TAP Vol 6 Issue 11 by Harborside Press LLC

Hematologic Disease 3, 20 | Prostate Cancer

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| Ovarian Cancer Risk

| Redefining Cancer

VOLUME 6, ISSUE 11

JUNE 25, 2015

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

ASCO Plenary Presentation

Elective Neck Dissection Beats Watch and Wait Approach in Early Oral Cancer

Considering Clonality in Precision Medicine

By Alice Goodman

By Michael Green, PhD

lective neck dissection of node-negative earlystage oral cancer at the time of primary surgery improves overall survival and disease-free survival compared with therapeutic neck dissection (ie, therapeutic neck dissection at the time of nodal relapse, or “watch and wait” approach), according to a major phase III randomized trial presented at the Plenary Session of the 2015 Annual Meeting of ASCO1 and published in The New England Journal of Medicine to coincide with this presentation.2 Elective neck dissection improved overall survival by 12.5%, reduced the risk of death by 36%, and reduced the risk of recurrence by 55% compared with therapeutic neck dissection (watch and wait approach) in the first 500 patients randomized to this trial. “Our conclusions are that elective neck dissection should be the standard of care for early node-negative squamous cell oral cancer. For every eight patients treated with elective neck dissection, one death is pre-

vented, and for every four patients treated with elective neck dissection, one recurrence is prevented,” stated lead author Anil K. D’Cruz, MBBS, MS, FRCS, Director, Tata Memorial Center, Head and Neck Services, Mumbai, India.

‘One and Done’

P ©ASCO/Scott Morgan

Anil K. D’Cruz, MBBS, MS, FRCS

“This study will affect the lives of over 300,000 people globally. The study shows that the ‘one and done’ surgical approach definitely improves survival compared with ‘watch and wait,’” stated Jyoti Patel, MD, ASCO expert, at an official press conference where these data were presented. “We never want to do more surgery than we have to, but for patients with continued on page 12

Expert’s Corner

ASCO Releases Details of Its Conceptual Framework for Assessing Value in Cancer Care A Conversation With Lowell E. Schnipper, MD By Jo Cavallo

efining and ensuring the delivery of high-value oncology care has been one of ASCO’s major goals for more than a decade. In 2007, ASCO formed the Task Force on the Cost of Cancer Care, now called the Value in Cancer Care Task Force, to identify the drivers of the increasing costs of oncology care (which are estimated to be rising from

$125 billion in 2010 to $158 billion in 2020).1 The Task Force was also charged with developing policy positions to ensure greater access to high-quality care, educating oncologists about the importance of discussing the cost of recommended treatments, and empowering patients to ask questions about the potential costs of their treatment options. Five years later, in response to the ChoosThe framework is meant to provide ing Wisely® campaign launched by the American a standardized approach to assist Board of Internal Mediphysicians and patients in assessing cine Foundation, ASCO identified five common the value of a new drug treatment clinical practices that were based on efficacy, toxicity, and cost not supported by scientific evidence to have clinical compared with the standard of care. value and that c ontributed —Lowell E. Schnipper, MD

recision cancer medicine entails treating patients based upon the molecular characteristics of their tumor. One could argue that we have been tailoring therapeutic regimens based upon tumor characteristics for years, whether it be treating patients based upon disease subtypes determined by histology or assessing markers by immunohistochemistry. However, precision medicine implies that therapeutics are directed precisely toward the identified molecular defect.

Mixed Success The first example of precision medicine in oncology is the use of imatinib to treat chronic continued on page 56

Dr. Green is Associate Professor at Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center in Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO Annual Meeting Multiple Myeloma �� 3 Breast Cancer �� 4–8 Melanoma �� 9 Sarcoma �� 14 Venous Thromboembolism �� 17 Chronic Lymphocytic Leukemia ��20 Prostate Cancer ��23 Direct From ASCO �� 26–29 Precision Oncology Care ��34 Clinical Trials �� 44 ASCO 2015 in Pictures ��58

continued on page 42

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A Harborside Press® Publication

The ASCO Post | JUNE 25, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Syed Abutalib, MD Cancer Treatment Centers of America

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

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

Chandrakanth Are, MD University of Nebraska Medical Center

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

Joseph S. Bailes, MD Texas Oncology

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

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

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

Jamie Von Roenn, MD American Society of Clinical Oncology Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

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

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

Rakesh Chopra, MD Artemis Healthsciences Institute Gurgaon, Haryana, India

Philip D. Bonomi, MD Rush University Medical Center

Stuart Lichtman, MD Memorial Sloan-Kettering Cancer Center Commack, New York

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

Richard Boxer, MD University of Wisconsin School of Medicine

Michael P. Link, MD Stanford University Medical Center

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Douglas W. Blayney, MD Stanford University Medical Center

Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2015 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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

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

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James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD City of Hope National Medical Center Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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PAGE 3

ASCO Annual Meeting Hematology

Single-Agent Daratumumab Activity Deemed ‘Remarkable’ in Refractory Multiple Myeloma By Caroline Helwick

eavily pretreated patients with multiple myeloma achieved rapid, durable, and deepening responses to the anti-CD38 monoclonal antibody daratumumab, in a phase II study presented at the 2015 ASCO Annual Meeting.1 “Daratumumab showed remarkable single-agent activity in heavily pretreated and refractory multiple myeloma patients who had exhausted other therapeutic options,” reported Sagar Lonial, MD, of Winship Cancer Institute of Emory University in Atlanta. “Based on these data, daratumumab represents a new standard of care for patients in the relapsed/refractory myeloma setting.” Daratumumab is a fully human monoclonal antibody that binds to CD38, a protein that is “highly expressed” on the surface of myeloma cells. This expression makes CD38 a “unique and potentially important target” in this disease, Dr. Lonial explained.

Based on these data, daratumumab represents a new standard of care for patients in the relapsed/refractory myeloma setting. —Sagar Lonial, MD

Response rates to single-agent daratumumab (16 mg/kg) reached 35% in the earlier GEN501 first-in-human study, and no maximum tolerated dose was demonstrated.2 “Based on this very exciting preliminary data,” Dr. Lonial noted, “the [U.S. Food and Drug Administration] FDA granted breakthrough designation for daratumumab in 2013, early on in its development.” The current MMY2002 SIRIUS trial enrolled patients with at least three

prior lines of therapy or with disease refractory to both a proteasome inhibitor and an immunomodulatory drug. To be eligible for the study, patients were required to have an absolute neutrophil count > 1 × 109/L, hemoglobin > 7.5 g/dL, platelet count ≥ 50 × 109/L, and creatinine clearance > 20 mL/min/1.73 m2. The objective response rate was the primary endpoint. Dr. Lonial called attention to these eligibility criteria. “Remember that

most early-phase clinical trials have much more stringent entry criteria. So this potentially speaks to the safety of giving immunotherapy or monoclonal antibody–based therapy in the context of relapsed disease.”

Challenging Treatment Population Investigators evaluated two dose schedules and established the recommended dose as 16 mg/kg every week for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter. Dr. Lonial reported the results for the 106 patients treated with this schedule. Patients had a median of five prior lines of therapy and a median time from diagnosis of about 5 years. Twenty percent had high-risk genetic profiles. He noted that baseline characteristics are important for the interpretation of continued on page 4

EXPERT POINT OF VIEW

uzanne Lentzsch, MD, PhD, Director of the Multiple Myeloma and Amyloidosis Program, Columbia University College of Physicians and Surgeons and New York Presbyterian

is that responses were rapid and improved over time,” she commented. Dr. Lentzsch compared the singleagent activity of daratumumab with that seen with other antibodies. In a

We see dramatic increases in response to monoclonal antibodies when these drugs are combined with immunomodulatory drugs, so I think, based on these data, monoclonal antibodies will be the backbone of myeloma treatments in the future. —Suzanne Lentzsch, MD, PhD

Hospital, served as the study’s discussant. She called the 29% response rate in this heavily pretreated or refractory population “quite remarkable” and emphasized that a subset achieved stringent complete responses and very good partial responses. “The drug is quite active in patients with heavily pretreated myeloma, including 95% who were double-refractory. What’s also important, and I have seen this in my own patients,

phase Ib study of heavily pretreated patients, SAR650984 (10 mg/kg) produced responses in 33%, including 11% complete responses.1 In contrast, elotuzumab, as a single agent, produced no responses, but 26.5% achieved stable disease.2

Monoclonal Antibodies in Combination When these monoclonal antibodies were combined with lenalidomide

(Revlimid) and dexamethasone, however, response rates increased for all drugs. With daratumumab/ lenalidomide/dexamethasone, the response rate was increased to 87%, with 50% ≥ very good partial responses, in a study presented at the 2014 ASH Annual Meeting and Exposition.3 “I think that’s remarkable, and responses increased and deepened over time,” she noted. With SAR650984 plus lenalidomide/dexamethasone, responses increased to 63%,4 and with elotuzumab/lenalidomide/dexamethasone, 92% of patients responded.5 She concluded, “We see dramatic increases in response to monoclonal antibodies when these drugs are combined with immunomodulatory drugs, so I think, based on these data, monoclonal antibodies will be the backbone of myeloma treatments in the future,… and I think it’s time for an R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] in myeloma!” n Disclosure: Dr. Lentzsch is on the advisory board of Celgene, Bristol-Myers Squibb, and Janssen and has received a research grant from Celgene.

References 1. Martin TG, Hsu K, Strickland SA, et al: A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8532. 2. Zonder JA, Mohrbacher AF, Singhal S, et al: A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120:552-559, 2012. 3. Plesner T, Arkenau H-T, Lokhorst H, et al: Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 84. 4. Martin TG, Baz R, Benson DM, et al: A phase 1b dose escalation trial of SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 83. 5. Richardson PG, Jagannath S, Moreau P, et al: Final results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/ refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 302.

The ASCO Post | JUNE 25, 2015

PAGE 4

ASCO Annual Meeting Breast Cancer

Palbociclib Slows Progression of Hormone Receptor–Positive Breast Cancer By Caroline Helwick

he oral CDK4/6 inhibitor palbociclib (Ibrance), combined with fulvestrant (Faslodex), more than doubled the duration of remission in a cohort of premenopausal and postmenopausal patients with advanced hormone receptor–positive, HER2negative breast cancer, investigators reported at the 2015 ASCO Annual Meeting.1 The findings were concurrently published in The New England Journal of Medicine.2

medical oncologist at The Royal Marsden in London. “This phase III trial identifies and confirms CDK4/6 as a key target for hormone receptor–positive breast cancer,” Dr. Turner commented at a press briefing. He said the growth of hormone receptor–positive breast cancer relies on cyclin-dependent kinases 4 and 6 (CDK4, CDK6), which promote progression from the G1 phase to the S

Palbociclib more than doubled the progression-free survival in this study, but importantly, it was very well tolerated. Very few patients had to stop because of side effects, and that will be key as palbociclib moves forward. —Nicholas C. Turner, MD

Compared with endocrine therapy alone, palbociclib increased progressionfree survival by more than 5 months in the phase III PALOMA3 trial, reported Nicholas C. Turner, MD, consultant

phase of the cell cycle. Targeting of CDK4/6 may represent a therapeutic strategy across a variety of mechanisms of acquired resistance to endocrine therapy, he explained.

Daratumumab in Myeloma

“What’s striking about this is not just that one in three patients with refractory, almost end-stage myeloma, had responses, but that we actually saw stringent complete responses and very good partial responses after a median of five prior lines of therapy,” Dr. Lonial pointed out. “It’s not only a testament to the activity of the agent but a testament to the concept that this novel mechanism of action may be important.” He predicted, “Depth of response may actually translate into overall survival. Follow-up is short, but we had hints of that.” Over a median follow-up of 9.3 months, initial responses deepened with continued daratumumab treatment in many patients. The median time to response was 1 month, and the median duration of response was 7.4 months.

continued from page 3

the response data. Of the 106 patients, 97% were refractory to their last line of treatment, 95% were double-refractory, and 66% were refractory to “three of the big four drugs” commonly used in myeloma: bortezomib [Velcade], lenalidomide [Revlimid], carfilzomib [Kyprolis], and pomalidomide [Pomalyst].”

Positive Outcomes The majority of patients had reductions in paraprotein, from baseline, including 39% with reductions > 50% and 16% with reductions > 90%. The overall response rate was 29%, including 3% stringent complete responses, 9% very good partial responses, and 17% partial responses. The clinical benefit rate was 34%.

Daratumumab in Refractory Multiple Myeloma ■■ The monoclonal antibody daratumumab produced high response rates, including some stringent complete responses, in heavily pretreated or refractory patients with multiple myeloma, in the phase II SIRIUS trial. ■■ The overall response rate was 29%, and many patients’ responses deepened over time. ■■ The estimated 1-year survival was 65%.

PALOMA3 Results on Palbociclib ■■ The oral CDK4/5 inhibitor palbociclib, when combined with fulvestrant, significantly prolonged disease control in hormone receptor–positive women with advanced breast cancer. ■■ Median progression-free survival was 9.2 months in the palbociclib/ fulvestrant arm and 3.8 months with fulvestrant alone, a 58% reduction in the risk of progression (P < .000001). ■■ Treatment was well tolerated.

PALOMA3 Details PALOMA3 enrolled 521 premenopausal or postmenopausal women who had progressed on prior endocrine therapy and had no more than one prior treatment for advanced cancer. They were randomized 2:1 to the combination arm (n = 347), which was palbociclib (125 mg/d for 3 weeks on, 1 week off) plus fulvestrant (500 mg) every 4 weeks, or fulvestrant plus placebo (n = 174). The primary endpoint was investigator-assessed progressionfree survival. At the time of the preplanned interim analysis, median progression-free survival was 9.2 months in the palbociclib/ fulvestrant arm and 3.8 months in the “Responses do occur quickly, and they can continue to deepen over time with additional treatment and subsequent follow-up,” Dr. Lonial said. By subgroup, response rates were consistent across the board, whether by age (including patients ≥ 75 years), creatinine clearance, lines of prior therapy, and even presence of extramedullary disease, he emphasized. Median progression-free survival was 3.7 months. Median overall survival was not yet reached, and estimated 1-year overall survival was 65%. Importantly, he added, 29 of 31 responders were still alive at data cutoff ( January 2015). Dr. Lonial noted that, in other datasets of double-refractory patients, median overall survival has been around 9 months. In this study, in comparison, many subjects were triple-refractory, and their estimated 1-year survival was 65%.

Good Tolerability Grade ≥ 3 treatment-emergent adverse events were observed in 30% of patients, primarily anemia (24%), thrombocytopenia (17%), neutropenia (11%), fatigue (3%), and back

placebo arm, producing a highly significant hazard ratio of 0.422 (P < .000001). The most common adverse events for the combination vs fulvestrant alone were neutropenia (any grade, 79% vs 3%) and leukopenia (any grade, 46% vs 4%). The incidence of febrile neutropenia was low in both arms (0.6%). The rate of treatment discontinuation due to adverse events was 2.6% and 1.7%, respectively. “There were frequent hematologic side effects, but the incidence of febrile neutropenia was very low. Symptomatic adverse events with palbociclib were largely similar to placebo. We saw small increases in fatigue, alopecia, and infections,” he said. continued on page 6

pain (3%). Most of the grade 3 anemia and thrombocytopenia occurred in nonresponders, who had poor hematologic reserve at baseline. Among responders, the incidence of grade 3 neutropenia was not high at all, and no patients developed febrile neutropenia, he added. Infusion-related reactions, unique to the delivery of monoclonal antibodies, occurred in 43% of patients and were predominantly grades 1 and 2. All but 10% were observed during the first infusion, and only 7% had subsequent infusion reactions. n

Disclosure: Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen.

References 1. Lonial S, Weiss BM, Usmani SZ, et al: Phase II study of daratumumab monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma: 54767414MMY2002 (Sirius). 2015 ASCO Annual Meeting. Abstract LBA8512. Presented June 2, 2015. 2. Lokhorst HM, Laubach J, Nahi H, et al: Dose-dependent efficacy of daratumumab as monotherapy in patients with relapsed or refractory multiple myeloma. ASCO 2014 Annual Meeting. Abstract 8513.

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The ASCO Post | JUNE 25, 2015

PAGE 6

ASCO Annual Meeting Palbociclib in Breast Cancer

EXPERT POINT OF VIEW

continued from page 4

He added, “We had a careful management plan for neutropenia that allowed many patients to stay on palbociclib 125 mg,” although he acknowledged 30% of patients required dose reductions.

oseph A. Sparano, MD, Professor of Medicine and Women’s Health at the Albert Einstein College

Further Discussion Asked by The ASCO Post how this doublet compares with everolimus (Afinitor) plus exemestane, Dr. Turner commented, “Palbociclib more than doubled the progression-free survival in this study, but importantly, it was very well tolerated. Very few patients had to stop because of side effects, and that will be key as palbociclib moves forward.” He also explained the choice of fulvestrant as the endocrine therapy. “We are identifying in hormone receptor– positive breast cancer that CDK4/6 is a key gene allowing these cancers to proliferate. This study confirms that as breast cancers become resistant to endocrine therapy, CDK4/6 is still a target, and palbociclib is still very active. It’s a standard hormone therapy and is likely the most active one…. We have significant laboratory data showing synergy between palbociclib and fulvestrant in two cell line models of endocrine resistance.” Angelo Di Leo, MD, principal investigator of the CONFIRM trial3 (which evaluated two different doses of fulvestrant in progressive disease), asked Dr. Turner to explain “the modest performance” of fulvestrant in the control arm (3.8 months). He noted that in CONFIRM, the 500-mg dose of fulvestrant yielded a median progression-free survival of 6.5 months, “despite the fact that in CONFIRM, the proportion of

subgroups that did not derive benefit, with the possible exception of patients who had a short disease-free interval.”

These findings confirm the strong signal observed in the phase II PALOMA1 trial, and there were no subgroups that did not derive benefit, with the possible exception of patients who had a short diseasefree interval. —Joseph A. Sparano, MD

of Medicine, New York, was the formal discussant of the study and commented, “These findings confirm the strong signal observed in the phase II PALOMA1 trial, and there were no patients with primary resistance to endocrine therapy was higher than here.” Dr. Turner responded that t he population of PALOMA3 was more heavily pretreated and at higher risk, which likely explains the lower progressionfree survival. He further pointed out that the benefit was similar to that observed with exemestane in BOLERO-2 (2.8 months).4 “We believe the progression-free survival we are seeing with fulvestrant reflects the reality of single-agent endocrine therapy in heavily pretreated patients,” he said. n

He offered that CDK4/6 inhibitors, a number of which are in development (including ribociclib and abemaciclib), represent an important treatment advance in estrogen Disclosure: The study was funded by Pfizer. Drs. Turner and Di Leo reported no potential conflicts of interest.

References 1. Turner NC, Ro J, Andre F, et al: PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2negative metastatic breast cancer that progressed on prior endocrine therapy. 2015 ASCO Annual Meeting. Abstract LBA502. Presented June 1, 2015. 2. Turner NC, Ro J, André F, et al: Pal-

receptor–positive metastatic breast cancer. “This represents an entirely new treatment modality,” he said. He also described several large trials in various settings that will further elucidate the role of palbociclib (Ibrance) in this disease. Adding commentary at the press briefing was Don Dizon, MD, designated ASCO expert and Clinical CoDirector of Gynecologic Oncology at Massachusetts General Hospital, Boston, who offered, “These results are incredibly important for hormone receptor–positive advanced or metastatic breast cancer patients. They present a new option for progressive disease. We now await the follow-up for overall survival and quality-of-life data.” n Disclosure: Drs. Sparano and Dizon reported no potential conflicts of interest.

bociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. June 1, 2015 (early release online). 3. Di Leo, A, Jerusalem G, Petruzelka L, et al: Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 28:4594-4600, 2010. 4. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520529, 2012.

2015 Class of Fellows of the American Society of Clinical Oncology (FASCO)

Erratum

he May 25 issue of The ASCO Post included a report presented at ASCO’s Annual Meeting on a study by Andrew James Martin, MD, of the NHMRC Clinical Trials Centre at the University of Sydney. The accompanying photo for Dr. Martin was incorrect. The correct photo is shown here. We apologize for this error. To view the full report “Simple Means of Preventing Nonmelanoma Skin Cancer Reported,” visit http://bit.ly/1dDT1Z8. For more on the study and to

Andrew James Martin, MD

view an interview with Dr. Martin conducted live during the ASCO Annual Meeting, visit http://video. ascopost.com/. n

The 2015 Class of Fellows of ASCO (FASCO) were inducted during the Annual Meeting. (left to right): Roscoe Morton, MD, FACP, FASCO; Kathy Albain, MD, FACP, FASCO; Craig Earle, MD, FASCO; Lori Pierce, MD, FASTRO, FASCO; Lillian Siu, MD, FRCPC, FASCO; Eric Small, MD, FASCO; Sandra M. Swain, MD, FACP, FASCO Photo by © ASCO/Scott Morgan 2015.

ASCOPost.com | JUNE 25, 2015

PAGE 7

ASCO Annual Meeting Breast Cancer

Routine Resection of Cavity Shave Margins Halved Reexcision Rates in Breast Cancer By Alice Goodman

aking additional tissue circumferentially around the cavity left by partial mastectomy (“cavity shave margins”) cut the rate of positive margins by nearly 50% and the rate of reexcision for margin clearance by more than 50% compared with standard partial mastectomy with or without the surgeon taking selective margins in suspicious areas of the cavity left by removing the tumor, according to a prospective randomized trial of women with stage 0 to III breast cancer.1 The study was presented at the 2015 ASCO Annual Meeting and published in The New England Journal of Medicine to coincide with the ASCO presentation.2 “Performing cavity shave margins on all patients undergoing standard partial mastectomy can cut the need for additional surgery by 50%, which has huge consequences for patients and for the

This is the first prospective randomized controlled trial [of this approach], and it provides level 1 evidence that cavity shave margins reduce the rate of positive margins and the need for reexcision by 50%. I believe it is practice-changing. —Anees B. Chagpar, MD, MPH

health-care system,” stated lead author Anees B. Chagpar, MD, MPH, Director of the Breast Center at Yale University’s Smilow Hospital, New Haven, Connecticut. “Cavity shave margins will spare patients the trauma of unnecessary surgery and allow them to start curative treatment more quickly, rather than delay the time until they can be treated with chemotherapy and radiation,” she continued. “This is the first prospec-

tive randomized controlled trial [of this approach], and it provides level 1 evidence that cavity shave margins reduce the rate of positive margins and the

need for reexcision by 50%. I believe it is practice-changing.” The study also found no difference in women’s perception of cosmesis

whether they were randomly assigned to shaved margins or selective margins. Interestingly, routine cavity shaving encontinued on page 8

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The ASCO Post | JUNE 25, 2015

PAGE 8

ASCO Annual Meeting Cavity Shave Margins continued from page 7

abled identification of cancer in 12% of patients previously deemed to have negative margins. “This calls into question the accuracy of margin status in predicting residual disease. Our study, and other studies, have shown that some patients with negative margins have multifocal disease detected only after cavity shaving,” Dr. Chagpar said. “Although the argument could be made that finding additional occult disease may not affect outcome, excising additional disease in more than 10% of patients may have a significant longterm effect on the rate of local recurrence,” she added. Partial mastectomy is commonly performed for women diagnosed with breast cancer, and margin status is a determinant of recurrence. About 20% to 40% of women have positive margins following partial mastectomy that require a reexcision for margin clearance. Prior to this study, some surgeons believed that cavity shave margins should be routinely performed, while others felt that taking selective margins while performing surgery was the best strategy, Dr. Chagpar explained.

Study Details The study randomly assigned 235 patients with stage 0 to III breast cancer who were undergoing planned partial

mastectomy with or without resection of selective margins (surgeon’s choice for best operation) to have further cavity shave margins resected (“shave group”) or not (“no-shave group”). Intraoperatively, the four surgeons in the study were given a sealed envelope with the randomization assignment, which they opened (by the circulating nurse) after they completed standard partial mastectomy. Surgeons were instructed to perform partial mastectomy according to their usual practice, whether or not this included resection of margins where the tumor was thought to be close to the edge of the specimen based on imaging, their own observation, or both. The rate of positive margins was the primary outcome measure. Positive margins were defined as tumor touching the edge of the excised specimen in invasive cancers and tumor within 1 mm of the edge of the excised specimen in ductal carcinoma in situ. Secondary outcomes included cosmesis and the volume of tissue resected. The median age of patients was 61 years. Final pathologic testing showed that 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. Clinical and demographic characteristics were well matched at baseline. The rate of positive margins prior to randomization but after partial mastectomy was similar in the shave and no-shave

Role of Cavity Shave Margins in Breast Surgery ■■ The routine practice of shaving the tissue around the cavity after breast tumor removal cut the positive margin rate as well as the need for reexcision by about 50% compared to standard partial mastectomy with surgeons taking selective margins in areas of suspicion. ■■ Patient perception of the cosmetic outcome was the same for the two groups. ■■ The cavity shave approach resulted in more tumor volume excised. ■■ About 10% of patients deemed to have negative margins actually harbored occult multifocal disease, which was identified with routine cavity shaving.

groups: 36% and 34%, respectively. Following randomization, the rate of positive margins was significantly lower in the shave group vs the no-shave group: 19% vs 34%, respectively (P = .01). Furthermore, the rate of reexcision for margin clearance was also significantly lower in the shave group: 10% vs 21%, respectively (P = .02). The volume of tissue prior to randomization was not significantly different between the shave and no-shave groups. The total volume of tissue excised was significantly larger in the shave group vs the no-shave group: 115.1 vs 74.23 cm (P < .001). The rate of complications was similar in the two groups. n

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

References 1. Chagpar AB, Killelea BK, Tsangaris TN, et al: Can routine cavity shave margins (CSM) improve local control in breast cancer? Initial results of the SHAVE trial, a prospective randomized controlled trial of routine CSM vs. standard partial mastectomy. 2015 ASCO Annual Meeting. Abstract 1012. Presented May 30, 2015. 2. Chagpar AB, Killelea BK, Tsangaris TN, et al: A randomized, controlled trial of cavity shave margins in breast cancer. N Engl J Med. May 30, 2015 (early release online).

