TAP Vol 6 Issue 11

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

ASCO Releases Details of Its Conceptual Framework for Assessing Value in Cancer CareA Conversation With Lowell E. Schnipper, MDBy Jo Cavallo

Defining and ensuring the delivery of high-value oncology care has been one of ASCO’s ma-

jor 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 on-cology 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 Choos-ing Wisely® campaign launched by the American Board of Internal Medi-cine Foundation, ASCO identified five common clinical practices that were not supported by scientific evidence to have clinical value and that contributed

ASCO Plenary Presentation

Precision cancer medicine entails treating patients based upon the molecular charac-

teristics 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 SuccessThe first example of precision medicine in

oncology is the use of imatinib to treat chronic

Considering Clonality in Precision Medicine

By Michael Green, PhD

Oncology Meetings CoverageASCO Annual Meeting

Multiple Myeloma �� 3Breast Cancer �� 4–8Melanoma �� 9Sarcoma ��14Venous Thromboembolism ��17Chronic Lymphocytic Leukemia ��20Prostate Cancer ��23

Direct From ASCO �� 26–29Precision Oncology Care ��34Clinical Trials �� 44ASCO 2015 in Pictures ��58

MORE IN THIS ISSUE

continued on page 42

Expert’s Corner

Elective Neck Dissection Beats Watch and Wait Approach in Early Oral CancerBy Alice Goodman

E lective neck dissection of node-negative early-stage oral cancer at the time of primary surgery

improves overall survival and disease-free survival compared with therapeutic neck dissection (ie, ther-apeutic 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 re-duced 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 recur-rence is prevented,” stated lead author Anil K. D’Cruz, MBBS, MS, FRCS, Direc-tor, Tata Memorial Center, Head and Neck Services, Mumbai, India.

‘One and Done’“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

Anil K. D’Cruz, MBBS, MS, FRCS

Hematologic Disease 3, 20 | Prostate Cancer 23, 32 | Ovarian Cancer Risk 37 | Redefining Cancer 46 VOLUME 6, ISSUE 11JUNE 25, 2015



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 standard of care.

—Lowell E. Schnipper, MD

Dr. Green is Associate Professor at Eppley Institute for Research in Cancer and Allied Diseases at the Univer-sity of Nebraska Medical Center in Omaha.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

A Harborside Press® PublicationBest of ASCO, Visit http://boa.asco.org/

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropri-ate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

James O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate EditorsJame Abraham, MD Cleveland Clinic

Syed Abutalib, MD Cancer Treatment Centers of America

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Chandrakanth Are, MD University of Nebraska Medical Center

Joseph S. Bailes, MD Texas Oncology

Laurence H. Baker, DO University of Michigan Health System

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

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

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Wisconsin School of Medicine

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Bishoy Morris Faltas, MD Weill Cornell Medical College

John A. Fracchia, MD New York Urological Associates

Alison Freifeld, MD University of Nebraska Medical Center

Louis B. Harrison, MD Moffitt Cancer Center

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

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

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

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

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

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

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

Michael P. Link, MD Stanford University Medical Center

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

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

William T. McGivney, PhD Philadelphia, Pennsylvania

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

George W. Sledge, MD Indiana University

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

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

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

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

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

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

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

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

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John F. Smyth, MD University of Edinburgh Edinburgh, Scotland

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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ASCOPost.com | JUNE 25, 2015 PAGE 3

ASCO Annual Meeting

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

Heavily pretreated patients with multiple myeloma achieved rapid,

durable, and deepening responses to the anti-CD38 monoclonal antibody dara-tumumab, in a phase II study presented at the 2015 ASCO Annual Meeting.1

“Daratumumab showed remarkable single-agent activity in heavily pretreat-ed and refractory multiple myeloma pa-tients who had exhausted other thera-peutic 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 ex-pressed” on the surface of myeloma cells. This expression makes CD38 a “unique and potentially important target” in this disease, Dr. Lonial explained.

Response rates to single-agent da-ratumumab (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. Lo-nial noted, “the [U.S. Food and Drug Administration] FDA granted break-through 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 re-fractory 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 recom-mended 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 diag-nosis of about 5 years. Twenty percent had high-risk genetic profiles.

He noted that baseline characteristics are important for the interpretation of

EXPERT POINT OF VIEW

Suzanne Lentzsch, MD, PhD, Di-rector of the Multiple Myeloma

and Amyloidosis Program, Columbia University College of Physicians and Surgeons and New York Presbyterian

Hospital, served as the study’s discus-sant. 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-re-fractory. What’s also important, and I have seen this in my own patients,

is that responses were rapid and im-proved over time,” she commented.

Dr. Lentzsch compared the single-agent activity of daratumumab with that seen with other antibodies. In a

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

Monoclonal Antibodies in Combination

When these monoclonal antibod-ies 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 re-sponses, in a study presented at the 2014 ASH Annual Meeting and Ex-position.3 “I think that’s remarkable, and responses increased and deep-ened over time,” she noted.

