicity risk of renal and oftoxicity tumor andofofany tumor solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, lysis syndrome lysis (TLS) syndrome with KYPROLIS (TLS) withtreatment KYPROLIS [see treatment Warnings[see andWarnings Precautions]. and Precautions]. Maintain adequate Maintain adequate KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, fluid volume status fluid volume throughout statustreatment throughout andtreatment monitor blood and monitor chemistries bloodclosely. chemistries Prior closely. to each Prior dose to in each dose in colorless If any discoloration particulate matter do is observed, not use the reconstituted colorless If anysolution. discoloration or particulateormatter is observed, not use thedoreconstituted Cycle 1, give Cycle 250 mL 1, give to 500 250mLmLoftointravenous 500 mL ofnormal intravenous salinenormal or othersaline appropriate or otherintravenous appropriatefluid. intravenous fluid.solution. product. 5. When administering in anbag, intravenous calculated dose and [see Dosage and product. 5. When administering in an intravenous withdrawbag, the withdraw calculatedthe dose [see Dosage Give an additional Give an250 additional mL to 250 500 mL mL to of 500 intravenous mL of fluids intravenous as needed fluids following as neededKYPROLIS following KYPROLIS and50dilute into Dextrose 50 mL 5% Dextrose USP bag. intravenous bag. from the vialfrom and the dilutevialinto mL 5% Injection, USPInjection, intravenous administration. administration. Continue intravenous Continue hydration, intravenousashydration, needed, in as subsequent needed, in cycles. subsequent Also cycles. monitorAlsoAdministration] monitor Administration] 6. Immediately the vialthe containing unused of reconstituted 6. Immediately discard the discard vial containing unused the portion. The portion. stabilitiesTheof stabilities reconstituted patients during patients this period during for thisfluid period overload for fluid [seeoverload Warnings [see andWarnings Precautions]. and Precautions]. Dexamethasone Dexamethasone KYPROLIS various and temperature container shown variousunder temperature containerand conditions areconditions shown in are Table 3. in Table 3. Premedication. Premedication. Pre‑medicatePre‑medicate with dexamethasone with dexamethasone 4 mg orally or4intravenously mg orally or intravenously prior to all doses priorofto allKYPROLIS doses of under Table of 3: Reconstituted Stability of Reconstituted Table 3:toStability KYPROLIS KYPROLIS KYPROLIS during KYPROLIS Cycle during 1 and prior Cycleto1alland KYPROLIS prior to all doses KYPROLIS during doses the first during cyclethe of dose first cycle escalation of dose to escalation 2 27 mg/m2 to 27 mg/m reduce the toincidence reduce the andincidence severity ofand infusion severity reactions of infusion [seereactions Warnings[see andWarnings Precautions]. and Precautions]. a Stabilitya perStability Container per Container Reinstate dexamethasone Reinstate dexamethasone premedicationpremedication (4 mg orally or(4intravenously) mg orally or intravenously) if these symptoms if these develop symptoms or develop or Storage of Conditions of Reconstituted Storage Conditions Reconstituted reappear during reappear subsequent during cycles. subsequent Dosecycles. Modifications Dose Modifications based on Toxicities. based on Recommended Toxicities. Recommended IV Bag IV Bag KYPROLIS KYPROLIS actions and dose actions modifications and dose modifications are presentedare in Table presented 2. in Table 2. Vial Vial Syringe Syringe (D5Wb) (D5Wb) a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor Toxicity during KYPROLIS duringTreatment KYPROLIS Treatment RefrigeratedRefrigerated (2°C to 8°C;(2°C 36°Ftoto8°C; 46°F) 36°F to 46°F) 24 hours 2424 hours hours 2424hours hours 24 hours HematologicHematologic Toxicity Recommended Action Toxicity Recommended Action

• Withhold dose. • Withhold dose. • Grade 3a or Neutropenia • 4Grade 3a or 4 Neutropenia Room Temperature Room Temperature (15°C to 30°C; (15°C 59°F to to 30°C; 86°F) 59°F to 86°F) 4 hours 4 hours 4 hours 4 4hours hours 4 hours • If fully recovered • If fully before recovered next scheduled before next dose, scheduled continue dose, continue • Grade 4 Thrombocytopenia • Grade 4 Thrombocytopenia a b b Total time fromaTotal reconstitution time fromtoreconstitution administration to should administration not exceed should 24 hours. not exceed 5% 24 Dextrose hours.Injection, 5% Dextrose USP. Injection, USP. at same doseatlevel. same dose level. [see Warnings[see andWarnings Precautions] and Precautions] AND PRECAUTIONS: AND PRECAUTIONS: Cardiac Arrest, Cardiac Congestive Arrest, Congestive Heart Failure, Heart Myocardial Failure, Myocardial • If recovered • toIf recovered Grade 2 neutropenia to Grade 2 or neutropenia Grade 3 or Grade 3 WARNINGS WARNINGS Ischemia. Death Ischemia. due toDeath cardiacdue arrest to cardiac has occurred arrest has within occurred a day of within KYPROLIS a day of administration. KYPROLIS administration. New New thrombocytopenia, thrombocytopenia, reduce dose by reduce one dose level by one dose level onset onset or of worsening pre‑existingofcongestive pre‑existingheart congestive failure with heartdecreased failure withleftdecreased ventricularleftfunction ventricular or function or 2 2 2 (from 27 mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from to 20 mg/m to or worsening myocardial ischemia myocardial have ischemia occurred have following occurred administration following administration of KYPROLIS. of Cardiac KYPROLIS. failure Cardiac events failure events 15 mg/m2). 15 mg/m2). (e.g., cardiac (e.g., failurecardiac congestive, failurepulmonary congestive,edema, pulmonary ejection edema, fraction ejection decreased) fractionwere decreased) reportedwere in 7% reported in 7% • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the of patients. Monitor of patients. for cardiac Monitorcomplications for cardiac complications and manage and promptly. manage Withhold promptly. KYPROLIS Withhold forKYPROLIS Grade 3 for Grade 3 previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or 4 cardiac events or 4 cardiac until recovery events until and recovery consider and whether consider to restart whether KYPROLIS to restart based KYPROLIS on a benefit/risk based on a benefit/risk Non-Hematologic Non-Hematologic Toxicity Toxicity Recommended Recommended Action Action assessment [see assessment Dosage [see and Administration]. Dosage and Administration]. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and Class III and IV heart myocardial failure,infarction myocardial in infarction the preceding in the6 preceding months, and 6 months, conduction and abnormalities conduction abnormalities Cardiac Toxicity Cardiac Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. IV heart failure, by uncontrolled medications by were medications not eligible werefornottheeligible clinicalfortrials. the clinical These patients trials. These may patients be at greater may be at greater • After of: resolution, • Afterconsider resolution, if restarting considerKYPROLIS if restarting at KYPROLISuncontrolled at Grade 3 or 4, new Grade onset 3 oror4,worsening new onsetof: or worsening 2 risk for cardiac riskcomplications. for cardiac complications. Pulmonary Pulmonary Hypertension. Hypertension. Pulmonary arterial Pulmonary hypertension arterial hypertension (PAH) (PAH) a reduced is appropriate dose is(from appropriate 27 mg/m (from to 27 mg/m2 to • congestive•heart congestive failure; heart failure; a reduced dose 2 2 2 2 2 was reported was in 2% reported of patients in 2% treated of patients with KYPROLIS treated with and KYPROLIS was Grade and 3 was or greater Grade in 3 less or greater than 1% in less of than 1% of 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m ). mg/m • decreased•leftdecreased ventricularleft ventricular 20 mg/m , OR20from patients. withEvaluate cardiac with imaging cardiac and/or imaging other and/or tests as other indicated. tests asWithhold indicated. KYPROLIS WithholdforKYPROLIS for • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedpatients. to the Evaluate function; function; pulmonary hypertension until resolveduntil or returned resolved to or baseline returned and to baseline considerand whether consider to restart whether to restart at the discretion dose at the of the discretion physician. of the physician.pulmonary hypertension • or myocardial • orischemia myocardial ischemia previous doseprevious KYPROLIS based KYPROLIS on a based benefit/risk on a assessment benefit/risk assessment [see Dosage[see and Dosage Administration]. and Administration]. Pulmonary Pulmonary [see Warnings[see andWarnings Precautions] and Precautions] Complications. Complications. Dyspnea wasDyspnea reported was in 35% reported of patients in 35% enrolled of patients in clinical enrolled trials. in clinical Grade 3trials. dyspnea Grade 3 dyspnea occurred no Grade in 5%; 4 events, no Grade and4 1events, death and (Grade 1 death 5) was (Grade reported. 5) was Monitor reported. and Monitor manage and manage Pulmonary Hypertension Pulmonary Hypertension • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. occurred in 5%; dyspnea immediately; dyspnea immediately; interrupt KYPROLIS interrupt until KYPROLIS symptoms until have symptoms resolved have or returned resolved to or baseline returned [see to baseline [see • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced [see Warnings[see andWarnings Precautions] and Precautions] 2 2 Administration and Administration and Adverse and Reactions]. AdverseInfusion Reactions]. Reactions. Infusion Infusion Reactions. reactions Infusion were reactions were to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20Dosage mg/m2 and Dosage dose (from 27dose mg/m (from 2 by a spectrum by ofa systemic spectrum symptoms of systemicincluding symptoms fever, including chills, arthralgia, fever, chills, myalgia, arthralgia, facialmyalgia, facial to 15 mg/m2),toat15themg/m discretion ), at the of the discretion physician. of the physician.characterizedcharacterized edema,facial vomiting, edema, weakness, vomiting, shortness weakness, of breath, shortness hypotension, of breath, syncope, hypotension, chest syncope, tightness, chest tightness, • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedflushing, to the facialflushing, or angina. reactions These canreactions occur immediately can occur following immediately or up following to 24 hours or up after to 24administration hours after administration of of previous doseprevious at the discretion dose at the of the discretion physician. of the physician.or angina. These KYPROLIS.dexamethasone Administer dexamethasone prior to KYPROLIS prior toto KYPROLIS reduce theto incidence reduce the andincidence severity and of severity of Pulmonary Complications Pulmonary Complications • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS. Administer reactions [seereactions Dosage [see and Administration]. Dosage and Administration]. Inform patients Inform of thepatients risk and of symptoms the risk andand symptoms to contactand to contact • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade 3 or• 4 Grade 3 or 4 physician if symptoms physicianofif symptoms an infusionofreaction an infusion occurreaction [see Patient occurCounseling [see PatientInformation]. Counseling Tumor Information]. LysisTumor Lysis 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to [see Warnings[see andWarnings Precautions] and Precautions] Syndrome. Tumor Syndrome. lysis syndrome Tumor lysis (TLS) syndrome occurred (TLS) following occurred KYPROLIS following administration KYPROLIS administration in < 1% of in < 1% of 2 202,mg/m OR from to 20 15 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m patients. Patients patients. withPatients multiple with myeloma multiple andmyeloma a high tumor and aburden high tumor should burden be considered should betoconsidered be at to be at • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedgreater to the risk for greater TLS. Prior risk for to receiving TLS. PriorKYPROLIS, to receivingensure KYPROLIS, that patients ensure that are well patients hydrated are well [seehydrated Dosage [see Dosage previous doseprevious at the discretion dose at the of the discretion physician. of the physician.and Administration]. and Administration]. Monitor for evidence Monitor for of TLS evidence duringoftreatment, TLS duringand treatment, manage and promptly. manage Interrupt promptly. Interrupt Hepatic Toxicity Hepatic Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS until KYPROLIS TLS is resolved until TLS[see is resolved Dosage [see and Dosage Administration].Thrombocytopenia. and Administration].Thrombocytopenia. KYPROLIS KYPROLIS • After consider resolution, if restarting considerKYPROLIS if restarting is KYPROLIS iscauses thrombocytopenia • Grade 3 or• 4 Grade elevation 3 orof4 elevation•of After resolution, causes thrombocytopenia with platelet with nadirsplatelet occurring nadirs around occurring Day 8around of each Day28‑day 8 of each cycle28‑day and cycle and may appropriate; be reinitiated may at beareinitiated reduced dose at a reduced (from doserecovery (from to baseline transaminases, transaminases, bilirubin or other bilirubin orappropriate; other recoverybytothe baseline start ofbythe thenext start28‑day of the cycle. next 28‑day In patients cycle. with In patients multiple with myeloma, multiple 36% myeloma, of 36% of 2 27 mg/m2 to 20 27 mg/m22, to OR20from mg/m 202mg/m , OR from to 15 20 mg/m mg/m22) to 15patients mg/m2) experienced liver abnormalities liver abnormalities patients experienced thrombocytopenia, thrombocytopenia, including Grade including 4 in 10%. Grade Thrombocytopenia 4 in 10%. Thrombocytopenia following following with frequentwith monitoring frequentofmonitoring liver function. of liver function. KYPROLIS administration KYPROLIS administration resulted in aresulted dose reduction in a dose in reduction 1% of patients in 1% and of patients discontinuation and discontinuation of of [see Warnings[see andWarnings Precautions] and Precautions] • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedtreatment to the with treatment KYPROLIS within KYPROLIS < 1% of patients. in < 1%Monitor of patients. platelet Monitor counts platelet frequently countsduring frequently treatment during treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician.with KYPROLIS. withReduce KYPROLIS. or interrupt Reduce dose or interrupt as clinically dose indicated as clinically [seeindicated Dosage [see and Dosage Administration]. and Administration]. Hepatic Toxicity Hepatic andToxicity Hepaticand Failure. Hepatic Cases Failure. of hepatic Cases failure, of hepatic including failure, fatalincluding cases, have fatalbeen cases, have been (continued) (continued)

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Geriatrics for the Oncologist

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ing investigators at the meeting. The SIOG 2014 Paul Calabresi Award was given to Martine Extermann, MD, PhD (Moffitt Cancer Center, Tampa, Florida) for her longstanding and major achievements. The Nursing and Allied Health Investigator Award was given to Cindy Kenis, RN, MSN (UZ Leuven, Belgium) for her work on the

prognostic value of geriatric screening and assessment for overall survival in older patients with cancer. The SIOG 2014 Young Investigator Award was given to Maria José Molina-Garrido, MD, PhD (General Hospital Virgen de la Luz, Cuenca, Spain), for her work on methods to detect and evaluate frailty. The SIOG 2014

Best Poster award was given to Emilie Ferrat, MD (Université Paris Est Créteil, France) for her poster “Predictors of One-Year Mortality in a Prospective Cohort of Elderly Patients with Cancer.” The National Representative of the Year award was given to Ravindran Kanesvaran, MD, MRCP (National Cancer Centre, Singapore).

B:11.25”

T:10.875”

S:10” B:11.25”

CMS Issues Final Decision to Cover Lung CT Screening S:10”

One event wasbOne Grade event 5 severity. was Grade 5 severity.

Watch future issues of The ASCO Post for continued discussion on geriatrics for the oncologist and practical tools to use with your older patients.

T:10.875”