EXPERT POINT OF VIEW

“T

his is a significant study. About 30% of patients who undergo breastconserving surgery or partial mastectomy are likely to have positive margins. Optimal treatment is to remove the entire tumor surgically and then

Routine use of cavity shave margins will not affect survival but will improve local control, reduce patient distress levels, and entail one surgery instead of two. —George Somlo, MD, FACP

follow with radiation. Standard practice requires reexcision for positive margins,” explained George Somlo, MD, FACP, Professor in the Department of Medical Oncology at City of Hope, Duarte, California. “Based on their experience, breast cancer surgeons sometimes shave extra tissue in the hope of achieving negative margins,” Dr. Somlo continued. “If you are a patient, cavity shave margins can save you distress. Routine use of cavity shave margins will not affect survival but will improve local control, reduce patient distress levels, and entail one surgery instead of two. Also, this would improve quality of life and has potential to reduce cost,” Dr. Somlo said. “The findings need to be validated. Surgeons will want evidence along the same lines as we had with sentinel node biopsy, which has the potential to spare patients further surgery and complications,” Dr. Somlo concluded. n Disclosure: Dr. Somlo reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Amir Steinberg, MD, FACP, on Experience as an Oncologist and Cancer Survivor see page 52

David B. Solit, MD, on Molecular Oncology and Precision Medicine see page 34

Visit The ASCO Post online at ASCOPost.com

Asher Chanan-Khan, MD, on Ibrutinib in Previously Treated CLL see page 20

ASCOPost.com | JUNE 25, 2015

PAGE 9

ASCO Annual Meeting Dermatologic Oncology

Not All Stage III Melanoma Patients Need Complete Nodal Dissection By Caroline Helwick

omplete lymph node dissection did not improve survival in melanoma patients randomized to this practice, vs sentinel lymph node biopsy alone, German investigators reported at the 2015 ASCO Annual Meeting.1 “This is the first study that tested the typical recommendation of complete lymph node dissection in patients with positive sentinel nodes, and we cannot confirm this recommendation,” said senior study author Claus Garbe, MD, Professor of Dermatology at the University of Tübingen, Germany, speaking at a press briefing. The multicenter DeCOG study found no significant treatment-related differences in 5-year recurrence-free

Based on our findings, complete lymphadenectomy cannot be recommended in melanoma patients with micrometastases. —Ulrike Leiter, MD

survival, distant metastases-free survival, and melanoma-specific survival between the complete lymph node dissection and observation arms, first study author Ulrike Leiter, MD, also of the University of Tübingen, reported at an ASCO session. “The group with complete lymphadenectomy showed better disease control in the regional lymph node basin, but completed lymphadenectomy was not associated with improved distant metastases-free survival, recurrencefree survival, or melanoma-specific survival,” said Dr. Leiter. “Based on our findings, complete lymphadenectomy cannot be recommended in melanoma patients with micrometastases.”

DeCOG Details Investigators screened 1,269 patients who had stage III cutaneous melanoma of the trunk and extremi-

ties and positive sentinel lymph node biopsy. All patients had micrometastases but no palpable nodes. Of them, 473 patients ultimately agreed to randomization and were in-

cluded in the intent-to-treat analysis: 233 in the observation arm and 240 in the complete lymph node dissection arm. Patients had a median tumor thickness of 2.4 mm, and about 40% of tumors were

ulcerated. Both cohorts underwent close monitoring for 3 years, including lymph node ultrasonography every 3 months and computed tomography/magnetic continued on page 10

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The ASCO Post | JUNE 25, 2015

PAGE 10

ASCO Annual Meeting Stage III Melanoma continued from page 9

resonance imaging or positron-emission tomography scans every 6 months. No statistically significant differences were observed in the primary endpoint— distant metastases-free survival—at 80.4% in the observation arm and 80.1% in the complete lymph node dissection arm (hazard ratio = 1.02, P = .92). The only significant difference was observed for regional recurrences (Table 1).

“The radical lymphadenectomy arm had less metastases in the regional nodal basin, which was the only statistically significant difference,” she noted. Poor prognostic factors included > 1 mm cancer in the sentinel lymph node biopsy sample (hazard ratio = 2.37, P < .0001) and tumor thickness > 2 mm (hazard ratio = 2.36, P = .007). Dr. Leiter emphasized that accrual to the study was difficult—only one of every three patients agreed to be

Role of Complete Nodal Dissection in Stage III Melanoma ■■ A German study of about 500 patients with stage III melanoma determined that complete lymph node dissection conferred no survival benefit. ■■ Five-year distant metastasis-free survival was approximately 80% in each arm. ■■ Radical lymphadenectomy was, however, associated with slightly fewer metastases in the regional nodal basin. ■■ Experts suggest a select group of low-risk patients may safely forgo complete lymph node dissection, but observation is not optimal for all stage III melanoma patients.

Table 1: Outcomes in DeCOG Trial Arm A (Observation) N = 233

Arm B (Radical Lymphadenectomy) N = 240

Cause of Death Malignant melanoma Other malignancy Other disease

38 (16.3%) 1 (0.42%) 5 (2.14%)

36 (15.00%) 0 (0.00%) 4 (1.6%)

.641

Recurrences Total Regional lymph nodes Distant

67 (28.7%) 34 (14.6%) 43 (18.6%)

59 (24.5%) 20 (8.3%) 42 (17.5%)

.349 .029 .811

randomized—and therefore the study population was smaller than designated by the study design. “It was powered to detect a difference of 10% [in the primary endpoint], and to date, that difference in both arms was only 1.1% and the difference in the 3-year distant metastasis free survival was 0.3% (80.4% vs 80.1%).” The investigators will conduct another analysis in 3 years. n

P Value

Disclosure: Drs. Leiter and Garbe reported no potential conflicts of interest.

Reference 1. Leiter U, Stadler R, Mauch C, et al: Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DeCOG trial. 2015 ASCO Annual Meeting. Abstract LBA9002. Presented May 30, 2015.

EXPERT POINT OF VIEW

ynn Schuchter, MD, of the University of Pennsylvania, Philadelphia, a designated ASCO expert, commented at the press briefing that the results might apply to a select group of patients concerned about lymphedema but not yet to the broader population. “I would say that this is a really important study, but it’s a relatively small one, and I don’t think we would make a complete change in our recommendations based on these data,” she offered. “I think we will wait to

sue and will provide much more definitive information, agreed Vernon Sondak, MD, Chair of the Cutaneous Oncology Department at Moffitt Cancer Center, Tampa, Florida, in an interview with The ASCO Post. “We found out that in the early analysis of this German study, there was no obvious harmful impact of not doing a node dissection after a positive sentinel node biopsy. That’s a lot different than saying we don’t ever need to do a node dissection on our patients,” Dr. Sondak said.

I don’t think we would make a complete change in our recommendations based on these data. I think we will wait to make definitive changes in our management until we have results from a larger study. —Lynn Schuchter, MD

make definitive changes in our management until we have results from a larger study.” The multinational MSLT2 trial with nearly 2,000 patients randomized is currently evaluating this is-

Dr. Sondak considers the findings predictable, pointing out that microscopic disease can take years to become apparent. By taking out the sentinel node, he said, “we have reset the clock and are waiting for

cancer in the other nodes, if it’s there, to show up. Hopefully, we can then intervene before it spreads.” According to Dr. Sondak, most melanoma specialists have considered it safe to forego complete lymph node dissection after a positive sentinel node biopsy in select, low-risk patients. The question is determining who this low-risk group is, he said. “The safe patients would be those with the most to gain and the least to lose by not having complete lymph node dissection,” he pointed out. This is most likely to be the patient with minimal amounts of melanoma in the sentinel node, he added.

Clarifying Misconceptions Dr. Sondak also clarified some misconceptions about complete lymph node dissection after a positive sentinel node biopsy. Both the incidence and morbidity associated with this surgery are less than those observed in the breast cancer setting or when the procedure is done for a macroscopic nodal metastasis from melanoma, he indicated. About 10% to 20% of complete lymph node dissection patients develop lymphedema, almost all of which is mild, when the procedure is done after a positive sentinel node biopsy. The incidence is higher among patients

Vernon Sondak, MD

who are obese or have other risk factors and lower among younger, fit patients. He also noted that upfront complete lymph node dissection produces less morbidity than the surgery that must be performed upon recurrence, which is usually more extensive and sometimes involves radiation. In conclusion, Dr. Sondak said the DeCOG study does not definitively answer the question of which patients can forego complete lymph node dissection, but “it gives us a little more confidence as we talk to our patients… and that knowledge will be helpful. If we properly choose and inform our patients, then I think it’s safe, at least in the short run, to consider a close observation approach with frequent follow-up in select patients,” he said. n Disclosure: Drs. Schuchter and Sondak reported no potential conflicts of interest.

ASCOPost.com | JUNE 25, 2015

PAGE 11

ASCO Annual Meeting Sexual Dysfunction After Gynecologic Cancer Treatment

study presented at the ASCO Annual Meeting showed decreased sexual activity in women following treatment for gynecologic cancers, down from 6 to 7 times per month before treatment to 3 to 5 times per month after treatment (abstract 9592).

“[Sexual dysfunction] is a topic that not many people want to talk about because it is uncomfortable,” said Saketh Guntupalli, MD, of the University of Colorado Cancer Center and the CU School of Medicine. He acknowledged, however, that it is an issue important to GAZYVA® (obinutuzumab)

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

maintaining quality of life after treatment for patients and their partners. Dr. Guntupalli and his team worked with researchers from Denver Health Medical Center, Columbia University, and Loma Linda University to survey 315 women about their sexual health. For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

The data showed an overall decrease in sexual frequency after cancer treatment but no accompanying increase in marital dysfunction. Dr. Guntupalli said counseling during cancer treatment may benefit a couple’s sexual health after treatment. n The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy. Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

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

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

Anemia

Leukopenia

Infections and infestations Urinary tract 6 2 infection

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

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

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

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

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

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

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

Thrombocytopenia 14

Leukopenia

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

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

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

Thrombocytopenia 15

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

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

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

Blood and lymphatic system disordersb Neutropenia 41 35 18

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

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

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

Chlorambucil n = 116

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

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

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

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

Constipation

Infections and infestations Nasopharyngitis 6 <1 Urinary tract infection

MedDRA coded adverse reactions as reported by investigators.

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

The ASCO Post | JUNE 25, 2015

PAGE 12

ASCO Annual Meeting Plenary Session

Elective Neck Dissection continued from page 1

early oral cancer, we now know that more extensive surgery saves lives.” Dr. Patel is Associate Professor at Northwestern University Feinberg School of Medicine, Chicago. Oral cancer is highly prevalent in both developed countries and developing coun-

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

Investigations

Chlorambucil n = 116

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

Lymphopenia

Leukopenia

Chemistry Hypocalcemia

Hyperkalemia

Hyponatremia

AST (SGOT increased)

Creatinine increased

ALT (SGPT increased)

Hypoalbuminemia

Alkaline phosphatase 18 increased

Hypokalemia

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

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

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

Lymphopenia

Leukopenia

Thrombocytopenia 48

Anemia

Chemistry Hypocalcemia

Hyperkalemia

Hyponatremia

AST 27 (SGOT increased)

ALT 28 (SGPT increased)

Hypoalbuminemia 23

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

tries, with a high incidence of tobacco and alcohol use. “Today [May 31] is World Tobacco Day, and what could be a better day to share these results,” said Dr. D’Cruz.

Controversial Topic The primary treatment of early nodenegative oral cancer is a small excision, but controversy surrounds whether or

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

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

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

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

not to do elective neck dissection at the time of primary surgery or to watch and wait until a node develops and then do a therapeutic node dissection, Dr. D’Cruz explained. Therapeutic neck dissection does not improve survival and can have associated morbidities associated with a second surgery. Performing both the primary

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

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by: Genentech, Inc.

Code Revision Date: December 2014

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

GAZYVA is a registered trademark of Genentech, Inc.

U.S. License No: 1048

and the neck dissection surgeries at the same time spares patients those effects.

Study Details and Results A large randomized controlled trial was mounted to address this issue. At the 2015 ASCO Annual Meeting, Dr. D’Cruz reported results in the first 500 patients enrolled in the trial between 2004 and 2014, with a median followup of 39 months. All patients had early stage I, node-negative, oral cancer and were randomized to undergo elective or therapeutic neck dissection. A second

Our conclusions are that elective neck dissection should be the standard of care for early node-negative squamous cell oral cancer. —Anil K. D’Cruz, MBBS, MS, FRCS

randomization was performed after surgery to ultrasound-guided surveillance vs clinical surveillance, but those data were not reported at the meeting. In the elective surgery group, there were 81 recurrences and 50 deaths, compared with 146 recurrences and 79 deaths in the therapeutic neck dissection group. At 3 years, overall survival was 80% in the elective dissection group vs 67.5% in the therapeutic dissection group, reflecting a significant 26% improvement in survival for elective surgery (P = .01). At 3 years, the rate of disease-free survival was 69.5% for elective dissection vs 45.9% for therapeutic dissection, a highly statistically significant difference (P < .001). The overall survival benefit of elective neck dissection was consistent across almost all prespecified subgroups, including stage, sex, grade, tumor depth, resected margin status, and use of radio-

Survival Benefit With Elective Neck Dissection for Early Oral Cancer ■■ Elective neck dissection performed at the same time as primary surgery extended overall survival and diseasefree survival compared with therapeutic neck dissection at the time of nodal relapse. ■■ Benefits favoring elective neck dissection were observed in almost all subgroups, except for buccal oral cancers—a minority of the patient population.

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ASCO Annual Meeting Study Limitation

We never want to do more surgery than we have to, but for patients with early oral cancer, we now know that more extensive surgery prolongs lives. —Jyoti Patel, MD

therapy. For the site of cancer, there was equipoise for both techniques for buccal mucosa oral cancers, but elective dissection was superior for cancers of the tongue or floor of the mouth. The large majority of cancers in this

trial were tongue cancers (85.3%), “so the results are most applicable to this primary site,” Dr. D’Cruz noted. The majority of patients with buccal cancers available for recruitment in this trial were not amenable to oral excision, he added.

A study limitation is that it did not address shoulder dysfunction, which afflicts a substantial proportion of patients subjected to neck dissection. Dr. D’Cruz suggested that future studies address procedures that might limit shoulder complications, such as sentinel lymph node biopsy and limited neck dissection. He also noted that a larger percentage of patients in the elective dissection group received adjuvant radiotherapy based on nodal status, and the study did not address whether this contributed to improved overall survival. n Disclosure: This trial was funded by the Department of Atomic Energy Clinical Trial

Centre, Membai, India. Dr. D’Cruz is on the speakers bureau of Merck Serono, and his institution has received research funding from GlaxoSmithKline. Dr. Patel reported no potential conflicts of interest.

References 1. D’Cruz AK, Dandekar M, Vaish R, et al: Elective versus therapeutic neck dissection in the treatment of early node negative squamous cell carcinoma of the oral cavity. 2015 ASCO Annual Meeting. Abstract LBA3. Presented May 31, 2015. 2. D’Cruz AK, Vaish R, Kapre N, et al: Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. May 31, 2015 (early release online).

EXPERT POINT OF VIEW

ormal discussant Hisham Mehanna, PhD, Chief of Head and Neck Surgery and Director of Head and Neck Studies and Education at the University of Birmingham, United Kingdom, congratulated Dr. D’Cruz on conducting an ambitious and difficult trial. “Like all studies, it has flaws, but the study has helped resolve an important outstanding controversy, and the data from the study have the potential to solve more controversies,” Dr. Mehanna noted. With longer follow-up, the role of ultrasound-guided surveillance vs clinical surveillance (from the second randomization) will become clear. The large repository of tissue samples from the trial will allow the study of biomarkers to determine which patients will go on to develop more nodal metastases. Dr. Mehanna pointed out that one-third of newly diagnosed patients who have node-negative disease on clinical and radiologic examinations actually have occult nodal

metastases. “Some node-negative patients will develop metastasis. Reoperations for these patients incur additional costs and toxicities. The advantages of elective neck dissection include reduced risk of recurrence, low morbidity, and negligible

dissection] in patients with nodal metastasis was significantly better in the node-positive patients in the elective surgery group than in those with nodal relapse in the therapeutic surgery group—over a 20% benefit. This is because when patients recur,

Like all studies, it has flaws, but the study has helped resolve an important outstanding controversy, and the data from the study have the potential to solve more controversies. —Hisham Mehanna, PhD

effect on quality of life. Some trials even show better survival, but about 5% of patients can have significant complications and shoulder disability,” he continued. “It is not an easy randomization to sell to patients.” “The results are astounding. The survival benefit [with elective node

they tend to have more advanced nodal disease, which is essentially a death sentence,” he explained.

More to Learn Dr. Mehanna would like to have seen more data on who got adjuvant therapy, the quality of radiotherapy,

the dose of chemotherapy, quality of life, and cost. “It is important to know if there is a survival difference in those who got adjuvant therapy and those who did not,” he said. Also, he looks forward to having the data on the type of follow-up in the future (ie, ultrasoundguided vs clinical surveillance). “The absence of this data limits our ability to make full recommendations,” he told listeners. Additionally qualityof-life and cost data are important for informing decision-making, and these data were not included. “At this time, we can say that in centers that do surveillance by clinical exam [ie, low-resource areas], we recommend elective neck dissection as standard of care instead of clinical surveillance, especially for tumors with > 3 mm thickness. We can’t make that recommendation regarding ultrasound-guided surveillance with the data we have at present. We await further results.” n Disclosure: Dr. Mehanna reported no potential conficts of interest.

The ASCO Post | JUNE 25, 2015

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ASCO Annual Meeting Sarcoma

Eribulin Improves Overall Survival in Difficult-To-Treat Sarcoma Types By Caroline Helwick

ribulin (Halaven), a cytotoxic agent approved for advanced/ metastatic breast cancer, may improve overall survival for patients with two common and difficult-to-treat forms of advanced/metastatic sarcoma, investigators reported at the 2015 ASCO Annual Meeting.1 Eribulin is a microtubule inhibitor that blocks cell division. In preclinical models, it also has been shown to impact tumor cells via vascular remodeling, reversal of epithelial-mesenchymal transition, as well as suppression of migration and invasion. In the global phase III study (Study 309), eribulin reduced the risk of death

The study population represents a high-risk group of patients with comorbid conditions, and therefore these results represent an important breakthrough. For me as a sarcoma oncologist, this is a clinically meaningful result, given the high unmet need in these rare, hard-totreat diseases. —Patrick Schöffski, MD

by 23%, compared with dacarbazine, in patients with advanced liposarcomas and leiomyosarcomas, reported Patrick SchÖffski, MD, of University Hospitals Leuven in Belgium. “Patients with advanced or metastatic disease have very poor outcomes, and their systemic treatment options are very limited,” he said. “The study’s primary endpoint of overall survival— a very reliable endpoint—was met. Eribulin had a favorable median survival of 13.5 months, vs the standard agent dacarbazine, 11.5 months (hazard ratio = 0.768; P = .0169).”

“The study population represents a high-risk group of patients with comorbid conditions, multiple prior drug regimens, and intermediate-to-high tumor grade, and therefore these results

represent an important breakthrough. For me as a sarcoma oncologist, this is a clinically meaningful result, given the high unmet need in these rare, hard-totreat diseases,” he said.

Study Details Study 309 is a randomized, open-label multicenter phase III trial in which 452 patients with advanced leiomyosarcoma or adipocytic sarcoma (ie, liposarcoma)

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ASCO Annual Meeting Eribulin vs Dacarbazine in Advanced Sarcoma ■■ In patients with advanced or metastatic leiomyosarcoma and adipocytic sarcoma, treatment with eribulin significantly improved overall survival by 2 months, compared with dacarbazine, in a global phase III trial. ■■ Median overall survival was 13.5 months with eribulin and 11.5 months with dacarbazine, for a reduction in mortality of 23%. ■■ Progression-free survival was not significantly different, 2.6 months per arm.

received eribulin (1.4 mg/m2 on days 1 and 8) or dacarbazine (850–1,200 mg/m2 on day 1) every 21 days until disease progression. More than 40% of patients had received more than two prior regimens. The primary endpoint was overall survival, which was significantly improved in the eribulin cohort. Secondary endpoints, however, were not signifi-

cantly different. Median progression-free survival was 2.6 months in both arms. The progression-free survival rate at 12 weeks was 33% for the eribulin arm and 29% for the dacarbazine arm. The toxicity of eribulin was consistent with prior experience. The most common adverse events grade ≥ 3 with the

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continued on page 16

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ASCO Annual Meeting Advanced Sarcoma continued from page 15

drug were neutropenia (35%) and fatigue (3%). About one-third of patients experienced some degree of nausea, alopecia, and constipation. There were two treatment-related deaths in the eribulin arm. Two ASCO experts commented on the study at a press briefing. Gary K.

Schwartz, MD, noted, “There’s never been a randomized study of this type showing a survival benefit in advanced sarcoma in the history of medical oncology. It’s a small step forward in oncology but a major step for sarcoma patients.” Press briefing moderator Don S. Dizon, MD, added, “This is going to be welcome news for patients with these two

rare sarcoma types, especially since we understand this study population was very heavily pretreated. Active agents have not been readily available for them.” n

Disclosure: Dr. SchÖffski has received honoraria from and served as a consultant or advisor to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Iteos Therapeutics, Mundipharma, Novartis, Pique, Plexxikon, Prime Oncology, Servier, Swedish Orphan

Biovitrum, Threshold Pharmaceuticals, and ThromboGenics. He is also on the speakers bureau of GlaxoSmithKline, Novartis, Prime Oncology, and Swedish Orpha Biovitrum. Drs. Schwartz and Dizon reported no potential conflicts of interest.

Reference 1. SchÖffski P, et al: 2015 ASCO Annual Meeting. Abstract LBA10502. Presented June 1, 2015.

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ASCOPost.com | JUNE 25, 2015

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ASCO Annual Meeting Supportive Care

Two Factors Predict for Recurrent Venous Thromboembolism in Patients With Cancer By Alice Goodman

atients with cancer who develop venous thromboembolism are at high risk of such obstructive disease

recurring despite adequate anticoagulation. A prespecified analysis of the CATCH trial identified two major pre-

dictors of recurrence: venous compression by the tumor and a diagnosis of hepatobiliary cancer.1

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“The analysis of this large randomized controlled trial that included more than 900 patients found that patients with a tumor mass compressing the venous system—typically gynecologic cancer patients—and patients with hepatobiliary malignancies were at highest risk of recurrent [venous thromboembolism]. These findings

The analysis of this large randomized controlled trial … found that patients with a tumor mass compressing the venous system and patients with hepatobiliary malignancies were at highest risk of recurrent [venous thromboembolism]. —Alok A. Khorana, MD, FACP

indicate that these patients should be monitored carefully for recurrent [venous thromboembolism] and we should consider more intensive anticoagulation once they develop a first [venous thromboembolism],” said lead author Alok A. Khorana, MD, FACP, Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland.

Study Details The CATCH study was a prospective, open-label, multicenter clinical trial that included more than 900 patients being treated for active cancer who developed acute, symptomatic proximal deep venous thromboembolism and/or pulmonary embolism.2 They were randomly assigned 1:1 to 6 months of anticoagulation with tinzaparin (Innohep) at 175 IU/kg once a day vs initial tinzaparin (low–molecular-weight heparin) continued on page 18

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ASCO Annual Meeting Venous Thromboembolism continued from page 17

transitioning to dose-adjusted warfarin (target of international normalized ratio [INR] 2–3). CATCH found that the incidence of venous thromboembolism was 6.9% with tinzaparin vs 10% with warfarin, for a significant 35% reduction in the risk of recurrent venous thromboembolism favoring tinzaparin (P = .07). Symptomatic nonfatal venous thromboembolism occurred in 2.7% of the tinzaparin arm vs 5.3% of the warfarin arm (P = .04). There was no difference between the two treatment arms for major bleeding, but clinically relevant nonmajor bleeding was significantly reduced in the tinzaparin arm, occurring in 50 (11%) vs 73 (16%) patients (P = .03). No difference in mortality was observed between the two treatments.

tors associated with recurrent venous thromboembolism. Interestingly, the Ottawa score,3 recently validated to predict recurrent venous thromboembolism, did not predict which patients were at risk in this trial. The Ottawa score is composed of four variables: sex, primary tumor site, tumor state, and history of venous thromboembolism.

Raising Awareness “[Venous thromboembolism] is a clinically important and common issue in cancer patients that may be overlooked. It is the second leading cause of death in cancer patients, equal with infection. This study should raise our awareness. The prespecified subgroup analysis of the CATCH trial adds to our

knowledge about which patients are at higher risk,” said Marc Carrier, MD, MSc, FRCPC, Associate Professor at the University of Ottawa, Canada, who was not involved in this analysis. “The risk of recurrent [venous thromboembolism] despite anticoagulation and of major bleeding while on anticoagulant therapy is increased in

ADVERTORIAL

Additional Data The post hoc analysis, presented at a poster session during the 2015 ASCO Annual Meeting, was designed to identify risk factors for recurrent [venous thromboembolism] in the CATCH trial. The investigators evaluated multiple clinical variables that were present at or prior to randomization. Metastatic disease was present in 492 patients (54%), 288 (32%) were on chemotherapy, 281 (31.8%) were recently hospitalized, 209 (23.2%), had [Eastern Cooperative Oncology Group (ECOG)] performance status of 2, 129 (14.3%) had venous compression from the tumor, and 92 (10.2%) had undergone recent radiation therapy. Multivariate analysis identified both venous compression (P < .001) and a diagnosis of hepatobiliary cancer (P = .018) as significant risk fac-

Venous Thromboembolism in Cancer Patients ■■ Two risk factors have been identified for recurrent venous thromboembolism in cancer patients: tumors that press on the venous system and a diagnosis of hepatobiliary cancer. ■■ Oncologists should monitor these high-risk patients with vigilance and should consider using aggressive anticoagulant therapy with a low–molecularweight heparin.

CANCER STEM CELLS

SIGNALING PATHWAYS

Cancer Stem Cells and Their Role Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7 Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells from ordinary cancer cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8

Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, may be highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis. 4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/STAT, Wnt/ β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

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ASCO Annual Meeting

Marc Carrier, MD, MSc, FRCPC

cancer patients. If we can identify who is at highest risk of a recurrent event, then clinicians can tailor their management accordingly,” Dr. Carrier continued. Low–molecular-weight heparin is recommended as first-line treatment of venous thromboembolism, he continued. “Due to its higher cost, low–molecular-weight heparin is not often used

REGROWTH

in the United States. When possible, physicians should try to push for [low– molecular-weight heparin] in cancer patients, especially in the high-risk groups identified in the Khorana study,” Dr. Carrier said. n

Disclosure: Dr. Khorana has received honoraria from and has served as a consultant/ advisor for AngioDynamics, Daiichi Sankyo,

APOPTOSIS

in Recurrence and Metastasis Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Learn more at www.bostonbiomedical.com

References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. 2015;112(6):18391844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics inThoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lungcancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells. PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/βcatenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149-160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

EDU-NPS-0027

5/2015

Genentech, Johnson & Johnson, Leo Pharma, Halozyme, Pfizer, and Sanofi. He has received research funding from Leo Pharma. Dr. Carrier has received research support from Leo Pharma and honoraria from Sanofi-Aventis, Pfizer, Boehringer Ingelheim, Leo Pharma, and Bayer and has served on scientific advisory boards for Sanofi-Aventis and Leo Pharma. For full disclosures of the CATCH study authors, view the study abstract at abstracts.asco.org.