With SAR650984 plus lenalido-mide/dexamethasone, responses in-creased to 63%,4 and with elotuzum-ab/lenalidomide/dexamethasone, 92% of patients responded.5

She concluded, “We see dramatic increases in response to monoclo-nal antibodies when these drugs are combined with immunomodulato-ry drugs, so I think, based on these data, monoclonal antibodies will be the backbone of myeloma treat-ments in the future,… and I think it’s time for an R-CHOP [ritux-imab, cyclophosphamide, doxoru-bicin, 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.

References1. 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, Sing-hal 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 daratu-mumab with lenalidomide and dexa-methasone in relapsed or relapsed, re-fractory 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 com-bination with lenalidomide and dexa-methasone in patients with relapsed/refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 302.

Hematology

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

continued on page 4

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

—Sagar Lonial, MD


ASCO Annual Meeting

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 my-eloma: bortezomib [Velcade], lenalido-mide [Revlimid], carfilzomib [Kypro-lis], and pomalidomide [Pomalyst].”

Positive OutcomesThe majority of patients had reduc-

tions in paraprotein, from baseline, including 39% with reductions > 50% and 16% with reductions > 90%. The overall response rate was 29%, includ-ing 3% stringent complete responses, 9% very good partial responses, and 17% partial responses. The clinical benefit rate was 34%.

“What’s striking about this is not just that one in three patients with re-fractory, 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 mecha-nism of action may be important.”

He predicted, “Depth of response may actually translate into overall sur-vival. Follow-up is short, but we had hints of that.” Over a median follow-up of 9.3 months, initial responses deep-ened with continued daratumumab treatment in many patients. The medi-an time to response was 1 month, and the median duration of response was 7.4 months.

“Responses do occur quickly, and they can continue to deepen over time with additional treatment and subse-quent follow-up,” Dr. Lonial said.

By subgroup, response rates were consistent across the board, whether by age (including patients ≥ 75 years), cre-atinine clearance, lines of prior therapy, and even presence of extramedullary disease, he emphasized.

Median progression-free survival was 3.7 months. Median overall sur-vival was not yet reached, and esti-mated 1-year overall survival was 65%. Importantly, he added, 29 of 31 re-sponders were still alive at data cutoff ( January 2015).

Dr. Lonial noted that, in other datasets of double-refractory pa-tients, 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 TolerabilityGrade ≥ 3 treatment-emergent ad-

verse events were observed in 30% of patients, primarily anemia (24%), thrombocytopenia (17%), neutro-penia (11%), fatigue (3%), and back

pain (3%). Most of the grade 3 ane-mia and thrombocytopenia occurred in nonresponders, who had poor he-matologic reserve at baseline. Among responders, the incidence of grade 3 neutropenia was not high at all, and no patients developed febrile neutro-penia, 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 in-fusion, and only 7% had subsequent in-fusion reactions. n

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

References1. Lonial S, Weiss BM, Usmani SZ, et al:

Phase II study of daratumumab monothera-py in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma: 54767414MMY2002 (Sirius). 2015 ASCO Annual Meeting. Abstract LBA8512. Pre-sented June 2, 2015.

2. Lokhorst HM, Laubach J, Nahi H, et al: Dose-dependent efficacy of daratumum-ab as monotherapy in patients with relapsed or refractory multiple myeloma. ASCO 2014 Annual Meeting. Abstract 8513.

Daratumumab in Myelomacontinued from page 3

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%.

Palbociclib Slows Progression of Hormone Receptor–Positive Breast CancerBy Caroline Helwick

The oral CDK4/6 inhibitor pal-bociclib (Ibrance), combined

with fulvestrant (Faslodex), more than doubled the duration of remission in a cohort of premenopausal and post-menopausal patients with advanced hormone receptor–positive, HER2-negative breast cancer, investigators reported at the 2015 ASCO Annual Meeting.1 The findings were concur-rently published in The New England Journal of Medicine.2

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

medical oncologist at The Royal Mars-den 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 re-ceptor–positive breast cancer relies on cyclin-dependent kinases 4 and 6 (CDK4, CDK6), which promote pro-gression from the G1 phase to the S

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.

PALOMA3 DetailsPALOMA3 enrolled 521 premeno-

pausal or postmenopausal women who had progressed on prior endo-crine therapy and had no more than one prior treatment for advanced can-cer. 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 pla-cebo (n = 174). The primary endpoint was investigator-assessed progression-free survival.

At the time of the preplanned interim analysis, median progression-free sur-vival was 9.2 months in the palbociclib/fulvestrant arm and 3.8 months in the

placebo arm, producing a highly signifi-cant 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 treat-ment 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. Symptom-atic adverse events with palbociclib were largely similar to placebo. We saw small increases in fatigue, alopecia, and infections,” he said.

Breast Cancer

continued on page 6

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

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.

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ASCO Annual Meeting

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

Further DiscussionAsked 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 ful-vestrant as the endocrine therapy. “We are identifying in hormone receptor–positive breast cancer that CDK4/6 is a key gene allowing these cancers to prolif-erate. This study confirms that as breast cancers become resistant to endocrine therapy, CDK4/6 is still a target, and pal-bociclib is still very active. It’s a standard hormone therapy and is likely the most active one…. We have significant labora-tory data showing synergy between pal-bociclib and fulvestrant in two cell line models of endocrine resistance.”