reported (< 1%). reported KYPROLIS (< 1%).can KYPROLIS cause elevations can causeof elevations serum transaminases of serum transaminases and bilirubin.and Withhold bilirubin.Description Withhold Description of SelectedofAdverse Selected Drug Adverse Reactions. Drug Renal Reactions. Events: Renal The Events: most common The most renal common renal KYPROLIS in KYPROLIS patients experiencing in patients experiencing Grade 3 or greater Gradeelevations 3 or greater of elevations transaminases, of transaminases, bilirubin, or other bilirubin,adverse or otherreactions adverse were reactions increasewere in blood increase creatinine in blood (24%) creatinine and renal (24%) failure and (9%), renal which failurewere (9%),mostly which were mostly liver abnormalities liver abnormalities until resolveduntil or returned resolved to or baseline. returned to After baseline. resolution, Afterconsider resolution, if restarting consider if restarting Grade 1 or Grade Grade 21 inorseverity. Grade 2Grade in severity. 3 renalGrade adverse 3 renal reactions adverse occurred reactions in 6% occurred of patients in 6%and of patients and KYPROLIS is KYPROLIS appropriate. is appropriate. Monitor liver Monitor enzymesliver frequently enzymes[see frequently Dosage [see and Dosage Administration and Administration and Gradeand 4 events Grade occurred 4 events in 1%. occurred Discontinuations in 1%. Discontinuations due to increased due to blood increased creatinine blood andcreatinine acute renal and acute renal Adverse Reactions]. AdverseEmbryo-fetal Reactions]. Embryo-fetal Toxicity. KYPROLIS Toxicity. canKYPROLIS cause fetal canharm cause when fetaladministered harm when administered to a failuretowere a 1% failure each. were In 1% one each. patient, In death one patient, occurred death withoccurred concurrent withsepsis concurrent and worsening sepsis andrenal worsening renal pregnant woman pregnant basedwoman on its mechanism based on itsofmechanism action and of findings actioninand animals. findings There in animals. are no adequate There are and no adequate and[see function function Dosage and [seeAdministration]. Dosage and Administration]. Peripheral Neuropathy: Peripheral Neuropathy: Peripheral neuropathy Peripheral(including neuropathy (including well‑controlledwell‑controlled studies in pregnant studieswomen in pregnant usingwomen KYPROLIS. using Carfilzomib KYPROLIS.caused Carfilzomib embryo‑fetal caused toxicity embryo‑fetal in all toxicity in of all events peripheral events ofsensory peripheral neuropathy sensoryand neuropathy peripheral andmotor peripheral neuropathy) motor occurred neuropathy) in 14% occurred of in 14% of pregnant rabbits pregnant at doses rabbits that were at doses lower thatthan were in patients lower than receiving in patients the recommended receiving the recommended dose. Femalesdose. of Females patientsofenrolled patients in clinical enrolled trials. in clinical Grade 3trials. peripheral Grade neuropathy 3 peripheraloccurred neuropathy in 1% occurred of patients. in 1%Serious of patients. Serious reproductive potential reproductive should potential be advised should to be avoid advised becoming to avoid pregnant becoming whilepregnant being treated while being with KYPROLIS. treated with KYPROLIS. peripheral neuropathy peripheralevents neuropathy occurred events in <occurred 1% of patients, in < 1%which of patients, resulted which in dose resulted reduction in dose in <reduction 1% in < 1% If this drug isIfused this drug duringis pregnancy, used duringorpregnancy, if the patient or ifbecomes the patient pregnant becomes while pregnant taking this whiledrug, taking thethis and drug,treatment the and discontinuation treatment discontinuation in < 1%. Withhold in < 1%. or discontinue Withhold or treatment discontinue as treatment recommended as recommended [see [see patient shouldpatient be apprised shouldofbethe apprised potential of hazard the potential to the hazard fetus [see to the Usefetus in Specific [see Use Populations]. in Specific Populations]. Dosage and Administration]. Dosage and Administration]. Herpes VirusHerpes Infection: Virus Herpes Infection: zosterHerpes reactivation zosterwas reactivation reportedwas in 2% reported in 2% ADVERSE REACTIONS: ADVERSE REACTIONS: The following adverse The following reactions adverse are discussed reactions are in greater discussed detail in in greater other detail sections in otherofsections patients. Consider of patients. antiviral Consider prophylaxis antiviralfor prophylaxis patients who for patients have a history who have of herpes a history zoster of herpes infection. zoster infection. of the labeling:of the labeling: DRUG INTERACTIONS: DRUG INTERACTIONS: Carfilzomib isCarfilzomib primarily metabolized is primarily via metabolized peptidasevia andpeptidase epoxide and hydrolase epoxide hydrolase • Cardiac Arrest, • Cardiac Congestive Arrest,Heart Congestive Failure,Heart Myocardial Failure,Ischemia Myocardial [seeWarnings Ischemia [see andWarnings Precautions] and Precautions] activities, andactivities, as a result, and the as apharmacokinetic result, the pharmacokinetic profile of carfilzomib profile ofiscarfilzomib unlikely toisbeunlikely affectedto by be affected by • Pulmonary •Hypertension Pulmonary Hypertension [seeWarnings [see andWarnings Precautions] and Precautions] concomitant administration concomitant administration of cytochromeofP450 cytochrome inhibitors P450 andinhibitors inducers.and Carfilzomib inducers.isCarfilzomib not expected is not expected • Pulmonary •Complications Pulmonary Complications [seeWarnings [see andWarnings Precautions] and Precautions] to influence exposure to influence of other exposure drugsof[see otherClinical drugs Pharmacology [see Clinical Pharmacology section of fullsection PI]. of full PI]. • Infusion Reactions • Infusion [see Reactions Warnings [see andWarnings Precautions] and Precautions] USE IN SPECIFIC USE IN POPULATIONS: SPECIFIC POPULATIONS: Pregnancy. Pregnancy. Pregnancy Category PregnancyD Category [see Warnings D [seeand Warnings and • Tumor Lysis•Syndrome Tumor Lysis [see Syndrome Warnings [see andWarnings Precautions] and Precautions] Females of potential reproductive potential shouldtobe advised to avoid becoming pregnant while Precautions].Precautions]. Females of reproductive should be advised avoid becoming pregnant while • Thrombocytopenia • Thrombocytopenia [seeWarnings [see andWarnings Precautions] and Precautions] treated withBased KYPROLIS. on itsofmechanism action and findingsKYPROLIS in animals, KYPROLIS being treatedbeing with KYPROLIS. on its Based mechanism action andoffindings in animals, • Hepatic Toxicity • Hepatic and Hepatic Toxicity Failure and Hepatic [seeWarnings Failure [see andWarnings Precautions] and Precautions] can harm causewhen fetal administered harm when administered a pregnant woman.caused Carfilzomib caused embryo‑fetal can cause fetal to a pregnanttowoman. Carfilzomib embryo‑fetal The most common The most adverse common reactions adverse (incidence reactions of (incidence 30% or greater) of 30%toorKYPROLIS greater) to observed KYPROLIS in clinical observed toxicity in clinical toxicity rabbits in pregnant rabbits doses thatthan wereinlower thanreceiving in patients the recommended in pregnant at doses thatatwere lower patients thereceiving recommended trials of patients trialswith of patients multiple with myeloma multiple were myeloma fatigue,were anemia, fatigue, nausea, anemia, thrombocytopenia, nausea, thrombocytopenia, dyspnea, dose. dyspnea, dose. Ifis KYPROLIS is pregnancy, used duringorpregnancy, or ifbecomes the patient becomes pregnant If KYPROLIS used during if the patient pregnant while taking while this taking this diarrhea, anddiarrhea, pyrexia. and Clinical pyrexia. Trials Clinical SafetyTrials Experience. Safety Experience. Because clinical Because trials clinical are conducted trials are conducted drug,should the patient shouldofbethe apprised of hazard the potential to the fetus.was Carfilzomib was administered drug, the patient be apprised potential to the hazard fetus. Carfilzomib administered under widely under varyingwidely conditions, varyingadverse conditions, reaction adverse ratesreaction observed rates in the observed clinicalintrials the of clinical a drugtrials cannot of a drug cannot intravenously to pregnant ratsduring and rabbits during period of organogenesis at doses intravenously to pregnant rats and rabbits the period of the organogenesis at doses of 0.5, 1, andof 0.5, 1, and be directly compared be directlywith compared rates in with the clinical rates intrials the clinical of another trialsdrug, of another and may drug, not and reflect maythenotrates reflect 2themg/kg/day rates 2inmg/kg/day in rats and 0.8inmg/kg/day in rabbits.was Carfilzomib was notatteratogenic at rats and 0.2, 0.4,and and0.2, 0.8 0.4, mg/kg/day rabbits. Carfilzomib not teratogenic observed in medical observed practice. in medical A total practice. of 526Apatients total of with 526 relapsed patients with and/or relapsed refractory and/or multiple refractory myeloma multiple any myeloma any dose tested.there In rabbits, was in an pre‑implantation increase in pre‑implantation at ≥ 0.4 mg/kg/day dose tested. In rabbits, was anthere increase loss at ≥ 0.4loss mg/kg/day received KYPROLIS received as KYPROLIS monotherapy as monotherapy or with pre‑dose or with dexamethasone. pre‑dose dexamethasone. Patients received Patients a median received of a median and in anearly increase in earlyand resorptions and post‑implantation loss andina fetal decrease in at fetal weight at and an ofincrease resorptions post‑implantation loss and a decrease weight four treatment fourcycles treatment with acycles median withcumulative a medianKYPROLIS cumulativedose KYPROLIS of 993.4 dose mg.ofDeaths 993.4 due mg. to Deaths all due to all thetoxic maternally of 0.8The mg/kg/day. of 0.4 and 0.8inmg/kg/day the maternally dose oftoxic 0.8 dose mg/kg/day. doses ofThe 0.4doses and 0.8 mg/kg/day rabbits arein rabbits are causes withincauses 30 days within of the30last days dose of the of KYPROLIS last dose of occurred KYPROLIS in 37/526 occurred (7%) in 37/526 of patients. (7%)Deaths of patients. not Deaths not approximately 20% and 40%, of respectively, of the recommended doseof in27humans 27 mg/m2 based approximately 20% and 40%, respectively, the recommended dose in humans mg/m2 of based attributed to disease attributed progression to diseasewere progression cardiac were in 5 patients cardiac (acute in 5 patients coronary (acute syndrome, coronary cardiac syndrome, arrest,cardiac on arrest, body surface on body area.surface Nursing area. Mothers. Nursing It isMothers. not known It iswhether not known KYPROLIS whetheris KYPROLIS excreted inishuman excreted in human cardiac disorder), cardiac end‑organ disorder),failure end‑organ in 4 patients failure in(multi‑organ 4 patients (multi‑organ failure, hepatic failure, failure, hepatic renal failure, failure),renalmilk. failure), Since many milk.drugs Since are many excreted drugs are in human excreted milkin and human because milk and of the because potential of for the serious potentialadverse for serious adverse infection in infection 4 patientsin (sepsis, 4 patients pneumonia, (sepsis, pneumonia, respiratory tract respiratory bacterial tract infection), bacterialdyspnea infection), anddyspnea and in nursing reactions reactions infants in nursing from KYPROLIS, infants from a decision KYPROLIS, should a decision be made should whether be made to discontinue whether tonursing discontinue nursing intracranial hemorrhage intracranial in hemorrhage 1 patient each, in 1 patient and 1 each, patientand found 1 patient dead offound unknown dead causes. of unknown Serious causes.orSerious to discontinue or tothe discontinue drug, taking the into drug,account taking into the importance account theofimportance the drug toofthe themother. drug toPediatric the mother. Pediatric adverse reactions adverse were reactions reportedwere in 45% reported patients. in 45% The patients. most common The most serious common adverse serious reactions adverse were reactions Use.were The safety Use.and Theeffectiveness safety and effectiveness of KYPROLISofin KYPROLIS pediatric patients in pediatric havepatients not been have established. not been established. pneumonia (10%), pneumonia acute (10%), renal failure acute (4%), renal pyrexia failure (4%), (3%),pyrexia and congestive (3%), andheart congestive failure (3%). heart Adverse failure (3%).Geriatric Adverse Use. Geriatric In studies Use. of KYPROLIS In studies there of KYPROLIS were nothere clinically weresignificant no clinically differences significantobserved differences in safety observed in safety reactions leading reactions to discontinuation leading to discontinuation of KYPROLIS occurred of KYPROLIS in 15% occurred of patients in 15% and of included patients and congestive included congestive and efficacy between and efficacy patients between less than patients 65 years less than of age 65 and yearspatients of age 65 andyears patients of age 65 and yearsolder. of age Renal and older. Renal heart failure (2%), heart failure cardiac(2%), arrest, cardiac dyspnea, arrest, increased dyspnea, blood increased creatinine, bloodand creatinine, acute renal andfailure acute (1% renal failure (1% Impairment. Impairment. The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS evaluated were in evaluated a Phase 2intrial a Phase in 2 trial in each). Adverse each). reactions Adverse occurring reactions at aoccurring rate of 10% at a or rate greater of 10% areorpresented greater are in Table presented 4. in Table 4. patients withpatients normal with renal normal functionrenal and function those with andmild, thosemoderate, with mild,and moderate, severe renal and severe impairment renal impairment on chronic patientsdialysis. on chronic On average, dialysis. patients On average, werepatients treated were for 5.5 treated cyclesforusing 5.5 cycles KYPROLIS using KYPROLIS Table 4: Incidence Table 4:ofIncidence Adverse Reactions of AdverseOccurring ReactionsinOccurring ≥ 10% of in Multiple ≥ 10% Myeloma of Multiple Myelomaand patients and 2 doses of 15 doses mg/m2ofon15Cycle mg/m 1,2 20 on mg/m Cycle 21,on20Cycle mg/m 2,2 and on Cycle 27 mg/m 2, and on27Cycles mg/m32 on andCycles beyond. 3 and beyond. Patients Treated Patients withTreated KYPROLIS with KYPROLIS The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS not influenced were notbyinfluenced the degreebyofthe baseline degreerenal of baseline renal Patients Patients (N = 526) (N = 526) impairment, including impairment, the including patients on thedialysis. patientsSince on dialysis. dialysisSince clearance dialysis of clearance KYPROLIS ofconcentrations KYPROLIS concentrations [n (%)] [n (%)] has not beenhas studied, not been the studied, drug should the drug be administered should be administered after the dialysis after procedure the dialysis[see procedure Clinical [see Clinical Grade Grade 3 4 GradePharmacology 4 All Grade 3 All Pharmacology section of fullsection PI]. Hepatic of full Impairment. PI]. Hepatic Impairment. The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of of a a EventsEvents Events Event GradesEvents Event Grades KYPROLIS have KYPROLIS not been have evaluated not been in evaluated patients with in patients baselinewith hepatic baseline impairment. hepatic Patients impairment. withPatients the with the following laboratory following values laboratory were excluded values were fromexcluded the KYPROLIS from theclinical KYPROLIS trials:clinical ALT/AST trials: ≥ 3ALT/AST × upper ≥ 3 × upper Fatigue Fatigue 292 (55.5) 292 (55.5) 38 (7.2) 38 (7.2)2 (0.4) 2 (0.4) limit of normallimit (ULN) of normal and bilirubin (ULN) ≥ and 2× bilirubin ULN [see ≥ 2Clinical × ULN Pharmacology [see Clinical Pharmacology section of fullsection PI]. Cardiac of full PI]. Cardiac Anemia Anemia 246 (46.8) 246 (46.8) 111 (21.1) 111 (21.1)7 (1.3) 7 (1.3) Impairment.Impairment. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and IV Class heartIII failure and IV were heartnot failure eligible were not eligible Nausea Nausea 236 (44.9) 236 (44.9)7 (1.3) 7 (1.3) 0 0 for the clinicalfortrials. the clinical Safety in trials. this Safety population in thishas population not beenhas evaluated. not been evaluated. Thrombocytopenia Thrombocytopenia 191 (36.3) 191 (36.3) 69 (13.1) 69 (13.1) 54 (10.3) 54 (10.3) OVERDOSAGE: OVERDOSAGE: There is no known There isspecific no known antidote specific for KYPROLIS antidote foroverdosage. KYPROLIS In overdosage. the event of In the an event of an b overdosage, monitor overdosage, the patient monitorand theprovide patientappropriate and providesupportive appropriatecare. supportive care. Dyspnea Dyspnea 182 (34.6) 182 (34.6) 25 (4.8) 25 (4.8)1 (0.2)b 1 (0.2) NONCLINICAL NONCLINICAL TOXICOLOGY: TOXICOLOGY: Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, and Impairment and Impairment of Fertility. of Fertility. Diarrhea Diarrhea 172 (32.7) 172 (32.7)4 (0.8) 4 (0.8)1 (0.2) 1 (0.2) Carcinogenicity Carcinogenicity studies have studies not beenhave conducted not beenwith conducted carfilzomib. withCarfilzomib carfilzomib.was Carfilzomib clastogenic wasinclastogenic the in the Pyrexia Pyrexia 160 (30.4) 160 (30.4)7 (1.3) 7 (1.3)2 (0.4) 2 (0.4) in vitro chromosomal in vitro chromosomal aberration testaberration in peripheral test in blood peripheral lymphocytes. blood lymphocytes. Carfilzomib was Carfilzomib not mutagenic was not mutagenic in the in vitro in bacterial the in vitro reverse bacterial mutation reverse (Ames) mutation test and (Ames) was test not and clastogenic was not in clastogenic the in vivo in the in vivo mouse mouse Upper respiratory Uppertract respiratory infectiontract infection 149 (28.3) 149 (28.3) 17 (3.2) 17 (3.2) 0 0 marrow micronucleus Fertility withhave carfilzomib have not beenNo conducted. No micronucleus assay. Fertilityassay. studies with studies carfilzomib not been conducted. Headache Headache 145 (27.6) 145 (27.6)7 (1.3) 7 (1.3) 0 0 bone marrowbone effects on reproductive were noted during 28‑day repeat‑dose rat and monkey toxicity effects on reproductive tissues weretissues noted during 28‑day repeat‑dose rat and monkey toxicity Cough Cough 137 (26.0) 137 (26.0)1 (0.2) 1 (0.2) 0 0 studies or in studies in and 6‑month rat and 9‑month monkey chronic toxicity studies. Animal and/ Toxicology and/ 6‑monthorrat 9‑month monkey chronic toxicity studies. Animal Toxicology Blood creatinine Blood increased creatinine increased 127 (24.1) 127 (24.1) 13 (2.5) 13 (2.5)1 (0.2) 1 (0.2) or Pharmacology. Monkeys administered single bolusdose intravenous dose ofatcarfilzomib or Pharmacology. Monkeys administered a single bolusa intravenous of carfilzomib 3 mg/kg at 3 mg/kg 2 2 1.3 times recommended doseofin27humans 27 mg/m (approximately(approximately 1.3 times recommended dose in humans mg/m ofbased on body based surface on body area) surface area) LymphopeniaLymphopenia 126 (24.0) 126 (24.0) 84 (16.0) 84 (16.0) 11 (2.1) 11 (2.1) experienced hypotension, experienced increased hypotension, heart increased rate, andheart increased rate, and serum increased levels of serum troponin‑T. levels ofThe troponin‑T. repeated The repeated Edema peripheral Edema peripheral 126 (24.0) 126 (24.0)3 (0.6) 3 (0.6) 0 0 bolus intravenous bolus administration intravenous administration of carfilzomibofatcarfilzomib ≥ 2 mg/kg/dose at ≥ 2 in mg/kg/dose rats and in 2 mg/kg/dose rats and 2 mg/kg/dose in in Vomiting Vomiting 117 (22.2) 117 (22.2)5 (1.0) 5 (1.0) 0 0 monkeys using monkeys dosingusing schedules dosingsimilar schedules to those similar usedto clinically those used resulted clinically in mortalities resulted inthat mortalities were that were due occurring to toxicities in occurring the cardiovascular in the cardiovascular (cardiac failure, (cardiac cardiac failure, fibrosis, cardiac pericardial fibrosis,fluid pericardial fluid Constipation Constipation 110 (20.9) 110 (20.9)1 (0.2) 1 (0.2) 0 0 due to toxicities accumulation,accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Neutropenia Neutropenia 109 (20.7) 109 (20.7) 50 (9.5) 50 (9.5)4 (0.8) 4 (0.8) (glomerulonephropathy, tubular necrosis, and pulmonary (glomerulonephropathy, tubulardysfunction), necrosis, dysfunction), and(hemorrhage/inflammation) pulmonary (hemorrhage/inflammation) Back pain Back pain 106 (20.2) 106 (20.2) 15 (2.9) 15 (2.9) 0 0 systems. The systems. dose of 2inmg/kg/dose in rats is approximately half the recommended dose in humans dose of 2The mg/kg/dose rats is approximately half the recommended dose in humans 2 Insomnia Insomnia 94 (17.9) 94 (17.9) 0 0 0 0 of 27 mg/m2ofbased 27 mg/m on body based surface on body area.surface The dose area. of 2The mg/kg/dose dose of 2 in mg/kg/dose monkeys isinapproximately monkeys is approximately equivalent to equivalent the recommended to the recommended dose in humans dose based in humans on body based surface on body area. surface area. Chills Chills 84 (16.0) 84 (16.0)1 (0.2) 1 (0.2) 0 0 PATIENT COUNSELING INFORMATION: INFORMATION: Discuss the following Discuss the withfollowing patients with priorpatients to treatment prior with to treatment with Arthralgia Arthralgia 83 (15.8) 83 (15.8)7 (1.3) 7 (1.3) 0 0 PATIENT COUNSELING KYPROLIS: Instruct KYPROLIS: patients Instruct to contact patients their to contact physiciantheir if they physician develop if they any of develop the following any of the symptoms: following symptoms: Muscle spasms Muscle spasms 76 (14.4) 76 (14.4)2 (0.4) 2 (0.4) 0 0 fever, chills, rigors, fever, chills, chest rigors, pain, cough, chest or pain, swelling cough,oforthe swelling feet oroflegs. the Advise feet or patients legs. Advise that patients KYPROLIS that KYPROLIS HypertensionHypertension 75 (14.3) 75 (14.3) 15 (2.9) 15 (2.9)2 (0.4) 2 (0.4) may cause fatigue, may cause dizziness, fatigue, fainting, dizziness, and/or fainting, drop inand/or blooddrop pressure. in blood Advise pressure. patients Advise not topatients drive ornot to drive or operate machinery operate if they machinery experience if theyany experience of these symptoms. any of theseAdvise symptoms. patients Advise that they patients maythat experience they may experience Asthenia Asthenia 73 (13.9) 73 (13.9) 12 (2.3) 12 (2.3)1 (0.2) 1 (0.2) shortness of shortness breath (dyspnea) of breath during (dyspnea) treatment during with treatment KYPROLIS. withThis KYPROLIS. most commonly This mostoccurs commonly withinoccurs within Hypokalemia Hypokalemia 72 (13.7) 72 (13.7) 14 (2.7) 14 (2.7)3 (0.6) 3 (0.6) a day of dosing. a day Advise of dosing. patients Advise to contact patientstheir to contact physicians theirif physicians they experience if theyshortness experience of shortness breath. of breath. Hypomagnesemia Hypomagnesemia 71 (13.5) 71 (13.5)2 (0.4) 2 (0.4) 0 0 Counsel patients Counsel to avoid patients dehydration, to avoid dehydration, since patientssince receiving patients KYPROLIS receivingtherapy KYPROLIS may therapy experience may experience vomiting and/or vomiting diarrhea. and/or Instruct diarrhea. patients Instruct to seek patients medical to seek advice medical if theyadvice experience if theysymptoms experience symptoms Leukopenia Leukopenia 71 (13.5) 71 (13.5) 27 (5.1) 27 (5.1)1 (0.2) 1 (0.2) lightheadedness, dizziness, lightheadedness, or fainting spells. or fainting Counsel spells. females Counsel of reproductive females of reproductive potential to use potential to use Pain in extremity Pain in extremity 70 (13.3) 70 (13.3)7 (1.3) 7 (1.3) 0 0 of dizziness, of effective contraceptive effective contraceptive measures to measures prevent pregnancy to preventduring pregnancy treatment during with treatment KYPROLIS. withAdvise KYPROLIS. the Advise the b Pneumonia Pneumonia 67 (12.7) 67 (12.7) 52 (9.9) 52 (9.9)3 (0.6)b 3 (0.6) patient that ifpatient she becomes that if she pregnant becomes during pregnant treatment, duringto treatment, contact hertophysician contact her immediately. physician immediately. Advise Advise Aspartate aminotransferase Aspartate aminotransferase increased increased 66 (12.5) 66 (12.5) 15 (2.9) 15 (2.9)1 (0.2) 1 (0.2) patients not topatients take KYPROLIS not to take treatment KYPROLIS while treatment pregnant while or breastfeeding. pregnant or breastfeeding. If a patient wishes If a patient to restart wishes to restart breastfeeding breastfeeding after treatment, after advise treatment, her to advise discuss her the to appropriate discuss the timing appropriate with her timing physician. with her Advise physician. Advise Dizziness Dizziness 66 (12.5) 66 (12.5)5 (1.0) 5 (1.0)1 (0.2) 1 (0.2) patientswith to discuss their physician with their anyphysician medication anythey medication are currently they are taking currently prior to taking starting prior to starting HypoesthesiaHypoesthesia 64 (12.2) 64 (12.2)3 (0.6) 3 (0.6) 0 0 patients to discuss treatment withtreatment KYPROLIS, withorKYPROLIS, prior to starting or prior anytonew starting medication(s) any new medication(s) during treatment during withtreatment KYPROLIS. with KYPROLIS. Anorexia Anorexia 63 (12.0) 63 (12.0)1 (0.2) 1 (0.2) 0 0 Pain Pain 63 (12.0) 63 (12.0) 12 (2.3) 12 (2.3) 0 0 Hyperglycemia Hyperglycemia 62 (11.8) 62 (11.8) 16 (3.0) 16 (3.0)3 (0.6) 3 (0.6) Chest wall pain Chest wall pain 60 (11.4) 60 (11.4)3 (0.6) 3 (0.6) 0 0 Hypercalcemia Hypercalcemia 58 (11.0) 58 (11.0) 13 (2.5) 13 (2.5)8 (1.5) 8 (1.5) Manufactured Manufactured for: Onyx Pharmaceuticals, for: Onyx Pharmaceuticals, Inc., 249 EastInc., Grand 249Avenue, East Grand Avenue, Hypophosphatemia Hypophosphatemia 55 (10.5) 55 (10.5) 24 (4.6) 24 (4.6)3 (0.6) 3 (0.6) South San Francisco, South San CAFrancisco, 94080 CA 94080 HyponatremiaHyponatremia 54 (10.3) 54 (10.3) 31 (5.9) 31 (5.9)3 (0.6) 3 (0.6) U.S. Patent Numbers: U.S. Patent7,232,818; Numbers:7,417,042; 7,232,818;7,491,704; 7,417,042;7,737,112 7,491,704; 7,737,112 05‑1088‑00 05‑1088‑00 a National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. ©2014 Onyx©2014 Pharmaceuticals, Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J Inc. TROPIC‑KYPR‑100826J November 2014 November 2014

The comprehensive nature of the meeting demonstrates the myriad problems faced by older cancer patients. It also emphasizes the vitality of the field and the need for further study. The next annual meeting will take place in Prague in November 2015. It will be chaired by Christopher Steer, MD (Border Medical Oncology, Wodonga, Australia). The meeting will be associated with the Multinational Association of Supportive Care in Cancer (MASCC), and will have the theme “Geriatric Oncology and Supportive Care: A Global Approach to Advance the Science.” To increase awareness and stimulate interest in the United States, there will be an SIOG Forum at the Moffitt Cancer Center in Tampa on April 11, 2015. Also, Memorial Sloan Kettering Cancer Center in New York will be holding a symposium, Cancer Care of the Older Adult Across the Cancer Continuum, on May 1, 2015. Older cancer patients constitute a majority of the patients we evaluate and treat. They need to become the focus of our endeavors. We all must become well-educated geriatric oncologists. Our elders deserve nothing less. n

arlier this month the Centers for Medicare & Medicaid Services (CMS) issued a final national coverage determination that provides for Medicare coverage of screening for lung cancer with low-dose computed tomography (LDCT). Effective immediately, Medicare will now cover lung cancer screening with LDCT once per year for Medicare beneficiaries who are age 55-77, and are either current smokers or have quit smoking within the last 15 years; have a tobacco smoking history of at least 30 “pack years”; and who receive a written order from a physician or qualified practitioner that meets certain requirements. n See page 66 in this issue of The ASCO Post for a full report on this recent decision.

The ASCO Post | FEBRUARY 25, 2015

PAGE 28

San Antonio Breast Cancer Symposium Breast Cancer

TNT Trial Supports Platinums in BRCA-Mutated Breast Cancer By Caroline Helwick

he TNT trial, presented at the 2014 San Antonio Breast Cancer Symposium, provided no evidence that unselected advanced triple-negative breast cancer patients are more likely to respond to carboplatin than to docetaxel.1 However, patients with BRCA1/2 mutations do have a greater response and a longer progressionfree survival with carboplatin, according to Andrew Tutt, MB, ChB, PhD, MRCP, FRCR, of Kings College and Institute of Cancer Research London. “The TNT trial supports BRCA1/2 genotyping to inform therapy choice in metastatic triple-negative breast cancer and familial breast cancer,” Dr. Tutt said.

TNT Details Subgroups within triple-negative breast cancers appear to share impaired DNA repair mechanisms—in particular, homologous recombination repair deficiency (HRD)—with BRCA1/2 germline mutation–positive patients. This impairment is thought to confer sensitivity to platinum agents. The TNT trial tested this hypothesis in women with recurrent locally advanced or metastatic BRCA-positive tumors or triple-negative breast cancer. According to Dr. Tutt, TNT is the first study to directly compare single-

agent platinum chemotherapy with the mechanistically distinct taxanes in these populations. The study included 376 patients (91% with metastatic disease) from 74 centers in the United Kingdom. A total of 43 mutations were identified. A BRCA1/2 germline mutation was noted for 9% of the carboplatin

improvement in response with carboplatin compared with docetaxel.

Unselected Population After a median follow-up of 11 months, objective responses were observed in 59 of 188 patients (31.4%) in the carboplatin arm and 67 of 188 patients (35.6%) in

Although the TNT trial gave no evidence to support superior activity of carboplatin over docetaxel in unselected triple-negative breast cancer patients, the results for germline BRCA-positive patients supported their greater sensitivity to carboplatin. —Andrew Tutt, MB, ChB, PhD, MRCP, FRCR

arm and 6.4% of the docetaxel arm. Patients were randomly assigned to receive carboplatin (area under the curve of 6 every 3 weeks) or docetaxel (100 mg/m2 every 3 weeks) for 6 to 8 cycles or until disease progression, with crossover possible on disease progression. The primary endpoint was intent-to-treat objective response rate to cycle 6. TNT aimed to detect a 15%

the docetaxel arm, for an absolute difference of –4.2% (carboplatin response rate minus docetaxel response rate; 95% confidence interval [CI] = –13.7% to 5.3%), which was not statistically significant (P = .44). Similarly, after crossover (n = 182), the response rates were 2.8% higher for the docetaxel cohort crossing over to receive carboplatin (95% CI = –9.6% to 15.2%), but again, this was not statisti-

cally significant (P = .73). The median progression-free survival was 3.1 months (95% CI = 2.5 to 4.2) in the carboplatin arm and 4.5 months (95% CI = 4.1 to 5.2) in the docetaxel arm (P = .29). The median overall survival was 12.4 months (95% CI = 10.4 to 15.3) and 12.3 months (95% CI = 10.5 to 13.6) respectively (P = .31), Dr. Tutt reported.

BRCA1/2-Positive Population Among the 43 BRCA-positive patients, however, a difference emerged between the regimens. The objective response rate was 68% with carboplatin and 33% with docetaxel, a 34.7% absolute difference (95% CI = 6.3% to 63.1%), which was statistically significant (P = .03). In contrast, for the 273 BRCA-negative patients, response rates were not significantly different at 28.1% and 36.6% (absolute difference = –8.5%, 95% CI = –19.6% to 2.6%), respectively (P = 0.16). “Carboplatin demonstrated significantly increased activity vs docetaxel in BRCA carriers, and there was a positive test for the interaction between the randomization arm and BRCA1/2 status (P = .01),” Dr. Tutt noted. This finding was obvious by the difference observed in the carboplatin arm according to BRCA status: BRCA-positive

EXPERT POINT OF VIEW

iscussion of the TNT trial was brisk at the 2014 San Antonio Breast Cancer Symposium. George Sledge, MD, Professor of Medicine and Chief of Oncology at Stanford University School of Medicine, Palo Alto, California, called the study “intriguing” and

George Sledge, MD

commented: “The platinum results, I believe, are pretty much what most of us would expect, but I am astonished at the response rate to docetaxel [in the non– basal-like subgroup]. This is the highest reported for a taxane in breast cancer.” Lead author Andrew Tutt, MB,

ChB, PhD, MRCP, FRCR, of Kings College and Institute of Cancer Research London, cautioned that this was shown in a small subpopulation that is not yet understood. “We will further analyze the non–basal-like subgroup, try to define how they are made up, and see where this result is coming from,” he said. “One might speculate there is a population within the non–basallike triple-negative group that has high chemotherapy sensitivity, but we need to understand the biology before concluding too much from this.” Ann Partridge, MD, Associate Professor of Medicine at Harvard Medical School, who moderated the session, commented for The ASCO Post in an interview and agreed with Dr. Sledge. “The most compelling things in this study are the extraordinary response rate to carboplatin for BRCA1/2 carriers and the very high response to docetaxel in non–basallike triple-negative breast cancer,” she

said. “These are findings that we definitely should look into further.” “It may be worth pursuing docetaxel in triple-negative breast cancer patients who are non-BRCA carriers. Whether this is true only for docetaxel or other taxanes, we don’t know. But a more

in determining who is best served by adding a platinum. It doesn’t appear that a platinum is going to be a panacea for triple-negative tumors across the board, though it’s a reasonable drug to try,” she continued. “HRD did not help us predict this, at least in this

A more than 70% response is astronomical, especially in a previously treated population, the vast majority of whom had had taxanes before. —Ann Partridge, MD

than 70% response is astronomical, especially in a previously treated population, the vast majority of whom had had taxanes before,” Dr. Partridge said. “The other take-home is that we are still not there yet, beyond BRCA,

study. The other thing is that carbo platin comes with a set of toxicities. Will it really be better than other standard agents? We don’t know yet.” n Disclosure: Drs. Sledge and Partridge reported no potential conflicts of interest.

ASCOPost.com | FEBRUARY 25, 2015

PAGE 29

San Antonio Breast Cancer Symposium patients had a median progression-free survival of 6.8 months (95% CI = 4.4 to 8.1), compared with 3.1 months (95% CI = 2.4 to 4.2) in patients with nonmutated BRCA receiving carboplatin. The differences were not seen with docetaxel. “In the metastatic setting, it’s important to know the BRCA status of patients and for a platinum to be considered among their treatment options,” Dr. Tutt said.

metastatic setting,” Dr. Tutt suggested. The investigators also observed similar performance between carboplatin and docetaxel in both core basal-like (by central immunohistochemistry) and PAM50-based Prosigna assay basal-like subgroups. However, in the nonbasal subtype by the PAM50-based Prosigna assay, response to docetaxel

was much greater than to carboplatin: 73.7% vs 16.7% with carboplatin (absolute difference = –55.5%, 95% CI = –82.4% to –28.6%, P = .01) The test for interaction was significant (P = .01). “Although the TNT trial gave no evidence to support superior activity of carboplatin over docetaxel in unselected triple-negative breast cancer patients, the

results for germline BRCA-positive patients supported their greater sensitivity to carboplatin,” Dr. Tutt concluded. n

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

Reference 1. Tutt A, et al: The TNT trial. 2014 San Antonio Breast Cancer Symposium. Abstract S3-01. Presented December 11, 2014.

Fulfilling the Promise of Precision Medicine The HRD score was available for 195 patients, with 81 patients classified as HRD “high” (≥ 42) and 114 as HRD “low” (< 42). (For 25 patients, the test failed.) Dr. Tutt explained that this score was the mean of three analyses by Myriad Genetics and is now the company’s published cut-point. “The dichotomized HRD score did not select for sensitivity to carboplatin over docetaxel when conducted on the primary tumor DNA,” Dr. Tutt indicated. “BRCA1/2-mutant tumors, as expected, had high HRD scores.” Response rates were 38.2% in HRDhigh patients receiving carboplatin and 42.6% for those receiving docetaxel (absolute difference = –4.4%, 95% CI = –26.0% to 17.2%, P = .82). Among the HRD-low patients, response rates were 29.2% to carboplatin and 34.7% to docetaxel (absolute difference = –5.4%, 95% CI = –22.7% to 11.9%, P = .55). The investigators proposed that nonmutated HRD-high cancers may more frequently reverse the homologous repair defect in metastases than mutated tumors. “We feel that further development of homologous recombination defect assays for BRCA status in non-BRCA1/2 tumors is required, especially in the

TNT Trial ■■ The 74-center TNT trial randomized patients with advanced triple-negative breast cancers to receive treatment with carboplatin or docetaxel. ■■ In the unselected population, outcomes were similar, but in patients with BRCA1/2 mutations, response to carboplatin and progression-free survival were much improved, vs docetaxel. ■■ Response to docetaxel among the small non–basal-like triple-negative breast cancer subgroup was nearly 74%, the highest ever reported for a taxane in breast cancer.

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Somatuline may decrease bioavailability of cyclosporine. Cyclosporine dose may need to be adjusted. Adverse Reactions: In the GEP-NET pivotal trial, the most common adverse reactions (incidence >10% and more common than placebo) in patients treated with Somatuline Depot vs placebo were abdominal pain (34% vs 24%), musculoskeletal pain (19% vs 13%), vomiting (19% vs 9%), headache (16% vs 11%), injection site reaction (15% vs 7%), hyperglycemia (14% vs 5%), hypertension (14% vs 5%), and cholelithiasis (14% vs 7%). You may report suspected adverse reactions to FDA at 1-800-FDA-1088 or to Ipsen Biopharmaceuticals, Inc. at 1-888-980-2889.

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The ASCO Post | FEBRUARY 25, 2015

PAGE 30

San Antonio Breast Cancer Symposium Breast Cancer

Shedding Light on the Mystery of Male Breast Cancer By Alice Goodman

ale breast cancer represents less than 1% of all breast cancers, which partially explains why so little is known about the disease. Two presentations at the 2014 San Antonio

SOMATULINE DEPOT® (lanreotide) Injection Brief Summary of Prescribing Information 1 INDICATION SOMATULINE DEPOT Injection 120 mg is indicated for the treatment of patients with unresectable, wellor moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. 4 CONTRAINDICATIONS SOMATULINE DEPOT is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide. 5 WARNINGS AND PRECAUTIONS 5.1 Cholelithiasis and Gallbladder Sludge Lanreotide may reduce gallbladder motility and lead to gallstone formation; therefore, patients may need to be monitored periodically [see Adverse Reactions (6.1)]. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with SOMATULINE DEPOT may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions (6.1)]. 5.3 Thyroid Function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated. 5.4 Cardiovascular Abnormalities In patients without underlying cardiac disease, SOMATULINE DEPOT may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to SOMATULINE DEPOT treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with SOMATULINE DEPOT in patients with bradycardia. In patients with baseline heart rates of ≥ 60 beats per minute (bpm) treated with SOMATULINE DEPOT in the GEP-NETs clinical trial, the incidence of heart rate < 60 bpm was 23% as compared to 16 % of placebo-treated patients; 12% of patients had documented heart rates < 60 bpm on more than one visit. The incidence of documented episodes of heart rate < 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia. 5.5 Drug Interactions The pharmacological gastrointestinal effects of SOMATULINE DEPOT may reduce the intestinal absorption of concomitant drugs. Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant-administration of SOMATULINE DEPOT and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience The safety of SOMATULINE DEPOT 120mg for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated in Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 were randomized to receive SOMATULINE DEPOT (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks. Patients treated with SOMATULINE DEPOT had a median age of 64 years (range 30-83 years), 53% were men and 96% were Caucasian. Eighty-one percent of patients (83/101) in the SOMATULINE DEPOT arm and eighty-two percent of patients (82/103) in the placebo arm did not have disease progression within 6 months of enrollment

Breast Cancer Symposium focused on the characteristics of male breast cancer drawn from a large international registry and genomic analysis of 59 male breast cancer cases.1,2 The wealth and had not received prior therapy for GEP-NETs. The rates of discontinuation due to treatment-emergent adverse reactions were 5% (5/101 patients) in the SOMATULINE DEPOT arm and 3% (3/103 patients) in the placebo arm. Table 1: Adverse Reactions Occurring in >5% in SOMATULINE DEPOT-Treated Patients and Occurring More Commonly Than Placebo-Treated Patients (>5% higher incidence) in the GEP-NETs Clinical Trial

Adverse Reaction

SOMATULINE DEPOT 120 mg (N=101) Any Severe† (%) (%)

Placebo (N=103) Any Severe† (%) (%)

Any Adverse 88 26 90 31 Reactions Abdominal 34* 6* 24* 4 pain1 Musculoskeletal 19* 2* 13 2 pain2 Vomiting 19* 2* 9* 2* Headache 16 0 11 1 Injection site 15 0 7 0 reaction3 Hyperglycemia4 14* 0 5 0 Hypertension5 14* 1* 5 0 Cholelithiasis 14* 1* 7 0 Dizziness 9 0 2* 0 Depression6 7 0 1 0 Dyspnea 6 0 1 0 1 Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 2 Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 3 Includes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling. 4 Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 5 Includes preferred terms of hypertension, hypertensive crisis 6 Includes preferred terms of depression, depressed mood * Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed. † Defined as hazardous to well-being, significant impairment of function or incapacitation 7 DRUG INTERACTIONS 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly. 7.2 Cyclosporine Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels. 7.3 Other Concomitant Drug Therapy The pharmacological gastrointestinal effects of SOMATULINE DEPOT may reduce the intestinal

of data are currently being parsed and analyzed. At present, understanding of male breast cancer is a work in progress. The first report—a joint effort by the European Organisation for Research and absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine. Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary. Vitamin K absorption was not affected when concomitantly administered with lanreotide. 7.4 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well-controlled studies in pregnant women. SOMATULINE DEPOT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (five times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (two times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.3 Nursing Mothers It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions from SOMATULINE DEPOT in animals and, potentially, in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, after taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use The GEP-NETs clinical trial did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment required. 8.6 Renal Impairment No effect was observed in total clearance of lanreotide in patients with mild to moderate renal impairment receiving SOMATULINE DEPOT 120 mg. Patients with severe renal impairment were not studied. 8.7 Hepatic Impairment SOMATULINE DEPOT has not been studied in patients with hepatic impairment. Manufactured by: Ipsen Pharma Biotech; Signes, France. Distributed by: Ipsen Biopharmaceuticals, Inc. Basking Ridge, NJ 07920 ©2014 Ipsen Biopharmaceuticals, Inc

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Treatment of Cancer (EORTC), Translational Breast Cancer Research Consortium, Breast International Group, and North American Breast Cancer Group—found similarities between male breast cancer and female breast cancer and some differences. More than 90% of male breast cancers were estrogen receptor–positive, whereas around 65% to 70% of female breast cancers are estrogen receptor–positive.