References 1. Khorana AA, Bauersachs R, Kamphuisen PW, et al: Clinical predictors of recurrent venous thromboembolism in cancer patients from a randomized trial of long-term warfarin versus warfarin for treatment: The CATCH study. 2015 ASCO Annual Meeting. Abstract 9621. Presented May 30, 2015. 2. Lee AYY, Kamphuisen P, Meyer G, et al: A randomized trial of long-term tinzaparin, a low molecular weight heparin (LMWH), versus warfarin for treatment of acute venous thromboembolism (VTE) in cancer patients: The CATCH Study. 2014 ASH Annual Meeting. Abstract LBA-2. Presented December 9, 2014. 3. Ahn S, Lim KS, Lee Y-S, et al: Validation of the clinical prediction rule for recurrent venous thromboembolism in cancer patients: The Ottawa score. Support Care Cancer 21:2309-2313, 2013.

For interviews with experts conducted live at the ASCO Annual Meeting on this study and others, visit http://video.ascopost.com/

The ASCO Post | JUNE 25, 2015

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ASCO Annual Meeting Hematology

Ibrutinib Plus Bendamustine/Rituximab Called a New Standard in Patients With Previously Treated CLL By Alice Goodman

he addition of ibrutinib (Imbruvica) to standard therapy with bendamustine (Treanda)/rituximab (Rituxan) significantly reduced the risk of disease progression or death and overall response rates compared with bendamustine/rituximab alone in previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to results of the phase III HELIOS trial reported at the 2015 ASCO Annual Meeting.1 “There are countless patients with

ease or unacceptable toxicity. Crossover to ibrutinib maintenance was allowed for patients with progressive disease in the placebo maintenance arm. Patients were eligible if they had active CLL/SLL requiring treatment, had relapsed/refractory disease following at least one prior line of systemic therapy, and measurable lymph node disease by computed tomography scan. Patients with deletions in 17p were excluded. At baseline, 26% were purine analog-refractory. About 49% received

These results represent a changing point in the treatment of CLL. The standard of care should now be ibrutinib plus bendamustine/rituximab for previously treated patients. —Asher Chanan-Khan, MD

CLL for whom this drug has been a blessing from God. Ibrutinib reduced the risk of progression or death by 80%. This is remarkable. It brings joy that such an impactful therapy changes the course of disease early on,” said lead author Asher Chanan-Khan, MD, of Mayo Clinic, Jacksonville, Florida. “HELIOS is one the largest studies of relapsed CLL/SLL, and the findings carry a lot of weight,” he added. Ibrutinib is now one of the preferred drugs for CLL in the National Comprehensive Cancer Network Guidelines.2 B-cell signaling plays a role in the development of CLL, and this signaling is tamed by the Bruton’s kinase inhibitor ibrutinib, so that the survival signal no longer reaches the cell, thereby preventing proliferation.

Study Details HELIOS is a randomized, doubleblind, placebo-controlled, international, phase III trial conducted in 21 countries. A total of 578 patients with previously treated CLL/SLL requiring treatment were randomized in a 1:1 ratio to receive ibrutinib plus standard bendamustine/rituximab followed by ibrutinib maintenance or placebo plus bendamustine/rituximab followed by placebo maintenance. Patients were treated with a maximum of six cycles, and maintenance therapy continued until progressive dis-

one prior line of therapy, about 25% received two prior lines of therapy, and about 26% received three or more prior lines of therapy.

More Evidence Supports Ibrutinib in Chronic Lymphocytic Leukemia ■■ Ibrutinib combined with standard bendamustine/rituximab reduced the risk of disease progression or death compared with bendamustine/rituximab alone in patients with previously treated chronic lymphocytic leukemia (CLL). The addition of ibrutinib also improved overall response rates. ■■ These phase III results of the HELIOS trial add to the weighty evidence supporting use of ibrutinib in CLL. ■■ The authors believe this study favors ibrutinib plus bendamustine and rituximab as the new standard of care for previously treated CLL patients.

The primary endpoint was progression-free survival as assessed by an Independent Review Committee. Median progression-free survival was not yet reached in the ibrutinib-containing arm vs 13.3 months with standard bendamustine/rituximab (P < .0001). The combination arm significantly reduced the risk of disease progression or death by 80% compared with placebo plus bendamustine/rituximab. Subgroup analysis favored ibrutinib across the board, including age, sex, diagnosis, Rai stage at screening, prior lines of therapy, bulky disease, baseline Eastern Cooperative Oncology Group

(ECOG) status, and presence or absence of del11q and IgVH. Overall survival has not been reached in either arm at a median follow-up of 17 months. These results are confounded by 90 patients in the placebo arm (31%) crossing over to receive single-agent ibrutinib. “Overall, ibrutinib reduced the risk of death by 37%,” he said. The overall response rate was significantly higher in the ibrutinib/bendamustine/rituximab arm vs placebo/bendamustine/rituximab: 82.7% vs 67.8%. No new safety signals emerged with the combination. Adverse events were continued on page 22

EXPERT POINT OF VIEW

eremy Abramson, MD, Clinical Director of the Center for Lymphoma at Massachusetts General Hospital, Boston, is not convinced that ibrutinib (Ibruvica) combined with bendamustine (Treanda) and rituximab (Rituxan) should be the new

all patients with relapsed CLL. Ibrutinib alone works remarkably well in relapsed disease, with response rates of approximately 90% and 3-year progression-free survival greater than 80% in subjects without deletions of either 17p or 11q. The study does

My answer now is ibrutinib alone based on data to date. I’m not convinced bendamustine/rituximab is needed. That was not addressed in this trial. —Jeremy Abramson, MD

standard of care for previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). He is, however, convinced that ibrutinib monotherapy is the treatment of choice in this population. “Ibrutinib monotherapy is well tolerated and already approved for

not tell us how much bendamustine/ rituximab adds to ibrutinib since ibrutinib alone works so remarkably well,” Dr. Abramson said. Ibrutinib is a highly active regimen, and it is remarkable that a novel agent added to chemoimmunotherapy reduced the risk of disease progression

or death by 80%, he continued. “But the clinician faces the decision of selecting the optimal therapy for patients previously treated with chemotherapy. My answer now is ibrutinib alone based on data to date. I’m not convinced bendamustine/rituximab is needed. That was not addressed in this trial.” Ongoing trials are currently looking at ibrutinib alone compared with chemoimmunotherapy in patients with previously untreated CLL, and until those data are available, “I do not think ibrutinib should be the standard of care for untreated patients without a 17p deletion. Those data, however, are likely to demonstrate that ibrutinib is superior to chemoimmunotherapy as initial treatment for CLL, and with less toxicity. In the not too distant future, most patients with CLL may never require chemotherapy,” Dr. Abramson stated. n Disclosure: Dr. Abramson has been a consultant (scientific advisory boards) for Pharmacyclics, Gilead, Infinity, and Juno.

Trusted to take a bite out * of G-CSF acquisition costs GRANIX® has gained >34% share of the US short-acting G-CSF hospital market in its first 17 months1 » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)2 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)2 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)2 » Offering a presentation for self-administration

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information

» Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of March 2015. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices. References: 1. This information is an estimate derived from the use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospital channel March 2015. IMS expressly reserves all rights, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength). 2. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

The ASCO Post | JUNE 25, 2015

PAGE 22

ASCO Annual Meeting Ibrutinib in CLL continued from page 20

consistent with the established safety profiles of all three drugs. The most frequent side effects were low blood cell counts, nausea, and diarrhea. This is the second phase III trial (joining the RESONATE trial) to demonstrate that ibrutinib significantly de-

lays relapse for previously treated patients with CLL/SLL. HELIOS is the first placebo-controlled study of ibrutinib in CLL/SLL and the first large phase III trial to evaluate a novel targeted drug with chemoimmunotherapy. “These results represent a changing point in the treatment of CLL. The standard of care should now be ibruti-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Merry-Jennifer Markham, MD

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

nib plus bendamustine/rituximab for previously treated patients,” Dr. Chanan-Khan stated. “This is a very promising time for CLL. All patients will eventually relapse/recur. These results are so exciting because they show that ibrutinib is an important drug to use with an established chemotherapy regimen in this patient population. This will help our patients with CLL live longer,” said Merry-Jennifer Markham, MD, ASCO expert and Assistant Professor of Medicine, Division of Hematology-Oncology, University of Florida, Gainesville. n

Disclosure: Drs. Chanan-Khan and Markham reported no potential conflicts of interest.

References 1. Chanan-Khan AAA, Cramer P, Demirkan F, et al: Ibrutinib combined with bendamustine and rituximab in previously treated chronic lymphocytic leukemia/ small lymphocytic lymphoma: First results from a randomized, double-blind, placebocontrolled, phase III study. 2015 ASCO Annual Meeting. Abstract LBA7005. Presented May 30, 2015. 2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Hodgkin’s Lymphomas, v4.2014. Available at http://www.nccn.

org/professionals/physician_gls/f_ guidelines.asp. Accessed June 8, 2015.

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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 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

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ASCOPost.com | JUNE 25, 2015

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ASCO Annual Meeting Genitourinary Cancer

Adjuvant Chemotherapy Proves Effective in Localized, High-Risk Prostate Cancer By Alice Goodman

or the first time, a large randomized trial has suggested that overall survival is improved by the addition of adjuvant chemotherapy to androgen suppression and radiotherapy in men with localized, high-risk, hormonesensitive prostate cancer. Docetaxel has been used to treat metastatic hormoneresistant prostate cancer for a number of years, and this new study—RTOG 0521—suggests that moving it up earlier in the course of treatment to the adjuvant setting may extend the lives of men with high-risk, hormone-sensitive prostate cancer.1 Results of RTOG 0521 are part of an emerging story, suggesting that docetaxel can be used earlier in the course of disease. Both the CHAARTED2 and STAMPEDE3 trials found that docetaxel improved survival in men with highrisk metastatic hormone-sensitive prostate cancer, whereas before these trials, docetaxel was confined to the hormoneresistant metastatic setting. RTOG 0521 was designed to assess

and STAMPEDE, and we look forward to sharing later results of RTOG 0521,” Dr. Sandler said. At a press conference where these data were discussed, ASCO expert Charles Ryan, MD, said, “This is the first study to demonstrate a survival benefit for high-risk localized prostate

Charles Ryan, MD

cancer with chemotherapy as adjuvant therapy plus androgen-deprivation therapy and radiation. The follow-up is relatively short, but there is significant separation of the survival curves at 5 to 6 years, and we would expect that to continue with longer follow-up.

This is the first study to show the potential benefit in [overall] survival of adjuvant docetaxel. These were highrisk patients with aggressive cancer. For the right patient, these data justify adding docetaxel. —Howard Sandler, MD

4-year survival, and the authors believe that with longer follow-up, the overall survival benefits of adjuvant docetaxel in this setting will continue to emerge. “We hypothesized that chemotherapy, known to be beneficial in metastatic hormone-resistant prostate cancer, would improve outcomes in nonmetastatic hormone-sensitive prostate cancer. This is the first study to show the potential benefit in [overall] survival of adjuvant docetaxel. These were highrisk patients with aggressive cancer. For the right patient, these data justify adding docetaxel. This 4-year analysis is relatively early, and additional follow-up will likely be enlightening,” said lead author Howard Sandler, MD, of CedarsSinai Medical Center, Los Angeles. “We have seen continued separation of the survival curves in CHAARTED

This is treatment with curative intent.” Dr. Ryan is Clinical Program Leader for Genitourinary Medical Oncology at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center.

Study Details RTOG 0521 enrolled 563 eligible patients between December 2005 and August 2009 and randomized them to either arm 1 (androgen suppression and radiotherapy) or arm 2 (androgen suppression, radiotherapy, docetaxel, and prednisone [10 mg]). Androgen suppression was given for 24 months; external-beam radiation therapy was given for 8 weeks; and docetaxel was given at 75 mg/m2 on day 1 for 6 cycles, starting 4 weeks after the completion of radiotherapy.

2015 ASPIRE Breast Cancer Research Awards Program Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peerreviewed grants program sponsored by Pfizer for investigators in the United States

Call for Research Proposals For complete information on the scope of research, please visit ASPIRE website at www.aspireresearch.org Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer. Awards 2015 ASPIRE Breast Cancer Research Awards program intends to fund three to six clinical studies within scope, for a total of approximately 3 million US dollars. It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts.

Submissions are due September 8, 2015

continued on page 24 www.aspireresearch.org

The ASCO Post | JUNE 25, 2015

PAGE 24

ASCO Annual Meeting High-Risk Prostate Cancer continued from page 23

Patients included in the trial had Gleason scores between 8 and 10, prostate-specific antigen (PSA) ≥ 20 ng/mL, or ≥ T2 stage. The median age was 66 years. The median PSA level was 15.1 ng/mL; 53% had Gleason scores of between 9 and 10; 31% had a Gleason score of 8; 16% had a Gleason score of 7; and 33% had node-negative disease. Dr. Sandler emphasized that the study was designed to detect an improvement in 4-year overall survival from 86% to 93% or a 51% relative reduction (hazard ratio = 0.49) in the yearly death rate. The investigators used a one-sided P value of .05 and 90% power, requiring at least 78 deaths and 486 cases for the primary analysis. At a median follow-up of 5.5 years, 4-year overall survival was 89% in arm 1 and 93% with docetaxel, for an absolute benefit of 4% (one-sided P value of .04). This represented a 30% reduction in risk of death favoring adjuvant docetaxel. A substantial reduction in diseasefree survival (disease-free survival, recurrence, or death from any cause) was observed with the addition of docetaxel: At 6 years, the rate of disease-free survival was 65% in arm 1 vs 55% in arm 2, for an absolute 10% difference between the 2 arms (P = .04). Docetaxel also achieved a reduction in distant metastases at any time during the trial compared with androgen suppression and radiotherapy alone; 41 events were observed in arm 1 and 26, in arm 2. The risk of biochemical failure was reduced by 20% in the docetaxelcontaining arm.

Deaths due to cancer were reported in 23 patients in arm 1 vs 16 patients in arm 2. Other causes of death included second primary cancer (12 in arm 1 and 5 in arm 2), protocol treatment (0 vs 2, respectively), and unknown (0 vs 4, respectively). Adverse events were as expected, with more grade 3 and 4 hematologic toxicity in the docetaxel arm. Published just prior to the ASCO Annual Meeting, the GETUG 12 trial found that docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localized prostate cancer.4 These investigators stressed that longer follow-up is needed to determine whether such therapy also improves metastasis-free or overall survival. n

Disclosure: This study was funded by the National Cancer Institute. Dr. Sandler has served as a consultant or advisor to AstraZeneca, Bayer, Eviti, Janssen Pharmaceuticals, and Medivation/ Astellas; and has received research funding from Myriad Genetics. Dr. Ryan reported no potential conflicts of interest.

References 1. Sandler HM, Hu C, Rosenthal SA, et al: A phase III protocol of androgen suppression and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). 2015 ASCO Annual Meeting. Abstract LBA5002. Presented May 31, 2015. 2. Sweeney C, Chen YH, Carducci MA, et al: Impact on overall survival with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: An ECOG-led phase III randomized trial. 2014 ASCO Annual Meeting. Abstract LBA2.

RTOG 0521: Overall Survival Benefit With Upfront Docetaxel ■■ Docetaxel extended overall survival as part of adjuvant treatment of highrisk localized prostate cancer. ■■ This is the first phase III study to demonstrate a benefit for docetaxel upfront in the treatment of prostate cancer. ■■ Longer follow-up is needed to demonstrate whether docetaxel should be used routinely in the adjuvant setting.

3. James ND, Spears MR, Clarke NW, et al: Survival with newly diagnosed metastatic prostate cancer in the ‘docetaxel era’: Data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). Eur Urol 67:1028-1038, 2015.

4. Fizazi K, Faivre L, Delva R, et al: Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): A phase 3 randomised controlled trial. Lancet Oncol. May 28, 2015 (early release online).

EXPERT POINT OF VIEW

ormal discussant of this trial Ian Tannock, MD, PhD, DSc, of Princess Margaret Cancer Centre and University of Toronto, Canada, took issue with the design of RTOG 0521. He questioned the use of one-sided P values instead of conventional two-sided P values, noting that overall survival would have been P = .08 and not statistically significant if a two-sided P value had been used. He also noted that a hazard ratio of 0.49 is an unlikely and unattainable target, since no phase III trial has shown greater than a 50% reduction in all-cause annual death rate. “An effect of docetaxel in reducing deaths from other causes or second primary cancers seems likely to be a statistical artifact,” stated Dr. Tannock.

Based on the one-sided P value, I question whether there is sufficient evidence to recommend docetaxel and androgen-deprivation therapy routinely to men with M0 [nonmetastatic] disease. —Ian Tannock, MD, PhD, DSc

“Based on the one-sided P value, I question whether there is sufficient evidence to recommend docetaxel and androgen-deprivation therapy routinely to men with M0 [nonmetastatic] disease. If there is no effect on survival, chemotherapy delayed is toxicity delayed and is the preferred strategy,” he said. “This might change with longer follow-up,” conceded Dr. Tannock. In contrast, he recommended docetaxel for men with high-risk metastatic disease at or soon after diagnosis, based on evidence from CHAARTED and STAMPEDE.

Causes of Death Dr. Tannock called the causes of death “strange” and said that seven more deaths due to prostate cancer only in the control arm were counterbalanced by six deaths due to toxicity or unknown causes in the docetaxel arm. Dr. Sandler said he would call the causes of death “perplexing” rather than strange. He pointed to the difficulty in accurately obtaining causes of death in a large trial conducted at many centers around the world. “Central review did the best they could, but there was probably some uncertainty in assigning cause of death,” Dr. Sandler commented. n Disclosure: Dr. Tannock reported no potential conflicts of interest.

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In relapsed multiple myeloma,

TO DISRUPT THE CYCLE OF DIMINISHING RESPONSES,

IS DEPTH THE ANSWER ?

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

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

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

The ASCO Post | JUNE 25, 2015

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Direct From ASCO

ASCO Releases Payment Reform Proposal to Support Higher Quality, More Affordable Cancer Care

SCO released a proposal to significantly improve the quality and affordability of care for cancer patients. ASCO’s Patient-Centered Oncology Payment: Payment Reform to Support Higher Quality, More Affordable Cancer Care

to high-quality, evidence-based care,” said ASCO Immediate Past President Peter Paul Yu, MD, FACP, FASCO. “Furthermore, we believe that PCOP would qualify as an alternative payment model, thereby helping to advance fed-

With today’s health-care system in profound transition, it is critically important that payment systems provide medical practices with the flexibility needed to be compensated fairly and adequately. —Robin Zon, MD, FACP, FASCO

(PCOP) proposal is designed to simultaneously improve services to patients and reduce spending for Medicare and other payers. “ASCO has developed a payment reform proposal that addresses the serious financial challenges facing today’s oncology practices, addresses the problems of affordability facing both payers and patients, and ensures that patients with cancer will be able to receive the full range of services that are critical

eral goals for improving the quality and affordability of health care.” According to ASCO, the PCOP proposal would meet the definition of an Alternative Payment Model as set out in recently enacted legislation that repealed Medicare’s Sustainable Growth Rate formula. The Medicare Access and CHIP Reauthorization Act of 2015 encourages development of alternatives to the current Medicare feefor-service payment system as a strat-

egy to achieve higher quality, more affordable care. ASCO’s proposal addresses major problems in today’s fee-for-service system, such as inadequate payment for the wide range of services critical to supporting patients with cancer, and managing a complex illness that often changes from day to day. The proposal acknowledges that oncology practices across the United States have different capabilities and face different challenges depending on their individual marketplace and practice environment. It provides examples of three different payment systems that practices can choose to adopt, all of which would cover many more cancer care services not currently covered by Medicare. “With today’s health-care system in profound transition, it is critically important that payment systems provide medical practices with the flexibility needed to be compensated fairly and adequately—preventing disruption to the care we provide patients, allowing physicians to tailor services to the unique needs of individual patients, and without increasing financial burdens

on patients,” said ASCO’s Past Clinical Practice Committee Chair Robin Zon, MD, FACP, FASCO. “ASCO’s PatientCentered Oncology Payment proposal not only provides that flexibility, but also introduces much-needed stability into cancer care, to ensure that patients receive the full range of services they need to fight their disease.” The PCOP proposal incorporates extensive input that ASCO received on an earlier draft proposal, Consolidated Payments for Oncology Care (CPOC), which was released in May 2014. Over the past year, many ASCO members and other stakeholders have endorsed the need for payment reform in oncology and provided suggestions on ways to improve the CPOC model—input used to develop the PCOP proposal. ASCO is soliciting comments on its payment reform model through July 20, 2015. For more information and the complete text version of the ASCO payment reform model, please visit www.asco.org/paymentreform. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Releases Updated, Expanded Set of Survivorship Care Planning Templates

SCO has issued an updated and expanded set of treatment and survivorship care plan templates for oncology care professionals and patients with cancer. The templates serve to enhance ASCO’s existing suite of tools to help providers and patients fully plan a course of cancer treatment, from diagnosis to survivorship care. This new release includes updated versions of ASCO’s disease-specific survivorship care plan templates for

breast cancer, colorectal cancer, small and non–small cell lung cancer, and diffuse large B-cell lymphoma, as well as a new prostate cancer survivorship care plan template. Also available is an updated version of ASCO’s treatment plan, which is intended to be given at the time of diagnosis, and sets the stage for the development of the treatment summary and followup care plan included in a survivorship care plan.

All told, the six ASCO disease-specific survivorship care plan templates cover more than 50% of all cancer diagnoses. The ASCO templates were developed based on the “American Society of Clinical Oncology Clinical Expert Statement on Cancer Survivorship Care Planning,” published in the Journal of Oncology Practice. This 2014 ASCO statement identified the essential components of a survivorship care plan, as

defined through a multidisciplinary consensus process, and has been endorsed by the Commission on Cancer of the American College of Surgeons. The templates are available as part of ASCO’s Cancer Survivorship Compendium at www.asco.org/practiceresearch/asco-cancer-survivorshipcompendium. n © 2015. American Society of Clinical Oncology. All rights reserved.

Registration Open for 2015 Community Research Forum Annual Meeting

egistration is now open for the Community Research Forum (CRF) Annual Meeting, which will take place on September 20 to 21, at ASCO Headquarters in Alexandria, Virginia. Join fellow physician investi-

gators and research staff from all types of community-based research sites and programs to discuss barriers and propose solutions to common challenges in conducting research. This year, CRF has also received a

grant from ASCO’s Conquer Cancer Foundation Mission Endowment Fund to award a stipend to up to 20 research staff from community-based research sites to attend the 2015 Meeting. Visit www.asco.org/communityre-

ASCOPost.com | JUNE 25, 2015

PAGE 27

Direct From ASCO

New Resources Developed by ASCO’s Community Research Forum

he ASCO Community Research existing resources covering a range program administration, budget ASCO’s 2015 Community Forum (CRF) is a solution-oriented of topics, including tips for getting management, study start up, project Research Forum Annual Meeting The need for specific resources venue for community research sites to started as a research site, minimum management, management of trial overcome barriers to conducting clinical standards and exemplary attributes participants, and data management. is typically identified through feedtrials. Each year, the CRF council, comof clinical trial sites, standard opThese tools and resources can be back received from participants at the prising ASCO member volunteers, selects erating procedures, good clinical found at asco.org/practice-research/ CRF’s Annual Meeting. This year’s continued on page 28 topic areas and specific solution-oriented research practices, general research community-research-forum. projects for working groups to make the projects a reality. These projects address challenges related to conducting clinical research in the community setting. Ultimately, the CRF and its initiatives faciliNOW ENROLLING tate community-based research. The CRF released several online tools and resources over the past year to help cancer researchers and their staffs conduct and manage clinical trials. Rea clinical trial program created by Pfizer to investigate sources include: the potential biosimilarity of several products • ASCO Clinical Trial Workload Astrastuzumab rituximab infliximab adalimumab bevacizumab sessment Tool: A free, user-friendly online resource to help research adCLINICAL TRIALS STUDY DESIGN ministrators assess clinical-trial associated workload of staff, based on the METASTATIC BREAST CANCER B327-02 complexity of research protocols and Patients with HER2+ mBC who have not received PF-05280014 + paclitaxel vs Herceptin® (trastuzumab) the number of patients assigned to each prior therapy in the first-line setting with the + paclitaxel in the first-line treatment of patients with exception of endocrine therapy staff member. The tool enables adminHER2+ metastatic breast cancer (mBC) Target enrollment: 690 patients istrators to more effectively monitor A global, phase 3, comparative clinical trial evaluating the and manage staff capacity, productivity, efficacy, safety, pharmacokinetics (PK), and immunogenicity 1:1 randomization and needs. Results from the tool can of PF-05280014, an investigational compound being double-blind studied as a potential biosimilar to Herceptin. be used in a variety of ways, including trastuzumab rituximab infliximab adalimumab bevacizumab • Primary endpoint: objective response rate (ORR) budgeting and new staff justifications. PF-05280014 + paclitaxel trastuzumab + paclitaxel • NCT01989676 The tool provides site-specific, individual staff–specific, and protocol-specific reports. Findings from a national study B328-06 FOLLICULAR LYMPHOMA using this tool are expected to be pubPatients with LTB-FL who have not received prior PF-05280586 vs Rituxan®/MabThera (rituximab) for lished later this year. therapy in the first-line setting the first-line treatment of patients with CD20-positive, • The ASCO Research Program Target enrollment: 394 patients low tumor burden follicular lymphoma (LTB-FL) Quality-Assessment Tool: Basics A global, phase 3, comparative clinical trial evaluating for a Quality Community-Based Rethe efficacy, safety, PK, and immunogenicity of 1:1 randomization search Site is a free, downloadable PF-05280586, an investigational compound being double-blind studied as a potential biosimilar to Rituxan/MabThera. tool designed to help community• Primary endpoint: ORR sites develop an inrituximab based research infliximab adalimumab bevacizumab PF-05280586 rituximab • NCT02213263 ternal quality assurance program and exceed the minimum standards of conducting clinical research. The tool ADVANCED NON-SQUAMOUS NSCLC B73910-03 also provides an overview of ASCO’s Eligible patients with advanced non-squamous recommendations for the compoPF-06439535 + paclitaxel and carboplatin vs NSCLC who have not received prior therapy in the nents needed for an internal qualityAvastin® (bevacizumab) + paclitaxel and carboplatin first-line treatment setting and who are eligible to receive carboplatin/paclitaxel/bevacizumab in the first-line treatment of patients with advanced assessment program. A checklist is inTarget enrollment: 798 patients non-squamous NSCLC cluded to help researchers conduct an A global, phase 3, comparative clinical trial evaluating assessment to see how their research 1:1 randomization the efficacy, safety, PK, and immunogenicity of program measures up to these key double-blind PF-06439535, an investigational compound being quality standards. The CRF recently studied as a potential biosimilar to Avastin. received a Conquer Cancer Founda• Primary endpoint: ORR PF-06439535 + paclitaxel bevacizumab + paclitaxel • NCT02364999 and carboplatin and carboplatin tion of the American Society of Clinical Oncology Mission Endowment PF-05280014, PF-05280586, and PF-06439535 are investigational compounds. grant to develop an online version of For more information about these trials, including secondary This information is current as of April 2015. this tool, which is expected to be reendpoints and eligibility criteria, please visit: HER2=human epidermal growth factor receptor 2; NSCLC=non-small cell lung cancer. leased in early 2016. Herceptin is a registered US trademark of Genentech Inc. www.pfizercancertrials.com and www.clinicaltrials.gov Rituxan is a registered US trademark of Biogen Idec Inc. • Resources for Researchers: Availor call the Pfizer clinical trial call center at 1-800-718-1021. MabThera is a trademark of F. Hoffman-La Roche AG. Avastin is a registered US trademark of Genentech, Inc. able on the CRF’s website, resources include comprehensive materials related to conducting and managing clinical trials. It includes links to

REFLECTIONS–

BIO741015-01

April 2015

The ASCO Post | JUNE 25, 2015

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Direct From ASCO

2015 ASCO Annual Meeting Planning Committees

he ASCO Annual Meeting highlights the latest research and treatment advances in oncology, with more than 28,000 oncology professionals attending each year. ASCO wishes to acknowledge the volunteers on this year’s Cancer Education and Scientific Program Committees, and thank them for their time and expertise in developing the Annual Meeting educational and scientific programs.