Angelo Di Leo, MD, principal in-vestigator 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 con-trol arm (3.8 months). He noted that in CONFIRM, the 500-mg dose of fulves-trant yielded a median progression-free survival of 6.5 months, “despite the fact that in CONFIRM, the proportion of

patients with primary resistance to en-docrine therapy was higher than here.”

Dr. Turner responded that the popu-lation of PALOMA3 was more heav-ily pretreated and at higher risk, which likely explains the lower progression-free survival. He further pointed out that the benefit was similar to that ob-served 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 en-docrine therapy in heavily pretreated patients,” he said. n

Disclosure: The study was funded by Pfizer. Drs. Turner and Di Leo reported no potential conflicts of interest.

References1. Turner NC, Ro J, Andre F, et al:

PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbo-ciclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that pro-gressed on prior endocrine therapy. 2015 ASCO Annual Meeting. Abstract LBA502. Presented June 1, 2015.

2. Turner NC, Ro J, André F, et al: Pal-

bociclib in hormone-receptor-positive ad-vanced 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 ful-vestrant 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 366:520-529, 2012.

Palbociclib in Breast Cancercontinued from page 4 EXPERT POINT OF VIEW

Joseph A. Sparano, MD, Profes-sor of Medicine and Women’s

Health at the Albert Einstein College

of Medicine, New York, was the for-mal discussant of the study and com-mented, “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 disease-free interval.”

He offered that CDK4/6 inhibi-tors, a number of which are in de-velopment (including ribociclib and abemaciclib), represent an impor-tant treatment advance in estrogen

receptor–positive metastatic breast cancer. “This represents an entirely new treatment modality,” he said. He also described several large tri-als in various settings that will fur-ther elucidate the role of palbociclib (Ibrance) in this disease.

Adding commentary at the press briefing was Don Dizon, MD, desig-nated ASCO expert and Clinical Co-Director of Gynecologic Oncology at Massachusetts General Hospital, Boston, who offered, “These results are incredibly important for hor-mone receptor–positive advanced or metastatic breast cancer patients. They present a new option for pro-gressive 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.

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 disease-free interval.

—Joseph A. Sparano, MD

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.

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

The May 25 issue of The ASCO Post included a report present-

ed 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 Nonmela-noma Skin Cancer Reported,” visit http://bit.ly/1dDT1Z8.

For more on the study and to

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

Andrew James Martin, MD


ASCO Annual Meeting

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

Taking additional tissue circumfer-entially around the cavity left by

partial mastectomy (“cavity shave mar-gins”) 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 mas-tectomy 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 addi-tional surgery by 50%, which has huge consequences for patients and for the

health-care system,” stated lead author Anees B. Chagpar, MD, MPH, Direc-tor of the Breast Center at Yale Univer-sity’s Smilow Hospital, New Haven, Connecticut.

“Cavity shave margins will spare patients the trauma of unnecessary sur-gery 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 evi-dence 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 en-

Breast Cancer

continued on page 8

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

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ASCO Annual Meeting

abled identification of cancer in 12% of patients previously deemed to have negative margins.

“This calls into question the ac-curacy 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 shav-ing,” Dr. Chagpar said.

“Although the argument could be made that finding additional occult disease may not affect outcome, excis-ing additional disease in more than 10% of patients may have a significant long-term effect on the rate of local recur-rence,” she added.

Partial mastectomy is commonly performed for women diagnosed with breast cancer, and margin status is a de-terminant of recurrence. About 20% to 40% of women have positive margins following partial mastectomy that re-quire 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 DetailsThe 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 enve-lope with the randomization assign-ment, which they opened (by the cir-culating 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 touch-ing 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 base-line. The rate of positive margins prior to randomization but after partial mastecto-my was similar in the shave and no-shave

groups: 36% and 34%, respectively.Following randomization, the rate of

positive margins was significantly low-er in the shave group vs the no-shave group: 19% vs 34%, respectively (P = .01). Furthermore, the rate of reexci-sion for margin clearance was also sig-nificantly lower in the shave group: 10% vs 21%, respectively (P = .02).

The volume of tissue prior to random-ization was not significantly different be-tween 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.

References1. Chagpar AB, Killelea BK, Tsan-

garis 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, Tsan-garis TN, et al: A randomized, controlled trial of cavity shave margins in breast can-cer. N Engl J Med. May 30, 2015 (early release online).

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.


“This is a significant study. About 30% of patients who undergo breast-conserving surgery or partial mastectomy are likely to have positive

margins. Optimal treatment is to remove the entire tumor surgically and then

follow with radiation. Standard practice requires reexcision for positive mar-gins,” 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.