Characteristics of Male Breast Cancer Positivity of both estrogen receptor and progesterone receptor was associated with outcome in male breast cancers, similar to female breast cancers. Androgen receptor positivity was also associated with outcome, but to a lesser extent than estrogen receptor and progesterone receptor expression. Metastatic disease and node positivity are associated with worse survival. “Male breast cancer is a rare disease, and there are no prospective or randomized data on management. Treatments are extrapolated from female breast cancer. Mortality lags behind that in female breast cancer, reflecting the need for further studies to improve outcomes. The International Male Breast Cancer Program was created to better understand this disease and improve its management. It has three parts: a retrospective joint analysis of 1,800 cases, a prospective international registry, and international clinical trials,” explained Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, who presented data on the characteristics of males with early-stage breast cancer. Dr. Cardoso is Secretary General of the EORTC. The first part of this program included 1,800 eligible patients enrolled from 1990 to 2010. About 90% were between the ages of 51 and 79 years or older (median age at diagnosis, 65 years), and more than 90% patients were evenly divided between the age groups of 51 to 65, 66 to 75, and 75 or older. Central laboratory assessments were available for 1,483 (82.4%): 1,394 from the European Union and 89 from the United States. The vast majority of cancers identified were invasive ductal carcinoma grade. 2 Male breast cancer is most commonly estrogen receptor–positive, progesterone receptor–positive, and androgen receptor–positive and of luminal A-like subtype; 9% were HER2-positive, and less than 1% were triple-negative breast

ASCOPost.com | FEBRUARY 25, 2015

PAGE 31

San Antonio Breast Cancer Symposium cancer. A total of 56% were node-negative, 31% were staged as N1, 5% had N2 disease, 3% had N3 disease, and 6% had an unknown nodal status. Although for the most part adjuvant radiation was given according to guidelines, 36% of N1 patients and 15% of N2 patients did not receive adjuvant radiation. Data on adjuvant radiotherapy were available for 819 of 1,054 patients

The median overall survival was 10.41 years for nonmetastatic nodenegative patients, 8.36 years for nonmetastatic node-positive patients, and 2.63 years for metastatic patients. Grade, Ki67 expression, and immunohistochemistry subtypes were not prognostic. This cohort will continue to be studied, and clinical trials will be designed and initiated, she said.

Male breast cancer is a rare disease, and there are no prospective or randomized data on management. Mortality lags behind that in female breast cancer, reflecting the need for further studies to improve outcomes. —Fatima Cardoso, MD

who were nonmetastatic at diagnosis; in node-negative patients, 32% had adjuvant radiation therapy after mastectomy, whereas 69% of node-positive patients had radiation post mastectomy. Even though 56% of patients had tumors suitable for breast-conserving surgery, only 29 patients (4%) took advantage of the less-extensive surgery; among the breast-conserving surgery cohort, 7 node-positive patients (100%) had adjuvant radiation, whereas 46% of 22 node-negative patients had radiation. Thirty percent of patients received adjuvant chemotherapy, mostly with anthracyclines or anthracyclines and taxanes. In M0 patients, 93% had strong estrogen receptor expression, but only 77% received adjuvant endocrine therapy, mainly with tamoxifen; 35% were strongly progesterone receptor–positive. Eighty-eight percent were androgen receptor–positive, 9% were HER2positive, and 25% were Ki67-positive.

Genomic Landscape Jorge S. Reis-Filho, MD, PhD, RCPath, gave a presentation on geF nome sequencing of 241 genes in samples from 59 patients with male breast cancer diagnosed and treated at Memorial Sloan Kettering Cancer Center in New York. The median age was 66 years, and the median tumor size was 2 cm. The vast majority were grades 2 and 3;

mutations were assessed clinically, 3 harbored BRCA2 germline mutations. Genomic analysis showed that estrogen receptor–positive male breast cancers are characterized by somatic mutations in PIK3CA, GATA3, TP53, and MAP3K1. Copy number changes include 1q+, 16q–, 16p+, and 8q+. Recurrent amplifications affect genes also amplified in luminal female breast cancer, including MYC and PPM1D. In males, luminal B-like tumors display the following alterations more frequently than luminal A-like tumors: GATA3 somatic mutations, mutations affecting DNA repair-related genes, and 11q losses. Male luminal breast cancers have similar mutation rates as female luminal breast cancers but have less frequent PIK3CA and TP53 mutations. As compared to luminal female breast cancers, luminal male breast cancers exhibit

Triple-negative breast cancer is very rare in men, and we do not know why. —Lajos Pusztai, MD

similar patterns of gene copy number alterations, and are more frequently 12q+. Luminal breast cancers in males, but not in females, are more frequently enriched for mutations affecting DNA repair-related genes. Jorge S. Reis-Filho, MD, PhD, FRCPath

all tumors were estrogen receptor–positive, and only two cases were HER2amplified. In 10 patients where germline

The Challenge of Male Breast Cancer ■■ Little is known about male breast cancer, which is found in less than 1% of all breast cancers. ■■ In the absence of evidence, treatment of male breast cancer is based on that of female breast cancer. ■■ A large international consortium has taken on the challenge of characterizing these cancers and is planning to conduct clinical trials. ■■ A second group has looked at genomics in 59 patients with male breast cancers and provides a snapshot of the genetic alterations.

Dr. Pusztai noted that the differences in estrogen receptor positivity between males and females suggest possible differences in etiology and origins of male breast cancer. “Triple-negative breast cancer is very rare in men, and we do not know why,” he wrote. “The second abstract is an independent molecular confirmation of the unusual molecular class distribution of male breast cancers. The authors pretty much confirm that male breast cancers are of the luminal subtype. They tested a number of preselected molecular abnormalities and found that the distribution of them is largely similar to what we already know and would expect from luminal cancers in women,” Dr. Pusztai continued. He said that the investigators were able to draw some testable hypotheses about altered pathways in male cancers that are less frequently observed in female breast cancers. “These hypotheses

What to Make of All This? Lajos Pusztai, MD, of Yale University School of Medicine, New Haven, congratulated the authors on tackling this rare disease entity. “Both of these studies are important in that they focus on an understudied, rare subset of male breast cancer. The first report from a very large consortium does not reveal any unexpected findings. The stage distribution and survival results are difficult to compare with female breast cancer results due to the heterogeneous dataset and the vastly different sample sizes for male and female breast cancer databases,” he wrote in an e-mail.

will need to be tested on independent samples, and hopefully the international consortium will take on this challenge. The consortium will also conduct clinical trials in male breast cancer, like FGFR signaling perturbations in male breast cancer, which are directly testable in the clinical setting,” he said. n

Disclosure: Drs. Cardoso, Reis-Filho, and Pusztai reported no potential conflicts of interest.

References 1. Cardoso F, Bartlett J, Slaets L, et al: Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. 2014 San Antonio Breast Cancer Symposium. Abstract S6-05. Presented December 12, 2014. 2. Piscuoglio S, Murray M, Ng CKY, et al: The genomic landscape of male breast cancers. 2014 San Antonio Breast Cancer Symposium. Abstract S6-06. Presented December 12, 2014.

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | FEBRUARY 25, 2015

PAGE 32

JCO Spotlight Gastrointestinal Oncology

ASCO Endorses ESMO Guideline on Hereditary Colorectal Cancer Syndromes By Matthew Stenger

pproximately 5% to 6% of cases of colorectal cancer are associated with germline mutations conferring an inherited predisposition for disease. As reported by Stoffel and colleagues in the Journal of Clinical Oncology,1 ASCO has endorsed, with qualifying statements, the European Society for Medical Oncology (ESMO) 2013 guideline on familial-risk colorectal cancer.2 The

Elena M. Stoffel, MD

Paul J. Limburg, MD

ASCO endorsement panel was cochaired by Elena M. Stoffel, MD, of University of Michigan, Ann Arbor, and Paul J. Limburg, MD, of the Mayo Clinic, Rochester, Minnesota.

Major Guideline Principles In brief, the guideline states that the possibility of hereditary cancer syndrome should be assessed for every patient at the time of colorectal cancer diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management of patients with colorectal cancer and their family members. Screening for hereditary cancer syndromes should include review of personal and family histories and testing of tumors for DNA mismatch-repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria. The summary of recommendations here uses or paraphrases the language of the original ESMO recommendations, with ASCOqualifying statements appearing in italics.

Testing and Management • Tumor testing for DNA mismatchrepair deficiency with immunohistochemistry for mismatch-repair proteins or microsatellite instability should be assessed in all colorectal cancer patients. As an alternative strategy, tumor testing should be carried out in colorectal cancer patients aged < 70 years and in those aged > 70 years who fulfill any of the revised Bethesda guidelines. • If loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or of MLH1 promoter methylation should be performed first to rule out a sporadic case. If tumor is mismatch-repair deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated. • If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1). • Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis. • Follow-up in mutation carriers includes colonoscopy every 1 to 2 years and gynecologic examination (with transvaginal ultrasound and aspiration biopsy) yearly. Prophylactic gynecologic surgery may be an

• •

•

APC and/or MUTYH. Full germline genetic testing of APC should include DNA sequencing and large rearrangement analysis. Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered. In families with classic familial adenomatous polyposis, sigmoidoscopy (or colonoscopy) should be carried out every 1 to 2 years starting at the age of 10 to 11 years and continued lifelong in mutation carriers. Surgery is indicated if there are large numbers of adenomas, including adenomas with a high degree of dysplasia. In families with attenuated familial adenomatous polyposis, colonoscopy should be carried out every 2 years starting at the age of 18 to 20 years and continued lifelong in mutation carriers. Surgery is indicated if there are large numbers of adenomas, including adenomas with a high degree of dysplasia. Some patients with attenuated familial adenomatous polyposis can be conservatively managed with a colonoscopy every 1 to 2 years and polypectomy. Type of colorectal surgery in familial adenomatous polyposis (total col-

The guideline states that the possibility of hereditary cancer syndrome should be assessed for every patient at the time of colorectal cancer diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management of patients with colorectal cancer and their family members. —Elena M. Stoffel, MD, and colleagues

option in female carriers from age 35 and after childbearing is completed. • Individuals with familial colorectal cancer X syndrome should have colonoscopy at 3- to 5-year intervals, starting 5 to 10 years earlier than the youngest case in the family. • Patients with multiple colorectal adenomas (> 10) should be considered for germline genetic testing of

ectomy plus ileorectal anastomosis vs proctocolectomy plus ileal pouch anal anastomosis) depends on age of the patient, severity of rectal polyposis, wish to have children, risk of developing desmoids, and possibly the site of the mutation in the APC gene. • After colorectal surgery, surveillance of the rectum or pouch should be carried out every 6 to 12 months

if rectal tissue remains and every 6 months to 5 years if ileoanal pouch is present, depending on polyp burden. Surveillance of the gastroduodenum should be performed every 6 months to 5 years depending on polyp burden. • In both classic and attenuated familial adenomatous polyposis, screening for extracolonic manifestations (gastroduodenal polyposis, thyroid cancer, desmoid tumors) should be considered when colorectal polyposis is diagnosed or at the age of 25 to 30 years, whichever comes first. • The suggested surveillance protocol for MUTYH-associated polyposis patients is similar to that for patients with attenuated familial adenomatous polyposis.

Surveillance Recommendations Lynch Syndrome • Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 20 to 25, or 5 years before the youngest case in the family. No upper limit established. • Endometrium and ovaries: Gynecologic examination, pelvic ultrasound (not CA-125), and aspiration biopsy every year, from age 30 to 35 years. Consider prophylactic hysterectomy and salpingoophorectomy when childbearing is completed. • Gastric cancer: Search for Helicobacter pylori, and subsequent eradication is recommended in mutation carriers. In case of a high incidence of gastric cancer in some populations, some experts recommend upper gastrointestinal endoscopy every 1 to 3 years. • Other Lynch-associated cancers: Surveillance is not recommended due to low sensitivity and specificity. (Although there are insufficient data supporting surveillance for other target organs, it may be considered in the context of family history.)

Classic Familial Adenomatous Polyposis • Colon and rectum: Sigmoidoscopy (or colonoscopy) every 1 to 2 years, starting at age 10 to 11 years and continued lifelong in mutation carriers. Once adenomas are detected, annual colonoscopy should be carried out until colectomy is planned. Surgery is indicated if there are large

ASCOPost.com | FEBRUARY 25, 2015

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JCO Spotlight

Attenuated Familial Adenomatous Polyposis • Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 18 to 20 years and continued lifelong in mutation carriers. Once adenomas are detected, colonoscopy should be carried out annually. • Gastroduodenal adenomas: Gastroduodenal endoscopy using both front- and side-view scopes starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance inter-

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vals are based on the Spigelman stage. • Thyroid cancer: Annual cervical ultrasonography may be considered starting at age 25 to 30 years. • Desmoid tumors: A baseline CT scan or MRI should be considered if risk factors are present (positive family history for desmoids and site of the mutation in APC). n

Disclosure: For full disclosures of the ASCO panel members, visit jco.ascopubs.org.

References BLEED:8.375” 1. Stoffel EM, Mangu PB, Grube SB, et TRIM:7.875” al: Hereditary colorectal cancer syndromes: American Society of SAFETY:7” Clinical Oncology clinical practice guideline endorsement of the familial risk–colorectal cancer: Euro-

See commentary by Patrick M. Lynch, JD, MD, on page 34.

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pean Society for Medical Oncology clinical practice guidelines. J Clin Oncol 33:209217, 2015. 2. Balmaña J, Balaguer F, Cervantes A, et al: Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol 24(suppl 6):vi73-vi80, 2013.

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numbers of adenomas, including adenomas with a high degree of dysplasia. • Gastroduodenal adenomas: Gastroduodenal endoscopy using both front- and side-view scopes starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage. • Thyroid cancer: Annual cervical ultrasonography may be considered starting at age 25 to 30 years. • Desmoid tumors: A baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan should be considered if risk factors (positive family history for desmoids and site of the mutation in APC).

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For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com. 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

The ASCO Post | FEBRUARY 25, 2015

PAGE 34

Perspective

ASCO Endorsement of ESMO Guidelines on Hereditary Colorectal Cancer Syndromes By Patrick M. Lynch, JD, MD

n a recent issue of the Journal of Clinical Oncology,1 and as reviewed in this issue of The ASCO Post, an ASCO expert endorsement panel reviewed and endorsed, with minor qualifications, the European Society for Medical Oncology (ESMO) clinical practice guidelines for management of familial/ genetic colorectal cancer predisposition.2 The guidelines address genetic testing strategies, clinical surveillance, and treatment logics for hereditary nonpolyposis colorectal cancer (HNPCC or “Lynch syndrome”) and for familial adenomatous polyposis. With this commentary, which generally represents a positive endorsement of this endorsement, I will note a few emerging areas of interest that were not raised by either ESMO or ASCO and will critique some specifics that could bear a revisit in the future.

Major Recommendations Key features of the ASCO/ESMO guidelines include the following: (1) All cases of colorectal cancer or, alternatively, patients aged < 70 years and those over 70 years who meet criteria suggesting higher likelihood of underlying HNPCC/Lynch syndrome (so-called Bethesda Guidelines) should be referred for tumor testing with immunohistochemistry for evidence of defective mismatch repair. This process selects patients who would benefit from germline mutation testing. Recognition is made of the frequent nonfamilial/genetic or sporadic loss of MLH1 expression due to promoter hypermethylation and the consequent need for a secondary assay (BRAF mutation or methylation). (2) The only firm surveillance recommendation for HNPCC/Lynch syndrome, and the only one with a solid evidence base, is colorectal screening by means of colonoscopy starting at age 20 to 25 years and repeated at 1- to 2-year intervals. While the lack of evidence base is acknowledged, there is nevertheless a recommendation for annual endometrial sampling and transvaginal ultrasound (ASCO, unlike ESMO, does not recommend CA-125). Other than Dr. Lynch is Professor of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston.

looking for evidence of Helicobacter pylori and perhaps esophagogastroduodenoscopy in high-risk geographies, no recommendation for upper gastrointestinal screening is offered, and no other extracolonic at-risk organs carry a positive screening recommendation. (3) For treatment in HNPCC/ Lynch syndrome, aspirin is supported as a chemopreventive intervention, but uncertainty as to proper dose leaves this as a “soft” recommendation. Consideration of risk-reducing total abdominal hysterectomy with bilateral salpingooophorectomy after childbearing is offered and does have some evidence base behind it. No real recommendation as to extent of surgery for colorectal cancer is offered, supporting, in effect, the status quo of segmental sur-

practice patterns between the United States and Europe. Surgical choice of colectomy/ileorectal anastomosis vs proctocolectomy/ileal J-pouch-anal anastomosis is based on well-established considerations. Upper gastrointestinal surveillance and endoscopic and surgical interventions are predicated on the high rate of duodenal adenomas, though little note is made of the tremendous difficulties that the multiple, large, flat polyps pose to both the endoscopist and surgeon. The challenges of managing desmoids and the controversial role for chemopreventive measures (typically nonsteroidal anti-inflammatory drugs) are noted and follow conventional wisdom. The ASCO guidelines suggest a greater willingness to consider routine

I am optimistic that the data on genetic testing and testing strategies will continue to improve and refine clinical practice guidelines in this area. Clinical surveillance guidelines, requiring carefully designed clinical trials, will take much longer to develop. I would challenge the professional societies to take up the challenge so that the era of ‘no recommendation for or against’ will come to an end. —Patrick M. Lynch, JD, MD

gery/postsurgical surveillance or subtotal colectomy, the choice depending on outcome of individualized surgeonpatient negotiation. (4) In familial adenomatous polyposis, APC (adenomatous polyposis coli) mutation testing of affected individuals is recommended as a foundation for predictive testing in at-risk relatives. In young mutation carriers, sigmoidoscopy at 2-year intervals starting at age 12 to 14 is recommended, with colonoscopy once adenomas are encountered. ASCO recommends starting younger (10 to 11 years), at intervals of 1 to 2 years, and would consider full colonoscopy as an alternative to sigmoidoscopy. These minor distinctions do, in my experience, echo a real difference in

imaging for desmoids in high-risk familial adenomatous polyposis patients. (5) The approach to recessively inherited MYH-associated polyposis is clinically similar to that of the attenuated form of familial adenomatous polyposis.

Unaddressed Issues As indicated above, the differences between the ESMO and ASCO guidelines are fairly minimal. My remaining comments are intended to call attention to several areas that are not addressed by either ESMO or ASCO. Although it is likely that these simply relate to lack of an established evidence base or expert consensus on controversial topics, the practitioner wishing to

manage these high-risk patients must be aware of certain problem areas. In the case of HNPCC/Lynch syndrome, risk assessment models have been offered as a basis for comprehensive mismatch-repair gene mutation testing (alone or as part of panels, as noted below) in a fashion similar to that used in familial breast/ovarian cancer to predict mutation likelihood.3-5 Such testing has been offered as an alternative to tumor-based testing (microsatellite instability/immunohistochemistry). This may be appropriate, so long as the clinician is aware of the limitations and is willing to return to the tumor if, as is often the case, germline DNA testing is not informative. Neither ESMO nor ASCO devotes much attention to this issue. The extent of use of risk models as a basis for germline mutation testing is unknown. Testing based on such models is being aggressively marketed in the United States, likely much more so than in Europe, and may account for the lack of attention by ESMO.

Panel Testing As the number of cancer predisposition genes increases, including those with lower penetrance or those that overlap other disorders, and as the cost of sequencing decreases, several commercial entities have recently begun to offer “panel” testing of 16 or more genes. Examples include APC, ATM, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 (http://www.genedx.com/ oncology-genetics/). Other labs offer a different number of genes that are either relatively specific for gastrointestinal cancer or are even broader in scope (Ambry, 14 genes: http://www.ambrygen.com/hereditary-cancer-panels; Myriad, 25 genes: http://www.myriad.com/productsservices/hereditary-cancers/myriskhereditary-cancer/). Academic centers such as the University of Washington and the City of Hope Cancer Center offer similar panels. They consist of massively parallel or next-generation DNA sequencing with or without rearrangement studies.6,7 Many elitists have scoffed at such “shotgun” testing. Yet, we must admit that there are cases in which a patient’s

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

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

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

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

11%% 23 23%%

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

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

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

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

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

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

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

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

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

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

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

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

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

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

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

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

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

Pregnancy: Pregnancy Category D.

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

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

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

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

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

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

All Grades (%)

Grades 3–4 (%)

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

SELECTED SAFETY INFORMATION

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

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

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

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

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

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | FEBRUARY 25, 2015

PAGE 35

Perspective

personal and family histories are sufficiently limited, conflicting, or otherwise confusing on the one hand, while on the other hand, his or her zeal for testing is high, so as to warrant consideration of such testing. This appears to make the testing easier for the clinician to whom the panels are being aggressively marketed. However, the less clear the clinical picture, the lower the yield of such testing. Thus, the clinician needs to guard against providing the patient a false sense of security when the panel is a nondiagnostic negative. Some form of clinical surveillance may still be warranted. Conversely, we are starting to see tests that are positive for mutations in genes that would not have been considered under a more-targeted testing strategy. This may be good in that it suggests a greater overall sensitivity for a shotgun approach. However, it may be problematic to the extent that a given positive test may be indicative of a very attenuated expressivity that will be hard to translate into an appropriate predictive testing and clinical surveillance strategy. I would encourage expert panels that have taken up guideline development to place panel testing on their agenda, even if lack of consensus for or against prevents taking a position. I emphasize this not because there is a strong evidence base, but simply because such testing is in fact already commercially available, and clinicians deserve some expert guidance on the matter.

Variants of Uncertain Significance The matter of “variants of uncertain significance”—that is, DNA germline sequence variants that may or may not be pathogenic—is not taken up by ESMO or ASCO. In patients with informative microsatellite instability/immunohistochemistry, suggestive of underlying HNPCC/Lynch syndrome, this can be especially vexing. In as many as 30% of cases, a variant of uncertain significance is identified.8 The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has put together an expert panel to more properly classify variants of uncertain significance,9 but the proportion that remains unclassified represents an ongoing challenge. Reports from reference labs performing clinical mutation testing generally provide excellent commentary on the meaning and limitations of

variants of uncertain significance. Although such variants are occasionally reclassified as pathogenic or harmless and supplemental clinical lab reports provided, these nuances of interpretation underscore the importance of having access to genetic counselors. Genetic counselors can provide vital assistance in helping clinicians to make sense of it all and to explain the limitations to patients. Because the genetic counseling ranks are well developed in the United States, relative to Europe, it is not surprising that ESMO does not comment on the role of genetic counselors. Nevertheless, ASCO and other U.S. guideline experts should, in this commentator’s view, provide a positive endorsement of the routine use of genetic counselors in managing high-risk patients.

Other Diagnostic Considerations Most of the ESMO guidelines assume that genetic counseling and testing have been conducted and a mutation found. In the case of familial adenomatous polyposis, this is not really a critical matter, as clinical surveillance eventually demonstrates the presence or absence of polyp phenotype. But in HNPCC/Lynch syndrome and in patients with oligopolyposis not otherwise specified, inability to identify a definite underlying germline mutation, in many cases, leaves considerable uncertainty regarding diagnosis and, consequently, the approach to clinical surveillance. In general, when microsatellite instability is present and is not attributable to methylation and/or shows BRAF mutation, HNPCC/Lynch syndrome is considered present even when no mutation is detected. Since this failure to detect germline mutation occurs in as many as half of all cases with informative microsatellite instability/immunohistochemistry, it is not a trivial consideration. First-degree relatives of such microsatellite instability– high but mutation nondiagnostic cases are considered at risk and screened “as if” they are carriers, since they cannot be proven not to be carriers. This is a challenging concept for such patients and their providers. This problem of the microsatellite instability–high but mutation nondiagnostic case has recently become more intriguing in light of evidence that colorectal cancers, in some cases— typically those with little or no family

history of HNPCC/Lynch syndrome tumors—may actually be sporadic as evidenced by apparently somatic mutations in both alleles of, say, MSH2, in the absence of methylation or BRAF mutation.10,11 Note this discussion is different from the situation in which no microsatellite instability is present but family history is strong, the so-called “familial colon cancer syndrome X.”

Need for Clinical Trials Guidelines for screening and management of HNPCC/Lynch syndrome and for familial adenomatous polyposis show minimal disagreement between ASCO and ESMO. A distressing thread that runs through the guidelines is the inability to offer positive recommendations for clinical screening and intervention in a host of settings. While this lack of evidence base supports the conservative positions taken by ESMO/ASCO, it should serve to prompt the clinical research community to design trials that would provide an evidence base for or against, for example, extracolonic surveillance in HNPCC/Lynch syndrome. Up to now, this would have been challenging due to the relatively small cohort of patients with known mismatch-repair mutations. However, a constellation of factors should be changing this and leading to such trials: (1) more routine microsatellite instability/ immunohistochemistry for colorectal cancer and endometrial cancer; (2) availability of mutation testing; (3) resultant increasing number of mutationpositive families tracked by various registries or otherwise accessible; (4) increasing patient advocacy; and (5) the existence of collaborative societies— ESMO, ASCO, American Society of Colon and Rectal Surgeons, GI societies such as the American Gastroenterological Association and American Society for Gastrointestinal Endoscopy, Collaborative Group of the Americas on Inherited Colorectal Cancer, InSiGHT, Cooperative Family Registries, and corresponding consortia in Europe—that individually or collectively ought to be taking up the challenge. I am optimistic that the data on genetic testing and testing strategies will continue to improve and refine clinical practice guidelines in this area. Clinical surveillance guidelines, requiring carefully designed clinical trials, will take much longer to develop. I would challenge the professional societies to take up the challenge so that the era of “no

recommendation for or against” will come to an end. n

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

References 1. Stoffel EM, Mangu PB, Grube SB, et al: Hereditary colorectal cancer syndromes: American Society of Cinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J Clin Oncol 33:209-217, 2015. 2. Balmana J, Balaguer F, Cervantes A, et al: Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol 24(suppl 6):vi73-vi80, 2013. 3. Kastrinos F, Steyerberg EW, Mercado R, et al: The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 140:73-81, 2011. 4. James PA, Doherty R, Harris M, et al: Optimal selection of individuals for BRCA mutation testing: A comparison of available methods. J Clin Oncol 24:707-715, 2006. 5. Dinh TA, Rosner BI, Atwood JC, et al: Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res 4:9-22, 2011. 6. Walsh T, Lee MK, Casadei S, et al: Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 107:12629-12633, 2010. 7. Hiraki S, Rinella ES, Schnabel F, et al: Cancer risk assessment using genetic panel testing: Considerations for clinical application. J Genet Couns 23:604-617, 2014. 8. Maxwell KN, Wubbenhorst B, D’Andrea K, et al: Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. December 11, 2014 (early release online). 9. Thompson BA, Spurdle AB, Plazzer JP, et al: Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46:107-115, 2014. 10. Carethers JM: Differentiating Lynch-like from Lynch syndrome. Gastroenterology 146:602-604, 2014. 11. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al: Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146:643-646.e8, 2014.