Cancer Education Committee The Cancer Education Committee, comprising 24 tracks, assesses the need for, plans, develops, and initiates the education programs of the Society, with special emphasis on the Annual Meeting. John V. Cox, DO, MBA, FASCO, Chair Apar Kishor Ganti, MD, MBBS, Chair-Elect Gini F. Fleming, MD, Immediate Past Chair Lillian L. Siu, MD, Board Liaison Breast Cancer Maxine S. Jochelson, MD, Track Leader Jennifer A. Brown, MD Angela DeMichele, MD Charles E. Geyer Jr, MD, FACP Raquel Nunes, MD Debra A. Patt, MD, MPH, MBA Hope S. Rugo, MD Julia R. White, MD Cancer Prevention, Genetics, and Epidemiology Joshua David Schiffman, MD, Track Leader Monique A. De Bruin, MD Jeri Kim, MD P. Kelly Marcom, MD Howard L. McLeod, PharmD

Community Research Forum continued from page 27

meeting, scheduled for September 20 to 21, 2015, will host presentations and panels geared toward health care professionals who conduct cancer clinical trials in a community setting. This meeting provides a unique forum for community-based researchers and research staff to discuss barriers and propose solutions to common challenges in conducting research, as well as provide input on ASCO programs and policy issues affecting clinical research. It also provides an exclusive opportuni-

Electra D. Paskett, PhD Ming Tai-Seale, PhD Donald Lawrence Wickerham, MD Care Delivery and Practice Management David G. Pfister, MD, Track Leader Aditya Bardia, MBBS, MPH Kelly Bugos, RN John Emmett Hennessy, MBA, CMPE Thomas H. Openshaw, MD Jeffery C. Ward, MD Central Nervous System Tumors Manmeet Singh Ahluwalia, MD, Track Leader Jaishri O’Neill Blakeley, MD Roger Stupp, MD Clinical Trials Janet Dancey, MD Sumithra J. Mandrekar, PhD Bhupinder Singh Mann, MBBS Apostolia Maria Tsimberidou, MD, PhD Developmental Therapeutics and Translational Research Roisin M. Connolly, MBBS, Track Leader Howard A. Burris, MD Francisco J. Esteva, MD, PhD John Charles Morris, MD Ethics Jon C. Tilburt, MD Beverly Moy, MD Gastrointestinal (Colorectal) Cancer Martin R.Weiser, MD, Track Leader Chris R. Garrett, MD Donald A. Richards, MD, PhD Henry Q. Xiong, MD Gastrointestinal (Noncolorectal) Cancer Matthew H. G. Katz, MD, FACS, Track Leader Tanios S. Bekaii-Saab, MD Jimmy J. Hwang, MD Se Hoon Park, MD Vincent J. Picozzi, MD Manish A. Shah, MD Genitourinary Cancer Andrea Borghese Apolo, MD, ty for participants to network and collaborate with investigators and research staff from all types of community-based research sites and programs. Learn more about the Community Research Forum at asco.org/practiceresearch/community-research-forum. n Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “New Resources Developed by ASCO’s Community Research Forum.” https://am.asco.org/new-resourcesdeveloped-asco’s-community-research-forum. All rights reserved.

Track Leader Thomas E. Hutson, DO, PharmD, FACP Jose A. Karam, MD John Ward McClean, MD Stephen Boyd Riggs, MD Nicholas J. Vogelzang, MD, FASCO Geriatric Oncology Andrew S. Artz, MD, MS William P. Tew, MD William W. Tse, MD Gynecologic Cancer Linda R. Duska, MD, Track Leader Helen Mackay, MD Matthew A. Powell, MD Head and Neck Cancer Anthony Cmelak, MD, Track Leader Matthew G. Fury, MD Apar Kishor Ganti, MD, MBBS John Truelson, MD Health Services Research and Quality of Care Jennifer W. Mack, MD, Track Leader Daniel J. Becker, MD Nina A. Bickell, MD, MPH Dawn L. Hershman, MD Bruce Lee Jacobs, MD Nicole Kuderer, MD Leukemia, Myelodysplasia, and Transplantation David Leibowitz, MD, Track Leader Jonathan Michael Gerber, MD Jeffrey E. Lancet, MD Lung Cancer Laura Quan Man Chow, MD, Track Leader Martin J. Edelman, MD Craig H. Reynolds, MD David R. Spigel, MD Glen J. Weiss, MD Mauro Zukin, MD Lymphoma and Plasma Cell Disorders Grzegorz S. Nowakowski, MD, Track Leader Jeffrey Matous, MD John M. Pagel, MD, PhD

Donna Ellen Reece, MD Michael A. Thompson, MD, PhD Melanoma/Skin Cancers Suraj S. Venna, MD, Track Leader Sanjiv S. Agarwala, MD Jason John Luke, MD, FACP Janice M. Mehnert, MD Ahmad A. Tarhini, MD, PhD Patient and Survivor Care Karen L. Smith, MD, Track Leader Deborah Mayer, PhD, AOCN, ANP-BC Barbara J. Miller, MS, PA-C Maria Alma Rodriguez, MD Nagendra Tirumali, MD Pediatric Oncology Gregory T. Armstrong, MD, MSCE, Track Leader Najat C. Daw, MD Stewart Goldman, MD Joel A. Weinthal, MD Professional Development Anne S. Tsao, MD, Track Leader Kristin Anderson, MD, MPH Kelly J. Cooke, DO Laura Williams Goff, MD Lee M. Krug, MD Jason Michael Samuelian, MD Sarcoma Gary K. Schwartz, MD, Track Leader L. Johnetta Blakely, MD Robert Mikael Henshaw, MD Min S. Park, MD, MS Tumor Biology Elizabeth A. Maher, MD, PhD, Track Leader Elise C. Kohn, MD Kimryn Rathmell, MD, PhD Eliezer Mendel Van Allen, MD

Scientific Program Committee The Scientific Program Committee, made up of 22 tracks and a biostatistical core, reviews and selects abstracts for presentation at the Annual Meeting and publication in the Programs/Proceedings. Members serve a 3-year term

Together, we’re taking it down.

While nearly 1 in 2 people will get cancer in their lifetime, 2 in 3 will survive it.* And that’s a profound testament to the progress you’ve helped forge as we work collectively to make it harder for cancer to survive.

Join The Campaign to Conquer Cancer at conquer.org/progress. #ConquerCancer * CancerProgress.Net. Progress & Timeline. Timeline. Major Milestones Against Cancer. Available at: http://cancerprogress.net/timeline/major-milestones-against-cancer. Accessed April 7, 2015.

ASCOPost.com | JUNE 25, 2015

PAGE 29

Direct From ASCO on the committee to plan, develop, and initiate the scientific sessions at the Annual Meeting. Alan P. Venook, MD, Chair Lynn Mara Schuchter, Chair-Elect Jedd D. Wolchok, MD, PhD, Immediate Past Chair Biostatistics Katherine Panageas, PhD, Track Leader Urania Dafni, ScD Susan G. Hilsenbeck, PhD Wendy B. London, PhD Ying Lu, PhD Sumithra J. Mandrekar, PhD Donna Niedzwiecki, PhD Breast Cancer—HER2/ER Priya Rastogi, MD, Track Leader Carey K. Anders, MD Tufia C. Haddad, MD Cornelia Liedtke, MD Shanu Modi, MD Patrick Glyn Morris, MD Alexandra Thomas, MD Breast Cancer—Triple-Negative/ Cytotoxics/Local Therapy Steven J. Isakoff, MD, PhD, Track Leader Eleanor Elizabeth Harris, MD Tari A. King, MD Pamela N. Munster, MD Deborah Toppmeyer, MD Tiffany A. Traina, MD Janice Maria Walshe, MD Cancer Prevention, Genetics, and Epidemiology James M. Foran MD, FRCPC, Track Leader Habibul Ahsan, MBBS, MSc Eric Andrew Collisson, MD Adam J. Olszewski, MD Brian M. Wolpin, MD Central Nervous System Tumors Andrew B. Lassman, MD, Track Leader Eric L. Chang, MD Howard Alan Fine, MD Daphne A. Haas-Kogan, MD Developmental Therapeutics—

Clinical Pharmacology and Experimental Therapeutics Miguel Angel Villalona-Calero, MD, Track Leader Emiliano Calvo, MD, PhD Ryan Bruce Corcoran, MD, PhD Gerald Steven Falchook, MD Herbert Hurwitz, MD Robin Kate Kelley, MD Scott Kopetz, MD Timothy Anthony Yap, PhD, MBBS, BSc, MRCP Developmental Therapeutics— Immunotherapy Neil Howard Segal, MD, PhD, Track Leader Charlotte Eielson Ariyan, MD, PhD Gregory Lawrence Beatty, MD, PhD Jonathan S. Cebon, MD, PhD Lawrence Fong, MD Zihai Li, MD, PhD Andrew Parsa, MD, PhD Gastrointestinal (Colorectal) Cancer Edward Chu, MD, Track Leader Chloe Evelyn Atreya, MD, PhD Nancy N. Baxter, MD Gong Chen, MD, PhD Steven J. Cohen, MD Gunnar Folprecht, MD Kimmie Ng, MD, MPH Bert H. O’Neil, MD Thomas John Semrad, MD, FACP Richard H. Wilson, MD Zhen Zhang, MD, PhD Gastrointestinal (Noncolorectal) Cancer Andrew H. Ko, MD, Track Leader Ghassan K. Abou-Alfa, MD Waddah B. Al-Refaie, MD Karyn A. Goodman, MD Syma Iqbal, MD Milind M. Javle, MD Lisa A. Kachnic, MD Geoffrey Yuyat Ku, MD, MBA Emil Lou, MD, PhD Nipun B. Merchant, MD James Posey, MD Genitourinary Cancer

Help Your Patients Catch Up on the Latest Research From the 2015 ASCO Annual Meeting

irect your patients to www.cancer.net/blog for podcasts with ASCO experts discussing the research that was presented at the 2015 ASCO Annual Meeting. This series of “Research Round Up” pod-

casts provides the latest information on treatment and care for people with cancer and will help your patients understand how it affects them. These podcasts will continue throughout the summer, and will cover new research on several different types of cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

Michael J. Morris, MD, Track Leader Peter Albers, MD Kathleen A. Cooney, MD Robert Dreicer, MD Terence W. Friedlander, MD Noah M. Hahn, MD Jonathan E. Rosenberg, MD Mark N. Stein, MD Cora N. Sternberg, MD Scott T. Tagawa, MD, MS Neha Vapiwala, MD Gynecologic Cancer David R. Spriggs, MD, Track Leader John K. Chan, MD Levi S. Downs Jr., MD Paul Haluska, MD, PhD Rebecca Sophie Kristeleit, MD, PhD Kunle Odunsi, MD Head and Neck Cancer Quynh-Thu Le, MD, Track Leader John F. Deeken, MD Robert L. Ferris, MD, PhD, FACS Robert I. Haddad, MD Vassiliki Papadimitrakopoulou, MD Health Services Research and Quality of Care Helen M. Parsons, PhD, Track Leader George J. Chang, MD, MS Shawn Dana Glisson, MD, FACP Monika K. Krzyzanowska, MD, MPH Rebecca A. Miksad, MD Arden M. Morris, MD Craig Evan Pollack, MD Leukemia, Myelodysplasia, and Transplantation Michael Russell Bishop MD, FACP, Track Leader Charalambos Andreadis, MD, MSCE Ravi Bhatia, MD Joseph G. Jurcic, MD Celalettin Ustun, MD Lung Cancer—Non–Small Cell Local-Regional/Small Cell/ Other Thoracic Cancers Gregory J. Riely, MD, PhD, Track Leader Edward B. Garon, MD Scott N. Gettinger, MD Thomas A. Hensing, MD Chuong D. Hoang, MD Tom John, PhD, FRACP, MBBS Feng Ming Kong, MD Lung Cancer—Non–Small Cell Metastatic Grace K. Dy, MD, Track Leader

Matthew A. Gubens, MD Mark G. Kris, MD Geoffrey R. Oxnard, MD Luis Paz-Ares MD, PhD Nathan A. Pennell, MD, PhD Jonathan Riess, MD Lecia V. Sequist, MD, MPH Lymphoma and Plasma Cell Disorders Saad Zafar Usmani, MD, FACP, Track Leader Ranjana H. Advani, MD Alexander M. Lesokhin, MD Sagar Lonial, MD Thomas G. Martin III, MD Owen A. O’Connor, MD, PhD Melanoma/Skin Cancers Svetomir Markovic, MD, PhD, Track Leader Paul B. Chapman, MD Adil Daud, MD Georgina V. Long, PhD, BSc, FRACP, MBBS Patient and Survivor Care Shari Beth Goldfarb, MD, Track Leader Tessa Cigler, MD, MPH Tara O. Henderson, MD, MPH Monica Alexandra Iriso, MD Arif Kamal, MD Kavitha Ramchandran, MD Charles L. Shapiro, MD Katherine Van Loon, MD, MPH Pediatric Oncology Lisa Diller, MD, Track Leader Steven G. DuBois, MD Jeffrey Toretsky, MD Sarcoma Jonathan C. Trent II, MD, PhD, Track Leader Venkata Ramesh Bulusu, MD, FRCR Eric K. Nakakura, MD, PhD Dennis A. Priebat, MD Tumor Biology Victoria Louise Seewaldt, MD, Track Leader Michael J. Birrer, MD, PhD Wolfgang Michael Korn, MD Mark M. Moasser, MD Andrew B. Nixon, PhD David Potter, MD, PhD Lawrence H. Schwartz, MD © 2015. American Society of Clinical Oncology. All rights reserved.

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

San Francisco Marriott Marquis

Boston, Massachusetts

San Francisco, California

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

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

Important Safety Information CONTRAINDICATIONS None.

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

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

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

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

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

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

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

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

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

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

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

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

The ASCO Post | JUNE 25, 2015

PAGE 32

News Cancer Research

National Cancer Institute Pulls PSA Data From SEER By Ronald Piana

n a move that reverberated through much of the cancer research community, the National Cancer Institute (NCI) recently announced that it had removed all prostate-specific antigen

B:16.75”

(PSA) data from its current Surveillance, Epidemiology, and End Results (SEER) data submission and associated SEER-Medicare programs. This action was in response to problems that

included the reporting of inaccurate PSA values and misinterpretation of PSA variables.1 Speaking with The ASCO Post, David F. Penson, MD, Director of the Center

for Surgical Quality and Outcomes, Department of Urologic Surgery, at Vanderbilt University, Nashville, cautioned, “Withdrawal of these data from SEER will have major impacts on the

T:16.25” S:14.625”

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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field of prostate cancer research and for administrators within the health-care community.”

Researchers Need to Rethink Large Databases Initiated in 1973 by the NCI, the SEER program is one of the oldest and most trusted registries in the world. The

SEER program is legislatively mandated to collect population-based cancer data from 17 regions across the United States, representing approximately 28% of the nation’s population. According to Dr. Penson, before pursuing analyses using SEER and SEER-Medicare programs, the data will have to be redesigned in light of the detected problems.

“Journals will not be able to accept SEER studies that rely on the PSA data as a primary variable of interest, including those that use PSA in risk-stratification systems to adjust for confounding or in cohort identification,” said Dr. Penson. The NCI is currently reviewing the entire data set and implementing protocols to ensure the quality of the data in

Dr. Penson raised a larger issue for health-care analyses beyond PSA data: If the data from SEER—one of the most highly regarded registries in the world— are problematic, it calls into question all other large data sets, such as those used by Medicare or Medicaid, the nation’s

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As a community, we have to do the really hard work and collect primary data. It’s time for us to stop doing big data fishing expeditions and taking the easy way out. S:10”

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

Loss of Trust Needs to Be Addressed

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reported (< 1%). reported KYPROLIS (< 1%).can KYPROLIS cause elevations can causeof elevations serum transaminases of serum transaminases and bilirubin.and Withhold bilirubin.Description Withhold Description of SelectedofAdverse Selected Drug Adverse Reactions. Drug Renal Reactions. Events: Renal The Events: most common The most renal common renal KYPROLIS in KYPROLIS patients experiencing in patients experiencing Grade 3 or greater Gradeelevations 3 or greater of elevations transaminases, of transaminases, bilirubin, or other bilirubin,adverse or otherreactions adverse were reactions increasewere in blood increase creatinine in blood (24%) creatinine and renal (24%) failure and (9%), renal which failurewere (9%),mostly which were mostly liver abnormalities liver abnormalities until resolveduntil or returned resolved to or baseline. returned to After baseline. resolution, Afterconsider resolution, if restarting consider if restarting Grade 1 or Grade Grade 21 inorseverity. Grade 2Grade in severity. 3 renalGrade adverse 3 renal reactions adverse occurred reactions in 6% occurred of patients in 6%and of patients and KYPROLIS is KYPROLIS appropriate. is appropriate. Monitor liver Monitor enzymesliver frequently enzymes[see frequently Dosage [see and Dosage Administration and Administration and Gradeand 4 events Grade occurred 4 events in 1%. occurred Discontinuations in 1%. Discontinuations due to increased due to blood increased creatinine blood andcreatinine acute renal and acute renal Adverse Reactions]. AdverseEmbryo-fetal Reactions]. Embryo-fetal Toxicity. KYPROLIS Toxicity. canKYPROLIS cause fetal canharm cause when fetaladministered harm when administered to a failuretowere a 1% failure each. were In 1% one each. patient, In death one patient, occurred death withoccurred concurrent withsepsis concurrent and worsening sepsis andrenal worsening renal pregnant woman pregnant basedwoman on its mechanism based on itsofmechanism action and of findings actioninand animals. findings There in animals. are no adequate There are and no adequate and[see function function Dosage and [seeAdministration]. Dosage and Administration]. Peripheral Neuropathy: Peripheral Neuropathy: Peripheral neuropathy Peripheral(including neuropathy (including well‑controlledwell‑controlled studies in pregnant studieswomen in pregnant usingwomen KYPROLIS. using Carfilzomib KYPROLIS.caused Carfilzomib embryo‑fetal caused toxicity embryo‑fetal in all toxicity in of all events peripheral events ofsensory peripheral neuropathy sensoryand neuropathy peripheral andmotor peripheral neuropathy) motor occurred neuropathy) in 14% occurred of in 14% of pregnant rabbits pregnant at doses rabbits that were at doses lower thatthan were in patients lower than receiving in patients the recommended receiving the recommended dose. Femalesdose. of Females patientsofenrolled patients in clinical enrolled trials. in clinical Grade 3trials. peripheral Grade neuropathy 3 peripheraloccurred neuropathy in 1% occurred of patients. in 1%Serious of patients. Serious reproductive potential reproductive should potential be advised should to be avoid advised becoming to avoid pregnant becoming whilepregnant being treated while being with KYPROLIS. treated with KYPROLIS. peripheral neuropathy peripheralevents neuropathy occurred events in <occurred 1% of patients, in < 1%which of patients, resulted which in dose resulted reduction in dose in <reduction 1% in < 1% If this drug isIfused this drug duringis pregnancy, used duringorpregnancy, if the patient or ifbecomes the patient pregnant becomes while pregnant taking this whiledrug, taking thethis and drug,treatment the and discontinuation treatment discontinuation in < 1%. Withhold in < 1%. or discontinue Withhold or treatment discontinue as treatment recommended as recommended [see [see patient shouldpatient be apprised shouldofbethe apprised potential of hazard the potential to the hazard fetus [see to the Usefetus in Specific [see Use Populations]. in Specific Populations]. Dosage and Administration]. Dosage and Administration]. Herpes VirusHerpes Infection: Virus Herpes Infection: zosterHerpes reactivation zosterwas reactivation reportedwas in 2% reported in 2% ADVERSE REACTIONS: ADVERSE REACTIONS: The following adverse The following reactions adverse are discussed reactions are in greater discussed detail in in greater other detail sections in otherofsections patients. Consider of patients. antiviral Consider prophylaxis antiviralfor prophylaxis patients who for patients have a history who have of herpes a history zoster of herpes infection. zoster infection. of the labeling:of the labeling: DRUG INTERACTIONS: DRUG INTERACTIONS: Carfilzomib isCarfilzomib primarily metabolized is primarily via metabolized peptidasevia andpeptidase epoxide and hydrolase epoxide hydrolase • Cardiac Arrest, • Cardiac Congestive Arrest,Heart Congestive Failure,Heart Myocardial Failure,Ischemia Myocardial [seeWarnings Ischemia [see andWarnings Precautions] and Precautions] activities, andactivities, as a result, and the as apharmacokinetic result, the pharmacokinetic profile of carfilzomib profile ofiscarfilzomib unlikely toisbeunlikely affectedto by be affected by • Pulmonary •Hypertension Pulmonary Hypertension [seeWarnings [see andWarnings Precautions] and Precautions] concomitant administration concomitant administration of cytochromeofP450 cytochrome inhibitors P450 andinhibitors inducers.and Carfilzomib inducers.isCarfilzomib not expected is not expected • Pulmonary •Complications Pulmonary Complications [seeWarnings [see andWarnings Precautions] and Precautions] to influence exposure to influence of other exposure drugsof[see otherClinical drugs Pharmacology [see Clinical Pharmacology section of fullsection PI]. of full PI]. • Infusion Reactions • Infusion [see Reactions Warnings [see andWarnings Precautions] and Precautions] USE IN SPECIFIC USE IN POPULATIONS: SPECIFIC POPULATIONS: Pregnancy. Pregnancy. Pregnancy Category PregnancyD Category [see Warnings D [seeand Warnings and • Tumor Lysis•Syndrome Tumor Lysis [see Syndrome Warnings [see andWarnings Precautions] and Precautions] Females of potential reproductive potential shouldtobe advised to avoid becoming pregnant while Precautions].Precautions]. Females of reproductive should be advised avoid becoming pregnant while • Thrombocytopenia • Thrombocytopenia [seeWarnings [see andWarnings Precautions] and Precautions] treated withBased KYPROLIS. on itsofmechanism action and findingsKYPROLIS in animals, KYPROLIS being treatedbeing with KYPROLIS. on its Based mechanism action andoffindings in animals, • Hepatic Toxicity • Hepatic and Hepatic Toxicity Failure and Hepatic [seeWarnings Failure [see andWarnings Precautions] and Precautions] can harm causewhen fetal administered harm when administered a pregnant woman.caused Carfilzomib caused embryo‑fetal can cause fetal to a pregnanttowoman. Carfilzomib embryo‑fetal The most common The most adverse common reactions adverse (incidence reactions of (incidence 30% or greater) of 30%toorKYPROLIS greater) to observed KYPROLIS in clinical observed toxicity in clinical toxicity rabbits in pregnant rabbits doses thatthan wereinlower thanreceiving in patients the recommended in pregnant at doses thatatwere lower patients thereceiving recommended trials of patients trialswith of patients multiple with myeloma multiple were myeloma fatigue,were anemia, fatigue, nausea, anemia, thrombocytopenia, nausea, thrombocytopenia, dyspnea, dose. dyspnea, dose. Ifis KYPROLIS is pregnancy, used duringorpregnancy, or ifbecomes the patient becomes pregnant If KYPROLIS used during if the patient pregnant while taking while this taking this diarrhea, anddiarrhea, pyrexia. and Clinical pyrexia. Trials Clinical SafetyTrials Experience. Safety Experience. Because clinical Because trials clinical are conducted trials are conducted drug,should the patient shouldofbethe apprised of hazard the potential to the fetus.was Carfilzomib was administered drug, the patient be apprised potential to the hazard fetus. Carfilzomib administered under widely under varyingwidely conditions, varyingadverse conditions, reaction adverse ratesreaction observed rates in the observed clinicalintrials the of clinical a drugtrials cannot of a drug cannot intravenously to pregnant ratsduring and rabbits during period of organogenesis at doses intravenously to pregnant rats and rabbits the period of the organogenesis at doses of 0.5, 1, andof 0.5, 1, and be directly compared be directlywith compared rates in with the clinical rates intrials the clinical of another trialsdrug, of another and may drug, not and reflect maythenotrates reflect 2themg/kg/day rates 2inmg/kg/day in rats and 0.8inmg/kg/day in rabbits.was Carfilzomib was notatteratogenic at rats and 0.2, 0.4,and and0.2, 0.8 0.4, mg/kg/day rabbits. Carfilzomib not teratogenic observed in medical observed practice. in medical A total practice. of 526Apatients total of with 526 relapsed patients with and/or relapsed refractory and/or multiple refractory myeloma multiple any myeloma any dose tested.there In rabbits, was in an pre‑implantation increase in pre‑implantation at ≥ 0.4 mg/kg/day dose tested. In rabbits, was anthere increase loss at ≥ 0.4loss mg/kg/day received KYPROLIS received as KYPROLIS monotherapy as monotherapy or with pre‑dose or with dexamethasone. pre‑dose dexamethasone. Patients received Patients a median received of a median and in anearly increase in earlyand resorptions and post‑implantation loss andina fetal decrease in at fetal weight at and an ofincrease resorptions post‑implantation loss and a decrease weight four treatment fourcycles treatment with acycles median withcumulative a medianKYPROLIS cumulativedose KYPROLIS of 993.4 dose mg.ofDeaths 993.4 due mg. to Deaths all due to all thetoxic maternally of 0.8The mg/kg/day. of 0.4 and 0.8inmg/kg/day the maternally dose oftoxic 0.8 dose mg/kg/day. doses ofThe 0.4doses and 0.8 mg/kg/day rabbits arein rabbits are causes withincauses 30 days within of the30last days dose of the of KYPROLIS last dose of occurred KYPROLIS in 37/526 occurred (7%) in 37/526 of patients. (7%)Deaths of patients. not Deaths not approximately 20% and 40%, of respectively, of the recommended doseof in27humans 27 mg/m2 based approximately 20% and 40%, respectively, the recommended dose in humans mg/m2 of based attributed to disease attributed progression to diseasewere progression cardiac were in 5 patients cardiac (acute in 5 patients coronary (acute syndrome, coronary cardiac syndrome, arrest,cardiac on arrest, body surface on body area.surface Nursing area. Mothers. Nursing It isMothers. not known It iswhether not known KYPROLIS whetheris KYPROLIS excreted inishuman excreted in human cardiac disorder), cardiac end‑organ disorder),failure end‑organ in 4 patients failure in(multi‑organ 4 patients (multi‑organ failure, hepatic failure, failure, hepatic renal failure, failure),renalmilk. failure), Since many milk.drugs Since are many excreted drugs are in human excreted milkin and human because milk and of the because potential of for the serious potentialadverse for serious adverse infection in infection 4 patientsin (sepsis, 4 patients pneumonia, (sepsis, pneumonia, respiratory tract respiratory bacterial tract infection), bacterialdyspnea infection), anddyspnea and in nursing reactions reactions infants in nursing from KYPROLIS, infants from a decision KYPROLIS, should a decision be made should whether be made to discontinue whether tonursing discontinue nursing intracranial hemorrhage intracranial in hemorrhage 1 patient each, in 1 patient and 1 each, patientand found 1 patient dead offound unknown dead causes. of unknown Serious causes.orSerious to discontinue or tothe discontinue drug, taking the into drug,account taking into the importance account theofimportance the drug toofthe themother. drug toPediatric the mother. Pediatric adverse reactions adverse were reactions reportedwere in 45% reported patients. in 45% The patients. most common The most serious common adverse serious reactions adverse were reactions Use.were The safety Use.and Theeffectiveness safety and effectiveness of KYPROLISofin KYPROLIS pediatric patients in pediatric havepatients not been have established. not been established. pneumonia (10%), pneumonia acute (10%), renal failure acute (4%), renal pyrexia failure (4%), (3%),pyrexia and congestive (3%), andheart congestive failure (3%). heart Adverse failure (3%).Geriatric Adverse Use. Geriatric In studies Use. of KYPROLIS In studies there of KYPROLIS were nothere clinically weresignificant no clinically differences significantobserved differences in safety observed in safety reactions leading reactions to discontinuation leading to discontinuation of KYPROLIS occurred of KYPROLIS in 15% occurred of patients in 15% and of included patients and congestive included congestive and efficacy between and efficacy patients between less than patients 65 years less than of age 65 and yearspatients of age 65 andyears patients of age 65 and yearsolder. of age Renal and older. Renal heart failure (2%), heart failure cardiac(2%), arrest, cardiac dyspnea, arrest, increased dyspnea, blood increased creatinine, bloodand creatinine, acute renal andfailure acute (1% renal failure (1% Impairment. Impairment. The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS evaluated were in evaluated a Phase 2intrial a Phase in 2 trial in each). Adverse each). reactions Adverse occurring reactions at aoccurring rate of 10% at a or rate greater of 10% areorpresented greater are in Table presented 4. in Table 4. patients withpatients normal with renal normal functionrenal and function those with andmild, thosemoderate, with mild,and moderate, severe renal and severe impairment renal impairment on chronic patientsdialysis. on chronic On average, dialysis. patients On average, werepatients treated were for 5.5 treated cyclesforusing 5.5 cycles KYPROLIS using KYPROLIS Table 4: Incidence Table 4:ofIncidence Adverse Reactions of AdverseOccurring ReactionsinOccurring ≥ 10% of in Multiple ≥ 10% Myeloma of Multiple Myelomaand patients and 2 doses of 15 doses mg/m2ofon15Cycle mg/m 1,2 20 on mg/m Cycle 21,on20Cycle mg/m 2,2 and on Cycle 27 mg/m 2, and on27Cycles mg/m32 on andCycles beyond. 3 and beyond. Patients Treated Patients withTreated KYPROLIS with KYPROLIS The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS not influenced were notbyinfluenced the degreebyofthe baseline degreerenal of baseline renal Patients Patients (N = 526) (N = 526) impairment, including impairment, the including patients on thedialysis. patientsSince on dialysis. dialysisSince clearance dialysis of clearance KYPROLIS ofconcentrations KYPROLIS concentrations [n (%)] [n (%)] has not beenhas studied, not been the studied, drug should the drug be administered should be administered after the dialysis after procedure the dialysis[see procedure Clinical [see Clinical Grade Grade 3 4 GradePharmacology 4 All Grade 3 All Pharmacology section of fullsection PI]. Hepatic of full Impairment. PI]. Hepatic Impairment. The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of of a a EventsEvents Events Event GradesEvents Event Grades KYPROLIS have KYPROLIS not been have evaluated not been in evaluated patients with in patients baselinewith hepatic baseline impairment. hepatic Patients impairment. withPatients the with the following laboratory following values laboratory were excluded values were fromexcluded the KYPROLIS from theclinical KYPROLIS trials:clinical ALT/AST trials: ≥ 3ALT/AST × upper ≥ 3 × upper Fatigue Fatigue 292 (55.5) 292 (55.5) 38 (7.2) 38 (7.2)2 (0.4) 2 (0.4) limit of normallimit (ULN) of normal and bilirubin (ULN) ≥ and 2× bilirubin ULN [see ≥ 2Clinical × ULN Pharmacology [see Clinical Pharmacology section of fullsection PI]. Cardiac of full PI]. Cardiac Anemia Anemia 246 (46.8) 246 (46.8) 111 (21.1) 111 (21.1)7 (1.3) 7 (1.3) Impairment.Impairment. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and IV Class heartIII failure and IV were heartnot failure eligible were not eligible Nausea Nausea 236 (44.9) 236 (44.9)7 (1.3) 7 (1.3) 0 0 for the clinicalfortrials. the clinical Safety in trials. this Safety population in thishas population not beenhas evaluated. not been evaluated. Thrombocytopenia Thrombocytopenia 191 (36.3) 191 (36.3) 69 (13.1) 69 (13.1) 54 (10.3) 54 (10.3) OVERDOSAGE: OVERDOSAGE: There is no known There isspecific no known antidote specific for KYPROLIS antidote foroverdosage. KYPROLIS In overdosage. the event of In the an event of an b overdosage, monitor overdosage, the patient monitorand theprovide patientappropriate and providesupportive appropriatecare. supportive care. Dyspnea Dyspnea 182 (34.6) 182 (34.6) 25 (4.8) 25 (4.8)1 (0.2)b 1 (0.2) NONCLINICAL NONCLINICAL TOXICOLOGY: TOXICOLOGY: Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, and Impairment and Impairment of Fertility. of Fertility. Diarrhea Diarrhea 172 (32.7) 172 (32.7)4 (0.8) 4 (0.8)1 (0.2) 1 (0.2) Carcinogenicity Carcinogenicity studies have studies not beenhave conducted not beenwith conducted carfilzomib. withCarfilzomib carfilzomib.was Carfilzomib clastogenic wasinclastogenic the in the Pyrexia Pyrexia 160 (30.4) 160 (30.4)7 (1.3) 7 (1.3)2 (0.4) 2 (0.4) in vitro chromosomal in vitro chromosomal aberration testaberration in peripheral test in blood peripheral lymphocytes. blood lymphocytes. Carfilzomib was Carfilzomib not mutagenic was not mutagenic in the in vitro in bacterial the in vitro reverse bacterial mutation reverse (Ames) mutation test and (Ames) was test not and clastogenic was not in clastogenic the in vivo in mouse the in vivo 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.Advise any of these 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 future. But Dr. Penson pointed out that the greater problem is the impact that the flawed PSA data have on the existing urologic literature. “SEER and SEER-Medicare data have been used to address a variety of clinical issues in prostate cancer, and many of the papers written on subjects ranging from comparative effectiveness of treatments, to what patients can expect for outcomes, to issues surrounding PSA screening, and so on, have been based on SEER data. So, now their results come into question,” stressed Dr. Penson.