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

Cavity Shave Marginscontinued from page 7

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

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

Visit The ASCO Post online at ASCOPost.com


ASCO Annual Meeting

Not All Stage III Melanoma Patients Need Complete Nodal DissectionBy Caroline Helwick

Complete lymph node dissec-tion 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 se-nior study author Claus Garbe, MD, Professor of Dermatology at the Uni-versity of Tübingen, Germany, speaking at a press briefing.

The multicenter DeCOG study found no significant treatment-related differences in 5-year recurrence-free

survival, distant metastases-free sur-vival, 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, report-ed at an ASCO session.

“The group with complete lymphad-enectomy showed better disease con-trol in the regional lymph node basin, but completed lymphadenectomy was not associated with improved distant metastases-free survival, recurrence-free survival, or melanoma-specific survival,” said Dr. Leiter. “Based on our findings, complete lymphadenectomy cannot be recommended in melanoma patients with micrometastases.”

DeCOG DetailsInvestigators screened 1,269 pa-

tients who had stage III cutaneous melanoma of the trunk and extremi-

ties and positive sentinel lymph node biopsy. All patients had micrometasta-ses 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

Dermatologic Oncology


Based on our findings, complete lymphadenectomy

cannot be recommended in melanoma patients with

micrometastases. —Ulrike Leiter, MD

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

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ASCO Annual Meeting

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 nod-al 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

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 pri-mary endpoint], and to date, that dif-ference in both arms was only 1.1% and the difference in the 3-year distant me-tastasis free survival was 0.3% (80.4% vs 80.1%).” The investigators will con-duct another analysis in 3 years. n

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

Reference1. Leiter U, Stadler R, Mauch C, et al:

Survival of SLNB-positive melanoma pa-tients with and without complete lymph node dissection: A multicenter, randomized DeCOG trial. 2015 ASCO Annual Meeting. Abstract LBA9002. Presented May 30, 2015.

Stage III Melanomacontinued from page 9


Lynn Schuchter, MD, of the University of Pennsylvania,

Philadelphia, a designated ASCO expert, commented at the press briefing that the results might ap-ply to a select group of patients con-cerned about lymphedema but not yet to the broader population. “I would say that this is a really impor-tant study, but it’s a relatively small one, and I don’t think we would make a complete change in our rec-ommendations based on these data,” she offered. “I think we will wait to

make definitive changes in our man-agement until we have results from a larger study.”

The multinational MSLT2 trial with nearly 2,000 patients random-ized is currently evaluating this is-

sue and will provide much more de-finitive information, agreed Vernon Sondak, MD, Chair of the Cutane-ous Oncology Department at Mof-fitt 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.

Dr. Sondak considers the find-ings 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 consid-ered it safe to forego complete lymph node dissection after a positive sen-tinel 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 MisconceptionsDr. Sondak also clarified some

misconceptions about complete lymph node dissection after a posi-tive 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 lymph-edema, almost all of which is mild, when the procedure is done after a positive sentinel node biopsy. The incidence is higher among patients

who are obese or have other risk fac-tors and lower among younger, fit patients.

He also noted that upfront com-plete lymph node dissection pro-duces less morbidity than the sur-gery 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 defini-tively 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 knowl-edge 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 obser-vation approach with frequent fol-low-up in select patients,” he said. n

Disclosure: Drs. Schuchter and Sondak reported no potential conflicts of interest.

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

Vernon Sondak, MD

Table 1: Outcomes in DeCOG Trial

Arm A (Observation) N = 233

Arm B (Radical Lymphadenectomy) N = 240

P Value

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

RecurrencesTotalRegional lymph nodesDistant

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

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

.349 .029 .811

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.


ASCO Annual Meeting

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 USAGEGAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONSNone.

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 LeukoencephalopathyJC 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)].

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.

5.4 Tumor Lysis SyndromeAcute 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.

5.5 InfectionsSerious 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.

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.

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

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

5.7 ThrombocytopeniaGAZYVA 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.

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.

5.8 ImmunizationThe 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 ADVERSE REACTIONSThe 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)]

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

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

The 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)

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.

Injury, poisoning, and procedural complicationsInfusion 69 21 0 0reactions

Blood and lymphatic system disordersb

Neutropenia 41 35 18 16

Thrombocytopenia 15 11 8 4

Anemia 12 5 10 4

Leukopenia 7 5 0 0

General disorders and administration site conditionsPyrexia 10 < 1 7 0

Respiratory, thoracic, and mediastinal disordersCough 10 0 7 < 1

Infections and infestationsUrinary tract 6 2 3 < 1infection

Musculoskeletal and connective tissue disorderBack pain 5 < 1 2 0

Adverse Reactions (MedDRAa) System Organ Class

GAZYVA + Chlorambucil

n = 336

Rituximab + Chlorambucil

n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %

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

Injury, poisoning and procedural complicationsInfusion 66 20 38 4reactions

Blood and lymphatic system disordersb

Neutropenia 38 33 32 28


Leukopenia 6 4 2 < 1

General disorders and administration site conditionsPyrexia 9 < 1 7 < 1

Gastrointestinal disordersDiarrhea 10 2 8 < 1

Constipation 8 0 5 0

Infections and infestationsNasopharyngitis 6 < 1 3 0

Urinary tract 5 1 2 < 1infection

a MedDRA coded adverse reactions as reported by investigators. b Adverse events reported under “Blood and lymphatic

system disorders” reflect those reported by investigator as clinically significant.