The ASCO Post | FEBRUARY 25, 2015

PAGE 36

Education in Oncology Professional Development

How Changes to ACGME’s Accreditation Standards Are Affecting Fellowship Training A Conversation With Jill Gilbert, MD By Jo Cavallo in Nashville, about the ACGME requirements and how the more targeted evaluations of performance are resulting in better-trained physicians.

ducation in Oncology focuses on faculty development, medical education curricula, fellowship training, and communication skills. The column is guest edited by Leora Horn, MD, MSc, Associate Professor of Medicine, Assistant Director of the Educator Development Program, and Clinical Director of the Thoracic Oncology Program at Vanderbilt University School of Medicine, Nashville.

New Requirements

Jill Gilbert, MD

wo years ago, the Accreditation Council for Graduate Medical Education (ACGME), the nonprofit organization that evaluates and accredits more than 9,000 medical residency programs in the United States, began phasing in implementation of its Next Accreditation System for graduate medical education, developed in conjunction with the American Board of Internal Medicine (ABIM). The new system requires all medical training programs to use milestones-based assessment and reporting through descriptive and observable behaviors for the evaluation of resident skills within these competencies as they progress through training.1 The internal medicine subspecialties use general “subspecialty reporting milestones,” which are not specific to any one area of internal medicine. Fellow progress in attainment of the subspecialty milestones is now reported every 6 months to the ACGME (and ultimately ABIM). The key is demonstrating that the fellow is “trusted” to perform the activities safely and independently prior to graduation. Hematology and clinical oncology work groups, sponsored by the American Society of Hematology (ASH) and ASCO, took this one step further and created Curricular Milestones to establish a real-life, relevant hematology-oncology framework, which can help inform subspecialty milestone reporting. The hope is that faculty will feel comfortable and confident evaluating fellow performance on core activities within the field and that valuable feedback will be provided to the trainee. The ASCO Post talked with Jill Gilbert, MD, Associate Professor of Medicine and Director of the Hematology/Oncology Fellowship Program at Vanderbilt University Medical Center

Please tell us about the changes in ACGME requirements for oncology fellows and residents and how they will improve clinical training. Our first Hematology/Oncology Subspecialty Milestones reporting for fellows and residents under the new requirements was due in January 2015. Prior to the Next Accreditation System, we judged fellows’ ability to graduate from the residency program based on the six core clinical competencies: patient care, medical knowledge, interpersonal and communication skills, professionalism, practice-based learning and improvement, and systems-based practice. The problem was that these competency requirements were very esoteric, broad concepts and were not grounded in actual activities that could be measured. In fact, we are not really sure that they were accurately measuring the ability of fellows to finish training and

Leora Horn, MD, MSc

observe and judge. However, this one activity includes multiple components (which fall within the aforementioned competencies and thus map to the subspecialty milestones). These milestones include knowing what to order on the biopsy/aspirate (medical knowledge and patient care), obtaining informed consent (interpersonal and communication skills), and having professional and successful interactions with the bone marrow technologist (system-based practice, professionalism). Thus, this one activity allows the faculty to evaluate multiple milestones (see box below).

On a global level, we hope these changes will have an impact on the kind of physician these fellows become, which ultimately will improve patient care. —Jill Gilbert, MD

be ready for independent practice. Now, we have moved to the Next Accreditation System, which includes outcomes-based milestones for resident performance within these six domains of clinical competence. The idea behind the change was that for every clinical rotation, there is a specific list of clinical activities called “entrustable professional activities” that can be observed and are considered essential for the fellow to demonstrate mastery over prior to graduation. Each entrustable professional activity can usually “map” or inform several of the subspecialty milestones. For example, if a fellow has a rotation in leukemia, one entrustable professional activity the fellow must show proficiency in prior to graduation is the ability to perform a bone marrow biopsy. The activity is something that faculty can actually

GUEST EDITOR

Projected Benefits What are some projected benefits of the Next Accreditation System? Fellows and residents can be assured that all the programs are standardized and teach and evaluate the same desired outcomes in terms of milestones. For faculty, the new milestones allow a more concrete activity-based way of evaluating fellows and providing feedback. Ideally, this system will help alleviate “grade inflation,” which often occurred in

the previous competency-based system when faculty did not understand what they were actually evaluating. Now, evaluations are graded in observable activities that faculty can grasp. Moreover, the Next Accreditation System emphasizes that trainees are on a trajectory of competence and should demonstrate progress, not perfection, as they progress in the fellowship.

Early Results What have been the results of the Next Accreditation System so far? Although the new requirements only recently went into effect, we have already gotten positive feedback from the fellows and faculty members. The fellows say that the Next Accreditation System provides specific tools to assess rotations, and faculty like the program because it allows them to evaluate performance based on actual observable skill. On a global level, we hope these changes will have an impact on the kind of physician these fellows become, which ultimately will improve patient care. n

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

Reference 1. The Internal Medicine Subspecialty Milestones Project. Available at acgme.org/ acgmeweb/portals/0/pdfs/milestones/internalmedicinesubspecialtymilestones.pdf. Accessed January 15, 2015.

More on Accreditation and Subspecialty Milestones For more information on ACGME, the Next Accreditation System, and Milestones Resources for Training Programs, visit: http://www.asco.org/professional-development/acgme-nas-and-milestonesresources-training-programs

BECAUSE YOU CAN’T DO THIS TO CLL…

THERE’S ZYDELIG® A first-in-class selective inhibitor of PI3Kδ, a protein that is expressed in normal and malignant B cells

ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed CLL in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities CLL=chronic lymphocytic leukemia; PI3Kδ=phosphatidylinositol 3-kinase delta.

IMPORTANT SAFETY INFORMATION BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended • Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation

CLL

Please see the following pages for additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING.

IMAGINE WHAT’S POSSIBLE

In relapsed CLL in combination with rituximab where rituximab alone is appropriate due to comorbidities

Imagine what’s possible: ZYDELIG®—A first-in-class PI3Kδ inhibitor ZYDELIG is the ONLY KINASE INHIBITOR APPROVED

IN COMBINATION WITH RITUXIMAB.

IDELALISIB + RITUXIMAB is A SUGGESTED TREATMENT REGIMEN in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed/refractory CLL.1*

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN®=National Comprehensive Cancer Network®. *In patients for whom rituximab monotherapy would be considered appropriate due to comorbidities, renal impairment, and/or grade ≥3 cytopenias due to prior therapy.1 Please see the complete version of the NCCN Guidelines® for Non-Hodgkin’s Lymphomas available on NCCN.org for specific recommendations.

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue

ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥10% and ≥2% than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting, and headache • Most frequent serious adverse reactions (SAR) were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%); SAR were reported in 49% of patients and 10% of patients discontinued due to adverse reactions • Most common lab abnormalities (incidence ≥30% and ≥5% than rituximab alone; all grades) were neutrophils decreased, hypertriglyceridemia, hyperglycemia, and ALT elevation Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates

Powerful efficacy, chemotherapy free ZYDELIG: Superior PFS in a phase 3 trial2†

CI=confidence interval; HR=hazard ratio; NR=not reached; PFS=progression-free survival. †Results of a randomized, double-blind, placebo-controlled study in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to comorbidities, cytopenias (grade ≥3 neutropenia or grade ≥3 thrombocytopenia), and/or renal impairment (creatinine clearance <60 mL/min). Patients must have received ≥1 anti-CD20–containing or ≥2 prior cytotoxic therapies. Patients were randomized to receive 8 doses of rituximab (first dose 375 mg/m2, subsequent doses 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for 3 infusions) with either oral placebo or ZYDELIG 150 mg, twice daily, until disease progression or unacceptable toxicity. The primary end point was PFS, as assessed by an independent review committee. PFS was defined as the interval from randomization to the earlier of the first documentation of definitive progressive disease or death from any cause; definitive disease progression was based on standard criteria other than lymphocytosis alone. The trial was stopped early for efficacy following the first prespecified interim analysis. Results are from the second interim analysis, conducted on October 9, 2013. Median duration of exposure to ZYDELIG was 5 months.2-4

• Most common adverse reactions (incidence ≥10% and ≥2% than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting, and headache; 10% of patients discontinued due to adverse reactions

Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the

dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued Please see the following pages for Brief Summary of full Prescribing Information, including BOXED WARNING. VISIT ZYDELIG.COM

IMAGINE WHAT’S POSSIBLE

S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions]. INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities. • ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies. • ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies. • Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information. Adult Starting Dose: One 150 mg tablet taken orally twice daily (BID), swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who required treatment longer than several months is unknown.

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration]. Fatal and serious pneumonitis occurred in ZYDELIG-treated patients. Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids. Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation. Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions. Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration]. Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations]. ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

The safety assessment of ZYDELIG 150 mg BID + rituximab (up to 8 doses) is based on data from 110 adult subjects with relapsed CLL (Study 1). The median duration of exposure to ZYDELIG was 5 months.

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment. Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge. CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN). WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis. • Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%). Subjects with Indolent Non-Hodgkin Lymphoma (iNHL): The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months). • Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%). DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine). • CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration]. • CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered. USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm. In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions]. Nursing Mothers: It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ZYDELIG, a decision should be made whether to discontinue nursing or ZYDELIG, taking into account the importance of ZYDELIG to the mother. Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established. Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed. • In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%). • In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%). Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions]. Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min. Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration]. 205858-GS-000-PI July 2014

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed January 7, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. 3. Furman RR, Sharman JP, Coutre SE, et al. Protocol for: idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. 4. Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. Poster presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 7012.

Gilead, the Gilead logo, and ZYDELIG are trademarks of Gilead Sciences, Inc., or one of its related companies. All other trademarks referenced herein are the property of their respective owners. © 2015 Gilead Sciences, Inc. All rights reserved. ZYDP0086 02/2015

S:13”

DOSAGE AND ADMINISTRATION:

treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use of ZYDELIG with hepatotoxic drugs. In all patients, monitor ALT and AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. If ALT or AST >3x ULN, monitor weekly until elevation resolves; if ALT or AST >5x ULN, withhold ZYDELIG and monitor AST, ALT and total bilirubin weekly until elevation resolves [See Dosage and Administration].

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Molecular Oncology Tumor Boards Invite Discussion of Growing Field in Cancer Care

ncologists and other related health-care providers now have an online platform for the discussion of the growing area of tumor molecular profiling tests and studies. In January, ASCO launched the Molecular Oncology Tumor Boards, a series of monthly user-driven discussions designed to

ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO. “All oncologists struggle to keep abreast of this information and to learn how to use tumor molecular profiling to deliver high-quality, personalized cancer care. We hope that this new educational program will foster learning about tumor

We hope that this new educational program will foster learning about tumor molecular genomics in an engaging and interactive format fueled by real-world case studies. —Richard L. Schilsky, MD, FACP, FASCO

T:13.75”

help health-care providers navigate new genetic and genomic tests as well as the integration of these tests and their results into the day-to-day clinical care of patients with cancer. The series, accessible through ASCO University at university.asco.org/motb, is an educational collaboration between ASCO, the College of American Pathologists, and the Association for Molecular Pathology.

New Educational Program “Understanding the results of tumor molecular profiling studies is challenging, and the field of cancer genomics is rapidly changing, with new information being generated at a dizzying pace,” said

molecular genomics in an engaging and interactive format fueled by real-world case studies.” Each month, the Molecular Oncology Tumor Boards will feature a new case discussion with topics that can vary from a genetic mutation most commonly seen in a specific subspecialty of oncology, to a specific genetic mutation affecting a variety of cancer types. The discussions will be moderated by rotating expert pathologists and medical oncologists. Unlike traditionally published case reports, this new series will rely on user-driven interactions and will encourage a multidisciplinary discussion of each patient case. All participants are

encouraged to read the cases and leave comments or questions relevant to the case in order to generate a wide discussion among the cancer care community.

Case Report: Extended RAS Mutation The first Molecular Oncology Tumor Board discussion went live online on January 14, 2015. Moderated by Stanley Hamilton, MD, a pathologist at The University of Texas MD Anderson Cancer Center, and Leonard Saltz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, the first case focused on extended RAS mutation. The patient case detailed a 62-yearold man with moderately differentiated adenocarcinoma with a BRAF and KRAS exon type wild-type tumor. Details on the patient’s medical history, imaging examinations, comorbidities, and diagnosis were also provided. As the case moderators, Drs. Saltz and Hamilton posted the case details and several questions to help fuel a discussion of relevant considerations, such as which cytotoxic chemotherapy might be used, whether a biologic should be considered, and if a decision about the use of biologics should be delayed until the results of tumor genotyping are received. After several professionals weighed in with their responses, Dr. Saltz posted a faculty response detailing his opinion on the best course of treatment for the patient, as well as

the relevant research to support his treatment decisions. The moderators also updated the patient case, detailing what eventual course of treatment was selected and how that might affect future consideration for the patient’s treatment. Each monthly case will be updated with new information throughout a 2-week period as user comments are added and additional questions are posed. After the 2-week discussion period, participants in the tumor boards can access additional course information, post-tests, and certificates of Continuing Medical Education credit, completion, and participation on ASCO University. ASCO’s Molecular Oncology Tumor Boards are free to access; participants just need to create an ASCO.org account to log in. n © 2015. American Society of Clinical Oncology. All rights reserved.

Conquer Cancer Foundation Researchers Lead Six Key Studies Featured in Clinical Cancer Advances 2015

ix of the studies featured in the recently released Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer were led by researchers that whom Conquer Cancer Foundation (CCF) funded early in their careers through its signature Young Investigator Award (YIA) and Career Development Award (CDA) programs. Now in its 10th year of publication, ASCO’s Clinical Cancer Advances is an in-

dependent review of the major advances in clinical cancer research and care, as well as emerging trends in the field. The report was published online in the Journal of Clinical Oncology on January 20.1 Many past CCF grantees appear in the pages of Clinical Cancer Advances 2015, with these six appearing as lead authors in key studies: • Emmanuel Antonarakis, MD (2009 Young Investigator Award) A study led by Dr. Antonarakis indicates that an experimental blood test may help identify men with prostate cancer who are resistant to the widely used hormone drugs enzalutamide (Xtandi) and abiraterone acetate (Zytiga), which target the androgen receptor. Should future research confirm

study findings, use of this test could lead to avoidance of unnecessary treatment in a large group of men who carry abnormal androgen receptors. • Marco Davila, MD, PhD (2010 Young Investigator Award) Dr. Davila led one of two small studies indicating that a new type of immunotherapy, known as chimeric antigen receptor–modified (CAR) Tcell therapy, may be the first effective treatment for relapsed acute lymphoblastic leukemia (ALL) in both adults and children. The researchers treated 16 adults with relapsed or chemotherapy-resistant B-cell ALL with a new CD19-directed CAR T-cell therapy. Complete cancer remissions occurred

in 88% of the patients, some as early as 7 to 10 days after CAR T-cell infusion. • Charles Fuchs, MD, MPH (1991 Young Investigator Award) Dr. Fuchs led the first study to show that an angiogenesis inhibitor can be as effective as a stand-alone therapy in a gastrointestinal cancer. The study findings led to the U.S. Food and Drug Administration (FDA) approval of ramucirumab (Cyramza) for the treatment of advanced stomach cancer or gastroesophageal junction adenocarcinoma in April 2014. This marks the first FDA-approved treatment for patients with advanced stomach cancer that worscontinued on page 42

The ASCO Post | FEBRUARY 25, 2015

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ASCO, AACR Call for Regulation of Electronic Nicotine Delivery Systems

SCO and the American Association for Cancer Research (AACR) released a joint statement in January to guide policymakers as they work to minimize the potential negative consequences of electronic cigarettes

delivery systems are not currently regulated by the U.S. Food and Drug Administration (FDA). Some state and local governments have enacted e-cigarette regulations, including imposing restrictions on the sale of e-cigarettes

to minors and prohibiting use of e-cigarettes in public places. Federal regulations have yet to be adopted, and manufacturing standards and quality controls on e-cigarettes are also absent. “While e-cigarettes may reduce smoking rates and attendant adverse health risks, we will not know for sure until these products are researched and regulated,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “The FDA has signaled its willingness to regulate e-cigarettes and other electronic nicotine delivery systems, and we urge the Agency to follow through on this intention.” The statement’s recommendations also focus on efforts to protect minors. “We cannot afford to wait to take prudent steps to stop those under 18 from using e-cigarettes,” said AACR President Carlos L. Arteaga, MD. “This is especially important since e-cigarette use is growing fast among this age group, as reported in the most recent National Youth Tobacco Survey.”

Noting that additional research is needed to inform the regulation of ecigarettes and other electronic nicotine delivery systems, the AACR and ASCO statement outlines steps that can be taken now in the interest of public health. Specifically, the policy recommendations include the following: • The FDA Center for Tobacco Products should regulate all electronic nicotine delivery systems that meet the statutory definition of tobacco products. Those that do not meet the statutory definition of tobacco products should be regulated by the FDA through other appropriate authorities. • Packaging and advertising of these products should be required to carry safety labels that include a warning regarding nicotine addiction. • Electronic nicotine delivery systems use should be prohibited in places where combustible tobacco product use is prohibited by federal, state, or local law, until the safety of secondhand aerosol exposure is established. • Funding generated through tobacco product taxes, including any potential taxes levied on electronic nicotine delivery systems, should be used to help support research on electronic nicotine delivery systems and other tobacco products and should not preclude the allocation of federal funding for this research. • All data related to electronic nicotine delivery systems composition, use, and health effects should be disclosed for dissemination and should inform policy decisions for electronic nicotine delivery systems product regulation. • State and local governments should

received AZD9291 experienced tumor shrinkage. • Alexander Shoushtari, MD (2014 Young Investigator Award) Few effective treatments are available for patients with tyrosine kinase inhibitor–resistant gastrointestinal stromal tumors (GIST) and other advanced soft-tissue sarcomas. Dr. Shoushtari and his team conducted a promising phase I study where dasatinib (Sprycel) was combined with immunotherapy ipilimumab (Yervoy) to treat patients with GIST and other advanced sarcomas. The drug combination showed promising clinical activity and could perhaps provide a new option for patients with GIST tumors.

• Jane Weeks, MD, MSc, FASCO (1992 Career Development Award) in memoriam A multi-institutional, observational study led by Dr. Weeks and her team looked at interinstitutional variation in management decisions for patients with four common types of cancer. A substantial variation in institutional practice among cancer centers reveals a lack of consensus about optimal management for common clinical scenarios. For clinicians, awareness of these variations should prompt discussions about patient preferences. For health systems, high variation can be used to prioritize comparative effectiveness

While e-cigarettes may reduce smoking rates and attendant adverse health risks, we will not know for sure until these products are researched and regulated. —Peter Paul Yu, MD, FACP, FASCO

(e-cigarettes) and other electronic nicotine delivery systems. Tobacco use, according to the statement, constitutes the largest preventable cause of death and disability in developed countries and is a rapidly growing health problem in developing nations. It is responsible for 30% of all cancer deaths and is associated with increased risk for at least 18 types of cancer. E-cigarettes and other electronic nicotine delivery systems, which are capable of delivering a nicotine solution in aerosolized form, have been promoted as safer alternatives to combustible cigarettes and potential tobacco cessation products. At the present time, however, insufficient data exist on the health consequences of electronic nicotine delivery systems use and their value as tobacco cessation aids.

Federal Regulations Needed Unlike combustible cigarettes and many other tobacco products, e-cigarettes and other electronic nicotine

Clinical Cancer Advances continued from page 41

ened during or after chemotherapy. Thus far there have been few treatment options for this aggressive and often symptomatic cancer. • Pasi Jänne, MD, PhD (2001 Young Investigator Award) Dr. Jänne led a phase I study to evaluate the effectiveness of experimental drug AZD9291 in patients with non–small cell lung cancer who harbor an EGFR mutation called T790M. This mutation is thought to be responsible for resistance to standard EGRFtargeted therapy. Remarkably, 50% of T790M-positive patients who

Policy Recommendations

implement related regulations appropriate for protecting the public’s health, including restricting the sale, distribution, marketing, and advertising of electronic nicotine delivery systems to youth. In addition, the AACR and ASCO encourage all oncologists to recommend FDA-approved cessation medications instead of e-cigarettes to individuals who are interested in or trying to quit smoking combustible cigarettes. The joint statement was published in ASCO’s Journal of Clinical Oncology1 and the AACR’s Clinical Cancer Research.2 Additional information on electronic nicotine delivery systems, as well as oncologist-approved tobacco cessation resources, can be found on ASCO’s patient information website at www.cancer .net/tobacco and on AACR’s website at www.aacr.org/e-cigs. n Selected portions reprinted from ASCO.org. © American Society of Clinical Oncology. “ASCO, AACR Call for Regulation of Electronic Nicotine Delivery” www.asco.org. January 12, 2015. All rights reserved. References 1. Brandon TH, Goniewicz ML, Hanna NH, et al: Electronic nicotine delivery systems: A policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. J Clin Oncol. January 8, 2015 (early release online). 2. Brandon TH, Goniewicz ML, Hanna NH, et al: Electronic nicotine delivery systems: A policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. Clin Cancer Res 21:514-525, 2015.

research, patient-provided education, or pathway development. CCF funds young investigators early in their careers to retain talent in the field of clinical oncology, accelerate breakthroughs, and ultimately improve the lives of patients and families impacted by cancer. n Reference 1. Masters GA, Krilov L, Bailey HH, et al: Clinical Cancer Advances 2015: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol. January 20, 2015 (early release online).

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Funding Promising Women Researchers: Women Who Conquer Cancer

omorrow’s cancer breakthroughs depend on making sure that talented young researchers have the chance to succeed today. Providing early funding for women in clinical oncology research is the singular

Women have incredible intellectual gifts and capabilities to share but are vastly underrepresented in our field. This kind of financial and moral support is pivotal to the futures of emerging women researchers. —Sandra M. Swain, MD, FACP

goal of Women Who Conquer Cancer, a meaningful program of the ASCOaffiliated Conquer Cancer Foundation. Now in its second year, Women Who Conquer Cancer is uniquely designed to offer critical support to young women in cancer research to help them build their careers and stay in the field. “Women have incredible intellectual gifts and capabilities to share but are vastly underrepresented in our field,” said Sandra M. Swain, MD, FACP, Chair of Women Who Conquer Cancer. “This kind of financial and moral support is pivotal to the futures of emerging women researchers. We all want to capture the creativity of the brightest young minds in oncology research.”

How You Can Get Involved Women Who Conquer Cancer invites women oncologists to get involved in this groundbreaking program to help outstanding young women launch careers in cancer research. This special fund also welcomes contributions from men wishing to honor the important women in their lives in this exceptional way. For easy ways to give, visit www.conquercancerfoundation.org/ wwcc.

“We want to make sure that great ideas don’t get swept away because of a lack of start-up funding,” said Eileen Melnick, Director, Grants & Awards, Conquer Cancer Foundation. “This is particularly important for young women, who face many competing de-

mands, often at the same time in their lives when they are working to get their research off the ground.” Last year, Women Who Conquer Cancer supported its first Young Investigator Award, given to Yanyan Lou, MD, PhD, of The University of

Texas MD Anderson Cancer Center. The grant supported Dr. Lou’s work in investigating tumor microenvironment immune phenotypes in epithelial-mesenchymal transition and EGFR tyrosine kinase inhibitor–resistant continued on page 44

The ASCO Post | FEBRUARY 25, 2015

PAGE 44

Direct From ASCO

Show Your Patients the Latest Research on Genitourinary Cancers Health-Care Issues Front and Center on Capitol Hill, in Statehouses This Year

s of January 6, Republicans hold the majority in both houses of the 114th Congress. They hold 54 seats in the U.S. Senate and 245 seats in the U.S. House of Representatives. At the state level, Republicans now hold an increased majority of governorships and legislatures that will consider numerous health-care issues during 2015, including Medicaid expansion, regulation and taxation of e-cigarettes, and “Right to Try” legislation. ASCO staff has begun meeting with members of the new Congress. The ASCO Government Relations Committee met with lawmakers in Washington, DC, in mid-February. Reforming Medicare Physician Payment, the 21st

Century Cures Initiative, and National Institutes of Health funding are among the cancer-related issues that ASCO will continue to discuss with Congress members. ASCO will seek opportunities to work with State Affiliates and stakeholders in the physician and patient advocacy communities to advance its Medicaid reform recommendations and oral parity at the state level. Additionally, ASCO will continue to support State Affiliates that are addressing issues related to chemotherapy safety standards being developed in their states. n

he 2015 Genitourinary Cancers Symposium takes place February 26 to 28 in Orlando, Florida. Direct your patients

Volume 7, Issue 3

May 2011

Journal of oncology Practice

new report from the Institute of Medicine (IOM) provides recommended guidelines about what data should be shared at key times in a clinical trial. In its report, Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk, an IOM committee concludes that sharing data is in the public interest, but a multistakeholder effort is needed to develop a culture, infrastructure, and policies that will foster responsible sharing. Because no authority currently exists to enforce the report’s recommendations, the IOM recommended that the 23 spon-

What’s Hot in

JOP

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

www.jop.ascopubs.org

IOM Report Recommends Guidelines for Sharing Clinical Trial Data sors of the study—including the National Institutes of Health, the U.S. Food and Drug Administration, several pharmaceutical and biotechnology companies, and charitable organizations—convene a multistakeholder body to address challenges associated with sharing clinical trial data. More information on the report can be found at www.nap.edu/catalog/18998/ sharing-clinical-trial-data-maximizingbenefits-minimizing-risk. n © 2015. American Society of Clinical Oncology. All rights reserved.

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

The Authoritative Resource for Oncology Practices

to www.cancer.net/blog to read about the latest research on prostate, bladder, kidney, testicular, and other genitourinary cancers being presented at the meeting. n

JOP.ascopubs.org Population-Based Assessment of Emergency Room Visits and Hospitalizations Among Women Receiving Adjuvant Chemotherapy for Early Breast Cancer by Katherine Enright, et al

Prevalence of Off-Label Use of Oral Oncolytics at a Community Cancer Center by Joseph A. Kalis, et al

Trends in Use and Safety of Image-Guided Transthoracic Needle Biopsies in Patients With Cancer by Melissa K. Accordino, et al

Escalation of Oncologic Services at the End of Life Among Patients With Gynecologic Cancer at an Urban, Public Hospital by Eijean Wu, et al

Women Who Conquer Cancer continued from page 43

non–small cell lung cancer, with implications for immunotherapy in the treatment of lung cancer. “Women Who Conquer Cancer is a

unique opportunity to advance the careers of women in oncology and show our commitment to their success,” said Dr. Swain. n

Why Bundled Payments Could Drive Innovation: An Example From Interventional Oncology by Joseph R. Steele, et al

Save the Date

Best of ASCO® Boston

Best of ASCO® San Francisco

July 31–August 1, 2015

August 7–8, 2015

Renaissance Boston Waterfront Hotel

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Boston, Massachusetts

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ASCOPost.com | FEBRUARY 25, 2015

PAGE 45

Hematology Expert Review Myeloid Neoplasm

Two Case Reports on the Evaluation of Myeloid Neoplasm By Syed A. Abutalib, MD, and Frederick G. Behm, MD

he ASCO Post is pleased to introduce “Hematology Expert Review,” a new feature including a case report detailing a particular hematologic condition followed by questions. Answers to each question appear on page 50 with expert commentary. In this first installment, we present two cases of older men with myeloid neoplasm.

Case 1: Prerequisites for classification of myeloid neoplasm by World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues A 65-year-old man is being evaluated for a myeloid neoplasm due to a recent development of pancytopenia. A manual 200-cell leukocyte differential of the peripheral blood shows a blast count of 10%. A bone marrow biopsy and aspirate are obtained from the same posterior iliac site. A portion of the marrow aspirate is sent for flow cytometry and cytogenetic studies. You review the bone marrow aspirate and core biopsy with an experienced hematopathologist. There is dysplasia in one lineage, and the blast count is 45% from the 500-cell count of multiple areas of cellular bone marrow aspirate. However, the flow cytometry study reports only 15% blasts.