—David F. Penson, MD

largest insurers. Despite this recent discovery, he noted, the SEER databases offer valuable information when answering difficult clinical and health-care policy issues. “These data banks have real-world longitudinal data from large numbers of patients that are highly generalizable, giving us answers that we could never get in prospective studies of prostate cancer patients,” said Dr. Penson. That said, Dr. Penson called into question the data-collection process. “I know that SEER and SEER-Medicare collect breast cancer data on hormone status, so what are the ramifications if those data are not collected properly? We live in this era of large powerful data sets, and they have a tendency to seduce continued on page 34

The ASCO Post | JUNE 25, 2015

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Expert’s Corner Molecular Oncology

Deciphering the Genetic Variability of Cancer to Advance Precision Oncology Care A Conversation With David B. Solit, MD By Jo Cavallo

David B. Solit, MD

n 2014, Memorial Sloan Kettering Cancer Center (MSKCC) in New York opened the Marie-Josée and Henry R. Kravis Center for Molecular Oncology with the sole purpose of expediting the translation of novel molecular discoveries into clinical innovations to turn the goal of precision oncology care into a reality. Occupying two floors in the cancer center’s research building, the molecular oncology center houses an integrated genomics operation and a next-generation sequencing lab. The genomics operation includes a multidisciplinary team of clinicians, pathologists, cancer biologists, and bioinformaticians. The next-generation sequencing lab performs retrospective analysis of tumor samples from patients enrolled in clinical studies to determine response to therapy. The Center for Molecular Oncology is also coordinating closely with the Molecular Diagnostic Service in the Department of Pathology, which is tasked with prospectively sequencing a patient’s tumor for enrollment in

PSA Data From SEER continued from page 33

us by their size and sheer amount of information. But we also forget some of the basics of clinical research and how these data are collected,” he said. “For instance, in the case of SEER PSA, the program is mandated to collect data (such as Gleason scores) at the individual sites by registrars, and I think that the administrative data on the utilization of tests is very good,” he said. “The problem with these studies is that they rely on clinical characteristics, such as PSA values and comorbidity indices, which these data sets are not truly designed to collect. After all, these data points are not

a clinical study or administration of a targeted therapy. Currently, the Center for Molecular Oncology is limiting prospective genomic sequencing to patients with metastatic solid tumors to potentially match them to clinical studies. Eventually, the center plans to sequence the tumors of all patients with cancer, including blood cancers, in both the primary and metastatic disease settings. To date, the center has sequenced the tumors of more than 4,000 patients and plans to increase that number to 10,000 patients a year. “We will learn a lot more from the clinical sequencing we are doing once we are able to sequence the tumors of a much larger number of patients, and we will know which of the significant mutations that have been discovered and linked to cancer biology are also predictive or prognostic clinically,” said Michael F. Berger, PhD, Associate Director of the Center for Molecular Oncology. In addition to identifying the biolog-

is to facilitate patient enrollment into basket studies, which are clinical trials based on a specific cancer gene or mutation rather than on a specific cancer type. MSKCC’s basket studies are investigating whether patients with many different disease types, such as ovarian,

In my opinion, there is no doubt that in the near future, genomic testing of every patient’s tumor will become standard of care. —David B. Solit, MD

colorectal, and lung cancers, but whose tumors carry a similar molecular signature, all respond to a particular molecularly targeted therapy. The ASCO Post talked with David B. Solit, MD, Director of MSKCC’s Center for Molecular Oncology, about how sequencing the DNA of cancer cells is resulting in improved patient outcomes, the potential of basket trials to accelerate patient enrollment in clinical studies and expedite the development of targeted therapies, and the use of liquid biopsies to select treatment and monitor patient response.

Testing for a Broader Range of Patients Michael F. Berger, PhD

ically relevant mutations in each cancer type and determining the most likely effective course of therapy, a primary goal of the Center for Molecular Oncology necessary for payment, and the law does not mandate their collection.”

Primary Data Needed Dr. Penson continued, “These large administrative data sets have tremendous value for our field if we use them properly, and that is the key. We have to stop publishing secondary data analyses from these large administrative data sets just because the data are relatively easy to obtain and analyze.” He noted that we should not expect these data sets to answer questions that they are not designed to address. “What happened with SEER is not NCI’s fault, nor is it the registries’ fault. They started

Our initial goal is to sequence patients with recurrent or metastatic solid tumors, since these are the patients most in need of novel therapeutic approaches. MSKCC is also in the process of developing a specific assay for patients with leukemia. As our capaci-

Currently, the Center for Molecular Oncology is sequencing the tumors of patients with advanced cancer to determine treatment and potentially enroll them in clinical studies. Will the center also analyze the tumors of all patients with cancer? out on a mandated task to study the incidence, prevalence, and general outcomes in cancer. But as a clinical research community, we’ve taken these data and expected them to answer tough clinical questions. And as time passed, we’ve actually become quite glib about the data,” he commented. “There are researchers in the community who buy a data set and run a single model with 20 variables and write 20 separate papers around that one data set,” Dr. Penson said. “This is done without first questioning whether these data have the power to answer that many questions. We need to reserve these data sets for research ques-

ty to analyze such tumors increases, we plan to offer testing to a broader range of patients with earlier-stage disease, including those whose tumors may be cured by surgery or radiation. We believe that such testing could provide prognostic information that would help doctors counsel patients more accurately on their risk for tumor recurrence and also help identify patients who would most benefit from adjuvant therapies, including chemotherapy.

Improving Patient Care Do you believe that sequencing the genome of all cancers will lead to improved patient outcomes? I believe that it is already proven that genomic profiling is improving patient outcomes in some diseases, such as lung cancer and melanoma. For these types of cancer, sequencing is now considered standard of care. Patients who have lung cancer with EGFR mutations continued on page 35

tions that they can answer in a valid and reliable manner.” Dr. Penson ended with a cautionary comment: “As a community, we have to do the really hard work and collect primary data. It’s time for us to stop doing big data fishing expeditions and taking the easy way out.” n

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

Reference 1. National Cancer Institute: PSA values and SEER data: SEER data, 1973– 2012 (November 2014 submission). Available at seer.cancer.gov/data/psavalues.html. Accessed June 8, 2015.

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Expert’s Corner Precision Oncology Care continued from page 34

are now being treated with newer drugs that are much more effective than the treatments available just a few years ago. Therefore, it is already a reality that this type of molecular profiling is improving patient care. There are still, however, many patients who die of cancer, and genomic profiling will help us identify new drug targets. It will also help direct patients to the trials of novel drugs that are most likely to work based upon their particular genetic profile. Thus, genomic profiling may accelerate the development of novel targeted agents.

‘Cure Is a High Bar to Reach’ Will tailoring therapy based on the biology of patients’ tumors allow more patients to be cured of their disease? The goal is to cure people, but a lot of the newer targeted agents have not been shown to be curative in most patients. For example, imatinib, which is among the biggest targeted therapy success stories, induces remission in the vast majority of patients with chronic myelogenous leukemia (CML). Although imatinib can induce a remission that lasts for many, many years, these patients are rarely cured, and if they stop taking the drug, the cancer usually returns. So cure is a high bar to reach, but that is our ultimate goal. There are examples of targeted agents that can be curative. For example, when given in the adjuvant setting for breast cancer, trastuzumab (Herceptin) can be curative in people whose disease would have likely recurred or become metastatic. It seems that with current drugs, if you use them earlier in the disease course, you may be able to cure patients who otherwise would die of their cancer, but if you wait until the cancer is too established and advanced, cure is difficult to achieve. But that doesn’t mean that there won’t be drugs in the future that could cure patients in this setting.

Identifying Driver Oncogenes What has sequencing cancer DNA told you so far about the disease? We have been working to identify the key driver oncogenes in cancer for over 30 years. The insights from these efforts have allowed us to classify tumors more precisely in terms of their prognosis and etiology, and almost all new drug targets that are being developed in this space have been the result of this type of genetic analysis. Next-generation sequencing is

revolutionizing the field by making genomic analyses dramatically more rapid and less costly. This has led to significant discoveries in just the past few years, including the identification of genes that no one previously knew were mutated in cancer and that are the genetic basis for why those cancers developed. This research will allow for the development of more rational therapies that target the underlying cause of individual tumors. For example, recent genetic studies allowed for the identification of ALK fusions in lung cancer, which then directly led to the testing of ALK inhibitors in those patients. These ALK inhibitors have dramatic activity in patients who have lung cancer with ALK fusions, a disease for which previously there were no effective systemic therapies. The same is true for the BRAF gene in melanoma and other cancers. But there are many patients for whom we do not yet know the drivers of their cancers, and there are many drivers for which we do not yet have an effective targeted therapy.

Next-generation sequencing: Lab at the Center for Molecular Oncology.

Developing Newer Targeted Agents There are a few hundred known mutations linked to cancer, but only a few dozen U.S. Food and Drug Administration (FDA)-approved drugs that target between 20 and 40 of them. How will it be possible to develop and approve drugs for hundreds and maybe thousands of mutations linked to cancer? We as a field have gotten very good at developing selective inhibitors of protein kinases. So if the growth of a cancer is driven by a kinase mutation, we are likely to be able to develop drugs to target the mutated protein. There are still many kinases for which there is no effective drug in clinical use, but there are many drugs in the pipeline, and some of them will surely be approved in the next few years. However, there are other driver mutations that are proving to be much more difficult to target, for example certain types of tumor suppressors in which the gene gets inactivated due to a mutation. It is much more difficult to restore the function of an inactivated protein than it is to inhibit an activated enzyme such as a kinase. Thus, there are many mutated targets in cancer that are clear drivers of transformation, such as TP53 or PTEN, for which we have yet to develop an effective therapeutic strategy. Without such drugs, the full potential of genetic sequencing will be difficult to achieve. In summary, you cannot initiate a

Flow cells: This particular flow cell contains eight lanes and allows researchers to sequence two different human genomes in 6 days at a cost of $5,000 per genome. To put this into perspective, it took 13 years and $2.7 billion for the first draft of the first human genome to be sequenced from 1990 to 2003.

genetic profiling program in a vacuum. It has to be tied with efforts to develop new therapies. We are thus working with a number of pharmaceutical companies to make newer targeted agents available to patients with particular mutation profiles using newer clinical trial designs, including basket studies.

Role of Basket Studies Please talk about the basket studies you have launched. How many of these trials have you opened? Unlike traditional clinical trials, basket studies are not focused on a particular tumor type, but rather on a specific mutation or gene. Thus, they are often open to patients with any cancer type. Currently, we have a halfdozen of these trials actively enrolling patients. Designing a trial that is focused on a mutation and not a specific disease is an effective way to develop drugs for mutations that are common in many cancer types but that are not overwhelmingly prevalent in any particular tumor type.

Is this how clinical trials will be designed in the future, based on the biology of the tumor and not on the cancer site? If you have a mutation that is present in 50% of the patients with a particular cancer type, you do not need a basket study to efficiently develop a drug to target that mutation. In that case, it may be better to do the trial using a traditional study design. But if you have a mutation that is present in 3% or 5% of 20 different tumor types, a basket trial allows the institution to open up just one study designed to test the effects of the drug in 20 different subtypes of cancer at the same time. Therefore, the basket study design is a rational approach for a specific type of mutation profile, but it is not the only type of study that we will be using in the future.

Liquid Biopsies Please talk about the promise of liquid biopsies as a diagnostic tool to spot early continued on page 36

The ASCO Post | JUNE 25, 2015

PAGE 36

Expert’s Corner Precision Oncology Care

The Future of Genetic Testing

continued from page 35

How would you evaluate the progress being made in the care of patients with cancer? We are in the midst of a revolution in the way we diagnose and treat patients with cancer. In my opinion, in just a few years, all patients will have genetic testing performed on their tumor, and this

cancers; treatment effectiveness and resistance; and cancer recurrence. The liquid biopsy approach is showing great promise in its ability to pick up snippets of circulating cancer DNA in a patient’s blood, and the technique is incredibly exciting. It is a technology we are developing along with many, many other groups and many companies. I can say, from our experience, that the technology really works, and in the future, it may be possible to forgo the need for a tumor biopsy in many scenarios. There are still a lot of logistical hurdles to overcome, and the technology is still too expensive and needs to be more accurate and comprehensive before it could be considered for broader use in the clinic. But I have no doubt that this is one method by which genetic testing will be performed in the near future. I do not believe that liquid biopsies will completely replace tumor testing in the near term, but in many situations, liquid biopsies may be more representative of a patient’s overall tumor burden, less expensive, and easier to perform. Liquid biopsy can be used to accomplish two separate goals. First, liquid biopsies can be used to figure out what mutations a tumor harbors, which can then be used to guide treatment selection. Second, the liquid biopsy approach is a potentially useful tool to monitor treatment response, because the amount of the mutation in the blood declines when the patient is responding to treatment and rises when the disease is progressing. Thus, quantitative measures of tumor DNA can be used as a surrogate biomarker of clinical benefit and may eliminate or reduce the need for computed tomography or magnetic resonance imaging to determine the state of a patient’s cancer.

information will be used to determine which treatments will be selected for a particular patient. I also believe that most patients will have germline testing to determine whether there is an inherited risk factor that contributed to why they developed cancer. It will take a bit of time for such testing to become widespread for all

cancer patients, because the technology is still expensive and the process needs to become more efficient. But, in my opinion, there is no doubt that in the near future, genomic testing of every patient’s tumor will become standard of care. n Disclosure: Dr. Solit reported no potential conflicts of interest.

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PAGE 37

Journal Spotlight Gynecologic Oncology

Meta-analysis Shows Increased Risk of Ovarian Cancer With Menopausal Hormone Therapy By Matthew Stenger

n a study reported in The Lancet, the Collaborative Group on Epidemiological Studies of Ovarian Cancer

found that use of menopausal hormone therapy was associated with increased risk of ovarian cancer, with risk being

highest among current users.1 The study consisted of meta-analyses of individual participant datasets from 52

epidemiologic studies, including 17 prospective and 35 retrospective studies. The principal analyses involved prospective studies, with last hormone therapy use extrapolated forward for up to 4 years.

Risk in Current and Past Users

We want to change the face of EGFR-targeted therapy Cutaneous toxicities are caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 Inhibition of wild-type and mutant EGFR in non–small cell lung cancer (NSCLC)

Cutaneous toxicities can be dose-limiting

Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

The symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

90% of patients treated with approved EGFR TKIs experience rash7,8

The future of EGFR inhibition

The skin is dependent on wild-type EGFR signaling for normal growth and differentiation.1,9,10 Druginduced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Strategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org /ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci .nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

During prospective follow-up in the principal analysis, 12,110 postmenopausal women developed ovarian cancer, including 6,601 (55%) who had used hormone therapy. Compared with never-users, current users had a similar significantly increased risk of ovarian cancer with < 5 years of use (relative risk [RR] = 1.43, P < .00001) and ≥ 5 years of use (RR = 1.41, P < .0001). Among past users with < 5 years since last use, risk was significantly increased among those with ≥ 5 years of use (RR = 1.29, P = .0008) and nonsignificantly increased in those with < 5 years of use (RR = 1.17, P = .08). Among past users with ≥ 5 years since last use, risk was significantly increased among those with ≥ 5 years of use (RR = 1.10, P = .02) but not among those with < 5 years of use (RR = 0.94, P = .1). In an analysis including all studies (9,378 cases in 35 retrospective studies), compared with never-users, current users had an increased risk with < 5 years of use (RR = 1.27, P = .00001) or ≥ 5 years of use (RR = 1.34, P < .00001). Risk was nonsignificantly increased in past users with < 5 years since last use who had < 5 years of use (RR = 1.11, P = .07) and significantly increased in those with ≥ 5 years of use (RR = 1.25, P = .00002). Among past users with ≥ 5 years since last use, risk was not increased among those with < 5 years of use (RR = 0.97, P = .3) and was significantly increased in those with ≥ 5 years of use (RR = 1.11, P = .008).

Risk With Current/Recent Use Compared with nonuse, current or recent use (defined as use of any duration stopped < 5 years before diagnosis) was associated with a significantly increased risk (RR = 1.37, P < .0001). This risk was similar in European (RR = 1.37, 99% confidence interval [CI] = 1.26–1.50) and American (RR = 1.35, 99% CI = 1.11–1.65) prospective studies and for prospective studies involving estrogen-only (RR = 1.37, 95% CI = 1.26–1.50) and estrogen-progestogen continued on page 38

The ASCO Post | JUNE 25, 2015

PAGE 38

Journal Spotlight Menopausal Hormone Therapy

Persistence of Risk

continued from page 37

Although risk declined with greater duration since last use, women who had used hormone therapy for at least 5 years (median duration = 9 years) and then stopped still had a significantly increased risk of ovarian cancer more than 5 years later (median time since last use = 10 years; RR = 1.10, P = .02). Risk of serous or endometrioid

hormone preparations (RR = 1.37, 95% CI = 1.26–1.48). Analysis in only retrospective studies did not show an increased risk (RR = 1.04, 99% CI = 0.93–1.16). In prospective studies, risk differed across the four main tumor types (P < .0001 for heterogeneity), with a sig-

The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1,000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1,700 users. —Collaborative Group on Epidemiological Studies of Ovarian Cancer

nificantly increased risk with hormone therapy use being observed for serous tumors (RR = 1.53, P < .0001) and endometrioid tumors (RR = 1.42, P < .0001) but not for mucinous tumors (RR = 0.93, 95% CI = 0.77–1.12). Hormone therapy use was associated with a reduced risk of clear cell tumors (RR = 0.75, 95% CI = 0.57–0.98).

tumors was higher at 10 years since last use (RR = 1.25, P = .005).

Estimates of Excess Incidence and Death Application of the relative risks identified in the prospective studies to age-specific ovarian cancer incidence and death rates in England

Hormone Therapy and Ovarian Cancer Risk ■■ Menopausal hormone therapy use was associated with a significantly increased risk of ovarian cancer. ■■ Among past users, risk was increased among those with ≥ 5 years of use.

yielded the following excess incidence and excess death estimates: for 5 years while they are taking hormone therapy (from age 50 to 54), their excess risk is 0.52; after they stop their excess risk is still elevated at age 55 to age 59, estimated to be 0.37 per 1,000; and at age 60 to age 64, there remains an excess incidence, estimated to be 0.1 per 1,000. The total for women who started hormone therapy at age 50 and used hormone therapy for 5 years is 1 per 1,000. The excess is greater the longer women take hormone therapy and the older they are when taking hormone therapy. In total, there would be 1 additional ovarian cancer per 1,000 users and 1 additional death per 1,700 users. For 10 years of hormone therapy use, the absolute excess in incidence would be 0.52, 0.67, and 0.61 for the three age groups. There would be 1

additional case of ovarian cancer per 600 users and 1 additional death per 800 users. The investigators concluded: “The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1,000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1,700 users.” n

Disclosure: The study was funded by the Medical Research Council, Cancer Research UK. The study authors reported no potential conflicts of interest.

Reference 1. Collaborative Group on Epidemiological Studies of Ovarian Cancer: Menopausal hormone use and ovarian cancer risk: Individual participant meta-analysis of 52 epidemiological studies. Lancet 385:1835-1842, 2015.