Adverse Reactions (MedDRAa) System Organ Class

GAZYVA + Chlorambucil

n = 241

Chlorambucil n = 116

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %

02-12478_R01_GAUS_BriefSummary_A_size.indd 1 1/29/15 3:00 PM

Sexual Dysfunction After Gynecologic Cancer Treatment

A study presented at the ASCO An-nual Meeting showed decreased

sexual activity in women following treatment for gynecologic cancers, down from 6 to 7 times per month be-fore 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 be-cause 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

maintaining quality of life after treat-ment 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.

The data showed an overall decrease in sexual frequency after cancer treat-ment but no accompanying increase in marital dysfunction. Dr. Guntupalli said counseling during cancer treatment may benefit a couple’s sexual health af-ter treatment. n


ASCO Annual Meeting

early oral cancer, we now know that more extensive surgery saves lives.” Dr. Patel is Associate Professor at North-western University Feinberg School of Medicine, Chicago.

Oral cancer is highly prevalent in both developed countries and developing coun-

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 TopicThe primary treatment of early node-

negative oral cancer is a small excision, but controversy surrounds whether or

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 associat-ed morbidities associated with a second surgery. Performing both the primary

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

Study Details and ResultsA 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 follow-up 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

randomization was performed after sur-gery 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, com-pared 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 thera-peutic dissection, a highly statistically sig-nificant difference (P < .001).

The overall survival benefit of elective neck dissection was consistent across almost all prespecified subgroups, in-cluding stage, sex, grade, tumor depth, resected margin status, and use of radio-

Plenary Session

Elective Neck Dissectioncontinued from page 1

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

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 disease-free 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.

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.

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.

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

(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 ImmunogenicitySerum 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 ExperienceWorsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere 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 DataIn 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.

8.3 Nursing MothersIt 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.

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

GAZYVA® [obinutuzumab]

Manufactured by: Genentech, Inc.

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

U.S. License No: 1048

Initial US Approval: 2013

Code Revision Date: December 2014

GAZYVA is a registered trademark of Genentech, Inc.

GAZ/011615/0009 1/15

© 2015 Genentech, Inc.

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)


HematologyNeutropenia 78 48 53 27

Lymphopenia 80 40 9 3


ChemistryHypocalcemia 38 3 33 2

Hyperkalemia 33 5 18 3

Hyponatremia 30 8 12 3

AST 29 1 16 0(SGOT increased)

Creatinine 30 < 1 20 2increased

ALT 27 2 16 0 (SGPT increased)

Hypoalbuminemia 23 < 1 15 < 1

Alkaline phosphatase 18 0 11 0increased

Hypokalemia 15 1 5 < 1



Leukopenia 84 35 62 16


Anemia 39 10 37 10

ChemistryHypocalcemia 37 3 32 <1

Hyperkalemia 14 1 10 <1


AST 27 2 21 <1(SGOT increased)


Hypoalbuminemia 23 <1 16 <1

8.5 Geriatric UseOf 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 ImpairmentBased 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 ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere 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 INFORMATIONAdvise 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)].

InvestigationsGAZYVA

+ Chlorambucil n = 241


All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %




n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %



ASCO Annual Meeting

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 dis-section 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 pri-mary site,” Dr. D’Cruz noted. The major-ity of patients with buccal cancers avail-able for recruitment in this trial were not amenable to oral excision, he added.

Study LimitationA study limitation is that it did not

address shoulder dysfunction, which af-flicts 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 percent-age 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.

References1. D’Cruz AK, Dandekar M, Vaish R, et

al: Elective versus therapeutic neck dissec-tion in the treatment of early node negative squamous cell carcinoma of the oral cav-ity. 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).


Formal discussant Hisham Mehanna, PhD, Chief of Head

and Neck Surgery and Director of Head and Neck Studies and Educa-tion at the University of Birming-ham, United Kingdom, congratu-lated 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 poten-tial 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 pa-tients who have node-negative dis-ease on clinical and radiologic exami-nations actually have occult nodal

metastases. “Some node-negative patients will develop metastasis. Re-operations for these patients incur additional costs and toxicities. The advantages of elective neck dissec-tion include reduced risk of recur-rence, low morbidity, and negligible

effect on quality of life. Some trials even show better survival, but about 5% of patients can have significant complications and shoulder disabil-ity,” he continued. “It is not an easy randomization to sell to patients.”

“The results are astounding. The survival benefit [with elective node

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,

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

More to LearnDr. 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 fol-low-up in the future (ie, ultrasound-guided vs clinical surveillance). “The absence of this data limits our ability to make full recommendations,” he told listeners. Additionally quality-of-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 clini-cal 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 regard-ing ultrasound-guided surveillance with the data we have at present. We await further results.” n

Disclosure: Dr. Mehanna reported no potential conficts of interest.

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

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.

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.