Question 1 In this patient, which statement is the one best explanation for the discrepancy observed between the blast percentage by

bone marrow aspirate visual inspection and the flow-cytometry study? A. The bone marrow specimen for flow cytometry is diluted with sinusoidal or peripheral blood. B. Flow-cytometry analyzes many more cells than the visual examination and thus is a more accurate blast measurement. C. Flow-cytometry study may not be identifying all of the blasts in the aspirate specimen. D. Blast cells were “lost” in the processing of the marrow aspirate for flow cytometry studies.

Question 2 How can hemodilution of bone marrow aspirates best be avoided? A. Perform a core biopsy prior to the aspirate. B. Perform an aspirate prior to the core biopsy. C. Collect no less than 0.4 mL of bone marrow aspirate in the first syringe for smear preparations. D. Reposition the aspirate needle if more than 0.5 mL of marrow aspirate is required for laboratory studies.

Question 3 Which of the following statements is part of the guidelines recommended by WHO (2008) for the evaluation of an initial specimen in patients suspected of having underlying myeloid neoplasms? A. Clinical findings should not be correlated with bone marrow findings, as they may lead to bias on the part of the hematopathologist. B. Cytogenetic and molecular genetic studies are not required.

C. At least 500 bone marrow nucleated cells should be counted on a cellular aspirate. D. Flow-cytometry determination of the blast percentage can be used as a substitute for visual inspection. Case 2: Optimal bone marrow core biopsy specimen in adults A 60-year-old man is referred by his family practitioner for evaluation of pancytopenia and splenomegaly. Complete blood cell count and manual differential show a white blood cell count of 10,500/μL, hemoglobin of 8.1 g/dL, and a platelet count of 154,000/μL. Review of the peripheral smear shows many teardrop red blood cells, small numbers of dysplastic myelocytes and metamyelocytes, and 5% blasts. Physical exam revealed splenomegaly, with no hepatic enlargement or lymphadenopathy. The clinical impression is a myeloproliferative neoplasm. A bone marrow aspirate and core biopsy are obtained. The marrow aspirate smears show a hemodilute specimen with no marrow particles but many myeloid and erythroid precursor elements, rare dysplastic megakaryocytes, and 10% blasts. The bone marrow core biopsy was 0.4 mm in length.

GUEST EDITORS

Syed A. Abutalib, MD

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

Frederick G. Behm, MD

Frederick G. Behm, MD, Frances B. Geever Professor and Head, Department of Pathology, University of Illinois at Chicago College of Medicine, Chicago, Illinois

Question 1 What is an acceptable size of a core biopsy specimen in adults? A. A minimum of two marrow core biopsies, each measuring 0.4 cm B. At least 0.5 cm C. The acceptable size of the marrow

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

core biopsy may vary depending on the suspected diagnosis. D. At least 1.5 cm See page 50 for answers and expert discussion. n

In melanomaâ&#x20AC;Ś

A T CELL IS ONLY AS EFFECTIVE

Dendritic cell

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.

AS THE ANTIGEN THAT ACTIVATES IT1

T cell

Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3 Learn more at

MelanomaAntigens.com

The ASCO Post | FEBRUARY 25, 2015

PAGE 48

Inside the Black Box

Pharmacokinetics and Exposure Response in Drug Development By Julie Bullock, PharmD, and Nitin Mehrotra, PhD

INSIDE THE BLACK BOX is an occasional column offering insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, former clinical pharmacology team leader Julie Bullock, PharmD, and current team leader Nitin Mehrotra, PhD, discuss how pharmacokinetics is used in new drug development. Dr. Bullock was a team leader for the hematology team, and Dr. Mehrotra is a team leader for the pharmacometrics team in the FDA’s Office of Clinical Pharmacology, Center for Drug Evaluation and Research.

linical pharmacokinetic studies are integral parts of drug development and provide critical information to help optimize the use of a therapy in an individual patient. Drug levels achieved in the blood of patients given a dose of a drug play a major role in whether a patient will respond to a therapy or have toxicity. Here, Drs. Julie Bullock and Nitin Mehrotra respond to questions on how the knowledge of pharmacokinetics and drug exposure helps in oncology drug development, approval, and labeling.

Role of Pharmacokinetics Why is it important to assess the pharmacokinetics of a drug in clinical trials? Dr. Bullock: A good understanding of a drug’s pharmacokinetic behavior—how it is absorbed, metabolized, and eliminated—can help maximize its therapeutic potential for a variety of patients. Information about drug exposure and how it relates to efficacy or toxicity can be leveraged to optimize drug development and use in the clinic. What kind of pharmacokinetic assessments are performed during drug development? Dr. Bullock: Early in development, pharmacokinetic assessments are frequent or, as we like to say, “intensive.” Intensive blood sampling allows for a thorough characterization of important pharmacokinetic exposure parameters—the area under the curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin). Inten-

sive sampling also gives us an idea of the drug’s half-life. When intensive sampling is included in the first-in-human trial, important information on how exposure increases with dose can be obtained. Depending on how a drug is administered, metabolized, and eliminated, further studies are conducted to discern whether pharmacokinetics is affected by fooddrug interactions and/or organ impairment. We encourage drug companies to conduct these evaluations early in the development timeline to determine whether the inclusion criteria of the efficacy trials can be broadened. Dr. Mehrotra: Later in drug development, pharmacokinetic assessments become less intensive or “sparse.” By this we mean that few blood samples

collected in late-phase trials are useful to understand the relationship of exposure with efficacy and safety and to evaluate the dosing recommendations.

Impact on Dosing Does pharmacokinetics influence how a drug is dosed? Dr. Bullock: Knowing how a drug is absorbed helps determine the route of administration (ie, oral, intravenous, or subcutaneous). Understanding the halflife is important in choosing a dosing interval (eg, once daily or twice daily). For drugs that are given orally, an understanding of how food will affect exposure is needed to decide whether a drug should be given with or without food. If exposure is linked to response or toxicity, those data can be used to further elucidate which dose should be taken to efficacy trials. Some drug companies are even using in vitro target concentrations to justify starting doses and doses taken forward in drug development based on concentrations achieved in humans. What’s the difference between dose and exposure? Dr. Bullock: Exposure in this context means blood levels achieved in the body after a drug is administered. I can give the same dose of a drug to 16 different patients, and all 16 patients may achieve vastly different exposures in

A decision to use or not use a drug, and at what dose, is a decision that should be made between the patient and physician. We try to provide as much information as possible in the labeling, to help make that decision an educated one. —Julie Bullock, PharmD

are collected per patient—eg, two to three samples per patient or even one predose sample per patient collected during the course of the trial. With the advent of new advanced computational methodologies, traditional exposure parameters can be precisely estimated, even when sparse data are collected. Pharmacokinetics data

FDA Clinical Reviewers

their blood depending on their concomitant medications, organ impairment, tumor burden, or genetics. Likewise I could give 16 different doses to 16 different patients and achieve similar exposures. Dose is just one component of exposure (AUC = dose ÷ clearance). So much of the focus in drug development is on getting the right dose. In

Julie Bullock, PharmD

Nitin Mehrotra, PhD

oncology, where the therapeutic margin between safety and efficacy is small, having a better understanding of the optimal exposure may benefit patients more than assuming that one dose fits all patients. How is it determined whether a drug should be dosed by body weight, body surface area, or as a flat dose? Dr. Mehrotra: Whether the drug should be given as a flat dose or dosed per body weight or surface area is largely dependent on the pharmacokinetics of the drug. If the exposure of the drug significantly changes with change in body weight or surface area, then dosing by body weight or surface area will result in more uniform exposures among patients than if a single/flat dose were used in everyone.

Exposure-Response Analysis What is exposure-response analysis? Can you provide an example to illustrate why understanding the relationship between exposure and response is important? Dr. Mehrotra: Exposure refers to drug levels achieved in the body. Response can be assessed in terms of ei-

ASCOPost.com | FEBRUARY 25, 2015

PAGE 49

Inside the Black Box ther efficacy or safety. Understanding the relationship between exposure and response is critical to finding a dose that optimally strikes a balance between drug efficacy and adverse events. For instance, if we observe that there is no change in efficacy with an increase in exposure while the toxicity of the drug sharply increases with an increase in exposure, lowering the dose may offer similar efficacy but a better safety profile. Understanding the exposure-response relationship also helps identify whether dose modifications are needed to minimize drug interactions or for patients with organ impairment. Cabozantinib (Cometriq) is approved for progressive medullary thyroid cancer.1 Dose modifications occurred in approximately 80% of patients in the trial, supporting the drug’s approval. The data from the trial also demonstrated that the drug appeared to have similar efficacy in patients with lower exposures and in those with higher exposures. On the other hand, patients with higher exposures had dose modifications earlier than patients with lower exposures.2 Based on these observations, it was decided that a lower dose may offer a better benefit-risk profile, and, accordingly, a postmarketing trial

to evaluate efficacy and safety of a lower dose was recommended. Do you worry more about exposures that are too high or exposures that are too low? Dr. Bullock: We are concerned about both scenarios. One of the reasons patients may experience greater toxicity could be an intrinsic or extrinsic factor that is causing higher exposures than in other patients treated at the same dose. However, we are also very concerned about factors that decrease exposure, as this could lead to exposure levels that are too low to elicit an efficacious response. So what are some things that can increase or decrease exposure? Dr. Bullock: Renal and hepatic impairment and drug-drug interactions are the most common reasons for exposure changes in patients. Once we know what intrinsic (age, weight, disease, genetic polymorphism, organ dysfunction, etc) or extrinsic (concomitant medications, herbal products, diet, smoking, etc) factors alter exposure, we can recommend dose adjustments so that patients with these characteristics have the opportunity to respond safely and effectively to a new treatment.

Individualized Dosing As an oncologist, how will I know if a dose adjustment needs to be made in my patient? Dr. Bullock: The FDA-approved prescribing information will contain important information regarding known scenarios that require dose adjustment. Even when faced with a lack of information, we strive to make the label useful for clinicians by incorporating what is known, even if no strong conclusions can be made from the data. For example, we may not know the effect of organ impairment on exposure, but we may summarize that four patients with moderate hepatic impairment were treated in the efficacy trial with no unusual safety or efficacy findings. Including information on specific patients or comedications excluded from clinical trials can also be helpful in pointing out that no data exist—so proceed with caution! A decision to use or not use a drug, and at what dose, is a decision that should be made between the patient and physician. We try to provide as much information as possible in the labeling, to help make that decision an educated one. n Disclosure: Drs. Bullock and Mehrotra reported no potential conflicts of interest.

GUEST EDITOR

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. References 1. Cometriq (cabozantinib) prescribing information, Exelixis, Inc, November 2012. Available at http://www.accessdata.fda.gov/ drugsatfda_docs/label/2012/203756lbl. pdf. Accessed February 5, 2015. 2. U.S. Food and Drug Administration Center for Drug Evalutation and Research: Clinical pharmacology and biopharmaceutics reviews for cabozantinib. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203756Orig1s000Cli nPharmR.pdf. Accessed February 5, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Josep Tabernero, MD, PhD, on Ramucirumab and Colorectal Cancer see page 1

Gary Deutsch, MD, MPH, on Melanoma Gastrointestinal Metastases see page 3

Richard J. Baron, MD, MACP, on Changes to ABIM’s MOC Program see page 1

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, on Translational Research see page 1

Eric Mellon, MD, on Locally Advanced Pancreatic Cancer see page 12 Angus G. Dagleish, MD, and Andrea Wang-Gillam, MD, on Pancreatic Cancer Drug Success see page 5 Christoph Röllig, MD, on Tyrosine Kinase Inhibitor in Acute Myeloid Leukemia see page 15

Michael Gordon Penniment, MD, on Radiotherapy in Advanced Esophageal Cancer see page 14

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | FEBRUARY 25, 2015

PAGE 50

Hematology Expert Review

Case Reports on Myeloid Neoplasm

Answers From Hematology Expert Review Questions on Page 45 Case 1: Prerequisites for classification of myeloid neoplasm Question 1: Which statement is the one best explanation for the discrepancy observed between the blast percentage by bone marrow aspirate visual inspection and the flow-cytometry study? Correct Answer: C. Flowcytometry study may not be identifying all of the blasts in the aspirate specimen.

no less than 0.4 mL of bone marrow aspirate…” and “Reposition the aspirate needle…” are also good choices and important to observe. A marrow aspirate collected after the initial 0.5 mL is

progressively diluted with sinusoidal blood. Repositioning the biopsy needle after obtainment of 0.5 mL of marrow will ensure a more cellular marrow aspirate specimen.

Question 3: Which of the following statememts is part of the guidelines recommended by WHO (2008) for the evaluation of an initial specimen in patients suspected of having

ADVERTORIAL

Expert Perspective Dilution of marrow specimens by peripheral blood, ie, hemodilution, is the explanation for most discrepancies between visual and flow-cytometry blast percentages. However, for the appropriately obtained marrow specimen, flow cytometry may fail to detect all blasts in the specimen if only one blast marker is being employed. For example, not all leukemic blasts express CD34, particularly monoblasts. If the visual differential includes early promyelocytes in the blast count as recommended by WHO, these cells may express no or little CD34. The addition of at least one additional marker expressed by blasts, such as CD117, CD38, CD123, CD133, or CD200, may aid in a more accurate blast enumeration. Although flow cytometry commonly interrogates over 10,000 cells, very little difference will be noted between a 500-cell visual differential and a 500 to 1,500 flow-cytometry analysis by flow cytometry of a nonhemodilute marrow specimen. For acute leukemia and myelodysplasia, neoplastic cell distribution does differ significantly in different areas of the bone marrow. However, this may not be true for some myeloid neoplasms, including myeloproliferative neoplasms, mastocytosis, and sometimes relapsed acute myeloid leukemia. Question 2: How can hemodilution of bone marrow aspirates best be avoided? Correct Answer: B. Perform an aspirate prior to the core biopsy.

Expert Perspective Hemodilution largely can be diminished by performing the marrow aspirate prior to the core biopsy. The core biopsy may activate the coagulation cascade, resulting in clotting of the subsequent marrow aspirate specimen with low bone marrow particle yield and hemodilution. Performing the aspirate before the core biopsy avoids this problem. Choices C and D, “Collection

Cancer Stem Cells

Signal Pathways

Understanding M

alignancies, like normal adult tissue, have been shown to contain a subset of cells that have the capacity to both selfrenew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

EDU-NPS-0009

12/2014

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6 Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence. Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

ASCOPost.com | FEBRUARY 25, 2015

PAGE 51

Hematology Expert Review

underlying myeloid neoplasms? Correct Answer: C. At least 500 bone marrow nucleated cells should be counted on a cellular aspirate.

Expert Perspective The percentage of blasts is important for diagnosis and classification of myeloid neoplasms. In the peripheral

blood, the blast percentage should be derived from a 200 cell leukocyte differential, and in the bone marrow, from the 500-cell count of cellular portions of the BM smear. Not providing detailed clinical information to the hematopathologist will possibly result in his/her performing additional studies that are not necessary, adding to the cost of care, and

possibly delaying the diagnosis. The accurate diagnosis and classification of myeloid neoplasms are often challenging. Thus, a multidisciplinary approach involving a hematologist, hematopathologist, and other specialists (eg, the cytogenetist or molecular pathologist as appropriate) is required to diagnose and classify myeloid neo-

plasms. Cytogenetic and molecular studies are required at the time of the diagnosis not only for recognition of specific genetically defined entities, but for establishing a baseline against which future studies can be judged to assess disease persistence or progression. Flow-cytometry determination of the blast percentage should not be used as a substitute for visual inspection as already discussed. Case 2: Optimal bone marrow core biopsy specimen in adults Question 1: What is an acceptable size of a core biopsy specimen in adults? Correct Answer: D. At least 1.5 cm

Expert Perspective

Regrowth

Metastasis

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

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

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

www.bostonbiomedical.com

The 2008 WHO classification states that the trephine/core specimen “… must be adequate…and at least 1.5 cm in length to enable the evaluation of at least 10 partially preserved inter-trabecular areas.” This guideline is particularly true for the classification of myeloproliferative neoplasms and for marrow evaluation of patients with a suspected diagnosis of myelodysplastic syndrome. One should not lose sight of the added requirement of “10 relatively preserved inter-trabecular areas,” since even a larger core may have excessive biopsy/ crush artifact or excessive aspiration artifact. Other core biopsies, even if 1.5 cm in length, may be suboptimal if they consist of significant amounts of cortical bone and subcortical marrow, the latter of which is normally hypocellular in elderly patients. Excessive amount of cortical bone and subcortical marrow is indicative of the wrong placement angle of the biopsy needle. It should be noted that fixation of core biopsies results in ‘shrinkage’ of 20% to 25%. Thus, the desired biopsy core sample size may have to be at least 2 cm in length. For young children, biopsies will necessarily be shorter. In our experience, two biopsies of two different sites provided no more information than obtaining the same amount of core biopsy from a single site. One can argue that the amount of assessable or intact marrow in the biopsy is of more importance than the total length for some hematopoietic neoplasms. For example, as little as 0.5 cm of an intact core biopsy is acceptable in a patient with over 20% myeloblasts in the blood and a suspected diagnosis of acute myeloid leukemia. However, in most adult patients with low blood blast counts, the initial clinical impression is not assured, and one must revert to obtaining the recommended biopsy size. continued on page 52

The ASCO Post | FEBRUARY 25, 2015

PAGE 52

In the Clinic Hematology

Ibrutinib for Waldenström’s Macroglobulinemia 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 January 29, 2015, the U.S. Food and Drug Administration (FDA) approved ibrutinib (Imbruvica) for treatment of patients with the B-cell malignancy Waldenström’s macroglobulinemia.1,2 The drug has previously been approved by FDA to treat mantle cell lymphoma and chronic lymphocytic leukemia.

Supporting Study The approval was based on demonstration of durable responses in a single-arm, multicenter trial in which 63 patients with previously treated disease received ibrutinib at 420 mg once daily.2 Patients had a median age of 63 years (range = 44–86 years), 76% were male, 95% were white, and all had Eastern Cooperative Oncology Group performance status of 0 or 1. Median time since diagnosis was 74 months, median number of prior treatments was two (range = 1–11), and median serum IgM level was 3.5 g/dL (range = 0.7–8.4 g/dL). The response rate was 61.9% (95% confidence interval = 48.8%–73.9%), including a very good partial response in 11.1% and a partial response in 50.8%. Median time to response was 1.2 months and median response duration was not reached (range = 2.8+ to 18.8+ months).

How It Works Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.

Hematology Review continued from page 51

With the thousands of bone marrow biopsy procedures performed in the U.S. every year, it is striking that little attention has been given to standardization of the procedure and the quality of performed biopsies. A notable exception is a recently published abstract that reports the results of a multi-institutional study of bone marrow core biopsy adequacy and variability in the United States and Canada.2 Interestingly, the authors of

Bruton’s tyrosine kinase activity via signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

How It Is Given The recommended dosage of ibrutinib in Waldenström’s macroglobulinemia is 420 mg orally once daily. Ibrutinib treatment should be interrupted for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutrope-

OF NOTE Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways implicated in the pathogenesis of B-cell cancers.

nia with fever, and grade 4 hematologic toxicities. With resolution of toxicity to grade 1 or baseline status, treatment can be reinitiated at the starting dose. The dose may be reduced to 280 mg and then to 140 mg for recurrent toxicity. Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, in-

OF NOTE Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity.

dinavir, ketoconazole) should be avoided. If a strong inhibitor is to be used for ≤ 7 days, interruption of ibrutinib during this period should be considered. If a moderate inhibitor must be used, the ibrutinib dose should be reduced to 140 mg. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. Since ibrutinib is metabolized in the liver, significant increases in exposure are expected in patients with hepatic impairment, and patients with aspartate transaminase or alanine transaminase levels ≥ 3.0 times the upper limit of normal were excluded from clinical trials. Use of ibrutinib should be avoided in patients with hepatic impairment; there are insufficient data to recommend a dose in such patients. Ibrutinib exposure is not altered in patients with creatinine clearance > 25 mL/min; there are no data in patients with severe renal impairment or on dialysis.

Safety Profile In the supporting trial, the most common nonhematologic adverse events of any grade were diarrhea (37%), rash (22%), nausea (21%), fatigue (21%), and muscle spasms (21%). Grade 3 or 4

Expanded Indication for Ibrutinib ■■ Ibrutinib (Imbruvica) has been approved for treatment of patients with the B-cell malignancy Waldenström’s macroglobulinemia. ■■ The recommended dosage of ibrutinib in Waldenström’s macroglobulinemia is 420 mg orally once daily.

this study found that “current benchmarks for bone marrow core biopsy adequacy are met in only a minority of cases.” Also noted but not explained was the observation that the “evaluable marrow space” decreased from 2001 to 2011. With the interest in the quality of health care, one should not be surprised if those funding or regulating health care will want assurance that bone marrow biopsies are adequate, informative and performed by individuals with documented competency. n

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

References 1. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissuse,

adverse events consisted of pneumonia in 6% and skin infection in 2%. Grade 3 or 4 hematologic toxicities consisted of thrombocytopenia in 13% (43% any grade), neutropenia in 19% (44% any grade), and anemia in 8% (13% any grade). Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies (including skin cancers and other carcinomas), tumor lysis syndrome, and embryo-fetal toxicity. Patients must be monitored for bleeding, fever and infection, and atrial fibrillation. Complete blood cell counts should be monitored monthly. Women must be advised of potential fetal risk and counseled to avoid pregnancy while taking ibrutinib. n References 1. U.S. Food and Drug Administration: Ibrutinib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm432240.htm. Accessed February 5, 2015. ® 2. Imbruvica (ibrutinib) capsules prescribing information, Pharmacyclics, Inc, 2015. Available at www.accessdata.fda.gov/dr ugsatfda_docs/ label/2015/205552s002lbl.pdf. Accessed February 5, 2015.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at 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).

4th ed. Lyon, France, IARC, 2008. 2. Merzianu M, Cheney R, Groman A, et al: Bone marrow core biopsy adequacy and variability in the United Stated and Canada: A multicenter retrospective study. 2014 ASH Annual Meeting and Exposition. Abstract 1316. Presented December 6, 2014.

Coming Soon in Hematology Expert Review Chronic myelogenous leukemia, BCR/ABL-positive

Joan is more than just a patient going through

CHEMOTHERAPY We see so much more than just cancer Joan is already busy enough with hockey practices, dance recitals, and science fair supply shopping. Now sheâ&#x20AC;&#x2122;s making room on the kitchen calendar for Q3W therapy sessions. People like Joan are at the heart of what drives Teva Oncology. With over 100 years of global pharmaceutical expertise, our mission is to develop and deliver solutions that advance cancer care and improve the lives of people affected by cancer.

We treat the person, not just the cancer

The ASCO Post | FEBRUARY 25, 2015

PAGE 54

Journal Spotlight Breast Cancer

No Benefit of Adding Iniparib to Gemcitabine/Carboplatin in Metastatic Triple-Negative Breast Cancer By Matthew Stenger

n a phase III trial reported in Journal of Clinical Oncology, Joyce O’Shaughnessy, MD, of Baylor Charles A. Sammons Cancer Center, Dallas, and colleagues found that the addition of iniparib to gemcitabine and carboplatin did not improve overall survival or progression-free survival in patients with metastatic triple-negative breast cancer.1 An exploratory analysis showed improved overall survival and progression-free sur-

Study Details In the open-label phase III trial, 519 patients with stage IV/locally recurrent triplenegative breast cancer who had received no more than two previous chemotherapy regimens for metastatic triple-negative breast cancer were randomly assigned between July 2009 and March 2010 to receive gemcitabine at 1,000 mg/m2 and carboplatin at area under the curve of 2 (days 1 and 8) alone (n = 258) or with iniparib

The suggestion of an improved survival outcome in second-/third-line patients warrants further evaluation of iniparib in combination with DNA-damaging chemotherapy in patient populations not restricted to [triple-negative breast cancer]. —Joyce O’Shaughnessy, MD, and colleagues

metastatic sites (lungs in 62% and 61%, liver in 38% and 44%, lymph nodes in 76% and 72%, bone in 33% and 30%, central nervous system in 8% in both), prior chemotherapy (89% and 90%), disease-free interval (≤ 18 months in 54% and 50%), and line of therapy (first in 57% and 58%). Before crossover, patients in the iniparib group received a median of six cycles of study therapy, and those in the control group received a median of five. The median number of cycles after crossover was two.

No Survival Differences Median overall survival was 11.8 months in the iniparib group vs 11.1 months in the control group (hazard ratio [HR] = 0.88, P = .28). Median progression-free survival was 5.1 vs 4.1 months (HR = 0.79, P = .027; did not meet P = .01 threshold). Objective response rates were 33.7% vs 30.2% (P = .395).

Exploratory Analysis vival with the iniparib-containing regimen in patients receiving it as second- or third-line therapy. Iniparib was originally identified and investigated as a poly(ADP-ribose) polymerase (PARP) inhibitor, with later studies indicating that it did not exhibit typical characteristics of these agents. An active metabolite of the drug appears to act by increasing production of reactive oxygen species to cytotoxic levels. Iniparib enhances the antiproliferative and cytotoxic effects of gemcitabine and carboplatin in triplenegative breast cancer models, and a randomized phase II study showed improved response rate, progression-free survival, and overall survival with the addition of iniparib to gemcitabine/ carboplatin.

at 5.6 mg/kg administered intravenously on days 1, 4, 8, and 11 (n = 261) every 3 weeks. Randomization was stratified by the number of prior chemotherapies. The coprimary endpoints were overall survival and progression-free survival in the intention-to-treat population, with predefined superiority P values of .04 for overall survival and .01 for progressionfree survival for the iniparib group. Patients in the gemcitabine/carboplatin group were permitted to cross over to iniparib at disease progression. The iniparib and control groups were generally balanced for age (median = 53 and 54 years, 65% in both ≥ 60 years), Eastern Cooperative Oncology Group performance status (0 for 57% and 53%, 1 for 41% and 45%), number of metastatic sites (2 in 34% and 26%, ≥ 3 in 58% and 60%),

An exploratory analysis by line of therapy showed median overall survival of 12.4 vs 12.6 months (HR = 1.11, 95% confidence interval [CI] = 0.78–1.57) and median progression-free survival of 5.6 vs 4.6 months (HR = 0.88, 95% CI = 0.67–1.17) among those receiving first-line treatment. Among those receiving second- or thirdline treatment, median overall survival was 10.8 vs 8.1 months (HR = 0.65, 95% CI = 0.46–0.91), and median progressionfree survival was 4.2 vs 2.9 months (HR = 0.68, 95% CI = 0.50–0.92). An updated overall survival analysis after 70% of patients had died showed median overall survival of 12.2 vs 11.1 months (HR = 0.85, 95% CI = 0.69– 1.04), including 12.3 vs 13.9 months (HR = 1.07, 95% CI = 0.80–1.40) among those receiving first-line therapy

and 12.1 vs 8.1 months (HR = 0.60, 95% CI = 0.45–0.82) among those receiving later-line therapy.

Toxicity Grade 3 or 4 adverse events occurred in 89% of the iniparib group and 86% of the control group, with the most common being neutropenia (62% vs 53%) and thrombocytopenia (29% vs 24%). The most common nonhematologic grade 3 or 4 toxicity was fatigue (8% vs 6%). Serious adverse events occurred in 38% vs 28%. Adverse events led to discontinuation of at least one component of treatment in 35% vs 29%. Adverse events led to death in four patients in the iniparib group, with one (upper gastrointestinal hemorrhage) considered related to treatment, and in two patients in the control group, neither of which was considered treatment-related. The investigators concluded: “[I] niparib added to [gemcitabine/carboplatin] did not benefit the overall treated [metastatic triple-negative breast cancer] population. The suggestion of an improved survival outcome in second-/ third-line patients warrants further evaluation of iniparib in combination with DNA-damaging chemotherapy in patient populations not restricted to [triplenegative breast cancer].” n

Disclosure: The study was supported by Sanofi. Dr. O’Shaughnessy has served as a consultant or advisor for Sanofi. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. O’Shaughnessy J, Schwartzberg L, Danso MA, et al: Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 32:3840-3847, 2014.