Hormonal Therapy and Risk of Ovarian Cancer By Ana I. Tergas, MD, MPH

varian cancer is the second most common gynecologic malignancy in the United States, with an estimated 21,290 new cases expected this year. Ovarian cancer causes 5% of all cancer deaths in women, making it responsible for the highest number of gynecologic cancer deaths.1 Age, family history, and inherited mutations such as BRCA1 and BRCA2 have been established as significant risk factors for the development of ovarian cancer. However, the role of menopausal hormone therapy remains questionable. In a study published by The Lancet, researchers in the Collaborative Group on Epidemiological Studies of Ovarian Cancer demonstrated that use of menopausal hormone therapy was associated with an increased risk of ovarian cancer, with risk being highest among current users.2 The study is summarized in this issue of The ASCO Post. Dr. Tergas is Clinical Instructor of Gynecologic Oncology, at Columbia University Medical Center, New York.

The study, funded by the Medical Research Council of Cancer Research UK, consisted of meta-analyses of individual participant data sets from 52 epidemiologic studies, including 17 prospective and 35 retrospective studies. The principal analyses involved prospective studies, with last hormone therapy use extrapolated forward for up to 4 years.

Risk in Current Users During prospective follow-up in the principal analysis, 12,110 postmenopausal women developed ovarian cancer, including 6,601 (55%) who had used hormone therapy. Compared with never-users, current users of menopausal hormonal therapy had about a 40% increased risk of developing ovarian cancer. This risk was similar for current users regardless of length of use (< 5 years of use: relative risk [RR] = 1.43, 95% confidence interval [CI] = 1.31–1.56; ≥ 5 years of use: RR = 1.41, 95% CI = 1.32–1.50). In an analysis including all studies (including 9,378 cases in 35 retrospective studies), compared

with never-users, current users had increased risk with < 5 years of use (RR = 1.27, 95% CI = 1.18–1.37) or ≥ 5 years of use (RR = 1.34, 95% CI = 1.28–1.41).

Risk With Current/Recent Use Compared with nonuse, current use or recent use (defined as use of any duration stopped < 5 years before diagnosis) was associated with a significantly increased risk (RR = 1.37, 95% CI = 1.27–1.48). This risk was similar in European and American prospective studies and for prospective studies involving estrogen-only and estrogen-progestogen hormone preparations. Analysis in retrospective studies only did not show an increased risk (RR = 1.04, 95% CI = 0.93–1.16).

Ovarian Cancer Subtypes This increased risk of ovarian cancer was only seen for certain histologic subtypes. Hormone therapy use was associated with an increased risk of serous tumors (RR = 1.53, 95% CI = 1.40–1.66) and endometrioid tumors

(RR = 1.42, 95% CI = 1.20–1.67) but not for mucinous tumors (RR = 0.93, 95% CI = 0.77–1.12). Hormone therapy use was associated with a reduced risk of clear cell tumors (RR = 0.75, 95% CI = 0.57–0.98).

Persistence of Risk Although risk declined with greater duration since last use, women who had used hormone therapy for at least 5 years (median duration = 9 years) and then stopped still had a modestly increased risk of ovarian cancer more than 5 years later, compared with never-users (median time since last use = 10 years; RR = 1.10, 95% CI = 1.01–1.20). There was no increased risk seen in women who reported less than 5 years of use more than 5 years ago (RR = 0.94, 95% CI = 0.88–1.02).

Estimates of Excess Incidence and Death The investigators interpreted their results as showing that “the increased risk may well be largely or wholly causal.” In this case, for 5 years of hor-

ASCOPost.com | JUNE 25, 2015

PAGE 39

Perspective

mone therapy use, the absolute excess in ovarian cancer incidence per 1,000 users would be 0.52 (from the expected incidence of 1.2 per 1,000 neverusers of hormone therapy) in women aged 50 to 54 years, 0.37 (from the expected 1.6) in those aged 55 to 59 years, and 0.10 (from expected 2.1) in those aged 60 to 64 years. In total, there would be 1 additional ovarian cancer per 1,000 users and 1 additional death per 1,700 users among women of all ages.

have biased the effect measure toward the null. Perhaps a more prudent approach would have been to explore the relationship between hormonal therapy and ovarian cancer in this group through a sensitivity analysis rather than exclude them outright. Additionally, the authors’ claim that hormonal therapy may be causal is not substantially supported. While the authors base their conclusions on

This study is an important contribution to the literature, with several strengths—particularly the large number of patients who were followed prospectively…. However, the results must be interpreted with the study limitations in mind.

Interpreting Results This study is an important contribution to the literature, with several strengths—particularly the large number of patients who were followed prospectively. As the authors point out, “the robustness of prospective data is demonstrated by the stability of the findings in various sensitivity analyses.” Their search strategy and analyses were comprehensive and included the grey literature in order to decrease the impact of publication bias. However, their results must be interpreted with the study limitations in mind. First, the exclusion of women less than 55 years of age who underwent hysterectomy results in possibly significant selection bias, given the frequency of prescribing hormonal therapy in this group. Since hysterectomy has been shown to decrease the risk of ovarian cancer,3 including these women would likely

effect of hormonal therapy based on histologic subtype. Reconciling why hormonal therapy would increase risk of serous and endometrioid but not clear cell or mucinous tumors is problematic, and the authors offer no substantive discussion on this issue. The authors claim that they demonstrate a dose-response relationship by showing that current users are at greatest risk of ovarian cancer, there-

—Ana I. Tergas, MD, MPH

prospective data, which provide evidence of a temporal relationship between the exposure and outcome of interest—thereby supporting their causal claim—there is little discussion about the proposed underlying mechanism by which hormonal therapy causes ovarian cancer. Hormonal therapy as a cause of ovarian cancer is inconsistent with the well-established protective link between oral contraceptive use and ovarian cancer. Further evidence against biologic plausibility is the differential

by lending further support for their causal claim. However, this is also problematic. Indeed, while current users are shown to have the highest risk compared to past users, there is no difference in risk for current users based on duration of use. Furthermore, there are no data on actual dose of hormonal therapy, and prescribing patterns for hormonal therapy have varied substantially over the years. The data as presented are insufficient to provide strong evidence of a dose-response relationship.

Closing Thoughts All in all, the study provides compelling evidence of a possible association between menopausal hormonal therapy use and serous and endometrioid ovarian cancers. However, the study provides insufficient evidence to claim that hormonal therapy causes ovarian cancer, and many important questions remain. When counseling patients, it is important to discuss these findings, particularly in terms of absolute risk, within the context of the known benefits of hormonal therapy. Women who are taking or are considering starting hormonal therapy should discuss their personal and family histories and symptoms with their physicians, who can help weigh the risks and benefits and discuss alternative treatments. n

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

References 1. American Cancer Society: Cancer Facts & Figures 2015. Atlanta, American Cancer Society, 2015. 2. Collaborative Group on Epidemiological Studies of Ovarian Cancer: Menopausal hormone use and ovarian cancer risk: Individual participant meta-analyses of 52 epidemiological studies. Lancet 385:1835-1842, 2015. 3. Falconer H, Yin L, Grönberg H, et al: Ovarian cancer risk after salpingectomy: A nationwide population-based study. J Natl Cancer Inst 107:dju410, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Anil K. D’Cruz, MBBS, MS, FRCS, on Elective Neck Dissection in Oral Cancer see page 1

Michael Green, PhD, on Clonality in Precision Medicine see page 1

Lowell E. Schnipper, MD, on Assessing Value in Cancer Care see page 1

Sagar Lonial, MD, on Daratumumab in Refractory Multiple Myeloma see page 3

Nicholas C. Turner, MD, on Palbociclib in Hormone Receptor–Positive Breast Cancer see page 4

Anees B. Chagpar, MD, MPH, on Cavity Shave Margins in Mastectomy see page 7

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The The Thefollowing following followingimportant important importantsigns signs signsand and andsymptoms symptoms symptomswarrant warrant warrantaaaprompt prompt prompt CICI=CI=confi =confi confi dence dence dence interval; interval; interval; Hct Hct Hct ==hematocrit. =hematocrit. hematocrit. 6,7 6,7 6,7 evaluation evaluation evaluationand and andsuggest suggest suggestPV PV PV :: : Figure Figure Figure 1.1.Kaplan-Meier 1.Kaplan-Meier Kaplan-Meier curve curve curve for for for total total total cardiovascular cardiovascular cardiovascular events. events. events. •••Elevated Elevated Elevatedhemoglobin hemoglobin hemoglobinor ororhematocrit hematocrit hematocritlevels levels levels From From From The The The New New New England England England Journal Journal Journal ofofMedicine. ofMedicine. Medicine. Marchioli Marchioli Marchioli R,R,Finazzi, R,Finazzi, Finazzi, G,G,Specchia G,Specchia Specchia G,G,et G,etal. etal.al. Cardiovascular Cardiovascular Cardiovascular events events events and and and intensity intensity intensity ofoftreatment oftreatment treatment ininpolycythemia inpolycythemia polycythemia vera. vera. vera. NNEngl NEngl Engl JJMed. JMed. Med. 2013;368(1):22-33. 2013;368(1):22-33. 2013;368(1):22-33. Copyright Copyright Copyright ©2013 ©2013 ©2013 •••Thrombotic Thrombotic Thromboticevents events events Massachusetts Massachusetts Massachusetts Medical Medical Medical Society. Society. Society. Reprinted Reprinted Reprinted with with with permission permission permission from from from Massachusetts Massachusetts Massachusetts Medical Medical Medical Society. Society. Society. •••Splenomegaly Splenomegaly Splenomegaly(with (with (withor ororwithout without withoutthrombocytosis thrombocytosis thrombocytosisand/or and/or and/or leukocytosis) leukocytosis) leukocytosis) Thrombosis, Thrombosis, Thrombosis,Splenomegaly Splenomegaly Splenomegalyand and andOther Other OtherDiseaseDiseaseDisease-

related related relatedSymptoms Symptoms Symptoms

In InInPV, PV, PV,aaawide wide widespectrum spectrum spectrumof ofofthrombotic thrombotic thromboticmanifestations manifestations manifestationsexists exists existsthat that that 14 1414 may may mayoccur occur occurbefore before beforethe the thedisease disease diseaseisisisdiagnosed. diagnosed. diagnosed. Palpable Palpable Palpablesplenomegaly splenomegaly splenomegaly isisisan an animportant important importantphysical physical physicalfifinding finding ndingbecause because becauseincreased increased increasedspleen spleen spleensize size sizeisisis 12 1212 present present presentin inin30% 30% 30%to toto40% 40% 40%of ofofpatients patients patientswith with withPV. PV. PV. Additional Additional Additionalsigns signs signsand and and Prognosis Prognosis Prognosisand and andRisk Risk RiskFactors Factors Factors symptoms symptoms symptomsof ofofPV, PV, PV,which which whichmay may maycontribute contribute contributeto totoaaasubstantial substantial substantialquality-ofquality-ofquality-of17 1717 In InInaaalarge large largepopulation-based population-based population-basedstudy study studyin ininmore more morethan than than4,000 4,000 4,000patients patients patients life life lifeburden burden burdenin ininpatients patients patientswith with withPV, PV, PV,include include include:: : with with withPV, PV, PV,life life lifeexpectancy expectancy expectancywas was was36% 36% 36%lower lower lowerthan than thanthat that thatof ofofthe the thegeneral general general •••Fatigue Fatigue Fatigue 13 1313 population. population. population. •••Pruritus Pruritus Pruritus •••Night Night Nightsweats sweats sweats

Clinical Clinical ClinicalConsiderations Considerations Considerations in in inManaging Managing ManagingPV PV PV

Clinical Clinical ClinicalNeed Need Needin in inPV PV PV

Phlebotomy Phlebotomy Phlebotomyto to tomaintain maintain maintainHct Hct Hctat at at<45% <45% <45% plus plus pluslow-dose low-dose low-doseaspirin aspirin aspirin

3,11 3,11 3,11 Therapeutic Therapeutic Therapeuticapproaches approaches approachesto totoPV PV PVfocus focus focuson on on :: : •••Controlling Controlling Controllingand and andmaintaining maintaining maintaininghematocrit hematocrit hematocritlevels levels levelsat atat<45% <45% <45% •••Treating Treating Treatingcomplications complications complicationsof ofofthrombosis thrombosis thrombosisand and andhemorrhage hemorrhage hemorrhage •••Reducing Reducing Reducingthrombotic thrombotic thromboticrisk risk riskand and andminimizing minimizing minimizingthe the therisk risk riskof ofof leukogenic leukogenic leukogenictransformation transformation transformation •••Managing Managing Managingsplenomegaly splenomegaly splenomegalyand and andother other otherdisease-related disease-related disease-related symptoms symptoms symptoms

••Poor •Poor Poor compliance compliance compliance or oror tolerance tolerance tolerance to toto frequent frequent frequent phlebotomy phlebotomy phlebotomy ••Symptomatic •Symptomatic Symptomatic or oror progressive progressive progressive splenomegaly splenomegaly splenomegaly ••High •High High risk risk risk of ofof thrombosis thrombosis thrombosis ••Severe •Severe Severe disease-related disease-related disease-related symptoms symptoms symptoms ••Progressive •Progressive Progressive myeloproliferation myeloproliferation myeloproliferation (leukocytosis (leukocytosis (leukocytosis or oror thrombocytosis) thrombocytosis) thrombocytosis)

Phlebotomy Phlebotomy Phlebotomyisisisusually usually usuallythe the thestarting starting startingpoint point pointof ofoftreatment treatment treatmentin ininpatients patients patients 2,11 2,11 2,11 with with withPV, PV, PV,in ininaddition addition additionto tototherapy therapy therapywith with withlow-dose low-dose low-doseaspirin. aspirin. aspirin. LowLowLowdose dose doseaspirin aspirin aspirinhas has hasbeen been beenshown shown shownto totoprevent prevent preventboth both botharterial arterial arterialand and andvenous venous venous 18 1818 thrombotic thrombotic thromboticcomplications complications complicationsin ininpatients patients patientswith with withPV. PV. PV. Cytoreductive Cytoreductive Cytoreductivetherapy therapy therapywith with withhydroxyurea hydroxyurea hydroxyureaor ororinterferon-alpha interferon-alpha interferon-alphamay may may also also alsobe be behelpful helpful helpfulin ininpatients patients patientswho who whohave have havediffi diffi diffi culty culty cultywith with withphlebotomy, phlebotomy, phlebotomy, who who whohave have havesymptomatic symptomatic symptomaticor ororprogressive progressive progressivesplenomegaly splenomegaly splenomegalyor ororwho who who 11 1111 experience experience experience severe severe severe symptoms. symptoms. symptoms. Although Although Although treatment treatment treatment with with with hydroxyurea hydroxyurea hydroxyureamay may maybe be betolerated tolerated toleratedby by bymost most mostpatients, patients, patients,itititisisisimportant important important to totoconsider consider considerthat that thatapproximately approximately approximately25% 25% 25%of ofofpatients patients patientswith with withPV PV PVdevelop develop develop 19, 19, 19, 20 2020 resistance resistance resistanceto totoor ororintolerance intolerance intoleranceof ofofhydroxyurea hydroxyurea hydroxyurea(Table (Table (Table1). 1). 1). Table Table Table1. 1.1. Assessment Assessment Assessmentof ofofhydroxyurea hydroxyurea hydroxyurea(HU) (HU) (HU)resistance resistance resistance and and andintolerance intolerance intolerance HU HU HUResistance Resistance Resistance

HU HU HUIntolerance Intolerance Intolerance

After After After12 12 12weeks weeks weeksof ofofHU HU HUat atat At At Atleast least least111of ofofthe the thefollowing: following: following: aaatotal total totaldose dose doseof ofof≥2 ≥2 ≥2g/day g/day g/dayor oror •••Neutropenia Neutropenia Neutropenia(absolute (absolute (absolute neutrophil neutrophil neutrophilcount count countof ofof at atatthe the themaximum maximum maximumtolerated tolerated tolerated 99 9 dose, dose, dose,ififif<2 <2 <2g/day g/day g/day <1.0 <1.0 <1.0xxx10 10 10/L) /L) /L) •••Need Need Needfor for forphlebotomy phlebotomy phlebotomy •••Platelet Platelet Plateletcount count countof ofof 99 9 to totomaintain maintain maintainHct Hct Hctlevel level level /L /L/L <100 <100 <100xxx10 10 10 at atat<45% <45% <45%or oror •••Hgb Hgb Hgblevel level levelof ofof<10 <10 <10g/dL g/dL g/dL •••Elevated Elevated Elevatedplatelet platelet plateletand and andwhite white white •••Leg Leg Legulcers ulcers ulcersor ororother other other blood blood bloodcell cell cellcounts counts countsor oror unacceptable unacceptable unacceptable •••<50% <50% <50%reduction reduction reductionin inin nonhematologic nonhematologic nonhematologic splenomegaly splenomegaly splenomegaly HU-related HU-related HU-relatedtoxicity toxicity toxicity Hct, Hct, Hct, hematocrit; hematocrit; hematocrit; Hgb, Hgb, Hgb, hemoglobin. hemoglobin. hemoglobin. 191919 Modifi Modifi Modifi ed ed ed from from from Barosi Barosi Barosi et etet al. al. al.

Despite Despite Despite current current current approaches, approaches, approaches, including including including phlebotomy, phlebotomy, phlebotomy, lowlowlowdose dose doseaspirin, aspirin, aspirin,interferon-alpha interferon-alpha interferon-alphaor ororcytoreductive cytoreductive cytoreductivetherapy therapy therapywith with with hydroxyurea, hydroxyurea, hydroxyurea,some some somepatients patients patientswill will willnot not notbe be beable able ableto totogain gain gainand and andmaintain maintain maintain 19,20 19,20 19,20 hematocrit hematocrit hematocritlevels levels levelsof ofof<45% <45% <45% (Figure (Figure (Figure 2). 2). 2). For For Forsome some somepatients patients patientswhose whose whosehematocrit hematocrit hematocritlevels levels levelsremain remain remainelevated, elevated, elevated, and and andfor for forthose those thosewho who whocontinue continue continueto totoexperience experience experienceclinical clinical clinicalsigns signs signs and and and symptoms symptoms symptoms such such such as as as fatigue, fatigue, fatigue, pruritus, pruritus, pruritus, night night night sweats sweats sweats 11,20 11,20 11,20 or oror splenomegaly, splenomegaly, splenomegaly, PV PV PV remains remains remains uncontrolled. uncontrolled. uncontrolled. Recently, Recently, Recently, standardized standardized standardizedcriteria criteria criteriafor for formonitoring monitoring monitoringand and andassessing assessing assessingresponse response response in ininPV PV PVhave have havebeen been beendeveloped developed developedfor for forclinical clinical clinicalresearch. research. research.Evaluation Evaluation Evaluation of ofof response response response includes includes includes such such such parameters parameters parameters as as as resolution resolution resolution of ofof splenomegaly splenomegaly splenomegalyand and andother other otherdisease-related disease-related disease-relatedsigns, signs, signs,hematocrit hematocrit hematocritof ofof <45%, <45%, <45%,blood blood bloodcount count countremission, remission, remission,absence absence absenceof ofofthrombotic thrombotic thromboticevents events events 21 2121 and and andbone bone bonemarrow marrow marrowhistology. histology. histology.

Hydroxyurea Hydroxyurea Hydroxyurea(HU) (HU) (HU)or or orinterferon-alpha interferon-alpha interferon-alphaas as as aa a first-line first-line first-linecytoreductive cytoreductive cytoreductivetherapy therapy therapyat at atany any anyage age age

••Patients •Patients Patients are are are intolerant intolerant intolerant of ofof or oror resistant resistant resistant to toto HU HU HU

Unmet Unmet Unmetneed need needexists exists existsfor for foraaasubset subset subsetof of ofpatients patients patients not not notmanaged managed managedappropriately appropriately appropriatelyby by bycurrent current currenttreatment treatment treatment strategies strategies strategies(alone (alone (aloneor or orin inincombination) combination) combination) Hct, Hct, Hct,hematocrit. hematocrit. hematocrit. aa a

All All All patients patients patients should should should be be be managed managed managed aggressively aggressively aggressively for for for their their their generic generic generic cardiovascular cardiovascular cardiovascular risk risk risk factors. factors. factors. HU HU HU should should should be be be used used used with with with caution caution caution in inin patients patients patients <40 <40 <40 years years years of ofof age; age; age; busulfan busulfan busulfan may may may be be be considered considered considered in inin elderly elderly elderly patients patients patients (>70 (>70 (>70 years). years). years).

111111 Figure Figure Figure 2.2.2. AAA practical practical practical management management management algorithm. algorithm. algorithm.

Learn Learn Learnmore more moreabout about aboutunderstanding understanding understanding the the theburden burden burdenof of ofPolycythemia Polycythemia PolycythemiaVera Vera Vera at at atwww.MPNConnect.com www.MPNConnect.com www.MPNConnect.com References References References 1.1.1. Vannucchi Vannucchi Vannucchi AM, AM, AM, Guglielmelli Guglielmelli Guglielmelli P,P,P, Tefferi Tefferi Tefferi A. A.A. CA CA CA Cancer Cancer Cancer JJClin. JClin. Clin. 2009;59:171-191. 2009;59:171-191. 2009;59:171-191. 2. 2.2. Marchioli Marchioli Marchioli R, R,R, Finazzi Finazzi Finazzi G, G,G, Specchia Specchia Specchia GGG et etet al. al.al. NNN Engl Engl Engl JJMed. JMed. Med. 2013;368:22-33. 2013;368:22-33. 2013;368:22-33. 3. 3.3. Tefferi Tefferi Tefferi A. A.A. Am Am Am JJHematol. JHematol. Hematol. 2013;88:507-516. 2013;88:507-516. 2013;88:507-516. 4. 4.4. Spivak Spivak Spivak JL. JL. JL. Blood. Blood. Blood. 2002;100:4272-4290. 2002;100:4272-4290. 2002;100:4272-4290. 5. 5.5. Spivak Spivak Spivak JL. JL. JL. Ann Ann Ann Intern Intern Intern Med. Med. Med. 2010;152:300-306. 2010;152:300-306. 2010;152:300-306. 6. 6.6. Tefferi Tefferi Tefferi A, A,A, Rumi Rumi Rumi E, E,E, Finazzi Finazzi Finazzi GGG et etet al. al.al. Leukemia. Leukemia. Leukemia. 2013;27:1874-1881. 2013;27:1874-1881. 2013;27:1874-1881. 7.7.7. Gruppo Gruppo Gruppo Italiano Italiano Italiano Studio Studio Studio Policitemia. Policitemia. Policitemia. Ann Ann Ann Intern Intern Intern Med. Med. Med. 1995;123:656-664. 1995;123:656-664. 1995;123:656-664. 8. 8.8. Data Data Data on on on fifile. fi le.le. Incyte Incyte Incyte Corporation. Corporation. Corporation. 9. 9.9. Verstovsek Verstovsek Verstovsek S. S.S. Postgrad Postgrad Postgrad Med. Med. Med. 2013;125:128-135. 2013;125:128-135. 2013;125:128-135. 10. 10. 10. Staerk Staerk Staerk J,J,J, Kallin Kallin Kallin A, A,A, Demoulin Demoulin Demoulin JB JB JB et etet al. al.al. JJBiol JBiol Biol Chem. Chem. Chem. 2005;280:41893-41895. 2005;280:41893-41895. 2005;280:41893-41895. 11. 11. 11. Barbui Barbui Barbui T,T,T, Barosi Barosi Barosi G, G,G, Birgegard Birgegard Birgegard GGG et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2011;29:761-770. 2011;29:761-770. 2011;29:761-770. 12. 12. 12. Passamonti Passamonti Passamonti F.F.F. Blood. Blood. Blood. 2012;120:275-284. 2012;120:275-284. 2012;120:275-284. 13. 13. 13. Hultcrantz Hultcrantz Hultcrantz M, M, M, Kristinsson Kristinsson Kristinsson SY, SY, SY, Andersson Andersson Andersson TML TML TML et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2012;30:2995-3001. 2012;30:2995-3001. 2012;30:2995-3001. 14. 14. 14. Falanga Falanga Falanga A, A,A, Marchetti Marchetti Marchetti M. M. M. Hematology Hematology Hematology Am Am Am Soc Soc Soc Hematol Hematol Hematol Educ Educ Educ Program. Program. Program. 2012;2012:571-581. 2012;2012:571-581. 2012;2012:571-581. 15. 15. 15. Marchioli Marchioli Marchioli R, R,R, Finazzi Finazzi Finazzi G, G,G, Landolfi Landolfi Landolfi RRR et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2005;23:2224-2232. 2005;23:2224-2232. 2005;23:2224-2232. 16. 16. 16. De De De Stefano Stefano Stefano V, V,V, Za Za Za T,T,T, Rossi Rossi Rossi EEE et etet al. al.al. Haematologica. Haematologica. Haematologica. 2008;93:372-380. 2008;93:372-380. 2008;93:372-380. 17. 17. 17. Mesa Mesa Mesa RA, RA, RA, Niblack Niblack Niblack J,J,J, Wadleigh Wadleigh Wadleigh M MM et etet al. al.al. Cancer. Cancer. Cancer. 2007;109:68-76. 2007;109:68-76. 2007;109:68-76. 18. 18. 18. Landolfi Landolfi Landolfi R, R,R, Marchioli Marchioli Marchioli R, R,R, Kutti Kutti Kutti JJet Jetet al. al.al. NNN Engl Engl Engl JJMed. JMed. Med. 2004;350:114-124. 2004;350:114-124. 2004;350:114-124. 19. 19. 19. Barosi Barosi Barosi G, G,G, Birgegard Birgegard Birgegard G, G,G, Finazzi Finazzi Finazzi GGG et etet al. al.al. Br BrBr JJHaematol. JHaematol. Haematol. 2010;148:961-963. 2010;148:961-963. 2010;148:961-963. 20. 20. 20. Alvarez-Larrán Alvarez-Larrán Alvarez-Larrán A, A,A, Pereira Pereira Pereira A, A,A, Cervantes Cervantes Cervantes FFet Fetet al. al.al. Blood. Blood. Blood. 2012;119:1363-1369. 2012;119:1363-1369. 2012;119:1363-1369. 21. 21. 21. Barosi Barosi Barosi G, G,G, Mesa Mesa Mesa R, R,R, Finazzi Finazzi Finazzi GGG et etet al. al.al. Blood. Blood. Blood. 2013;121:4778-4781. 2013;121:4778-4781. 2013;121:4778-4781.

The ASCO Post | JUNE 25, 2015

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Expert’s Corner Issues in Oncology

Value in Cancer Care continued from page 1

to the rising cost of cancer care.2 In 2013, ASCO developed another Top Five list of tests, procedures, and treatments that are not supported by available evidence.3 Later that year, ASCO’s Board of Directors charged the Task Force with developing a framework for comparing the relative clinical benefit, toxicity, and cost of oncology treatments. The result of that effort is the “American Society of Clinical Oncology Statement: A Framework to Assess the Value of Cancer Treatment Options,” published online in the Journal of Clinical Oncology on June 22 for public comment.4 At the clinical level, the framework is meant to provide a standardized approach to assist physicians and patients in assessing the value of a new drug treatment based on efficacy, toxicity, and cost compared with the prevailing standard of care to calculate a net health benefit. Because clinical concerns and decisions vary depending on disease prognosis, two versions of the preliminary framework have been developed—one for advanced cancer and another for potentially curative disease. The ASCO Post talked with Lowell E. Schnipper, MD, Co-Chair of ASCO’s Value in Cancer Care Task Force, Theodore W. and Evelyn G. Berenson Professor in the Department of Medicine at Harvard Medical School, and Clinical Director of the Cancer Center and Chief of Hematology/Oncology at Beth Israel Deaconess Medical Center, Boston, about the development of the value framework and its projected impact on oncology care.