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

(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 ImmunogenicitySerum 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 ExperienceWorsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere 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 DataIn 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.

8.3 Nursing MothersIt 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.

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

GAZYVA® [obinutuzumab]

Manufactured by: Genentech, Inc.

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

U.S. License No: 1048

Initial US Approval: 2013

Code Revision Date: December 2014

GAZYVA is a registered trademark of Genentech, Inc.

GAZ/011615/0009 1/15

© 2015 Genentech, Inc.






ChemistryHypocalcemia 38 3 33 2

Hyperkalemia 33 5 18 3


AST 29 1 16 0(SGOT increased)

Creatinine 30 < 1 20 2increased


Hypoalbuminemia 23 < 1 15 < 1

Alkaline phosphatase 18 0 11 0increased

Hypokalemia 15 1 5 < 1



Leukopenia 84 35 62 16


Anemia 39 10 37 10

ChemistryHypocalcemia 37 3 32 <1

Hyperkalemia 14 1 10 <1


AST 27 2 21 <1(SGOT increased)


Hypoalbuminemia 23 <1 16 <1

8.5 Geriatric UseOf 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 ImpairmentBased 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 ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere 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 INFORMATIONAdvise 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)].




All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %




n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %


http://www.ipos-apos2015.org/


ASCO Annual Meeting

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

E 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, investi-gators reported at the 2015 ASCO An-nual Meeting.1

Eribulin is a microtubule inhibitor that blocks cell division. In preclinical models, it also has been shown to im-pact tumor cells via vascular remodel-ing, reversal of epithelial-mesenchymal transition, as well as suppression of mi-gration and invasion.

In the global phase III study (Study 309), eribulin reduced the risk of death

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 meta-static 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. Er-ibulin 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 co-morbid conditions, multiple prior drug regimens, and intermediate-to-high tu-mor 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-to-treat diseases,” he said.

Study DetailsStudy 309 is a randomized, open-label

multicenter phase III trial in which 452 patients with advanced leiomyosarcoma or adipocytic sarcoma (ie, liposarcoma)

Sarcoma

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-to-

treat diseases. —Patrick Schöffski, MD

Advertisement not displayed in digital edition at advertiser’s request


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 pro-gression. More than 40% of patients had received more than two prior regimens.

The primary endpoint was overall survival, which was significantly im-proved 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 com-mon adverse events grade ≥ 3 with the




ASCO Annual Meeting

drug were neutropenia (35%) and fatigue (3%). About one-third of patients expe-rienced some degree of nausea, alopecia, and constipation. There were two treat-ment-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 oncol-ogy. 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 un-derstand 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.

Reference1. SchÖffski P, et al: 2015 ASCO Annual

Meeting. Abstract LBA10502. Presented June 1, 2015.

Advanced Sarcomacontinued from page 15



ASCO Annual Meeting

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

P atients with cancer who develop venous thromboembolism are at

high risk of such obstructive disease

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

dictors of recurrence: venous compres-sion by the tumor and a diagnosis of hepatobiliary cancer.1

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

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

Study DetailsThe CATCH study was a prospec-

tive, open-label, multicenter clinical tri-al that included more than 900 patients being treated for active cancer who de-veloped acute, symptomatic proximal deep venous thromboembolism and/or pulmonary embolism.2 They were ran-domly assigned 1:1 to 6 months of anti-coagulation with tinzaparin (Innohep) at 175 IU/kg once a day vs initial tinza-parin (low–molecular-weight heparin)

Supportive Care


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



ASCO Annual Meeting

transitioning to dose-adjusted warfarin (target of international normalized ra-tio [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 thromboem-bolism favoring tinzaparin (P = .07). Symptomatic nonfatal venous throm-boembolism 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 non-major bleeding was significantly re-duced in the tinzaparin arm, occur-ring in 50 (11%) vs 73 (16%) patients (P = .03). No difference in mortal-ity was observed between the two treatments.

Additional DataThe 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 evalu-ated multiple clinical variables that were present at or prior to randomiza-tion. 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 Oncol-ogy Group (ECOG)] performance status of 2, 129 (14.3%) had venous compression from the tumor, and 92 (10.2%) had undergone recent radia-tion therapy.

Multivariate analysis identified both venous compression (P < .001) and a diagnosis of hepatobiliary can-cer (P = .018) as significant risk fac-

tors associated with recurrent venous thromboembolism.

Interestingly, the Ottawa score,3 re-cently validated to predict recurrent ve-nous thromboembolism, did not predict which patients were at risk in this trial. The Ottawa score is composed of four vari-ables: sex, primary tumor site, tumor state, and history of venous thromboembolism.

Raising Awareness“[Venous thromboembolism] is a

clinically important and common is-sue in cancer patients that may be over-looked. 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 anticoagu-lation and of major bleeding while on anticoagulant therapy is increased in

Venous Thromboembolismcontinued from page 17

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–molecular-weight heparin.