Iniparib: The Fairy Tale Dream Comes to an End By Denise A. Yardley, MD

he first poly ADP ribose polymerase (PARP) inhibitor was developed in the early 1990s. Since then, the activity of PARP inhibitors has been explored in a variety of settings, including and perhaps most enthusiastically in the treatment of cancer. The greater dependence of several

cancers on PARP, an important regulator of the DNA base-excision-repair pathway, paved the road for this polymerase as an attractive therapeutic target for cancer. After nearly 25 years of investigation of the mechanisms of action and efficacy of this class of agents, olaparib

(Lynparza) became the first PARP inhibitor in a new class of drugs to be approved for use in cancer treatment in December 2014. The drug is approved for use in women with advanced heavily pretreated ovarian cancer associated with specific abnormalities in the BRCA gene determined by a compan-

ion diagnostic called BRACAnalysis CDx which detects BRCA gene mutations in blood samples from patients with ovarian cancer.

Initial Enthusiasm When preliminary data from a randomized phase II study of the PARP

ASCOPost.com | FEBRUARY 25, 2015

PAGE 55

Perspective

inhibitor iniparib in women with triple-negative breast cancer were presented at the ASCO 2009 Annual Meeting, there was abundant enthusiasm over an emerging novel targeted therapy with a potential indication in this disease setting. Preclinical studies showed that combining PARP inhibitors with platinum chemotherapy, which induces DNA damage through adducts and crosslinking, may potentiate chemotherapy toxicity. This excitement was paired with a growing and strong rationale for treating triple-negative breast cancer with DNA-damaging agents like the platinums, based on the similarities in the gene-expression profiles of BRCA1deficient and sporadic triple-negative breast cancers. Thus, in that phase II trial published in 2011,1 123 patients were randomized to receive gemcitabine and carboplatin alone or with the addition of iniparib. The study demonstrated an extension of progressionfree survival from 3.6 to 5.9 months and a statistically significant overall survival advantage from 7.7 to 12.3 months with the addition of iniparib, with few or no additional side effects. Despite its limitations and the slight imbalance in prognostic factors favoring the iniparib group, the study provided proof of concept. On the basis of these thrilling results, iniparib was welcomed as the first promising targeted agent for triple-negative breast cancer. The great enthusiasm generated by the fairy tale phase II trial findings in a poor prognostic breast cancer subgroup desperately in need of a success was widely embraced with open arms. The resulting high expectations, despite the underwhelming performance and modest activity of the gemcitabine/ carboplatin doublet in this trial, generated great uptake of this combination in triple-negative breast cancer.

Overwhelming Disappointment The subsequent open-label phase III trial adequately powered to assess the addition of iniparib to gemDr. Yardley is Senior Investigator, Breast Cancer Research Program, at Sarah Cannon Research Institute in Nashville, Tennessee.

citabine-carboplatin accrued rapidly, and an expanded access program to provide triple-negative breast cancer patients with access to iniparib prior to the planned U.S. Food and Drug Administration submission and approval ensued. The outcome of the trial—final results of which were recently reported by O’Shaughnessy and colleagues,2 as reviewed in this

in second- and third-line patients, but it is difficult to generate a hypothesis to explain this further. Although it is well recognized that triple-negative breast cancers are a heterogeneous group, perhaps the clinical assays used to identify patients for study eligibility were not sufficient for identifying the subgroup most likely to benefit from

PARP inhibitors still look to be an effective class of drug, although current evidence indicates that their benefit is largely restricted to BRCA-mutation carriers. —Denise A. Yardley, MD

issue of The ASCO Post—was an overwhelming disappointment; the coprimary endpoints were not met, with iniparib treatment being associated with nonsignificant increases of 1 month in median progression-free survival and 2.5 months in median overall survival. This trial’s unfortunate results were followed by a phase III trial in squamous cell lung cancer and a phase II trial in platinum-resistant ovarian cancer, which also failed to demonstrate an advantage for iniparib-containing treatment. In June 2013, the manufacturer dropped development of the drug.

What Went Wrong? So, what went wrong with the phase III trial, particularly following such exciting phase II data? The use of iniparib was clearly biologically plausible, and its evaluation in the triple-negative breast cancer population seemed ideal, since these tumors bore elements and features similar to those of BRCA-mutant tumors. In addition, emerging data in BRCAassociated ovarian cancer suggested a signal of efficacy for this class of drug. The randomized open-label trial enrolled 519 patients with baseline characteristics that were well balanced, with 57% receiving first-line therapy and 43% receiving secondor third-line therapy. Exploratory subgroup analyses by prior lines of therapy suggested a potential benefit

PARP inhibition. The signal that a given subgroup may benefit and that iniparib might work in certain molecular subtypes of triple-negative breast cancer suggests that perhaps intrinsic subtyping may be of benefit. However, extensive biomarker analyses performed after the initial phase III results came out failed to identify a clear predictive marker. Analysis of the molecular subtyping of specimens from more than 300 patients enrolled in the trial with regard to exposure and response to iniparib may help to further define characteristics associated with benefit or no benefit. The fact that patients in the control group of this trial were permitted to cross over to iniparib has been implicated as potentially biasing the overall survival results. Overall, 59% of patients in the control arm were allowed to cross over and receive iniparib after central confirmation of disease progression. As usual, allowance of a sequential exposure to iniparib in the control arm, which greatly facilitated rapid accrual to the trial, could reflect receipt of a more active therapy of proven value than the subsequent lines of standard chemotherapy administered beyond disease progression in the investigational arm. Confounding this further were subsequent reports detailing that the mechanism of action of iniparib was not a true PARP inhibitor; it exhibits 1,000-fold less activity than other

PARP inhibitors, a feature attributed to a carboxyl group that potentially weakens its bond to PARP. This difference in mechanism of action may also result in its apparent lack of toxicity seen with other PARP inhibitors, such as the recently approved olaparib, particularly in combination with chemotherapy. The signal of benefit noted in the phase II trial and in the second- and third-line patients in the phase III trial suggests that iniparib probably works differently from what was originally expected and from a true PARP inhibitor.

Challenges Ahead PARP inhibitors still look to be an effective class of drug, although current evidence indicates that their benefit is largely restricted to BRCA-mutation carriers. The ability to combine these agents with chemotherapy has been and remains challenging. For the future, use of molecular diagnostics may help to predict who may be best suited to benefit from PARP inhibitors. The iniparib story is a tale of caution and underscores the challenges in the development of novel therapeutics. A number of challenges continue to confront trial designs designated for regulatory agency approvals of targeted agents, so selection of comparators and identification of specialized populations become even more critical. In addition, although a lack of crossover design is poorly received by patients, physicians, and advocates alike, this may have certainly played a role in iniparib’s plummeting descent. Although iniparib fumbled and shattered dreams, the shards left continue to be a stark reminder of the work that remains undone. n

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

References 1. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011. 2. O’Shaughnessy J, Schwartzberg L, Danso MA, et al: Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 32:38403847, 2014.

The ASCO Post | FEBRUARY 25, 2015

PAGE 56

In the Clinic Hematology

Blinatumomab in Philadelphia Chromosome–Negative Relapsed/Refractory B-Cell Precursor ALL

Supporting Trial Approval was based on results of a single-arm trial in 185 patients showing achievement of durable complete remission/complete remission with partial hematologic recovery. Blinatumomab was administered by continuous infusion for 4 weeks of a 6-week cycle. In the first cycle, the initial dose was 9 µg/d for week 1, then 28 µg/d for the remaining 3 weeks. The target dose of 28 µg/d was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Among treated patients, the median age was 39 years (range, 18–79 years), 34% had undergone hematopoietic stem cell transplantation prior to receiving blinatumomab, and 17% had received more than two prior salvage therapies. Complete remission/complete remission with partial hematologic recovery within two cycles of treatment, the primary endpoint, was achieved in 77 patients (41.6%, 95% confidence interval [CI] = 34.4%–49.1%), including complete remission in 60 patients (32.4%, 95% CI = 25.7%–39.7%). The majority of responses (62/77, 81%) occurred within cycle 1 of treatment. Minimal residual disease response (< 104 on polymerase chain reaction) occurred in 80% of patients with complete remission, 58.8% of those with complete

OF NOTE Blinatumomab carries boxed warnings for potentially fatal cytokinerelease syndrome and neurologic toxicity.

remission/complete remission with partial hematologic recovery, and 75.3% of responders in both groups. Median durations of response were 6.7 months (range, 0.46–16.5 months) in patients

How It Works Blinatumomab is a bispecific CD19directed CD3 T-cell engager (BiTE) that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B cells. The agent mediates formation of a synapse between the T cell and the tumor cell, upregulation of cell adhe-

Blinatumomab in Acute Lymphoblastic Leukemia ■■ Blinatumomab (Blincyto) was granted accelerated approval for use in treating Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. ■■ A single cycle of treatment consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval, with the treatment course entailing up to two cycles of induction followed by three cycles for consolidation. ■■ For patients weighing ≥ 45 kg, cycle 1 consists of blinatumomab at 9 µg/d on days 1 to 7 and 28 µg/d on days 8 to 28. In subsequent cycles, the dose is 28 µg/d on days 1 to 28.

sion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, resulting in redirected lysis of CD19positive cells.

How It Is Given A single cycle of treatment consists of 4 weeks of continuous intravenous infusion followed by a 2-week treatment-free interval. For patients weighing ≥ 45 kg, cycle 1 consists of blinatumomab 9 µg/d on days 1 to 7 and 28 µg/d on days 8 to 28. In subsequent cycles, the dose is 28 µg/d on days 1 to 28. A treatment course consists of up to two cycles of induction followed by three cycles for consolidation. Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for at least 4 hours), supervision by a health-care professional or hospital-

providers about the serious risks and the potential for preparation and administration errors.

Safety Profile Safety was evaluated in 212 patients with B-cell precursor relapsed/refractory ALL who received at least one dose of blinatumomab. Patients had a median age of 37 years (range, 18–79 years), 63% were male, and 79% were white, 3% were Asian, and 3% were black or African American. The most common adverse events of any grade were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%). Adverse events of grade ≥ 3 occurred in 80% of patients, with the most common being “other pathogen” infection (25%), febrile neutropenia (23%), neutropenia (15%), anemia (13%), and bacterial infection (12%). Serious adverse events occurred in

OF NOTE Blinatumomab is a bispecific CD19directed CD3 T-cell engager that promotes lysis of CD19-positive malignant B cells.

65% of patients, with the most common (≥ 2%) consisting of febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, staphylococcal bacteremia, and headache. Overall, neurologic toxicity occurred in approximately 50% of patients and was a frequent reason for interruption of therapy. Adverse events led to discontinuation of treatment in 18%, with the most common reasons including encephalopathy and sepsis. Adverse events led to death in 15% of patients, most commonly due to infection. No fatal adverse events occurred on treatment among patients in remission. Blinatumomab carries boxed warnings for cytokine-release syndrome and neurologic toxicity, both of which may be severe, life-threatening, or fatal. It also carries warnings/precautions for infections, effects on ability to drive and use machines, and preparation and administration errors. n References 1. U.S. Food and Drug Administration: Blinatumomab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm425597.htm. Accessed December 12, 2014. 2. Blincyto (blinatumomab) for injection prescribing information, Amgen Inc, December 2014. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2014/125557lbl.pdf. Accessed December 12, 2014.

S:13 in

n December 3, 2014, blinatumomab (Blincyto) was granted accelerated approval for use in treating Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).1,2

ization is recommended. Blinatumomab should be withheld for grade 3 cytokine-release syndrome and neurologic toxicity and for other grade 3 adverse reactions and restarted at 9 µg/d. It should be discontinued for grade 4 cytokine-release syndrome, neurologic toxicity, or occurrence of more than one seizure. Treatment discontinuation should be considered for other grade 4 adverse events. As emphasized in the labeling, “It is very important that the instructions for preparation (including admixing) and administration … are strictly followed to minimize medication errors (including underdose and overdose).” The U.S. Food and Drug Administration approval of blinatumomab comes with a Risk Evaluation and Mitigation Strategy (REMS), consisting of a communication plan to inform health-care

T:14 in

with complete remission, 5.0 months (range, 0.13–8.8 months) in those with complete remission with partial hematologic recovery, and 5.9 months in both groups. The hematopoietic stem cell transplantation rate among those who achieved complete remission/complete remission with partial hematologic recovery was 39%.

B:14.25 in

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.

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

NSCLC=non-small cell lung cancer.

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

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

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

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

•

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

•

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

•

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

•

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

•

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

1.0

10.5

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

15% INCREASE IN MEDIAN OS

MONTHS

0.8

OS PROBABILITY

MAJOR OUTCOME MEASURE

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

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

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

527

415

329

231

156

103

501

386

306

197

129

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

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

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

Use in Specific Populations •

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

•

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

•

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

Most Common Adverse Reactions •

•

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

•

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

•

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

Drug Interactions •

No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

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

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

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

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

CONTRAINDICATIONS None.

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

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

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

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

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

10 40 <1

50 9

11 <1

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

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

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

CYRAMZA® (ramucirumab) injection

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

RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION

ASCOPost.com | FEBRUARY 25, 2015

Integrative Oncology By Jyothi Gubili, MS

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

Capsaicin Scientific name: 8-methyl-N-vanillyl6-nonenamide Brand names: Zostrix cream 0.025% or 0.075%, Salonpas Gel-Patch Hot, Sinus Buster (homeopathic intranasal spray).

he use of dietary supplements by patients with cancer has increased significantly over the past 20 years despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. We chose capsaicin for this issue because of its increasing use as a pain reliever by cancer patients.

Jyothi Gubili, MS

Capsaicin is marketed in capsule form and as an ingredient in topical creams, gels, and lotions. Prescriptionstrength dermal capsaicin products are available for the management of pain.

The Science

Capsaicin is believed to cause depolarization of C-fiber polymodal nociceptors, thereby releasing substance P, a neurotransmitter that relays pain signals to the brain. Following application of capsaicin, the sensation of pain increases due to release of substance P

Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, of Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, of Memorial Sloan Kettering Cancer Center.

Overview

CYRAMZA® (ramucirumab) injection

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Capsaicin is a colorless, pungent ingredient found in cayenne pepper, a shrub that originated in Central and South Americas and is now cultivated in many tropical and subtropical climates. An important spice in many cuisines around the world, including Creole, Cajun, Mexican, Asian, and Southern Italian, cayenne pepper is valued in Ayurvedic and Chinese medical systems as a remedy for digestive and circulatory problems, poor appetite, and muscle and arthritic pain. Today, topical capsaicin is used to treat pain associated with osteoarthritis, rheumatoid arthritis, mastectomy, postherpetic neuralgia, and diabetic neuropathy and to reduce the severity of psoriasis and pruritus. Capsaicin has been studied in oral and topical forms. Current evidence suggests utility of topical capsaicin in controlling postoperative pain in cancer patients. However, data are limited to assess its effectiveness for arthritic pain and neuropathic pain associated with AIDS, diabetes, and mastectomy.

but subsides when its levels are depleted at the afferent neurons.1, 2 Topical capsaicin has been shown to be effective against psoriasis,3 prurigo nodularis,4 pruritus ani;5 a dermal capsaicin patch was found to be safe and effective for the treatment of postherpetic neuralgia.6 In another study, a combination of capsaicin and isoflavone improved hair growth in healthy volunteers with alopecia.7 Furthermore, capsaicin in intranasal form was shown to improve nasal congestion and sinus pain associated with nonallergic rhinitis.8 Data also indicate that capsaicin cream can control postoperative pain in cancer patients,9 but it was ineffective against distal symmetric peripheral neuropathy associated with AIDS.10 Capsaicin’s value in alleviating arthritic pain has not been fully established.11,12 A review of studies of capsaicin for neuropathic pain associated with HIV, diabetes, and mastectomy concluded that available data preclude full assessment of its benefits and that additional welldesigned clinical trials are needed.13 continued on page 62

The ASCO Post | FEBRUARY 25, 2015

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Integrative Oncology Capsaicin continued from page 61

Capsaicin, reported to have carcinogenic effects,14 was shown to be safe in a study of mice.15 Interestingly, studies following this observation found that capsaicin exerted chemopreventive properties.16,17 Proposed mechanisms of action include induction of apoptosis,18 inhibition of epidermal growth factor–induced invasion, and migration

OF NOTE Physicians should be aware of the potential for skin irritation associated with the use of topical capsaicincontaining products and for capsaicin-prescription drug interactions.

of tumor cells.19 A case report of a patient with prostate cancer showed that capsaicin may slow the doubling time of prostate-specific antigen (PSA).20

Adverse Effects

Increased arterial blood pressure and acute myocardial infarction were reported after ingestion of large amounts of chili peppers.21 Coronary vasospasm and acute myocardial infarction were observed following use of a topical capsaicin patch for 6 days. Improvement was seen after treating the symptoms and removal of the patch.22 Cases of serious burns have occurred after the use of over-the-counter topical products. In some cases, hospitalization was required.23

Herb-Drug Interactions Antihypertensive medications: Capsaicin may affect the actions of antihypertensive medications.21 n

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

References 1. Lynn B: Capsaicin: Actions on noci-

ceptive C-fibres and therapeutic potential. Pain 41:61-69, 1990. 2. Marsh SJ, Stansfeld CE, Brown DA, et al: The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro. Neuroscience 23:275-289, 1987. 3. Ellis CN, Berberian B, Sulica VI, et al: A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 29:438-442, 1993. 4. Ständer S, Luger T, Metze D: Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol 44:471-478, 2001. 5. Lysy J, Sistiery-Ittah M, Israelit Y, et al: Topical capsaicin—a novel and effective treatment for idiopathic intractable pruritus ani: A randomised, placebo controlled, crossover study. Gut 52:1323-1326, 2003. 6. Backonja MM, Malan TP, Vanhove GF, et al; C102/106 Study Group: NGX4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomized, double-blind, controlled study with an open-label extension. Pain Med 11:600-608, 2010. 7. Harada N, Okajima K, Arai M, et al: Administration of capsaicin and isoflavone promotes hair growth by increasing insulinlike growth factor-I production in mice and in humans with alopecia. Growth Horm IGF Res 17:408-415, 2007. 8. Bernstein JA, Davis BP, Picard JK, et al: A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis. Ann Allergy Asthma Immunol 107:171-178, 2011. 9. Ellison N, Loprinzi CL, Kugler J, et al: Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 15:2974-2980, 1997. 10. Paice JA, Ferrans CE, Lashley FR, et al: Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symptom Manage 19:45-52, 2000. 11. McCarthy GM, McCarthy DJ: Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 19:604-607, 1992.

GUEST EDITOR

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. 12. Deal CL, Schnitzer TJ, Lipstein E, et al: Treatment of arthritis with topical capsaicin: A double-blind trial. Clin Ther 13:383395, 1991. 13. Derry S, Lloyd R, Moore RA, McQuay HJ: Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev (4):CD007393, 2009. 14. Toth B, Gannett P: Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice. In Vivo 6:59-63, 1992. 15. Park KK, Chun KS, Yook JI, Surh YJ: Lack of tumor promoting activity of capsaicin, a principal pungent ingredient of red pepper, in mouse skin carcinogenesis. Anticancer Research 18:4201-4205, 1998. 16. Thoennissen NH, O’Kelly J, Lu D, et al: Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER2 pathway. Oncogene 29:285-296, 2010. 17. Yang ZH, Wang XH, Wang HP, et al: Capsaicin mediates cell death in bladder cancer T24 cells through reactive oxygen species production and mitochondrial depolarization. Urology 75:735-741, 2010. 18. Kim MY, Trudel LJ, Wogan GN: Apoptosis induced by capsaicin and resveratrol in colon carcinoma cells requires

nitric oxide production and caspase activation. Anticancer Res 29:3733-3740, 2009. 19. Hwang YP, Yun HJ, Choi JH, et al: Suppression of EGF-induced tumor cell migration and matrix metalloproteinase-9 expression by capsaicin via the inhibition of EGFR-mediated FAK/Akt, PKC/Raf/ ERK, p38 MAPK, and AP-1 signaling. Mol Nutr Food Res 55:594-605, 2011. 20. Jankovic B, Loblaw DA, Nam R: Capsaicin may slow PSA doubling time: Case report and literature review. Can Urol Assoc J 4:E9-E11, 2010. 21. Patanè S, Marte F, Di Bella G, et al: Capsaicin, arterial hypertensive crisis and acute myocardial infarction associated with high levels of thyroid stimulating hormone. Int J Cardiol 134:130-132, 2009. 22. Akçay AB, Ozcan T, Seyis S, Acele A: Coronary vasospasm and acute myocardial infarction induced by a topical capsaicin patch. Turk Kardiyol Dern Ars 37:497-500, 2009. 23. U.S. Food and Drug Administration: FDA Drug Safety Communication: Rare cases of serious burns with the use of over-the-counter topical muscle and joint pain relievers. Available at http://www.fda. gov/Drugs/DrugSafety/ucm318858.htm. 2012. Accessed February 5, 2015.

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Issues in Oncology Maintenance of Certification continued from page 1

ternists and medical specialty societies. Some believe ABIM has turned a deaf ear to practicing physicians and has not adequately developed a relevant, meaningful program for them as they strive to keep up to date in their fields. ABIM is listening and wants to be responsive to your concerns. While ABIM’s Board believes that a more-continuous certification helps all of us keep up with the rapidly changing nature of modern medical practice, it is clear that parts of the new program are not meeting the needs of physicians like yourself. We got it wrong and sincerely apologize. We are sorry.

Next Steps As a result, ABIM is taking the following steps: • Effective immediately, ABIM is suspending the Practice Assessment, Patient Voice and Patient Safety requirements for at least 2 years. This means that no internist will have his or her certification status changed for not having completed activities in these areas for at least the next 2 years. Diplomates who are currently not certified but who have satisfied all requirements for Maintenance of Certification except for the Practice Assessment requirement will be issued a new certificate this year. • Within the next 6 months, ABIM will change the language used to publicly report a diplomate’s MOC status on its website from “meeting MOC requirements” to “participating in MOC.” • ABIM is updating the Internal Medicine MOC exam. The update will focus on making the exam more reflective of what physicians in practice are doing, with any changes to be incorporated beginning fall 2015, with more subspecialties to follow. • MOC enrollment fees will remain at or below the 2014 levels through at least 2017. • By the end of 2015, ABIM will assure new and more flexible ways for internists to demonstrate self-assessment of medical knowledge by recognizing most forms of ACCME-approved

Continuing Medical Education. Please visit our frequently asked questions page at http://www.abim. org/maintenance-of-certification/ moc-faq/default.aspx for more information about these changes. I do want you to know that, since the changes being made are significant, it will take time until your individual status page is updated on the ABIM website. ABIM is changing the way it does its work so that it is guided by, and integrated fully with, the medical community that created it. However, I know that actions will speak louder than words. Therefore, ABIM will work with medical societies and directly with diplomates to seek input regarding the MOC program through meetings, webinars, forums, online communications channels, surveys, and more. The goal is to cocreate an MOC program that reflects the medical community’s shared values about the practice of medicine today, and provides a professionally created and publicly recognizable framework for keeping up in our discipline. It remains important for physicians to have publicly recognizable ways— designed by internists—to demonstrate their knowledge of medicine and its practice. Internists are justifiably proud of their knowledge and skills. However, the current MOC program can and should be improved. Over the next few months, you’ll see communication from me and ABIM leadership, asking about your vision for internal medicine, the MOC program and your opinions about what it means to be a doctor today. We have also created “Transforming ABIM,” a Google+ Community that you can join, to ask questions and share ideas, and a blog. I have heard you, and ABIM’s Board has heard you. We will continue to listen to your concerns and evolve our program to ensure it embodies our shared values as internists. Thank you for your input and feedback—and for the important clinical work you do each and every day. n —Richard J. Baron, MD, MACP President and Chief Executive Officer American Board of Internal Medicine

ASCO President on ABIM Decision

eter Paul Yu, MD, FACP, FASCO, ASCO President, made the following remarks following ABIM’s recent announcement concerning maintenance of certification: “Last year, the American Board of Internal Medicine (ABIM) released a new process for maintenance of certification (MOC) that many physicians felt was onerous and lacked relevance to how physicians in practice learn today. In rePeter Paul Yu, MD, sponse, ASCO and our sister professional sociFACP, FASCO eties began a dialogue with ABIM to let them know our concerns, concerns that ABIM publicly acknowledged [earlier this month]. Effective immediately, ABIM is suspending the Practice Assessment, Patient Voice, and Patient Safety requirements for at least 2 years. “This news comes as a welcome announcement to us and to all our members who were facing these proposed changes. ASCO and its leaders have been working on this issue and expressing concern consistently for months. We spoke out, you spoke out, and ABIM listened. As your professional society, we are here to help drive changes that help our members and improve patient care. In the coming months, we will continue to work with the ABIM leadership as it institutes these and other changes—and we will be sure to keep you, our members, informed. “ASCO intends to work collaboratively with ABIM to develop a better system that reassures the public that their physician meets the highest professional standards as determined by their peers and that creates a designation of Board Certification that we are all proud to maintain.” n

Statement from the NBPAS

he National Board of Physicians and Surgeons (NBPAS) President Paul Teirstein, MD, released his own statement shortly after Dr. Baron’s letter was released: “ABIM’s recent press release is clearly a step in the right direction. Suspending the practice assessment and patient safety requirements of the MOC program was a good decision. Plans for a more open dialogue resulting in future MOC upPaul Teirstein, MD dates are welcome. However, it must be stressed that the changes disclosed today are only a very partial, initial fix. The current MOC requirements are still onerous, not clinically relevant, and too expensive. The ABIM’s announcement validates the work so many have done on this issue. NBPAS has launched an alternative continuous board certification program, which already has hundreds of applicants. The NBPAS website has received thousands of visitors, many leaving salient comments. Enrollment is open to most of the American Board of Medical Specialties (ABMS) non-surgical specialties. Life-long learning does not come in a one-size-fits-all package. No single program will ever meet everyone’s needs. NBPAS is now providing physicians with a much-needed alternative. n

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Announcements

ASTRO Announces Additions to Management Team

he American Society for Radiation Oncology’s (ASTRO) Board of Directors has announced three additions to the Society’s management team: Emily Wilson has been named Executive Vice President; Dave Adler has been promoted to Vice President of Advocacy; and Anne Hubbard has been promoted to Director of Health Policy.