Determining Net Health Benefit Please describe the purpose of ASCO’s value framework and how the framework works. By 2020, the costs associated with caring for people with cancer are projected to become astronomic, largely because there will be a lot more people with cancer due to an aging population and because cancer is increasingly becoming a chronic illness for which very costly medications are being used for long periods of time. This effort was borne out of the imperative to improve cancer therapies and the awareness that many new treatments offer only small increments of benefit, sometimes with added side effects. That said, the associated costs for

these new agents are enormous. While patients need good therapy, they are becoming increasingly vulnerable to insurance copays, which are becoming larger and larger as insurance companies share more of the costs of these highly expensive agents with patients. Patients and their families often suffer financial harm and/or devastation paying for medicines that might only provide small degrees of survival gain, perhaps just a few weeks or months. We felt a framework was needed that could put these elements—clinical benefit, toxicity, and cost of new agents when compared with the standard of care—into context so that the doctor and patient could talk about the available options for treating a specific cancer and come up with a sense of how

Consistent Treatment Evaluation How is ASCO defining “value” in cancer care? The value that we are defining is expressed in terms of a new drug’s net health benefit. So some regimens that we have included in our article show a very small net health benefit or almost none when you add up the clinical benefit and the toxicity. Others have a rather substantial net health benefit, like the adjuvant treatment for breast cancer. ASCO is essentially trying to help the patient and the doctor arrive at a consistent way of thinking about different treatments they might choose utilizing the regimen’s net health benefit assessment in addition to information on cost.

Drugs represent only a small part of the overall problem, but they happen to be the component that is rising most rapidly in cancer care and also a part of the problem that affects patients greatly due to insurance copays. —Lowell E. Schnipper, MD

much benefit the patient is expected to derive, based on the patient’s treatment goals. Using the framework, physicians can take this composite of the clinical impact of treatment, such as the survival benefit or how long disease progression is delayed, and either add or subtract points depending on whether the treatment is less or more toxic than the current standard of care to generate a net health benefit.

From Concept to Physician-Guided Tool Currently, the framework is in the form of an algorithm that physicians can use to calculate a drug’s net health benefit. Will the framework eventually become part of a software program physicians can use on their mobile devices? Right now, the initial version of the value framework is available for public comment. After we get commentary from all stakeholders and the details of the framework are finalized, we plan to convert the information into a software application that will calculate a regimen’s clinical benefit, toxicity, and cost. It will then be at the physician’s and patient’s fingertips when they have discussions about treatment options. We envision that it will ultimately be a physicianguided tool for use in the clinical setting.

Most patients will say “I don’t care what the treatment costs—my life is being threatened,” and, of course, that consideration trumps just about everything else and it should. Using the algorithm, patients can actually see that the benefits of some treatments will be very small and the cost impact might be very large. Some may choose the drug no matter what the cost or degree of benefit, and others might choose the less expensive drug that looks to be just as efficacious but has a much lower degree of financial toxicity, which may be important to them.

Physician Reaction What has been the reaction from physicians about ASCO’s value framework concept? Some physicians are quite forwardthinking on this issue and see the discussion as a responsibility that is not to be shied away from, but rather, to be engaged in thoughtfully and empathetically. However, some physicians feel quite committed to the notion that it is not ethical for a doctor to be thinking about cost. My response is that I respect that sentiment to the nth degree. Nevertheless, within that general perspective of worrying primarily about our patients’

well-being—which I and all of our Task Force members agree is the central motivating factor—it is important for patients to be able to consider the cost factor when making their treatment decisions. I want to go on record as saying that while we are talking about drug regimens and their relative value as assessed by clinical trials, we are doing so because ASCO is primarily a society of medical oncologists. However, if you look at cancer care costs more broadly, it is fair to say that there are many factors contributing to the rising cost of health care other than medications, including soaring hospitalization costs and new surgical and radiologic interventions. There is a tendency to make drug manufacturers the fall guys for the skyrocketing costs. Drugs represent only a small part of the overall problem, but they happen to be the component that is rising most rapidly in cancer care and also a part of the problem that affects patients greatly due to insurance copays. Even so, if there weren’t any copays, insurance premiums would still be rising because of the confluence of factors I mentioned. For complete details of the ASCO statement on its value framework, visit the Journal of Clinical Oncology website at jco.ascopubs.org. The period for public commentary on the framework will close on August 21, 2015. To provide feedback, go to asco.org/value. n

Disclosure: Dr. Schnipper is Co-Chair of ASCO’s Value in Cancer Care Task Force.

References 1. Mariotto AB, Yabroff KR, Shao Y, et al: Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 103:117-128, 2011. 2. American Society of Clinical Oncology: 2012 Top Five list: Choosing Wisely—ASCO identifies five key opportunities in oncology to improve value of patient care. Available at www.asco.org/practiceresearch/2012-top-five-list. Accessed June 9, 2015. 3. American Society of Clinical Oncology: ASCO’s 2013 Top Five list in oncology. Available at www.asco.org/practice-research/ascos-2013-top-five-list-oncology. Accessed June 9, 2015. 4. Schnipper LE, Davidson NE, Wollins DS, et al: American Society of Clinical Oncology statement: A framework to assess the value of cancer treatment options. J Clin Oncol. June 22, 2015 (early release online).

ASCOPost.com | JUNE 25, 2015

PAGE 43

Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photo below is 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 ‘Frozen Sleep’ as Cancer Treatment, Springfield, Illinois, 1939

uring the 1930s, a wide variety of physical-chemical therapies were devised for cancer treatment. Heat, cold, vibration, ultrasound, diathermy, hydrotherapy, and all forms of electrical energy were employed. This photograph from a Springfield hospital presents “Frozen Sleep, Medical Science’s Newest Treatment for Cancer.” The experiment was disclosed after the patient was thawed back to consciousness. For 5 days, the patient remained frozen “under the scrutiny of three physicians.” The image captures James Graham, MD, and Alex Jones, MD, removing a covering of ice and preparing to restore the patient to consciousness. The frustration with failure to improve survival rates for cancer patients resulted in the creation of numerous additions to already combined therapies. The medical community hoped that perhaps by adding one more parameter of attack, a breakthrough would occur. Study of medical history has clearly shown that all kinds of treatments are tried when the true cause of a disease is unknown. When the cause is discovered, some treatments may seem totally absurd, while others prove close to the mark. Only time will tell.

■

Excerpted from Oncology Tumors & Treatment, A Photographic History, The Anesthesia Era: 1845–1875 by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive.

The medical community hoped that perhaps by adding one more parameter of attack, a breakthrough would occur.

The ASCO Post | JUNE 25, 2015

PAGE 44

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Oral Cavity and Oropharyngeal Cancers Compiled by Liz Janetschek

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with oral cavity and oropharyngeal cancers. The trials are investigating combination therapies, treatment toxicity, specialized adjuvant therapies, and proton therapy. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

struments/devices, such as wide-field fluorescence imaging point spectroscopy and/or brush cytology, can help health

care providers find mouth cancer more quickly than a standard oral clinical exam Primary Outcome Measures:

Performance of the POS, PS2, and VELscope as Diagnostic Aid for Oral Cancer [time frame: 1 day]

PHASE I Study Type: Phase I/interventional/ single-group assignment Study Title: A Phase I Trial of Vorinostat in the Treatment of Advanced Laryngeal, Hypopharyngeal, Nasopharyngeal, and Oropharyngeal Squamous Cell Carcinoma of the Head And Neck. Study Sponsor and Collaborators: The Ohio State University Comprehensive Cancer Center, National Comprehensive Cancer Network Purpose: To study the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in treating patients with stage III or stage IVa squamous cell cancer of the oropharynx which is either unresectable or borderline resectable Primary Outcome Measures: Maximum tolerated dose of vorinostat in combination with concurrent chemoradiation therapy, the toxic effects of the combination of vorinostat and cisplatin using NCI CTCAE v. 40 [time frame: weekly during treatment; every 2 weeks for the first month after treatment completion; then every 4 weeks until day 153] Principal Investigator: Theodoros Teknos, MD, The Ohio State University; 614-293-8074, ted.teknos@osumc.edu ClinicalTrials.gov Identifier: NCT01064921 Study Type: Phase I/interventional/ single-group assignment Study Title: Evaluation of Diagnostic Aids for Detection and Diagnosis of Oral Cancer Study Sponsor and Collaborators: MD Anderson Cancer Center, National Institutes of Health, William Marsh Rice University Purpose: To find out if certain in-

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PAGE 45

Clinical Trials Resource Guide

Principal Investigator: Ann M. Gillenwater, MD, BA, MD Anderson; 713-792-6920 ClinicalTrials.gov Identifier: NCT02251639 Study Type: Phase I/II/Interventional/single-group assignment Study Title: A Phase I/II Study of T-

Cell Receptor Gene Therapy Targeting HPV-16 E6 for HPV-Associated Cancers Study Sponsor and Collaborators: National Cancer Institute, National Institutes of Health Clinical Center Purpose: To determine a safe number of white blood cells harvested from the respective patient modified with retrovirus to infuse and to see if these particular

tumor-fighting cells (anti-HPV E6) can shrink tumors associated with HPV Primary Outcome Measures: To determine the objective tumor response rate and duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated with autologous T cells expressing the E6 TCR plus aldesleukin [time frame: 4 years]

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

Principal Investigator: Christian S. Hinrichs, MD, National Cancer Institute; 301-496-4164, Christian_Hinrichs@mail.nih.gov ClinicalTrials.gov Identifier: NCT02280811

PHASE II Study Type: Phase II/interventional/ parallel assigment Study Title: A Phase II Window of Opportunity Trial With GSK1120212 in Surgically Resectable Oral Cavity Squamous Cell Cancer Study Sponsor and Collaborators: Washington University School of Medicine, National Comprehensive Cancer Network Purpose: To study how trametinib affects tumor cells in patients with oral cavity squamous cell carcinoma that can be removed by surgery Primary Outcome Measures: To analyze tumor-specific changes in putative tumor-initiating cell populations as defined by cell surface CD44 and intracellular phospho-ERK1/2 staining after treatment with GSK1120212 [time frame: baseline and day 15] Principal Investigator: Ravindra Uppaluri, MD, PhD, Washington University School of Medicine; 314-3626599, uppalurir@ent.wustl.edu ClinicalTrials.gov Identifier: NCT01553851

PHASE III Study Type: Phase III/interventional/parallel assignment Study Title: Adjuvant De-escalation, Extracapsular Spread, P16+, Transoral (A.D.E.P.T.) Trial for Oropharynx Malignancy Study Sponsor and Collaborators: Washington University School of Medicine Purpose: To study the intensity of adjuvant therapy required in p16 positive oropharynx cancer patients, who have had all known disease removed surgically by a minimally invasive approach, and who have extracapsular spread in their lymph nodes Primary Outcome Measures: Disease-free survival [time frame: 2 years] Principal Investigator: Bruce Haughey, MBChB, Washington University School of Medicine; 314-3620365, haugheyb@ent.wustl.edu ClinicalTrials.gov Identifier: NCT01687413 Editor’s Note: The clinical trials presented here do not represent all the trials listed on ClinicalTrials.gov. For the complete list, go to ClinicalTrials.gov. n

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Expert’s Corner Novel Therapies

Redefining Cancer

A Conversation With Patrick Soon-Shiong, MD, FRCS(C), FACS By Jo Cavallo

Patrick Soon-Shiong, MD, FRCS(C), FACS

he ability to interrogate cancer cells at the genomic, proteomic, immunologic, and metabolomic levels will transform oncology care from one that relies mainly on trial-and-error treatment strategies based on the anatomy of the tumor to one that is more precisely based on the tumor’s molecular profile at the proteomic level, enabling many cancers to be turned into manageable chronic disease, and providing patients with long-term high quality of life, according to Patrick Soon-Shiong, MD, FRCS(C), FACS, who is returning to academia as visiting professor at the Imperial College of London and pending appointment as Adjunct Professor of Surgery at the University of California, Los Angeles (UCLA). Dr. Soon-Shiong is the inventor of nab-paclitaxel (Abraxane), the first U.S. Food and Drug Administration (FDA)approved nanotechnology-based chemotherapeutic agent. He is also the Founder and CEO of NantWorks and its subsidiary NantHealth, a cloud-based biomolecular medicine and bioinformatics company that uses high-frequency, high-throughput tumor genome sequencing to analyze the DNA, RNA, and protein levels of an individual patient’s cancer cells. During this year’s ASCO Annual Meeting, Dr. Soon-Shiong presented results from a study that used his GPS (genome/proteome sequencing) nextgeneration sequencing technology to analyze genomic (DNA) and transcriptomic (RNA) sequencing data to identify driver variants between somatic and germline DNA.1 Using this technology, Dr. Soon-Shiong and his colleagues determined expression of identified mutations in a cohort of 3,784 patients to establish therapeutic relevance of the mutated genes overcoming the limitations of the cancer gene panels. The study, which included sequencing on 19 anatomic tumor types, found that genetic mutations

in gene panels do not always result in protein expression and concluded that “an informed molecularly driven clinical treatment decision requires insight into downstream protein expression and not just DNA alterations alone.” Dr. Soon-Shiong also presented findings from his study integrating wholegenome and RNA sequencing with quantitative proteomics to inform treatment selection.2 In this study, over 50 unique tumors from primary and metastatic disease were selected for panomic tumor profiling. The investigators found that many mutations showed little or no expression at the transcriptomic level. Because the molecular signature of a patient’s cancer is independent of the anatomic tumor type and since many gene mutations were not expressed, the study authors again concluded that clinical treatment decisions need to be based

has committed a $1 billion philanthropic fund to make grants available to cancer institutions throughout the United States and in countries around the world to provide the financial resources necessary for more patients with cancer to benefit from genomic sequencing. The ASCO Post talked with Dr. Soon-Shiong about his vision for oncology care based on highly sophisticated molecular science.

Evolving Concept of Cancer You have said that the ability to sequence the cancer genome is turning every cancer into a rare disease. Please talk about the implications of that premise. The commonly held belief that cancer is a single clonal disease is a misplaced assumption. With the advent of next-generation sequencing, the realization has emerged that patients with can-

We have discovered that in many instances, mutations identified in cancer gene panels may not be expressed at the RNA level, and, hence, these mutations are not translated to protein, which is the key target to identify for targeted therapeutic intervention. —Patrick Soon-Shiong, MD, FRCS(C), FACS

on both downstream protein expression and DNA alterations.

Advancing the Next Paradigm of Cancer Care To advance cancer care for patients based on the latest innovative molecular science, Dr. Soon-Shiong has established an omics network—an international cadre of clinicians, scientists, pharmaceutical manufacturers, employers, patient advocates, and health insurance companies—to build a think tank of thought leaders who can define and implement “the next paradigm of cancer care in the era of genomics, proteomics, and immuno-oncology.” Late last year, Dr. Soon-Shiong launched the Chan Soon-Shiong Institute of Molecular Medicine, a nonprofit medical research organization designed to support and fund the delivery of personalized, data-driven, molecular-based medicine to patients with cancer. To date, the Institute has provided grants to the University of Oxford in London and Phoenix Children’s Hospital in Arizona. Over the next 2 years, Dr. Soon-Shiong

cer face the enormous challenge of interand intrapatient tumor heterogeneity. It has only recently become clear to us that cancer progression is a result of genetic expression of a multiclonal disease— driven not just by one genetic mutation, but in many instances driven by tens and even hundreds and perhaps thousands of mutations, rearrangements, and structural changes in the genome, dynamically changing across time and space. Having discovered multiple abnormal variants from a single patient, the critical question we have explored is, which of these variants transcribe downstream and drive tumor growth or cell immortality? Thus, it’s not just about the identification of mutations and genomic hotspots, some of which may be expressed while others remain dormant, but the protein products expressed downstream that are important to identify in order to improve decision-making and optimize treatment options. We have discovered that in many instances, mutations identified in cancer gene panels may not be expressed at the RNA level, and, hence, these mutations

are not translated to protein, which is the key target to identify for targeted therapeutic intervention. Clearly, it is those mutations that are expressed and, therefore, affect downstream signaling of the protein pathways that should be uncovered to better inform clinical treatment decisions. We established the GPS Cancer test to address this challenge. The GPS Cancer test is a comprehensive single test that analyzes the entire genome of both normal and cancer tissue samples from the same patient, combined with a whole-exome analysis to identify variants in the tumor exome to normal tissue from the patient, in addition to expression analysis that measures transcription of the mutated downstream molecules through RNA sequencing. This comprehensive test will thus provide the necessary data to more accurately identify the protein pathway driving tumor growth in that patient and finally match this comprehensive molecular information to FDA-approved drugs or drugs in clinical trials. Recognizing that practicing physicians will find it impossible to keep up with this deluge of scientifically complex data key to the patient’s care, we began building the infrastructure over the past decade and an oncology knowledge database to provide physicians with validated evidence-based information. To address the challenge of large-scale deployment of this decision support engine, we have partnered with large insurance companies such as Blue Cross to provide this actionable information at the point of care in the form of a downloadable decision support app called Eviti. This system is now available in all 50 states and will drive an adaptive learning system at scale, since we will now have the capability to measure outcomes over the life of the patient and drive transformational innovation utilizing real-world clinical care experience. As to why we now consider cancer as a set of rare diseases, the unfortunate reality is that the pathways involved in cancer are hugely complex and result in multiple mechanisms of cell growth. That is what I mean about cancer being divided into rare diseases, based not just on its genomic variation but also on the pathway clusters. One of the serious implications of adjusting to this concept of cancer as a set of rare diseases is that no single incontinued on page 48

Pediatric Oncology Research –

Funding Available! Introduction

The Pediatric Oncology community has invested a major effort over many years to collect and analyze long-term data in the pediatric population. Bristol-Myers Squibb seeks to fund research for Pediatric Oncology investigators to further the surveillance of pediatric/ adolescent/young adult patients treated with targeted agents and Immunotherapy to assess for short- and long-term adverse events.

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Application Process

In 2015, the Pediatric Oncology Research Program seeks to:

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» Support research to further strengthen the science and knowledge of Pediatric Oncology

• Click on Pediatric Oncology Research Funding

» Support the development of future clinical researchers

• Set up an ISR login

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» M.D. pediatric oncology fellows or investigators

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» Desire to enhance knowledge within the field of Pediatric Oncology

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» Faculty member identified to serve as project mentor at the applicant’s institution

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All support for Fellows Research Training Program Grants is awarded at the sole discretion of Bristol-Myers Squibb based on the above and other criteria that Bristol-Myers Squibb considers applicable to research grants.

ONCUS15UB00500-01-01 05/15

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Expert’s Corner Patrick Soon-Shiong, MD, FRCS(C), FACS continued from page 46

stitution will have enough patients with that particular pathway or abnormal signature to enable the validation of a treatment regimen based on the patient’s unique molecular signature. We are now faced with not just a subset of patients, but a subset of a subset of a subset of patients, and in order to achieve sufficiently high numbers of patients to test therapies and compare outcomes, we need a large collaborative omics network—a molecularly sophisticated network of oncologists to share outcome data and create an “adaptive learning system.” This will require an infrastructure for sharing of outcomes in real time as well as an infrastructure to receive an in-depth whole-genome, RNA, and proteome sequence analysis in a timely manner to take advantage of real-time knowledge that may better inform a clinical decision. Supported by our family foundation and NantHealth, the global omics network was established to serve that purpose.

Nab-Paclitaxel and Beyond If cancers are divided into many types of rare diseases, how will drugs be discovered and tested for individual patients? That is the issue we started addressing in 2001, when we conceived [nabpaclitaxel] as a “protein-based cell-signal transduction delivery platform.” We had this view that cancer in the metastatic phase is what I call a “dance of proteins,” and it is how and why we developed nabpaclitaxel to treat different cancer types— because we believed that the “nab” [nanoparticle albumin-bound] addresses a fundamental dance of a gp60 albumin receptor, caveolin-1, and caveolae formation at the endothelial cell level to initiate transcytosis and drive the paclitaxel molecule to the tumor microenvironment. Most importantly, we believed this would occur independent of the cancer type. From 2001 to 2005, this idea that a single taxane molecule could have a significant effect on tumors as diverse and challenging as triple-negative breast cancer, stage IV pancreatic cancer, and squamous cell lung cancer was met with great skepticism. We persisted in the belief that we were addressing a fundamental biology of overexpressed gp60 proteins occurring during the dynamic changes of metastatic disease—and that this biology was ubiquitous across all tumor types. We launched tens of phase II trials and multiple randomized phase III trials in breast, lung, and pancreas indications simultaneously to prove this hypothesis.

Fortunately, we were proven correct in this unconventional thinking, and today the drug is approved globally in all three indications. What is most gratifying is recent data from a head-to-head trial against weekly paclitaxel in neoadjuvant breast cancer, presented late last year at the San Antonio Breast Cancer Symposium.3 These data showed a remarkable and statistically significant improvement with nab-paclitaxel in triple-negative breast cancer. This year marks the 10th anniversary since [nab-paclitaxel] was approved, and the lesson I have learned is that we,

toxic and ineffective therapies. How do we effectively attack this multiclonal disease that changes its gene expression over time and space? I believe the way to do that is to explore ubiquitous pathways driving proliferation and metabolism of the cancer cell, to attack both the stem and metastatic cancer cells, to recognize that the biology of these two cell types differ, and to use multiple drugs focused on multiple points of attack, targeting the cell’s nucleus, DNA, cell signal pathways, and metabolism all simultaneously. We must pursue a path of combination therapy

Only through collaboration with sharing of outcomes data on a global scale can we hope to rapidly advance the field and unravel the complexity of the biology of this disease. —Patrick Soon-Shiong, MD, FRCS(C), FACS

meaning the collective oncology community and the pharmaceutical industry, have an urgent need to completely rethink the strategy of cancer treatment. With regard to long-term remission, rather than short-term gains, we need to address the cancer stem cell as well as the proliferating metastatic cell. The cancer stem cell, the progenitor cancer cell, and the metastatic cancer cell may be hugely different in their molecular profile and, more importantly, in their biology— both in terms of proliferation and metabolism. For the first time, we now have the molecular tools to gain insights into the biology and immunology of cancer at these multicellular levels. In 2005, we began a movement at our organization to identify how to address each of these cell types independently and began building the tools required to perform genomic, proteomic, immunologic, and metabolomic interrogation at the cellular level. We spent almost a decade building this molecular infrastructure as well as the omics network needed to implement the studies, and we now have these tools as well as a committed network of global collaborators to begin to address a whole new paradigm of cancer care. Perhaps most importantly, a change in our thinking must include the recognition that under the misconception that cancer was a single clonal disease, drug development and clinical trials have evolved under what I strongly believe is a flawed model of testing and administrating a single dose of chemotherapy at its maximum tolerated dose. Unfortunately, this flawed model may have contributed to the sad fact that we have not won the war against cancer and, in many cases, unnecessarily harmed the patient with

and immunotherapy, which I term “quantum oncotherapeutics,” to address the need for combination therapies that will change over time in step with the inevitable dynamic molecular changes that will occur in response to our treatment. Through constant molecular interrogation and through the application of liquid biopsies, we can establish predictive modeling and be prepared for the almost inevitable resistance. Furthermore, instead of using high-dose chemotherapy in the standard regimens, which impairs the patient’s immune system, the model we should pursue is to use metronomic, low-dose combination therapy that maintains the already impaired immune system of a patient afflicted with cancer and perhaps, if administered correctly, a regimen that may actually stimulate the immune system. For example, low-dose fluorouracil (5-FU) has been known to stimulate the immune system, and low-dose paclitaxel may increase the activity of natural killer cells. We are now working on an exciting program involving the development of allogeneic, off-the-shelf activated natural killer cells, which have the capability of being grown in a blood bag, doubling every 28 to 52 hours. By targeting these natural killer cells with specific human antibodies against epitopes unique to the tumor cell, we may successfully achieve direct killing, while also exploiting the innate immune system to destroy both proliferating cells and cancer stem cells. We are about to enter phase I and phase II trials in multiple indications, in both blood and solid tumor cancers, using these techniques. The way we are going to create drugs for this vast array of multiple rare diseases is by finding the ubiquitous pathways of the cancer cell, by going after the cancer stem

cells as well as the metastatic cells, and by enhancing the patient’s immune system. I think we will then have a chance of changing the paradigm of how we manage cancer patients. Eventually, by more deeply understanding the biology of the cancer stem cell, we will provide long-lasting remission and get closer to a cure for cancer. How soon will you be able to treat patients with the method you described? We will begin a phase II clinical trial very soon with low-dose metronomic nabpaclitaxel combined with 5-FU and combination regimens. We will be launching natural killer cells to enhance the innate immunity of patients receiving these lowdose combinations. We have supported a next-generation “basket” clinical trial, the PANGEA (Personalized Antibodies for Gastro-Esophageal Adenocarcinoma) trial, at the University of Chicago Medicine under Daniel Catenacci, MD [Assistant Professor of Medicine]. He is performing next-generation sequencing and proteomic analysis to identify the molecular profile of patients to enter into the appropriate treatment arm based on this comprehensive molecular analysis.

Rethinking the Paradigm Based on this multipronged approach, do you think it will it be possible to cure more cancers or convert them into chronic diseases people can live with? I think the first issue we need to address is the terrible quality of life patients endure when diagnosed with “incurable” metastatic disease. In that disease setting, the standard of care is to give patients multiple high doses of chemotherapy in a linear fashion—see what happens, then try again. If the treatment fails, the patient enters a difficult end-of-life course. That entire paradigm can and must be changed by rethinking the current strategy of ordering the maximum tolerated dose of single chemotherapy. Encouraging early results of this paradigm shift are seen in our current management of patients with advanced pancreatic cancer, where we are administering low-doses of nab-paclitaxel, 5-FU, and oxaliplatin to attack the cancer at its different cellular levels. Attacking the tumor in this way and stimulating the immune system completely change the paradigm and take us down a path to a potential cure for cancer. Together with colleagues at UCLA and UCSF, we are testing this low-dose combination therapy in patients with stage IV metastatic pancreatic cancer. In early-stage case studies, we are seeing very encouraging results, and, this year, we will be implementing a formalized phase II trial called PANGENA (Pancreatic Genomic Abraxane).