EDU-NPS-0027 5/2015 ©2015 Boston Biomedical

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

Learn more at www.bostonbiomedical.com

Cancer Stem Cells and Their Role 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.

in Recurrence and MetastasisCANCER STEM CELLS SIGNALING PATHWAYS REGROWTH APOPTOSIS

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):1839-1844. 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 in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lung-cancer-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/β-catenin 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.

ADVERTORIAL

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ASCO Annual Meeting

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 contin-ued. “Due to its higher cost, low–mo-lecular-weight heparin is not often used

in the United States. When possible, physicians should try to push for [low–molecular-weight heparin] in cancer pa-tients, 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,

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, Kam-

phuisen 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. Pre-sented December 9, 2014.

3. Ahn S, Lim KS, Lee Y-S, et al: Valida-tion of the clinical prediction rule for recur-rent venous thromboembolism in cancer patients: The Ottawa score. Support Care Cancer 21:2309-2313, 2013.

Marc Carrier, MD, MSc, FRCPC

For interviews with experts conducted live at the

ASCO Annual Meeting on this study and others, visit

http://video.ascopost.com/

EDU-NPS-0027 5/2015 ©2015 Boston Biomedical

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

Learn more at www.bostonbiomedical.com

Cancer Stem Cells and Their Role 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.

in Recurrence and MetastasisCANCER STEM CELLS SIGNALING PATHWAYS REGROWTH APOPTOSIS

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):1839-1844. 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 in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lung-cancer-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/β-catenin 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.

ADVERTORIAL

00699-BBI_R04_Advertorial_ISL.indd 2-3 5/21/15 5:27 PM

http://www.bostonbiomedical.com/home


ASCO Annual Meeting

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

The addition of ibrutinib (Imbru-vica) 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 pre-viously 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

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. Ibruti-nib is now one of the preferred drugs for CLL in the National Comprehen-sive Cancer Network Guidelines.2

B-cell signaling plays a role in the de-velopment 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 prevent-ing proliferation.

Study DetailsHELIOS is a randomized, double-

blind, placebo-controlled, interna-tional, 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 maxi-mum of six cycles, and maintenance therapy continued until progressive dis-

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 ac-tive 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 an-alog-refractory. About 49% received

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

The primary endpoint was progres-sion-free survival as assessed by an In-dependent Review Committee. Median progression-free survival was not yet reached in the ibrutinib-containing arm vs 13.3 months with standard benda-mustine/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 ab-sence 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/ritux-imab: 82.7% vs 67.8%.

No new safety signals emerged with the combination. Adverse events were


Jeremy Abramson, MD, Clinical Director of the Center for Lympho-

ma at Massachusetts General Hos-pital, Boston, is not convinced that ibrutinib (Ibruvica) combined with bendamustine (Treanda) and ritux-imab (Rituxan) should be the new

standard of care for previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). He is, however, convinced that ibruti-nib monotherapy is the treatment of choice in this population.

“Ibrutinib monotherapy is well tolerated and already approved for

all patients with relapsed CLL. Ibru-tinib 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

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 re-duced the risk of disease progression

or death by 80%, he continued. “But the clinician faces the decision of selecting the optimal therapy for pa-tients previously treated with chemo-therapy. 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 look-ing 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 chemoim-munotherapy as initial treatment for CLL, and with less toxicity. In the not too distant future, most patients with CLL may never require chemothera-py,” Dr. Abramson stated. n

Disclosure: Dr. Abramson has been a consultant (scientific advisory boards) for Pharmacyclics, Gilead, Infinity, and Juno.

Hematology

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


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.

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

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40681 May 2015.

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» 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

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ASCO Annual Meeting

consistent with the established safety profiles of all three drugs. The most fre-quent side effects were low blood cell counts, nausea, and diarrhea.

This is the second phase III trial (joining the RESONATE trial) to dem-onstrate that ibrutinib significantly de-

lays relapse for previously treated pa-tients with CLL/SLL. HELIOS is the first placebo-controlled study of ibru-tinib in CLL/SLL and the first large phase III trial to evaluate a novel target-ed drug with chemoimmunotherapy.

“These results represent a chang-ing point in the treatment of CLL. The standard of care should now be ibruti-

nib plus bendamustine/rituximab for previously treated patients,” Dr. Chan-an-Khan stated.

“This is a very promising time for CLL. All patients will eventually re-lapse/recur. These results are so excit-ing 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 Hematolo-gy-Oncology, University of Florida, Gainesville. n

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

References1. 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, placebo-controlled, phase III study. 2015 ASCO Annual Meeting. Abstract LBA7005. Pre-sented May 30, 2015.

2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Prac-tice 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.

Ibrutinib in CLLcontinued from page 20

Merry-Jennifer Markham, MD

The ASCO Post Wants to Hear

From YouWe encourage readers to share

their opinions and thoughts on issues of interest to the

oncology community.