Emily Wilson

Dave Adler

Anne Hubbard

“Congratulations to Ms. Wilson, Mr. Adler, and Ms. Hubbard for their extraordinary achievements during their combined 18-plus years at ASTRO,” said Chief Executive Officer Laura I. Thevenot. “Health policy, quality, and advocacy are among the top five priorities identified in our 2014 member survey; they will meet those priorities exceptionally well. They will play a critical role in ASTRO’s continued success to strengthen services to our members, to the radiation oncology specialty, and to the more than one million cancer patients who receive radiation therapy each year.” In her new role as Executive Vice President, Ms. Wilson will provide strategic vision to ASTRO’s Board of Directors, CEO, and staff to ensure continued success across the organization to meet the goals of ASTRO’s Strategic Plan. She will also continue to oversee ASTRO’s Clinical Affairs division

which leads important safety, quality, and policy initiatives that support ASTRO members. They include the soonto-be launched APEx (Accreditation Program for Excellence) and quality efforts including a Cloud-based Physician Quality Reporting System (PQRSwiz-

ard), Integrating the Healthcare Enterprise-Radiation Oncology (IHE-RO), Guidelines, Best Practices, and White Papers. Ms. Wilson began at ASTRO as Director of Government Relations, where her efforts were instrumental in averting cuts to radiation oncology in

the Deficit Reduction Act of 2005 and Medicare reimbursement cuts to radiation oncology in 2009 and 2010. As Vice President of Advocacy and Clinical Affairs since 2010, she formed the Clinical Affairs and Quality Council for ASTRO’s Board of Directors and

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Announcements

D: 15.4” 15.15”

14.15”

Laura I. Thevenot

has played a key role in ASTRO’s Target Safely campaign, which includes launching RO-ILS: Radiation Oncology Incident Learning System, Choosing Wisely, PQRSwizard, and IHE-RO. In his new role as Vice President of Advocacy, Mr. Adler will oversee both ASTRO’s Government Relations and Health Policy departments. These de-

partments are responsible for ASTRO’s legislative and regulatory advocacy with federal policymakers, including the White House, Congress, agencies within the Department of Health and Human Services [such as the Centers for Medicare and Medicaid Services (CMS), the National Institutes of Health (NIH), and the U.S. Food and

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Drug Administration (FDA)], and the Nuclear Regulatory Commission. Mr. Adler will also lead ASTRO efforts to collaborate with medical specialty societies, patient advocacy organizations, and other health-care coalitions. Mr. Adler was previously ASTRO’s Director of Government Relations. He was responsible for leading several significant advocacy campaigns protecting radiation oncology Medicare reimbursement, advancing efforts to end abuse of the physician self-referral law in cancer treatment, and developing ASTRO’s payment reform action plan. Ms. Hubbard, promoted to Director of Health Policy, first joined ASTRO as Assistant Director of Health Policy. In her new role, Ms. Hubbard leads ASTRO’s efforts regarding the economics of managing a radiation oncology practice, as well as the development of ASTRO’s payment reform initiative. She serves as ASTRO’s staff advisor to the American Medical Association’s (AMA) Current Procedural Terminology (CPT) Editorial Panel and the Relative Value Scale (RVS) Update Committee. Additionally, Ms. Hubbard represents ASTRO at the Medicare Payment Advisory Commission and the Advisory Panel on Hospital Outpatient Payment Meeting and works closely with the AMA and other medical specialty societies. n

Contact BLEED: 10.825”

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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

Introducing Making the human connection

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

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The ASCO Post | FEBRUARY 25, 2015

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Health-Care Policy Cancer Screening

At Long Last: CMS Will Cover Lung Cancer Screening By Ronald Piana

ew issues in health-care debates are more contentious and polarizing than population screening for the early detection of cancer. After a decades-long battle, lung cancer screening advocates have just received what they have long sought: Medicare has approved national lung cancer screening coverage for qualified beneficiaries. Speaking with The ASCO Post, Ella Kazerooni, MD, Director of Cardiothoracic Radiology at the University of Michigan Health System said, “This is a victory for cancer prevention and will ultimately save the lives of thousands of Americans at high risk of developing lung cancer.” Medicare will now pay for an annual lung cancer screen with low-dose computed tomography for beneficiaries aged 55 to 77 years who have a 30 pack-year history or have quit smoking within the past 15 years. Qualified beneficiaries must also have a written order from a physician or qualified nonphysician. Notably, the coverage also includes a visit for counseling and shared decision-making on the risks and benefits of lung cancer screening. According to the Lung Cancer Alliance, there are about 4 million Medicare beneficiaries nationwide who will meet eligibility requirements for screening. Critics of lung cancer screening have long argued that screening is fraught with problems such as an inordinate amount of false-positive results, which increase unnecessary morbidity and inflate costs to the health-care system. But according to Dr. Kazerooni, “This is one tough decision in which

CMS listened to the body of professionals who were invested in making sure that the evidence supporting the use of lung cancer screening was fully analyzed. Nothing in health care is perfect, but the data from the National Lung Screening Trial are solid proof that screening saves countless thousands of lives. All the hard work was worth it.”

The Beginning of a Long Road Is this the end of the road in this hard-fought battle? Dr. Kazerooni responded, “Certain aspects of the lung cancer screening conflict are over now

cancer screening into the mainstream of medical practice, and that’s a major victory for our high-risk populations.” Some experts have argued that the CMS eligibility criteria place undo administrative burdens on screening facilities, which, for instance, must collect and submit data to a CMSapproved national registry for each low-dose computed tomography lung cancer screening performed. The data collected and submitted to a CMS-approved national registry must include at least 13 data elements. “The registry reporting requirements are to ensure that the screening

This is one tough decision in which CMS listened to the body of professionals who were invested in making sure that the evidence supporting the use of lung cancer screening was fully analyzed. This is a victory for cancer prevention. —Ella Kazerooni, MD

that CMS has made its decision. That said, it’s also the beginning of a long road, because we now have to put the screening mechanisms in place so the majority of eligible people can get screened. Frankly, I am disappointed that CMS is only covering beneficiaries up to the age of 77 years, instead of 80, which was what the U.S. Preventive Services Task Force (PSTF) recommended. But this decision will bring lung

Landmarks in Lung Cancer Screening ■■ February 2015: CMS finalized its guidelines for lung cancer screening; national coverage goes into effect immediately. ■■ May 2014: The Medicare Evidence & Coverage Advisory Committee voted against recommending national Medicare coverage for lung cancer screening. ■■ December 2013: The U.S. Preventive Services Task Force recommended annual lung cancer screening in adults aged 55 to 80 years who have a 30 pack-year smoking history and current smokers or those who have quit within 15 years. ■■ August 2011: The National Lung Screening Trial reports its results in The New England Journal of Medicine: Screening with low-dose computed tomography represented a 20% relative reduction in lung cancer mortality. ■■ April 2004: The National Lung Screening Trial reached its accrual target. ■■ September 2002: The National Lung Screening Trial, a U.S. National Cancer Institute–sponsored study, is jointly conducted by Lung Screening Study screening centers.

adheres to best practices quality and safety. The reporting also inhibits the overutilization of downstream tests and gives us information on how screening is performing in real practice as opposed to a scientific study. But like anything done on a large scale, there’s an adaptability curve: The more you do a task, the better you become at it,” said Dr. Kazerooni.

The Challenges Ahead The screening data from the National Lung Screening Trial were collected from comprehensive institutions that were equipped to handle large standardized testing. Rolling out highquality screening programs in multiple independent institutions across the nation is challenging. However, despite reservations from certain faultfinders, Dr. Kazerooni asserted that it is doable, explaining that health care is a lot different now than when mammography rolled out. “Over the past 30 years, we’ve learned a lot from the mammography experience, and the demand for return on investment in health care is different now than a couple of decades ago. We also have the added advantage of

James L. Mulshine, MD

integrated electronic health records to connect to the screening registries. Not to say that many smaller practices won’t have a period of adjustment to work through, but we’re at a good starting point,” noted Dr. Kazerooni. Moreover, she stressed that we need to look at lung cancer screening as a population health measure: It is not for people who have symptoms of one disease or another. It screens millions and millions of eligible people who have met a set of criteria. “Just because Medicare has granted coverage, we can’t expect the system to immediately be up to speed. It is going to take a lot of effort from the radiology community and health-care facilities to monitor and input the data and work with the various vendors to get all the kinks out,” said Dr. Kazerooni.

Cost Issues Critics of national lung cancer screening have also argued that population screening would place an untenable cost burden on Medicare and private payers. However, numerous studies counter that concern, such as one published in Health Affairs. In this study report, James L. Mulshine, MD, and colleagues concluded that “the cost per life-year saved would be below $19,000, an amount that compares favorably with screening for cervical, breast, and colorectal cancers.” Dr. Kazerooni commented, “The initiation of lung cancer screening in high-risk populations will serve as an example of how we can roll out largescale cost-effective health programs. It’s also important to note that lung cancer screening can serve as an educational instrument for smoking cessation programs. Then there’s the data collection, which also adds to our cumulative bank of knowledge. So there are many positives that will come from this hard-won CMS decision.” n Disclosure: Dr. Kazerooni reported no potential conflicts of interest.

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Through the Lens of Oncology History

A Century of Progress The text and photographs on these pages are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The Radium Era: 1916–1945.” To view additional photos from this series of books, visit burnsarchive.com.

The RADIUM Era 1916-1945 Skull Sarcoma Removed Under Local Anesthesia, East Prussia, Circa 1921

n this case, Heinrich Braun, MD, removes a large sarcoma of the skull. The development of a local anesthetic solution with adrenalin was a major step forward in expanding the possibilities of major surgery using regional block anesthesia. The first photograph (A) shows the lesion with a central depressed area. A line has been drawn on the photograph

showing a portion of the area to be injected; 75 cc of 1% “novacaine-suprarenin” is necessary to attain the proper depth of anesthesia and blood control. The second photograph (B) shows the entire defect after excision of the tumor. The third photograph (C) shows the skin flap that has been prepared from the adjacent area. This skin flap will be swung over to cover the defect. The fi-

nal photograph (D) shows the end result, a remarkable postoperative view of a “cured patient.” There is hair growing in most of the area of the excision, though the adjacent skull from which the flap was taken is devoid of hair. Dr. Braun emphasizes that his procedure allows bloodless and painless surgery, even in the scalp, which is notoriously prone to bleeding. Most opera-

tions involving the scalp required head tourniquets. During the first decades of the 20th century, local anesthesia was used by numerous surgeons to expand their capabilities in dealing with a variety of diseases. It became especially important in operating on elderly patients and those with significant cardiovascular decompensation. Excerpted from Oncology Tumors & Treatment, A Photographic History, The Radium Era: 1916-1945 by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive. n

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Patient’s Corner

Twenty Years After a Diagnosis … and Counting

After 2 decades of coping with advanced colorectal cancer and metastases in my lungs and liver and a diagnosis of breast cancer, I’ve learned how to maintain a sense of control. By Margaret G. Werts, PhD

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n 1995, I was diagnosed with advanced colorectal cancer and given little chance to live. The dire diagnosis came years after being assured by several physicians that the problem I was having with rectal bleeding and anemia was nothing more than the result of an internal hemorrhoid. Busy raising two teenage boys, running a household, and holding down a full-time job, I went about my daily activities undeterred until the bleeding became more than I could ignore. Determined to get the issue resolved, I made an appointment with another primary care physician who referred me to a colorectal surgeon. After performing a sigmoidoscopy exam, the

tive fluorouracil (5-FU) and leucovorin chemotherapy, followed by pelvic radiation, abdominoperineal resection with a colostomy, followed by more of the same chemotherapy. The treatment was grueling; however, I somehow managed to take care of my children, continue to work, and attend university classes for my doctoral degree.

Coping With Cancer Recurrence My husband later told me that my chance of surviving this cancer was extremely low. Miraculously, the treatment was successful, and I was declared cancer-free. I finished my doctorate, got a wonderful new job in preparing

It is so important for survivors to communicate their concerns to their loved ones and members of their medical team. Voicing our concerns gives us power and provides the medical team with vital information ... Our voice gives us back our sense of control. —Margaret G. Werts, PhD

doctor told me that the mass was not a hemorrhoid and that I would need further tests, including a colonoscopy, before an accurate diagnosis could be made. Although he was somewhat evasive when I asked if it could be serious, I could tell by his demeanor that my problem fell into the “it may be something more serious” category. And it was. A physical exam and a biopsy of the tumor showed that I had a large colorectal cancer that was fixed anteriorly to my uterus. When I told my husband, Day Werts, PhD, a radiation biologist in a radiation oncology department, about my diagnosis, he just stared and shook his head. He knew what was waiting for me and that my prognosis was not good. Determined to beat this cancer, I told him, “Don’t put nails in my coffin yet.” I underwent a regimen of preopera-

special education teachers, and began a new phase in my life. Then, in 2003, 8 years after my original diagnosis, the cancer recurred in my left lung and liver. One surgeon advised me there was nothing he could do. I was to go home and get my life in order. Yet, we persisted, and I had surgery to remove the lower lobe of my left lung and to install a chemotherapy pump in my abdomen for hepatic arterial infusion, to send the drug (fluorodeoxyuridine) directly to my liver alternating with capecitabine (Xeloda) and oxaliplatin (FOLFOX) chemotherapy for the systemic disease. Once again, the treatment was successful, and I remained stable with no apparent disease and returned to work. But 3 years later, in 2006, the cancer returned with a vengeance, this time surfacing in both lungs.

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Patient’s Corner

More grueling chemotherapy followed, including 12 cycles of 5-FU infusion and irinotecan (FOLFIRI) combined with 10 cycles of bevacizumab (Avastin), lasted over a year, and left me bald and unable to read, think clearly, or perform any of my routine activities. Somehow, I managed to get through the emotional and physical trauma of another cancer recurrence and treatment and eventually was able to return to my life and work, again with no evidence of disease.

A Life Interrupted However, this respite from cancer lasted a short time, just 18 months, before it recurred in my right lung, requiring wedge resection surgery to remove the nodule. This was followed by nine cycles of additional chemotherapy, which included a biologic agent, cetuximab (Erbitux), along with irinotecan and capecitabine. As the side effects

built, my oncologist asked repeatedly how I felt about continuing treatments, and although I asked him to “Give me everything to rid me of this cancer,” I almost had more than I could take. The treatment regimen put me back into a nonfunctional mode, and I spent most of my time sleeping, unable to work, and barely able to leave the house for more than a few minutes at a time. Currently, I continue working full time and am on a maintenance regimen of cetuximab, which I receive every 2 weeks. And while the treatment has so far kept my colorectal cancer from recurring, in 2012, I was diagnosed with early-stage invasive ductal carcinoma in my right breast. I had a lumpectomy followed by partial breast radiation therapy and continuing doses of anastrozole. Compared to my previous cancer experiences, this latest one has presented only a small bump in the road to getting my life back.

Having a Voice in Treatment Decisions Today, my life has returned to normal, or at least what has become normal for me. I am often asked about the changes my family and I have gone through as a result of my cancer and its aftermath. All I can say is we all have gone through hard times and the experience has changed us. My husband has learned to cook because the smells of cooking dinner were nauseating to me. My children learned to run errands. But most of all, we learned to appreciate the small moments and to resist complaining. Perhaps the biggest change for me is a permanent sense that I have little control over many things. Throughout my numerous treatments, I told myself that I was in charge. I could choose when to start and stop the therapies. My doctors encouraged me to report any side effects I was experiencing to my medical team. But even though I was part

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

of the decision-making process, I was dependent on my medical team to determine the best treatment plan for me. Oftentimes, I felt frustrated because of all that was happening. I learned to use my voice to express my needs but not to insist on my “way.” We all have different levels of tolerance for pain and the reduced quality of life a diagnosis of advanced cancer often brings. It is so important for survivors to communicate their concerns to their loved ones and members of their medical team. Voicing our concerns gives us power and provides the medical team with vital information about the type of care we want and what we are willing to endure. Our voice gives us back our sense of control. n Margaret G. Werts, PhD, is a Professor in the Department of Reading Education and Special Education at Appalachian State University in Boone, North Carolina.

The ASCO Post Wants to Hear From You

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

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Editorial Correspondence

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

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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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2015

2015 Oncology Meetings February

March

Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org

5th Annual Texas Adolescent and Young Adult Oncology Conference February 27-28 • Houston, Texas For more information: www.mdanderson.org 6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/ meetings/32nd-Annual-Miami-BreastCancer-Conference Society of Interventional Radiology February 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms. For more information, visit www.lymphcon.ch/imcl/index.php

Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcareprofessionals/conferences/ conferences

ESMO Symposium on Signalling Pathways in Cancer 2015 March 13-14 • Barcelona, Spain For more information: www.esmo.org/Conferences/ Signalling-Pathways-2015Personalised-Medicine 8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http://www.gotoper.com/ conferences/ipcc/meetings/8thAnnual-Interdisciplinary-ProstateCancer-Congress 25th Annual Interdisciplinary Breast Center Conference March 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting

2015 Multidisciplinary Head and Neck Cancer March 6-7 • Weston, Florida For more information: www.clevelandclinicmeded.com/live/ courses/headandneck/overview.asp

ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp

Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial SloanKettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse

14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch

Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-14 • Hollywood, Florida For more information: www.nccn.org/AC2015

Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/

EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index. cfm Melanoma and Cutaneous Malignancies Meeting April 10-11 • New York, New York For more information: www.healio.com/meeting/ hemonctodaymelanoma/ home?promocode689-8045 Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919 International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org HPV-Induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx ASCO/C-KIN Joint Session at Cancer & the Kidney International Network’s First Annual Conference (C-KIN 2015) April 14-15 • Brussels, Belgium For more information: www.c-kin.org/conference2015/

continued on page 79

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Announcements

Susan M. O’Brien Joins UC Irvine/Chao Family Comprehensive Cancer Center

usan M. O’Brien, MD has joined UC Irvine Health as Associate Director for Clinical Science for the Chao Family Comprehensive Cancer Center and Medical Director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research. A renowned researcher and clini-

tee, a member of the NCCN Acute Lymphoblastic Leukemia Guidelines Committee, and the hematology member of the Southwest Oncology Group Executive Committee. As Associate Director for Clinical Science, Dr. O’Brien will be respon-

sible for overseeing and coordinating clinical cancer research across the entire UC Irvine Health enterprise, including medical oncology, radiation oncology, surgical B:7.875” oncology, and gynecologic oncology. T:7.625” Dr. O’Brien will S:6.875” take the lead with

UC Irvine Health clinical investigators to expand the portfolio of early-phase clinical trials and launch a formal Experimental Therapeutics Program in her role as Medical Director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research. n

NOW APPROVED

Susan M. O’Brien, MD

cian, Dr. O’Brien’s leadership will help UC Irvine Health and the Chao Family Comprehensive Cancer Center increase both the number and complexity of innovative, outcomes-focused clinical trials. Her appointment was effective January 1, 2015. “This is an exciting time for cancer research. UC Irvine Health has an opportunity to build on its decades-long commitment to serving our region with leading-edge treatments and access to clinical trials,” said Richard A. Van Etten, MD, PhD, Director, Chao Family Comprehensive Cancer Center, University of California, Irvine. “As a comprehensive cancer center, we have an obligation to lead the way in our region and nationally,” he said. “Dr. O’Brien’s appointment is a critical step toward achieving those goals.”

Multiple Accomplishments Dr. O’Brien comes to UC Irvine from the University of Texas MD Anderson Cancer Center, where she was the Ashbel Smith Professor in the Department of Leukemia, Division of Cancer Medicine. She has been principal investigator for more than 40 funded clinical research protocols and has authored more than 600 articles in peer-reviewed journals, 30 invited articles, and numerous book chapters and abstracts. Dr. O’Brien is the Chair of the National Comprehensive Cancer Network (NCCN) Chronic Myelogenous Leukemia Guidelines Commit-

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

The first approved PARP inhibitor 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. • In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/ musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort

FOR MORE INFORMATION VISIT www.LYNPARZA.com Please see next page for Important Safety Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2014 AstraZeneca. All Rights Reserved. 3051313 Last updated 11/14

The ASCO Post | FEBRUARY 25, 2015

PAGE 76

Announcements

NCI-Funded Program on Screening for Psychosocial Distress Accepting Applications

unded by a grant from the National Cancer Institute (NCI), the Screening for Psychosocial Distress Program is a joint project of Yale University School of Nursing and the American Psycho-

social Oncology Society (APOS). The Screening for Psychosocial Distress Program trains cancer care providers on how to develop, implement, and maintain psychosocial screening programs within

their facilities, in order to meet the Commission on Cancer’s (CoC) new quality care standard. The CoC is a program of B:7.875” the American College T:7.625” of Surgeons. Applications to attend are now being acS:6.875”

cepted. The deadline for submission is April 1, 2015. With an international faculty of leading psychosocial cancer care professionals and researchers, the program will

IMPORTANT SAFETY INFORMATION There are no contraindications for LYNPARZA. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Coadministration of drugs which are potent inhibitors or inducers of CYP3A could increase or decrease exposure to LYNPARZA and should be avoided. Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. LYNPARZA is Pregnancy Category D. LYNPARZA is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), moderate renal impairment or severe renal impairment, since safety and efﬁcacy have not been established. Please see adjacent Brief Summary of the full Prescribing Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2014 AstraZeneca. All Rights Reserved. 3051313 Last updated 11/14

ASCOPost.com | FEBRUARY 25, 2015

PAGE 77

Announcements

train two cancer care providers from a single cancer care facility over 2 years. The first year includes a beginning 1-day workshop held at the APOS conference in Washington, DC, on July 29, 2015, and continues with four conference call teaching sessions throughout the year. The second year includes an advanced 1-day workshop and two conference call

teaching sessions throughout the year. Having two providers from each cancer care facility attend the training will enhance the successful implementation and the ongoing maintenance of a psychosocial screening program. Funding for the Screening for Psychosocial Distress Program covers the APOS conference registration and al-

LYNPARZA (olaparib) capsules, for oral use Rx ONLY Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE 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 Full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 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. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/ companiondiagnostics. 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.

T:10.5”

B:10.75”

S:9.875”

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]. 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].

lows for a stipend for each person toward covering the cost of attending the program. The program enrolls up to 18 cancer care facilities each year, for a total of 36 participants. More information and an application can be found at http://apos-society.org/ APOS/Distress_Screening_ Program/Distress_Home.aspx. n

Table 1 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction

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

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

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 % % 90 15

Decrease in hemoglobin (anemia) 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.

• Pneumonitis [see Warnings and Precautions]

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.

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.

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.

ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions]

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 measurable disease) [see Clinical Studies] 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.

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

The ASCO Post | FEBRUARY 25, 2015

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Announcements

Roswell Park Cancer Institute Announces Candace S. Johnson, PhD, as 15th President and Chief Executive Officer

he Roswell Park Cancer Institute (RPCI) Board of Directors has named Candace S. Johnson, PhD, as the Institute’s 15th President and Chief Executive Officer (CEO). Dr. Johnson will

be the first female leader for this 117-yearold comprehensive cancer center. “Over the past few months, we have met some highly qualified cancer leaders from around the country who were

Table 3 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions

Lynparza N=53 Grades 1-4 %

Blood and Lymphatic disorders Anemia 25 Gastrointestinal disorders Abdominal pain/discomfort 47 Decreased appetite 25 Nausea 75 Vomiting 32 Diarrhea 28 Dyspepsia 25 Dysgeusia 21 General disorders Fatigue (including asthenia, 68 lethargy) Infections and infestations Nasopharyngitis/Pharyngitis/ 43 URI Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal 32 pain Myalgia 25 Back pain 25 Nervous system disorder Headache 25 Respiratory, Thoracic, Mediastinal disorders Cough 21 Skin and Subcutaneous Tissue Dermatitis/Rash 25

Placebo N=43

Grades 3-4 %

Grades 1-4 %

Grades 3-4 %

0 0 2 4 4 0 0

58 14 37 9 21 14 9

2 0 0 0 2 0 0

Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Speciﬁc Populations]. 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.

2 6

12 21

0 0

Lynparza N=53 Grades 1-4 Grades 3-4 % % 85 8

Placebo N=43 Grades 1-4 Grades 3-4 % % 58 2

Decrease in hemoglobin Decrease in absolute neutrophil 32 8 23 0 count Decrease in platelets 26 6 19 0 Mean corpuscular volume 85 44 elevation Increase in creatinine* 26 0 5 0 *Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]

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 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.

Trump, MD, FACP, retired last fall,” says Michael Joseph, Chair of the RPCI Board of Directors. “There wasn’t a member of the board, community

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.

Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter*

interested in pursuing this job. Through this process of discovery, the search committee took note of the incredible job Dr. Johnson has been doing in leading this organization since Donald

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]. 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]. 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. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death. PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) Dosing Instructions Inform patients on how to take Lynparza [see Dosage and Administration]. 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]. 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]. 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]. 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 and Use in Specific Populations]. Nursing Mothers Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations]. 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.

Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: Patheon Pharmaceuticals, Inc. Cincinnati, OH 45237 Issued: 12/2014 ©AstraZeneca 2014

3051313 last updated 12/14

Candace S. Johnson, PhD

leader, RPCI employee, or cancer center friend who hasn’t realized that our future leader was right in front of us.” Dr. Johnson has led the scientific strategies and achievements of RPCI for 13 years. During that time, she has helped secure the National Cancer Institute’s Cancer Center Support Grant for the Institute twice and has built the foundation for successfully recompeting for this prestigious allocation in 5 years. “Roswell Park Cancer Institute is one of the founding organizations of Buffalo. The community and state leaders who established this cancer center and built this region’s center of excellence deserve to have their legacy continue. I am committed to creating an organization and Institute culture that allows our region to take pride in having a leading cancer center in its midst—one that continues to generate discoveries that diminish the burden that cancer places on our loved ones and friends throughout the world,” said Dr. Johnson. Prior to becoming President and CEO of RPCI in October 2014, Dr. Johnson was the Deputy Director and Chair of the Department of Pharmacology and Therapeutics,and the Wallace Family Chair for Translational Research and Professor of Oncology. Since November 2014, she has also served as Cancer Center Director for the Institute. Before coming to RPCI, she served as Deputy Director of Basic Research at the University of Pittsburgh Cancer Institute and Professor of Pharmacology and Medicine at the University of Pittsburgh School of Medicine. Dr. Johnson earned her doctoral degree in immunology from The Ohio State University. She completed research and postdoctoral fellowships in immunology and cell biology at the Michigan Cancer Foundation. n

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2015

2015 Oncology Meetings continued from page 74

ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23-26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015 3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum Fourth Annual Cancer Pain Conference April 24-26 • Scottsdale, Arizona For more information: www.cancerpainconference.org

May

13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu

Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

June

July

International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-AssociatedCancer

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html IMPAKT 2015 Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer

The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org/meetinginformation .html

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: http://www.apos-society.org

16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/ World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/ ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

The ASCO Post | FEBRUARY 25, 2015

PAGE 80

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER First-Line Crizotinib Superior to Pemetrexed-Plus-Platinum Chemotherapy in Patients With ALK-Positive NSCLC Crizotinib (Xalkori) treatment “was superior to pemetrexed-plusplatinum chemotherapy with respect to progression-free survival, objective response rate, reduction in lung-cancer symptoms, and improvement in quality of life” in patients with previously untreated advanced anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC), according to an open-label, phase III trial reported in The New England Journal of Medicine. Progression-free survival, the primary endpoint of the trial, “was significantly longer with crizotinib than with chemotherapy,” reported Benjamin J. Solomon, MB, BS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues. The median progression-free survival was 10.9 months in the group receiving crizotinib vs 7.0 months in the group receiving standard chemotherapy (hazard ratio [HR] progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35–0.60; P < .001). Crizotinib is an oral small-molecule tyrosine inhibitor of ALK and other kinases. Present in 3% to 5% of patients with NSCLC, rearrangements of ALK “define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that have adenocarcinoma histologic characteristics,” the authors explained. Patients were randomly assigned to receive oral crizotinib at 250 mg twice daily or intravenous chemotherapy with pemetrexed (Alimta) plus, at the choice of the investigator, either cisplatin or carboplatin every 3 weeks for up to 6 cycles. Among the 340 patients receiving treatment, 171 were in the crizotinib group and 169 were in the chemotherapy group, with 91 receiving pemetrexed-cisplatin and 78 receiving pemetrexed-carboplatin. Treatment was continued until disease progression, unacceptable toxic effects, death, or withdrawal of consent. Patients receiving chemotherapy could cross over to crizotinib treatment after disease progression. The median age was 52 years in the

crizotonib group and 54 years in the chemotherapy group. More than 60% of patients had never smoked. “The objective response rate was significantly higher with crizotinib than with chemotherapy,” 74% vs 45% (P < .001), the investigators reported. “The median duration of response was 11.3 months vs 5.3 months.” The median overall survival was not reached. The authors estimated that “the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy.” The most common adverse events were vision disorders, diarrhea, nausea, and edema among patients receiving crizotinib and nausea, fatigue, vomiting, and decreased appetite among those receiving chemotherapy. Adverse events associated with permanent discontinuation of treatment occurred in 12% of patients in the crizotinib group and 14% of the chemotherapy group, with 5% in the crizotinib group and 8% in the chemotherapy group “deemed by the investigator to be related to treatment.” Patients receiving crizotinib reported a greater improvement in quality of life and a greater reduction in pain, dyspnea, and insomnia. Solomon BJ, et al: N Engl J Med 371:2167-2177, 2014.

LARYNGEAL CANCER Primary Surgical Therapy Results in Higher 5-Year Survival for Patients With Advanced-Stage Disease Bucking national trends toward preserving the larynx in patients with advanced laryngeal cancer, treatment of patients for stage IV disease at Louisiana State University (LSU) HealthShreveport were more likely to involve primary surgical therapy, including total laryngectomy, and more likely to achieve 5-year survival than the national average. “This contributes to a growing body of literature that suggests that initial surgical therapy for advanced-stage disease may result in increased survival compared with organ-preservation protocols,” Blake Joseph LeBlanc, MD, and colleagues from LSU-Health Shreveport stated in JAMA Otolaryngology–Head & Neck Surgery. The authors compared survival outcomes for initial surgical treat-

ment of advanced-stage primary tumors in the Louisiana health system with outcomes in the National Cancer Database (NCDB), a joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. At LSU-Health, an academic tertiary referral hospital, 117 of 165 patients (70.9%) with laryngeal cancer in the tumor registry from 1998 to 2007 presented with advanced-stage (III/ IV) disease, compared with 46.7% nationwide (P < .01). Among the LSU patients with advanced disease, 64 patients (54.70%) underwent primary surgical therapy, including total laryngectomy or pharyngolaryngectomy. “Data from the NCDB indicate that the rate of laryngectomy declined from 40% to 60% in the 1980s to 32% in 2007,” the investigators noted. “For stage IV disease, our 5-year survival rate was 55.54% (95% CI, 43.4%–66.1%) compared with 31.6% (95% CI, 30.4%–32.9%) nationally (P < .05). Our proportion of uninsured patients was 23.7% vs 5.1% of patients nationally (P < .001), and our patients traveled farther distances for care, with 60.5% traveling 50 miles or more, compared with 15.9% nationally (P < .001),” Dr. LeBlanc and coauthors reported. “We believe that upfront laryngectomy may explain our higher survival rates for advanced-stage laryngeal cancer,” the authors stated.