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Expert’s Corner Liquid Biopsies Will sophisticated genomic sequencing provide physicians with more effective methods for earlier detection of cancer, for example, with liquid biopsies? We are looking at a number of different aspects of liquid biopsies currently. One of our established liquid biopsy programs is developing technology that simplifies the procedure of transforming tumor and normal cells embedded in formalin-fixed paraffin sections and converting these laserdissected cells into liquid lysate to allow us to measure the protein level in the tumor. As an example of this early research work, we can now quantitatively measure protein biomarkers, such as HER2/HER3, and we have shown that these findings are significantly more accurate compared with immunohistochemistry and even fluorescence in situ hybridization tests. The second element of our liquid biopsy platform is our ability to analyze a cancer patient’s blood sample to detect circulating tumor cells and use this information to understand the disease biology, determine treatment, and anticipate the resistance factor that is going to be generated as a consequence of the treatment. We are also looking deeply at the role that cell-free tumor DNA plays in cancer. The entire GPS Cancer, whole-genome, whole-exome, and RNA platform will shed new light on circulating tumor cells, cell-free tumor DNA, and the role that these diagnostic tests will play in the continuum of cancer care across the dynamic of quantum oncotherapeutics.

contribute to this common cause. n

Disclosure: Dr. Soon-Shiong is the majority shareholder in NantWorks and its affiliated companies: NantHealth, NantOmics, and Conkwest, a natural killer cell immunotherapy company.

References 1. Benz SC, Rabizadeh S, Sanborn JZ, et al: Protein expression by genetic mutations

identified in gene panels (hotspots) and efficacy of targeted treatments. 2015 ASCO Annual Meeting. Abstract 11005. Presented June 1, 2015. 2. Rabizadeh S, Benz SC, Burrows J, et al: Genomics, transciptomics, and proteomics in the clinical setting. 2015 ASCO Annual Meeting. Abstract 11093. Presented May 31, 2015.

Trim: 7.625 x 10.5

Coming soon…

Major Challenge What do you think is the greatest impediment to advances in oncology care? The challenge now is to overcome the long-held dogma that cancer is a single clonal disease rather than a multiclonal disease and understand cancer to be many rare diseases. We need to unlearn the standard of single-agent maximum tolerated dose and empiric trial and error. I believe overcoming dogma and the “comfort” of pursuing “tried-and-true” regimens is going to be the largest impediment to advances in cancer care, but, hopefully, we will be able to overcome that dogma and drive cancer advances based on 21st century molecular science. To achieve that objective, there is a need to establish an adaptive learning system to validate molecular-driven cancer care. Only through collaboration with sharing of outcomes data on a global scale can we hope to rapidly advance the field and unravel the complexity of the biology of this disease. I sincerely hope that the omics network we have established will

3. Untch M, Jackisch C, Schneeweiß A, et al: A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solventbased paclitaxel followed by anthracyline/ cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. 2014 San Antonio Breast Cancer Symposium. Abstract S2-07. Presented December 10, 2014.

The ASCO Post | JUNE 25, 2015

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2015

2015 Oncology Meetings June ASCO Review 2015 June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/2015/ASCO15/default.asp 2nd EACR Special Conference on Cancer Genomics June 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org

Palliative Medicine and Supportive Oncology 2015 July 23-25 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/pallmed15/overview.asp APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: www.apos-society.org 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

IO360–Immuno-Oncology 360o June 29-June 30 • New York, New York For more information: http://theconferenceforum.org/ conferences/immuno-oncology-360/ overview/

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

July

August

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

Advances in Cancer ImmunotherapyTM August 7 • Washington, DC For more information: www.sitcancer.org

Gynecologic Oncology Group July 15-19 • Denver, Colorado For more information: www.gog.org 14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com

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/

The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September 2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/ International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/ international-palliative-care-workshops 25th World Congress of the International Association of Surgeons, Gastroenterologists, and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org 16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org 25th World Congress of Lymphology September 7-11 • San Francisco, California For more information: www.lymphology2015.com 29th Annual Canadian Association of Radiation Oncology (CARO) Annual Scientific Meeting September 9-12 • Kelowna, Canada For more information: www.caro-acro.ca

American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/ 18th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) September 16-20 • Xiamen, China For more information: www.csco.ac.cn American Society of Hematology (ASH) Meeting on Hematologic Malignancies September 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/ ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting HPV 2015–30th International Papillomavirus Conference September 17-21 • Lisbon, Portugal For more information: www.hpv2015.org 3rd Annual Hematology/Oncology Pharmacy Association (HOPA) Oncology Pharmacy Practice Management Program September 18-19 • Chicago, Illinois For more information: www.hoparx.org/education/2015Practice-Management-Program/2015practice-management-programwelcome.html 2nd International Symposium of the Cancer Research Center of Lyon (CRCL) September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/ 2015 Breast Cancer Symposium September 25-27 • San Francisco, California For more information: http://breastcasym.org

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

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Patient’s Corner Perspective

Carpe Diem By Amir Steinberg, MD, FACP

y life as a cancer survivor and an oncologist has taught me the importance of living every day to the fullest. Sometimes we all need a little reminding to appreciate life to the fullest. When I think of my former patient, Marc, that is what comes to mind. When I was a senior in high school, I was diagnosed with Hodgkin lymphoma. It was tough going, but I had a lot of support from my family, friends, teachers, and my doctor Fredrick B. Hagemeister, MD (Professor of Medicine in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center in Houston). Dr. Hagemeister told me on my first day meeting him to “Live your life as normally as possible.” Since undergoing therapy over 20 years ago, I have tried to do just that. Along the way, I used my life experience as a cancer survivor as motivation to pursue a career in medicine. Like Dr. Hagemeister, I wanted to be a lymphoma specialist, working at a large hospital, involved in research. And through the various stages of my medical training, hematology-oncology fellowship, and bone marrow transplantation fellowship, that continued to be my goal. However, sometimes when one is so goal oriented, life becomes all about pursuing the next step and not appreciating the present. Although it is important to think about the future and plan for that future, one can lose sight of living in the present day. My experience with Marc has helped remind me that today is equally important to focus on, as are the future tomorrows.

A Life Interrupted I met Marc during my first year as an attending physician in Los Angeles. He was close to finishing his education at

a local university with a degree in art. He had been studying abroad in Hong Kong, doing what he does best, living life to the fullest. While there, he developed chest discomfort. An x-ray of his chest was performed and showed a mediastinal mass. He returned to California, where a surgeon performed a biopsy and diagnosed him with T-cell lymphoblastic lymphoma. He was soon referred to my team, and we took over his care. The therapy for his diagnosis would require several

lymphoma. As a result, he needed to undergo an allogeneic stem cell transplant. Although his sister’s stem cells were not a match for his immune system, fortunately, a near-match was found from the National Marrow Donor Program registry. After his transplant, Marc went through several difficult months, but slowly his new immune system began doing its job, and he had no evidence of recurrent lymphoma. Marc began to feel well enough, and it became safe

We are so preoccupied with what we are supposed to be doing, we often miss out on what we would most like to be doing. And if it is possible to pursue the things we love, get out of our rut, and seize the day, then maybe we should. —Amir Steinberg, MD, FACP

months of intense treatment, mainly inpatient. This precluded Marc from completing his last semester in college. I remember Marc often challenging me with complex questions about his therapy. He would ask me what he could and could not do physically, and he was most concerned about whether he could continue surfing, one of his great loves. Through it all, he tried living his life to the fullest, just as he had done prior to his diagnosis. After undergoing 8 months of intense chemotherapy, and getting ready to start his 2-year maintenance chemotherapy, Marc began noticing blood in his urine and some discomfort on urination. A bladder mass was noted, and he was found to have recurrent

enough, to resume his education and complete his degree, and most importantly to Marc, to get back to the sport he loved, surfing, and living his life. Throughout his illness and therapy, Marc had used art as an outlet to deal with his diagnosis and recovery. When I was leaving Los Angeles to take a position at Mount Sinai Hospital in New York, Marc presented me with a print he had created titled “Land of the Blind.” It depicts a wrinkled, worn face resembling Marc (though he indicated to me he did not consciously intend for there to be a resemblance), blind in one eye, wearing a crown with a “king” label, which now hangs on my office wall. It is an allusion to Erasmus’ phrase, “In the land of the blind, the

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

one-eyed man is king.” What was the meaning of this image to Marc? Clearly, the face (perhaps subconsciously his face) depicted in the print has been through a struggle and looks aged, thin, and weary from that struggle. And yet, in terms of the overarching message, perhaps Marc’s message was that until we have all been through such a difficult ordeal, we are blind to the meaning and the essence of life. And he is no longer completely blind to the essence and meaning of life because he’s been through a life-threatening situation, so he feels he can grasp life a bit more robustly than everyone else and put things into perspective a little bit better. And yet, even with this ordeal, no one truly knows the meaning of life, hence, continuing to be blind in one eye. At least that is my interpretation of his print.

Patient/Physician/ Cancer Survivor Bond A few months into my new job, I got an e-mail from Marc. He was driving across the country in a truck. During the drive, he explored the towns and cities he passed through and visited national parks and other tourist attractions he passed along the way. He would surf when he had the opportunity and then sleep in his truck to help maximize his finances for the trip. This was the essence of who Marc was and is. He knew that he had an opportunity to do this trip and that it would allow him to see America and enjoy surfing along the way. And he knew he should take advantage of this opportunity while he was healthy and could enjoy the journey without worrying what the next day would bring, truly following the Latin maxim carpe

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PAGE 53

Patient’s Corner

diem (seize the day). Doing things a little bit on the fly, doing them off the beaten path, and doing them because it was something new, something enjoyable, and something educational. Marc arrived in the Big Apple and wanted to drop by for a visit. We hugged when we saw each other and then reminisced about his experiences as a cancer patient and about the experiences I had shared with him regarding my own journey as a cancer patient 20 years earlier. There was no doubt that we had formed a patient and physician bond, but I sensed we had also developed a bond as two former cancer patients, both diagnosed at a young age. The difference of those 20 years from where Marc was in his life and in the healing process and where I was in my life truly put my role as a physician into focus and showed me how I gave meaning to my own diagnosis by becoming an oncologist and helping provide Marc and other patients the opportunity to overcome their cancers and to live, long, healthy, productive lives. I asked Marc what his future plans were and he replied “I’m not sure yet.” He did indicate, however, that he would seek out something he enjoyed doing. A few years later, I decided to email Marc and see what he was up to. It turns out he had just returned from spending several months in Indonesia. He had worked at a local electronics shop in California to earn money to go on this trip. He spent his time surfing and experiencing the local cuisine and culture. I found it quite apropos for Marc that he would go on this trip. Once again, he was seizing the day. “Carpe diem!”

Living in the Present Some may wonder why Marc doesn’t settle down, get a steady job, and start a family. Maybe someday he will do all those things, but right now his experience as a cancer survivor has given him different priorities and perspective on life. After all he has been through, he wants to take advantage of every day. I understand and appreciate Marc’s “live for the day” philosophy. And I’ve learned important lessons from him. We get so caught up in our busy lives sometimes we lose sight of the essence, the spice, and the meaning of life. We are so preoccupied with what we are supposed to be doing, we often miss out on what we would most like to be doing. And if it is possible to pursue the things we love, get out of our rut, and

seize the day, then maybe we should. Marc is a young man, and if his cancer stays in remission, he has his whole life ahead of him to do what he is “supposed to do.” That being said, none of us knows when the next tragedy in life may strike, so why not enjoy life to the fullest right now, while we are still healthy and can pursue our dreams?

Talking with Marc and reflecting on my own life choices have prompted me to look inward as well and to try to get out of my comfort zone a bit. I’ve also learned to appreciate the little things in life every day, whether it is talking with my parents over the phone, reading to my son, taking my daughter to school, treating the family

to ice cream, or having a thought-provoking discussion with my wife. Like Marc, I’m seizing every day. Carpe diem! n Dr. Steinberg is Assistant Professor in Medicine in the Division of HematologyOncology at Mount Sinai Hospital in New York.

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PAGE 54

In the Literature

Emerging Clinical Data on Cancer Management LEUKEMIA Patients With Relapsed/ Refractory CLL That Progresses Early on Ibrutinib Have Poor Outcomes Most patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who discontinued ibrutinib (Imbruvica) early “were difficult to treat and had poor outcomes,” according to a study of patients enrolled in four different clinical trials of ibrutinib, with or without rituximab (Rituxan), at The University of Texas MD Anderson Cancer Center. Among the 127 total patients, 33 patients (26%) discontinued ibrutinib. Few salvage treatment options are available for these patients, Preetesh Jain, MD, and colleagues reported in Blood. Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory-CLL. “Response rates with ibrutinib are high; however, some patients develop progressive CLL or transform when receiving ibrutinib,” the researchers wrote. The majority of patients discontinuing ibrutinib in the four trials “had highrisk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype,” the investigators noted. Causes of treatment discontinuation were adverse events in 11 patients and serious adverse events/deaths in 3 additional patients, disease transformation in 7 patients and progressive CLL in an-

other 7 patients, stem cell transplantation in 3 patients, and miscellaneous reasons in 2 patients. “There does not appear to be any significant difference in reasons for discontinuation between patients enrolled on studies with rituximab vs those without,” the researchers stated. The median age of the patients was 61 years old. The median number of therapies received prior to ibrutinib was two, and 45% of patients received three or more prior therapies. The median duration of ibrutinib therapy before treatment discontinuation was 13 months. The median overall survival after ibrutnib discontinuation was 3.1 months, and 25 patients (76%) died after discontinuing ibrutinib. The “foremost” take-home lesson from this study is “the very poor prognosis and overall survival of CLL patients who discontinued the drug regardless of the reason,” according to an accompanying commentary, which was written by Javier Pinilla-Ibarz, MD, PhD, and Julio Chavez, MD, of Moffitt Cancer Center in Tampa, Florida. “Definitely, ibrutinib has dramatically changed the landscape of [relapsed/refractory] CLL treatment and constitutes an important paradigm in the molecularly targeted approach of this disease, with excellent efficacy and tolerability,” the commentators added. “However, patients who discontinue treatment represent a challenge to the practicing oncologist, and treatment options are very limited. In the near future, early identification of very high-risk patients treated with ibrutinib should be the target of new combi-

natorial therapies that can improve the outcomes in this population. This report highlights that the road toward a cure (or effective disease control) of CLL has not ended and that, instead, we might be facing a new unmet need in this disease.” Jain P, et al: Blood 125:2062-2067, 2015. Pinilla-Ibarz J, Chavez JC: Blood 125:2013-2014, 2015.

MELANOMA Patients’ Desire for Rapid Notification of Skin Biopsy Results Leads to Preference for Phone Call Over Face-to-Face Visit Patients’ preference for how they receive biopsy results “has shifted from face-to-face visit to discussion over the telephone because of a desire for rapid notification,” according to a survey of 301 patients recruited at three different melanoma clinics. Although 67.1% of the patients preferred to speak directly with their physician by telephone to receive their skin biopsy results, being notified in person at a clinic visit was “a distant second choice,” preferred by only 19.5%, Aditi Choudry, MD, of the Veterans Affairs Medical Center, San Francisco, and colleagues reported in JAMA Dermatology. Voice message and online patient portal were each preferred by 5.1% of patients, e-mail was preferred by 2.7%, and text message was preferred by 0.3%. “Experience with online portal delivery of results favorably inclined patients toward that modality,” the researchers noted. The online portal was also favored by younger and more highly educated patients. The authors recommended that the biopsy consent form include a question about how patients preferred to be notified of the results.

Survey Details

Patients 18 years or older were recruited consecutively between July 1, 2012, and July 31, 2013, from melanoma clinics at three academic tertiary referral medical centers: University of California, San Francisco; University of Pennsylvania, Philadelphia; and Duke University, Durham, North Carolina. The response rate was 98.7%, with 301 of 305 patients agreeing to participate. The mean age of respondents was 54 years; 96.3% were white; 88.6% had a history of melanoma; and 35.6% had a family history of melanoma. “In

our study, women outnumbered men (53.4% vs 46.6%); in contrast, in the United States, more men (58%) are diagnosed as having melanoma than women,” the authors noted.

Preferred Method of Notification by Patients Patients completed the questionnaire while waiting to be seen by their physician and before their clinic visit started and so did not know at that time whether a biopsy would be needed at that visit. They were asked their preferred method of being notified of a biopsy result in order of preference, why they chose a specific method, and if they preferred different methods of notification for normal and abnormal results. “The most important consideration for patients was a communication modality that provided test results in the most rapid manner; 51.7% wanted a method that was rapid, and 7.8% preferred a method that was not only speedy but also allowed them an opportunity to ask questions,” the researchers reported. Meeting with the physician in person was rated very important by 19.5% of patient respondents. Although 59.5% indicated they would choose the same communication method regardless of the biopsy results, 40.5% preferred different modes. For normal results, more of these patients would prefer voice message or e-mail rather than telephone, but for abnormal results, they would prefer to speak directly with the physician by telephone.

Preferred Method of Notification by Physicians A second survey asked physicians at the three institutions to score the various methods of relaying normal and abnormal test results to patients. The response rate was 56% (47 of 84 physicians). The mean age of physicians was 43 years; the mean number of years in practice was 11; and 59.6% were women. “Physicians’ overall preferred method of contacting patients aligned with patient preference for speaking by telephone (56.5%). However, for benign results, 31.2% of physicians chose to speak by telephone, whereas patients preferred voicemail (32.1%),” the authors noted. n Choudhry A, et al: JAMA Dermatol 151:513-521, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | JUNE 25, 2015

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Letters to the Editor

Response to May 10 Cartoon

s a medical writer specializing in oncology, an ASCO member, and someone who tries to build sensitivity to patients into all my work, I was concerned about the cartoon I saw in the May 10, 2015, issue of The ASCO Post. On page 46, there is a cartoon of someone being thrown off a cliff because he has no other options under his health plan. Your publication is mostly read by practitioners. Is this the attitude to promulgate? As a writer, I know that words

Contact

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

count; words shape attitudes, even if not consciously. I use empathetic terminology such as referring to “patients with cancer,” not “cancer patients,” and “the treatment failed,” not “the patient failed treatment.” The cartoon isn’t funny, and it reinforces the experiences many of us have of not being heard; of being told by our

insurance companies that medications we need to keep us alive aren’t going to be covered, but we’re welcome to pay out of pocket; of feeling a doctor’s time is always more important than ours, but that we are free to go somewhere else. These experiences often feel like being shoved off a cliff. I’ll assume no harm was intended by

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your choice of cartoon, but I will also suggest harm was done. There’s a lot of really funny stuff out there, and those of us with life-threatening diseases certainly have our dark sense of humor about them, but their place in a cancer publication could also be questioned. n —Lynne Lederman, PhD Mamaroneck, New York

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PAGE 56

Perspective Michael Green, PhD continued from page 1

myeloid leukemia (CML) with the BCRABL translocation. Other examples have followed, but they have had mixed success, and only a few of them have impacted the clinical management of patients. With the announcement of a precision medicine initiative by the National Institutes of Health, there will be renewed vigor in this endeavor. However, in attempting to replicate the model of imatinib in CML, it is important to understand the biologic context behind its great success, specifically the impact clonal evolution has on precision cancer medicine.

Imatinib: Targeting the Root of the CML Evolutionary Tree In 1976, Peter C. Nowell, MD, proposed a model of clonal evolution in Science magazine in which he suggested “tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines.” As we approach the 40th anniversary of this theory and stand upon the doorstep of being able to therapeutically target acquired genetic alterations in a variety of diseases, this concept of clonal evolution becomes increasingly important. The theory itself has been validated in countless studies showing that the sequential acquisition of mutations results in gains in evolutionary fitness. Furthermore, tumor initiator clones (also often referred to as cancer stem cells) have been identified in a subset of cancers and highlight the potential for a genetically “simple” tumor cell progenitor to propagate disease relapse. There is perhaps no disease with greater evidence of this than CML. The initiating event in CML is acquisition of the t(9;22)(q34;q11) translocation, which creates a fusion between the BCR and ABL1 genes. This alteration can be found in hematopoietic stem cells and traced through the lineage to CML cancer cells. Secondary genetic alterations, such as mutations of TP53, RB1, and CDKN2A, can be acquired after the BCR-ABL translocation and may play a role in progression of CML from an early chronic phase to a more aggressive blast phase. The introduction of imatinib, a small molecule inhibitor of ABL family kinases including the BCR-ABL fusion gene, revolutionized the way that CML is managed and dramatically improved outcomes for these patients. But why was imatinib so successful when therapies targeting other important “driver

mutations” in other diseases have failed to produce similar results? An important factor contributing to the success of imatinib is that it targets the initiating event in the clonal evolution of CML. This means that all daughter cells that evolve following this initial event (ie, every cell in the clonal pool) also carry the BCRABL translocation and are susceptible to the effects of imatinib. The efficacy of imatinib is confounded by stromal interactions that protect the tumor-initiating clone and prevent clearance of the disease. However, the fact that this event is acquired early in clonal evolution and is in every evolved CML clone makes this disease manageable for extended periods, until an escapee mutant inhibits or circumvents the drug’s activity.

Is Every ‘Actionable’ Mutation Worth Acting On? The terms “driver mutation” and “passenger mutation” were coined to discriminate between (1) those mutations that play an active role in disease pathogenesis (ie, driver mutations)

them to overtake less-fit clones at different rates. This means that some driver mutations, despite occurring as late events in disease evolution, may appear to be present in the majority of tumor cells because they provide a significant boost to clonal fitness, and the subclone has therefore expanded prior to the time of sampling. However, in many cases, late driver mutations can be identified by variant allele frequencies (the representation of mutant alleles as a proportion of all sequencing reads over that nucleotide), which indicate they are subclonal events. Currently, the majority of cancer subtypes lack a repertoire of “actionable” mutations that are matched to targeted therapies for oncologists to routinely make treatment decisions based upon tumor genotype. However, the perceived future of precision medicine is one in which patients will receive a report of “actionable” mutations matched to suggested therapeutics or clinical trials, which their oncologist can use in the formulation of their treatment strategy.

Not all driver mutations are created equal. Some driver mutations occur early and play a role in disease genesis, whereas others occur later and play a role in disease progression. —Michael Green, PhD

and (2) those mutations that do not contribute to disease pathogenesis but undergo clonal expansion alongside one that does (ie, passenger mutations). However, the model for clonal evolution implies that not all driver mutations are created equal but rather are acquired in an ordered hierarchy. That is, some driver mutations occur as early events during clonal evolution and play a role in disease genesis (early drivers), whereas others occur as later events during clonal evolution and play a role in disease progression (late drivers/accelerators). Early driver mutations that have a role in disease genesis, such as the BCR-ABL translocation, will therefore be present in every tumor cell, whereas late driver mutations may only be present within a subset of tumor cells (ie, in a subclone). To further complicate understanding and measurement of the clonal origin of mutations, each driver mutation will confer a variable boost in evolutionary fitness, which will cause

The question will then be is every “actionable” mutation worth acting on? In addition to the questions of efficacy and toxicities that are asked of all therapies, the clonal origins of each mutation and the desired outcome of the treatment will be important factors in this decision for “actionable” mutations. This is because early mutations are more likely to reside with a tumor progenitor cell compartment that propagates relapse, whereas late mutations may not. Assuming that these therapies eliminate every cell that carries the targeted mutation, the targeting of an early driver mutation that is clonally dominant may therefore provide the best chance of cure. In contrast, targeting a late driver mutation that has expanded to become clonally dominant may clear a large number of tumor cells and induce remission but may not eradicate tumor-initiating cells that propagate a relapse. This situation may result in a clinical management strategy akin to a game of subclone whack-a-mole, but it could potentially extend patient survival. However,

targeting a subclonal mutation may have little or no effect on tumor burden and could waste valuable time. Understanding the hierarchical order in which somatic mutations are acquired in each disease will therefore be an important consideration in ranking therapeutic targets for drug development, but this is a complex scientific undertaking. At the very least, the reporting of mutations in molecular genetic tests should incorporate a measure of clonal representation (allelic frequency) for each mutation, so that oncologists can be more informed about the biology of the tumor they are treating.

Concluding Remarks Clonal evolution and clonal dominance will be important considerations in precision medicine as an increasing repertoire of mutations becomes “actionable.” However, it is necessary to discriminate between the importance of subclonality with regard to precision medicine and prognostication. A mutation that is associated with an inferior outcome but is present only in a subclone may still maintain its prognostic value. This is because investigators often do not discriminate between clonal and subclonal events when identifying associations with prognosis. In addition, adverse mutations residing within a subclone are likely to be associated with inferior outcome because of their role in therapeutic resistance and/ or increased clonal fitness, which are functions that can facilitate clonal expansion and disease progression regardless of the initial size of the subclone within the total tumor cell pool. Accurate assessment of the clonal representation of mutations will require a method for estimating the total tumor content of samples that are submitted for sequencing, so the variant allele frequency can be normalized to the estimated fraction of tumor cells present within the sample. This can be achieved by pathology review of sections prior to DNA extraction, but this approach is cumbersome and therefore unlikely to become standard practice. New approaches are therefore required for automated tumor content assessment, but, until the time that such technology is available, variant allele frequencies should nonetheless be reported and used in the interpretation of sequencing results. Furthermore, the credential of “early driver mutations” should be used to prioritize therapeutic targets for drug development and “actionable” mutations for clinical decision-making. n Disclosure: Dr. Green reported no potential conflicts of interest.

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PAGE 58

ASCO Annual Meeting

Scenes From ASCO 2015

1. Suzanne Eleanor Dahlberg, PhD, presents Basket Trial Designs. Photo by © ASCO/David Eulitt 2015 2. Clinical Trial Participation Award Recipients. Photo by © ASCO/Max Gersh 2015 3. Christine Marie Walko, PharmD, BCOP. Photo by © ASCO/Max Gersh 2015 4. International Development and Education Award (IDEA) Networking Event at the ASCO. Photo by © ASCO/Max Gersh 2015 5. Ananth Bhogaraju and Raj Mantena, RPh. Photo by © ASCO/Zach Boyden-Holmes 6. William Gradishar, MD, FACP, Robert Carlson, MD, FACS, and V. Craig Jordan, OBE, PhD, DSc, FMedSci. Photo by © ASCO/Scott Morgan 2015 7. David N. Hayes, MD, MPH, presents Clinical-Grade Deep Sequencing for Cancer during Expediting the Learning Curve for Applied Cancer Genomics. Photo by © ASCO/Max Gersh 2015 8. ASCO and CCF CEO Allen Lichter, MD, FASCO, and Evie Lichter at the Conquer Cancer Foundation Campaign Kickoff Dinner during the ASCO Annual Meeting. The dinner celebrated the launch of The Campaign to Conquer Cancer, a multi-year effort to do one BIG thing: take down cancer. Photo by © ASCO/Zach Boyden-Holmes 2015 9. Peter Paul Yu, MD, FACP, FASCO, and his family Photo by © ASCO/Scott Morgan 2015 10. Jane Hertzmark Hudis, Clifford Hudis, MD, FACP, and Margaret Tempero, MD. Photo by © ASCO/Zach Boyden-Holmes 2015 11. Opening Press Briefing: Media, including Caroline Helwick (second in line), reporter for The ASCO Post. Photo by © ASCO/Scott Morgan 2015 12. General Views at ASCO. Photo by © ASCO/David Eulitt 2015.

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