“While it seems logical that triple-modality therapy would confer improved survival at the expense of increased morbidity, the question arises as to whether we should be advising upfront surgical therapy more frequently for the advanced T-stage tumors,” the researchers wrote. “Current National Comprehensive Cancer Network guidelines display the options of concurrent systemic therapy vs laryngectomy vs induction chemotherapy for advanced T-stage glottic and supraglottic carcinomas. At our institution, [patients with] T4 tumors with cartilage and extralaryngeal involvement are uniformly offered total laryngectomy in favor of organ preservation, which resulted in a higher percentage of primary surgical patients at LSU-Health when compared with the NCDB.” LSU-Health Shreveport “is a public hospital with a large proportion of uninsured and Medicaid [patients] and those with low socioeconomic status,” the authors noted. “Our data suggest that despite disparities in insurance and socioeconomic status, improvements in survival can be achieved with primary surgical treatment.” n LeBlanc BJ, et al: JAMA Otolaryngol Head Neck Surg. November 27, 2014 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

NEW—LIQUID FORMULATION

Start with TREANDA® (bendamustine HCI) Injection for established front-line CLL therapy

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia. Please see accompanying brief summary of Full Prescribing Information on the following pages. Learn more at TREANDAHCP.com

The ASCO Post | FEBRUARY 25, 2015

PAGE 82

Announcements

Thomas J. Smith, MD, Honored by the American Cancer Society

homas J. Smith, MD, has been selected by the American Cancer Society to be the recipient of the 2015 Trish Greene Quality of Life Award. This award honors the life and work of the late Patricia (Trish) Greene, RN, PhD.

As progress in the detection and treatment of cancer prolonged lives and increased the number of cancer survivors, quality-of-life research became an emerging field of investigation. Dr. Greene was an early pioneer who recognized the future implications of innovative treatment

models to provide the best care. The award honors and recognizes the importance of those who have devoted a significant portion of their careers to the various areas of quality of life and have accomplished outstanding Thomas J. Smith, MD

™

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once nonhematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution. Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of TREANDA must be completed within this period. 3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5mL or 180 mg/2mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing

continued on page 83

TREANDA® (bendamustine hydrochloride) Injection reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial.The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).

ASCOPost.com | FEBRUARY 25, 2015

PAGE 83

Announcements

Physician-Scientist Guido Marcucci, MD, Joins City of Hope

enowned physician and researcher Guido Marcucci, MD, has joined City of Hope in a key leadership role within the institution’s new Hematologic Malignancies and Stem Cell Transplantation Institute. As Director of the Gehr Family Center for

Leukemia Research and as Chief of the Division of Hematopoietic Stem Cell and Leukemia Research, Dr. Marcucci will guide research into improved treatments for leukemia and other hematologic malignancies. Dr. Marcucci, who will also serve

as Professor of Hematology & Hematopoietic Cell Transplantation, joins City of Hope from Ohio State University, where he was Professor of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, and Pharmaceutics in the Division of Guido Marcucci, MD

TREANDA® (bendamustine hydrochloride) Injection

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1. 16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons. 16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.

Number (%) of patients TREANDA (N=153) System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

Chlorambucil (N=143)

All Grades

Grade 3/4

All Grades

Grade 3/4

121 (79)

52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

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

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

5 (3)

11 (7)

3 (2)

2 (1)

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150

Chlorambucil N=141

Laboratory Abnormality

All Grades n (%)

Grade 3/4 n (%)

All Grades n (%)

Grade 3/4 n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved. (Label Code: 00016287.06) 9/2013 TRE-40161 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

Hematology at the University’s Comprehensive Cancer Center. At City of Hope, he will head one of six cornerstone centers in the institution’s recently launched hematologic institute, setting scientific priorities and guiding the development of new approaches to treating leukemia and related diseases, especially those involving hematopoietic stem cell transplantation. “City of Hope is extremely fortunate to have a scientist and physician of Dr. Marcucci’s caliber and accomplishments as Chief of our new leukemia center,” said Steven T. Rosen, MD, Provost and Chief Scientific Officer at City of Hope. “With his guidance and vision, we will be able to develop and bring to fruition revolutionary new treatments for leukemia and other diseases.” “I’m extremely pleased to join such a remarkable institution as it expands its commitment to developing new treatment approaches,” Dr. Marcucci said. n

Thomas J. Smith, MD continued from page 82

research that benefits cancer patients and their families. Dr. Smith is The Harry J. Duffey Family Professor of Palliative Medicine and Palliative Medicine Director at Johns Hopkins School of Medicine. Dr. Smith is a pioneer in palliative care who has dedicated his career to the specialty. “I think of palliative care as being open and honest in communication with patients, setting medically appropriate goals, and symptom management,” Dr. Smith says. The issues to which Dr. Smith refers are sensitive but significant, and include things like future decisions about lifesupport, hospice versus home care, and even patients’ remaining goals. Talking with patients about these subjects when they can adequately ponder them, that is, when they have 6 months or even 2 years to live, can make an enormous difference to their quality of life. n

The ASCO Post | FEBRUARY 25, 2015

PAGE 84

In the News Breast Cancer

Atypical Hyperplasia as a Predictor of Future Breast Cancer: Focus on Chemoprevention and Screening By Charlotte Bath

typical hyperplasia of the breast has “special importance as a predictor of future breast cancer,” according to a special report in The New England Journal of Medicine.1 That special importance is based on the high incidence of atypical hyperplasia—found in around 10% of the 1 million breast biopsies with benign results performed annually in the United States—and the high risk—“with a cumulative incidence of breast cancer approaching 30% at 25 years of follow-up.” Because of the incidence, high risk, and “availability of effective breast cancer prevention strategies, atypical hyperplasia is the benign breast diagnosis that is the most important to act on clinically,” the authors averred. The suggested clinical actions are more intensive screening using magnetic resonance imaging (MRI) and chemoprevention using selective estrogen-receptor modulators and aromatase inhibitors.

High Risk Not Widely Recognized The two types of atypical hyperplasia—atypical ductal hyperplasia and atypical lobular hyperplasia—“occur with equal frequency and confer similar risks of later breast cancer”; they also are referred to together in the report as atypical hyperplasia. The high cumulative incidence approaching 30% at 25 years “is not widely recognized, and thus women with atypical hyperplasia are not included in many high-risk guidelines,” the authors acknowledged. A longitudinal cohort study considered a landmark study reported in 1985 and found that women with atypical hyperplasia had a 4.4 relative risk for later invasive breast cancer.2 Other studies reported since then have consistently found a fourfold increase in relative risk. “More recent data on absolute risk from the Nashville Breast Cohort (unpublished data) and another large cohort

at the Mayo Clinic confirm the cumulative high risk of breast cancer among women with atypical hyperplasia. Specifically, 25 years after a biopsy that showed atypical hyperplasia, breast cancer (either in situ or invasive) developed in 30% of the women in the Mayo Clinic cohort. Similar updated results were obtained in the Nashville Breast Cohort, with either in situ or invasive disease developing in 27.5% of participants (unpublished data),” according to the report.

Potential Impact on Screening Guidelines These newer data show a level of risk that meets the current standard for MRI screening in guidelines for breast cancer screening for high-risk women. “Those guidelines say that a lifetime risk of 20% to 25% is a high enough risk to justify MRI for screening for breast cancer,” study coauthor Amy C. Degnim, MD, of the Department of Surgery, Mayo

Clinic, Rochester, Minnesota, told The ASCO Post. A “caveat” to those recommendations, Dr. Degnim noted, is that “women with atypical hyperplasia were not thought to have a risk high enough to warrant MRI screening. Now our data show that their breast cancer risk is high enough to justify MRI screening.” “They’ve got a legitimate point,” American Cancer Society (ACS) Chief Medical Officer Otis Brawley, MD, is quoted as saying in a Reuter’s health article3 about the report. That article also reported that Dr. Brawley said women with atypical hyperplasia probably should be getting an MRI. Currently, the ACS “recommends breast MRI as an adjunct to mammography for high-risk patients who have a lifetime risk of approximately 20% to 25% or greater,” the report authors pointed out. “It is my understanding that the American Cancer Society is going to be looking at updating those

Expect Questions About Atypical Hyperplasia as an Important Risk Factor for Breast Cancer

special report in The New England Journal of Medicine concluded that atypical hyperplasia of the breast “confers an absolute risk of later breast cancer of 30% at 25 years of follow-up.1” This is higher than previously recognized, and

Degnim said. The younger a woman is when diagnosed with atypical hyperplasia, the more likely it is that breast cancer will eventually develop over the course of her lifetime. “The data are strong enough that we can say that for any

The younger a woman is when diagnosed with atypical hyperplasia, the more likely it is that breast cancer will eventually develop over the course of her lifetime. —Amy C. Degnim, MD

the report’s authors urged “more intensive screening and prevention strategies based on accurate risk estimates.” In an interview with The ASCO Post, study coauthor Amy C. Degnim, MD, of the Department of Surgery, Mayo Clinic, Rochester, Minnesota, discussed how physicians can explain the findings to patients.

Start With the Risk Estimate “The important thing is to start with how high the patient’s risk is,” Dr.

woman who has atypical hyperplasia, whether she is younger or older, a general estimate for her risk of developing breast cancer is about 1% per year,” Dr. Degnim stated. “So if you are a younger woman, you are expected to live longer, and so you would accumulate a higher risk compared to an older woman who has only a 10-year life expectancy.” However, an individual woman’s risk estimate can be refined by knowing the number of sites (or ‘foci’) of atypical hyperplasia, with more foci adding

up to more risk. Women with three or more foci of atypical hyperplasia have “had a risk of 47% at 25 years,” Dr. Degnim said, “or about 2% per year.”

Then Look at Managing the Risk “The second point is to discuss options to manage a woman’s breast cancer risk through two different but related strategies —surveillance and prevention. Surveillance approaches include looking closer to find a cancer if it is there (ie, MRI in addition to yearly mammography) or looking more frequently (alternating mammography and MRI every 6 months). Beyond looking to find very early cancers, prevention approaches take steps to prevent breast cancers from happening.” Dr. Degnim explained that although current screening guidelines do not specifically recommend magnetic resonance imaging (MRI) for women with atypical hyperplasia of the breast, they do recommend MRI as an adjunct to mammography for women who have a lifetime risk of breast cancer of 20% to 25%. The risk for women with atypical hyperplasia meets or exceeds that level. Prevention medications involve

the use of selective estrogen-receptor modulators and aromatase inhibitors. In certain cases, bilateral mastectomy might be considered, but that is generally avoided due to long-term physical and psychological risks.

‘The Other Way Around’ “The last point is understanding that atypical hyperplasia is not breast cancer,” Dr. Degnim stressed. “Because it is not cancer, and even though the data show that 30% of women with atypical hyperplasia developed breast cancer in 25 years, you can look at it the other way around—70% of them did not.” “Even among those in whom breast cancer does develop,” the report concluded, “it can usually be treated successfully, and the diagnosis may occur at an age at which their risk of death from other causes is higher than their risk of death from breast cancer.” n

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

Reference 1. Hartmann LC, Degnim AC, Santen RJ, et al: Atypical hyperplasia of the breast—risk assessment and management options. N Engl J Med 372:78-89, 2015.

ASCOPost.com | FEBRUARY 25, 2015

PAGE 85

In the News

guidelines,” Dr. Degnim said. The American College of Radiation “cites a lifetime risk of only 15% to 20% among women with atypical hyperplasia and thus concludes that the usefulness of screening these women with MRI is ‘still in question,’” the report authors noted. The National Comprehensive Cancer

ities. “Our hope is that this report may help to drive the field to start including the number of foci as a standard part of the pathology report,” Dr. Degnim said.

To Excise or Not to Excise “If a woman has a needle biopsy and the pathologist reports one focus of atypia, that does not mean the patient

may not have more; to get that information, you would need to excise the site of atypia, get a little more tissue, and find out if it really is just one focus or more,” Dr. Degnim said. She noted that it is sometimes possible to detect multiple foci with a needle biopsy. “Generally, our standard for atypical ductal hyperplasia is to re-excise the

site surgically, because about 15% of the time, those women may actually have cancer there; in order to find that out, we have to excise it,” Dr. Degnim said. If excision revealed more sites of atypical hyperplasia, that “would help us to estimate how high the woman’s breast cancer risk is for the long term,” she added. continued on page 86

JCO: Otis Brawley, MD

Network (NCCN) recommends annual MRI screening “for women with a lifetime risk greater than 20%, as defined by models that are dependent largely on family history,” the authors added, but “for women with atypical hyperplasia specifically, they state that there is insufficient evidence to make recommendations for or against MRI screening.”

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‘Scientifically Justified’ Whether or not guidelines are revised to incorporate a recommendation to use MRI to screen women diagnosed with atypical hyperplasia, “physicians should be discussing it with their patients as a possibility,” Dr. Degnim advised. “If a woman feels that her risk is high enough and she is interested in pursuing MRI, I think that based on our study, there is a very strong case to argue that it is scientifically justified.”

Further Stratification of Risk Existing risk prediction models, such as the Breast Cancer Risk Assessment Tool (BCRAT) and the International Breast Cancer Intervention Study (IBIS) model, perform poorly among women with atypical hyperplasia, according to the report. The authors advised using instead cumulative risk data to counsel women about their risk for breast cancer. Knowing the number of foci of atypical hyperplasia can further stratify the risk. “We found that for women who had three or more foci of atypical hyperplasia, at 25 years, their risk was 47%, so almost 50%, or about a 2% risk per year,” Dr. Degnim said. The number of foci is not always known; it “has not been a standard item found in pathology reports,” Dr. Degnim noted. “The current expectation,” she said, is that the pathologist’s report would include whether or not there is atypical hyperplasia or other abnormal-

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The ASCO Post | FEBRUARY 25, 2015

PAGE 86

In the News Atypical Hyperplasia continued from page 85

“For the lobular type of atypical hyperplasia, more recent data indicate that it may not need to be excised surgically. When atypical lobular hyperplasia is found on a needle biopsy, as long as the findings are all concordant—what is on the mammogram looks consistent with atypical lobular hyperplasia, does not look worrisome for a cancer—it is safe not to excise that surgically and just to follow it,” Dr. Degnim said. “It might be the case that there is one focus of atypical lobular hyperplasia on a core biopsy, and we think there is a low risk of cancer, so the patient does not have it surgically excised. She may have more foci of atypical lobular hyperplasia there, which would help us to predict her breast cancer risk long term. But then you have to weigh that balance: Is it worth doing an operation just to get that information? Currently, probably we would say no. But that would be something to discuss with individual patients. Then it could be handled based on their priorities. If it is very important for them to have that additional information, a surgical biopsy could be done.”

Prophylactic Mastectomy Not Generally Indicated Atypical hyperplasia is “generally not an indication” for prophylactic mastectomy, according to the report. “Ultimately, it is really a matter of a woman’s choice,” Dr. Degnim stressed. “However,

we would favor other approaches, such as prevention medications and MRI screening rather than mastectomy. The potential psychological effects, as well as the physical effects—how mastectomies change a woman’s body and what impact that will have on her—can be serious. Because prophylactic mastectomy “is an irrevocable step,” before we would do that, there would be thorough counseling and time for consideration of that decision,” Dr. Degnim said. “This is why it is important to be able to estimate breast cancer risk for each individual woman with atypical hyperplasia. Although the majority of all women with atypical hyperplasia do not get breast cancer, the risk is quite high in some individuals. At 25 years, the risk of breast cancer for women with three or more foci of atypical hyperplasia was 47%. For women with BRCA mutations, the risk was generally quoted as between 50% and 80%,” Dr. Degnim said. “Not all women with atypical hyperplasia appear to have the same level of risk, but for some women who might be in that high-risk group of three or more foci of atypia, their risk level appears to be similar to that of a BRCA carrier. And bilateral mastectomy is considered for women who have a risk that high. So it is a possibility,” Dr. Degnim said, although chemoprevention is usually favored over prophylactic mastectomy.

Chemoprevention Medications Several statements in the special report support the use of selective estrogen-receptor modulators and aroma-

tase inhibitors to prevent breast cancer in women with atypical hyperplasia. They include reported results from several large breast cancer chemoprevention trials, as well as subgroup analyses showing relative risk reductions ranging from 41% to 79%, “which suggested an even greater benefit than in the total population treated with active agents in those trials,” the authors noted. “The high level of estrogen-receptor expression in the large majority of breast cancers that develop in women with atypical hyperplasia provide an additional rationale for the use of antiestrogen therapy for prevention,” the authors added. With a cumulative risk of approximately 1% per year, women with atypical hyperplasia “clearly meet” the ASCO guideline, stating “that for women with a 5-year projected absolute risk of breast cancer of 1.7% or higher, the use of a chemopreventive agent should be discussed,” the authors pointed out.

Infrequently Prescribed, Infrequently Used Chemopreventive agents, however, “are infrequently prescribed and infrequently used,” according to the report. One of the reasons cited for infrequent prescribing is that “physicians feel insufficiently informed about these agents.” “That’s a big challenge,” Dr. Degnim noted, adding that education is a key step in meeting that challenge. “We are hoping that publishing this article will help to raise awareness and better inform providers.” Challenges for patients often in-

volve the perception of side effects. Although some side effects do occur, they occur much less frequently than most women think. Side effects include venous thromboembolism associated with all selective estrogenreceptor modulators, an increased risk of endometrial cancer associated with tamoxifen (but not other selective estrogen-receptor modulators), and vasomotor symptoms in many women taking selective estrogen-receptor modulators or aromatase inhibitors. “We hope that having more accurate assessment of an individual woman’s risk will help patients to benefit from prevention medications,” Dr. Degnim said. Knowing that their risk approaches 30% at 25 years “may motivate them more strongly to stay on their risk-reduction medication.” n

Disclosure: Dr. Degnim reported no potental conflicts of interest.

References 1. Hartmann LC, Degnim AC, Santen RJ, et al: Atypical hyperplasia of the breast—risk assessment and management options. N Engl J Med 372:78-89, 2015. 2. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146151, 1985. 3. Emery G: Suspicious breast mass may pose greater risk than previously thought. Reuters January 1, 2015. Available at http://in.reuters.com/article/2014/12/31/us-breast-biopsycancer-risk-idINKBN0K918A20141231. Accessed February 6, 2015.

Visit The ASCO Post Newsreels at ASCOPost.com For important news and interviews with experts filmed live during the 2014 ASH Annual Congress in San Francisco and the San Antonio Breast Cancer Symposium, visit www.ASCOPost.com and select the “Newsreels” tab. Video interviews include but are not limited to: From ASH Richard M. Stone, MD, on the SAL-SORAML Trial and the UK NCRI AML 17 Trial Linda J. Burns, MD, on the BLAST Study and CAR T-cell Therapy in ALL Bertrand Coiffier, MD, PhD, on the RO-CHOP Study Alan F. List, MD, on Rigosertib in Relapsed/Refractory Higher-Risk Myelodysplastic Syndrome Julie M. Vose, MD, MBA, FASCO, on the AETHERA trial Hagop Kantarjian, MD, on Treating Philadelphia Chromosome–Positive ALL Keith McCrae, MD, on Managing Heparin-Induced Thrombocytopenia

From SABCS Lisa A. Carey, MD, on Pembrolizumab in Advanced Triple-Negative Breast Cancer William M. Sikov, MD, on the CALGB 40603 Trial Jack Cuzick, PhD, on the IBIS-I Trial Gunter von Minckwitz, MD, on the Phase III ICE Trial Matthew J. Ellis, MD, on Endocrine Therapy–Resistant Breast Cancer Jame Abraham, MD, FACP, on Immunotherapy in Triple-Negative Breast Cancer Prudence Francis, MD, and Hope Rugo, MD, on the Phase III SOFT Trial Clifford A. Hudis, MD, FACP, on Enzalutamide in Androgen Receptor–Positive, Triple-Negative Breast Cancer

ASCOPost.com | FEBRUARY 25, 2015

PAGE 87

Announcements

ASCO to Launch Journal of Global Oncology, Names Founding Editor-in-Chief

SCO has announced the appointment of David Kerr, MD, DSc, as founding Editor-in-Chief of the Society’s new Journal of Global Oncology (JGO). Dr. Kerr will set the editorial scope and vision for JGO, an onlineonly, open-access journal, which will focus on cancer care, research, and care-delivery issues unique to countries and settings with limited healthcare resources. It is estimated that today nearly twothirds of all cancer deaths occur in lowand middle-income countries, and this

Oxford Cancer Foundation and has fostered international collaborations with organizations around the world that share the goal of improving cancer research and care. He has published countless peer-reviewed articles and has served on the editorial boards of

several prestigious oncology journals, including the Annals of Oncology (former Editor-in-Chief). “There is a growing need for highquality clinical cancer research in lowand middle-income countries, and I am honored to support the Society’s vision

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ADVANCING THE STANDARD OF CANCER CARE TM

March 12 – 14, 2015 • The Diplomat • Hollywood, Florida

David Kerr, MD, DSc

is forecast to increase to 70% by 2030. While some journals publish special issues and sections focused on global oncology, currently there are no journals solely dedicated to this area of research. The inaugural issue of JGO will publish later this year and feature high-quality original research, editorials, and other articles that address the unique challenges of cancer care in low- and middle-income countries.

‘A Peer-Reviewed Platform’ “The Journal of Global Oncology will fulfill a growing need in clinical oncology literature, by providing a peer-review platform for authors to publish research on the array of challenges that low- and middle-income countries face in conducting research and caring for patients with cancer,” said ASCO President Peter Paul Yu, MD, FASCO. “Dr. Kerr’s distinguished oncology career and expertise in the international research community are valuable assets to this exciting new project, and we are thrilled to have his leadership to help guide the journal’s launch.” Dr. Kerr is Professor of Cancer Medicine at the University of Oxford, Honorary Consultant Medical Oncologist at Oxford University Hospitals Trust, and Adjunct Professor of Medicine at Weill Cornell Medical College. He is a past President of the European Society of Medical Oncology and has served on numerous medical society international committees and working groups. Dr. Kerr cofounded the Africa

to help improve cancer care and delivery in these areas,” said Dr. Kerr. The Journal of Global Oncology is funded through the Conquer Cancer Foundation of ASCO, with the support of the Doris Duke Charitable Foundation and Novartis Oncology. n

NCCN celebrates 20 years!

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Commemorative Events: Thursday, March 12, 2015 • Keynote Address: 20 Years of Improving the Quality, Effectiveness, and Efficiency of Cancer Care CME/CE credits are not available for this session.

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• 20 Years of Improving Cancer Care Together— An NCCN Roundtable Discussion CME/CE credits are not available for this session.

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• Welcome Reception (Exhibition Hall) Join NCCN for a reception in celebration of our 20th Anniversary.

New for 2015! Customize your learning with Track Sessions throughout the conference.

Track Session Topics: Breast Cancer Lung Cancer Hematologic Malignancies

Friday, March 13, 2015 • Roundtable: Value-Based Decision-Making at the Bedside Moderator: Clifford Goodman, PhD, The Lewin Group

Skin Cancer Gastrointestinal Cancer

Saturday, March 14, 2015

Genitourinary Cancer

• Roundtable: What are the Characteristics of an Optimal Clinical Practice Guideline?

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Moderator: F. Marc Stewart, MD, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance

Visit NCCN.org/AC2015 to register

or to view more information for this educational program. JNCCN-N-0203-0215

The ASCO Post | FEBRUARY 25, 2015

PAGE 88

Letters to the Editor

More on Ramucirumab in Metastatic Colorectal Cancer

am writing in regard to the report and commentary in this issue on the RAISE Trial (see pages 1, 4, and 5). To begin, a discussion of this phase III clinical trial presented at the 2015 Gastrointestinal Cancers Symposium (RAISE study) may not be the most appropriate forum to air legitimate views on finances and operating business practices of the drug industry. Although this is a bigger societal, governmental, and professional practice issue, one must be careful not to overlook the fact that in this well‐conducted trial of more than 1,000 patients, ramucirumab (Cyramza) was shown to be an active agent that prolonged patient survival of patients with metastatic colorectal cancer in second-line therapy. However, this also may not have been the best forum to establish appropriate clinical use of an unapproved drug. It is important to remember that, as Dr. Tabernero mentioned (see page 1), studies are needed to establish through available tools (genomic, proteomic, etc) which subpopulations of patients were most likely to benefit on the RAISE trial and other ongoing trials. That said, I do agree with Dr. Saltz that since ramucirumab has been approved by the U.S. Food and Drug Administration for other indications, there is perhaps some more merit in this situation to ask the question about the appropriateness of its use outside of a clinical trial in colorectal cancer. Although I said at the meeting that ramucirumab should be used only in the context of a clinical trial, I do think it was probably going too far to say it would be irresponsible to use it off-label, ever. Historically, clinicians have used approved agents off‐label when patients had no better options, and so would it be completely irrational, inappropriate (or irresponsible) to use the drug in any situation off-label outside of a clinical trial in

colorectal cancer? We need to be openminded and not categorically exclude the possibility, as there is probably a chance that the drug may extend survival in a specific patient who may have already been exposed to the approved antiangiogenic agents. In my own practice, I have seen disease control more than I would have expected, for example, from aflibercept in patients who were previously exposed to bevacizumab (Avastin), including beyond disease progression. Can we define precisely who is likely to benefit today as someone who does not have similar or better options? I think the answer is no. Should we make it virtually impossible (or frowned upon or possibly looked at as unethical) to use a drug such as ramucirumab in patients who may have no better option given their treatment history and in the judgment of their treating physician? I think the answer there should also be no. After all, we just learned it is an active drug when added to FOLFIRI (leucovorin, fluorouracil, irinotecan) in a large randomized phase III study vs placebo added to FOLFIRI, and it hasn’t yet been compared with other antiangiogenic options in randomized trials, as was noted. In the era of personalized medicine, where we must acknowledge a lack of sufficient knowledge in many situations regarding responders vs nonresponders or outliers who may have dramatic responses, it should still be acceptable for treating physicians to consider all available options, discuss these options with their patients, make informed decisions, and hopefully report on their positive experiences. Low-level evidence but evidence nonetheless may be helpful to others. n —Wafik S. El-Deiry, MD, PhD, FACP Fox Chase Cancer Center Philadelphia, Pennsylvania

Glioblastoma Clinical Trials

am writing in regard to the recent installment to “Clinical Trials” on Glioblastoma published in The ASCO Post (February 10, 2015, pages 6971). As a principal investigator, I’d also like to call attention to the following glioblastoma trial, which remains open.

PHASE II Study Type: Phase I/II/interventional/single-group assignment Study Title: Phase I/II Prospective Trial for Newly Diagnosed GBM, With Upfront Gross or Subtotal Resection, Followed by Ketogenic Diet With Radiotherapy and Concurrent Temodar Chemotherapy Followed by Adjuvant Temodar Chemotherapy. Study Sponsor and Collaborators: St. Joseph’s Hospital and Medical Center, Phoenix Purpose: To determine if reducing blood sugar and increasing ketones can increase survival and enhance the effects of standard radiation and chemotherapy treatments in newly diagnosed glioblastoma multiforme. Ages Eligible for Study: 18 years

and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of participants with adverse events, (time frame: 8 weeks) Principal Investigator: Adrienne C Scheck, PhD, Barrow Neurological Institute at St. Joseph’s Hospital and Medical Center; adrienne.scheck@ dignityhealth.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02046187 n —Adrienne C. Scheck, PhD Barrow Brain Tumor Research Center Phoenix, Arizona Editor’s note: On an occasional basis, The ASCO Post publishes listings of NCI-supported clinical trials on various tumor types. This list of clinical trials is compiled from information available on ClinicalTrials.gov. It is not meant to be all inclusive, but rather to provide an overview of NCI-funded clinical trials open for recruitment. We invite readers to share information about ongoing NCI-funded clinical trials.