Write to The ASCO Post at [email protected]

Phone: 631.692.0800 Fax: 631.692.0805

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BRIEF SUMMARY OF PRESCRIBING INFORMATION FORGRANIX® (tbo-fi lgrastim) injection, for subcutaneous useSEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEGRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically signifi cant incidence of febrile neutropenia.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Splenic RuptureSplenic rupture, including fatal cases, can occur following administration of human gran-ulocyte 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 gran-ulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infi ltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.5.3 Allergic ReactionsSerious 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 fi lgrastim or pegfi lgrastim.5.4 Use in Patients with Sickle Cell DiseaseSevere 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 ben-efi ts 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 SyndromeCapillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating 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 CellsThe 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 REACTIONSThe 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 ExperienceBecause 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 refl ect 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 fi lgras-tim product were used as controls. Both GRANIX and the non-US-approved fi lgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least fi ve days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

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-US-approved fi lgrastim product).LeukocytosisIn 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 attribut-able to leukocytosis were reported in clinical studies.Additional Adverse ReactionsOther 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 ImmunogenicityAs 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 per-formed.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 consid-ered when interpreting bone-imaging results.8 USE IN SPECIFIC POPULATIONS 8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-fi lgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substan-tially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus.Animal DataIn an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-fi lgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-fi lgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embry-ofetal fi ndings 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-fi lgrastim dose of 5 mcg/kg/day.8.3 Nursing Mothers It is not known whether tbo-fi lgrastim 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 ImpairmentThe safety and effi cacy 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 ImpairmentThe safety and effi cacy of GRANIX have not been studied in patients with hepatic impair-ment.10 OVERDOSAGENo 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 19454U.S. License No. 1803Product of IsraelGRX-40581 January 2015This brief summary is based on TBO-004 GRANIX full Prescribing Information.

KJob Number: 21282Revision No: 0Date: 5/14/15

724-43395 DIGITAL

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

For the first time, a large random-ized 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, hormone-sensitive prostate cancer. Docetaxel has been used to treat metastatic hormone-resistant prostate cancer for a number of years, and this new study—RTOG 0521—suggests that moving it up ear-lier 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 docetax-el can be used earlier in the course of disease. Both the CHAARTED2 and STAMPEDE3 trials found that docetaxel improved survival in men with high-risk metastatic hormone-sensitive pros-tate cancer, whereas before these trials, docetaxel was confined to the hormone-resistant metastatic setting.

RTOG 0521 was designed to assess

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 chemothera-py, known to be beneficial in metastatic hormone-resistant prostate cancer, would improve outcomes in nonmeta-static hormone-sensitive prostate can-cer. This is the first study to show the potential benefit in [overall] survival of adjuvant docetaxel. These were high-risk patients with aggressive cancer. For the right patient, these data justify add-ing docetaxel. This 4-year analysis is rel-atively early, and additional follow-up will likely be enlightening,” said lead au-thor Howard Sandler, MD, of Cedars-Sinai Medical Center, Los Angeles.

“We have seen continued separation of the survival curves in CHAARTED

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

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

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 DetailsRTOG 0521 enrolled 563 eligible pa-

tients between December 2005 and Au-gust 2009 and randomized them to either arm 1 (androgen suppression and radio-therapy) or arm 2 (androgen suppres-sion, radiotherapy, docetaxel, and pred-nisone [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.


ASCO Annual MeetingGenitourinary Cancer


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

—Howard Sandler, MD

Charles Ryan, MD

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

Call for Research Proposals

For complete information on the scope of research, please visit ASPIRE website at

www.aspireresearch.org

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, peer-

reviewed grants program sponsored by Pfizer for investigators in the United States

www.aspireresearch.org

https://www.aspireresearch.org/index.aspx

https://www.aspireresearch.org/index.aspx


ASCO Annual Meeting

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 im-provement in 4-year overall survival from 86% to 93% or a 51% relative re-duction (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 abso-lute benefit of 4% (one-sided P value of .04). This represented a 30% reduc-tion in risk of death favoring adjuvant docetaxel.

A substantial reduction in disease-free survival (disease-free survival, re-currence, or death from any cause) was observed with the addition of docetax-el: 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 sup-pression 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 docetaxel-containing arm.

Deaths due to cancer were report-ed in 23 patients in arm 1 vs 16 pa-tients 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). Ad-verse events were as expected, with more grade 3 and 4 hematologic tox-icity in the docetaxel arm.

Published just prior to the ASCO Annual Meeting, the GETUG 12 trial found that docetaxel-based chemother-apy 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 me-tastasis-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.

References1. 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 che-motherapy with docetaxel and predni-sone for localized, high-risk prostate can-cer (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 meta-static prostate cancer: An ECOG-led phase III randomized trial. 2014 ASCO Annual Meeting. Abstract LBA2.

3. James ND, Spears MR, Clarke NW, et al: Survival with newly diag-nosed 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: An-drogen deprivation therapy plus docetaxel and estramustine versus androgen depriva-tion therapy alone for high-risk localised prostate cancer (GETUG 12): A phase 3 randomised controlled trial. Lancet Oncol. May 28, 2015 (early release online).

High-Risk Prostate Cancercontinued from page 23

RTOG 0521: Overall Survival Benefit With Upfront Docetaxel

■ Docetaxel extended overall survival as part of adjuvant treatment of high-risk 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.


Formal 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 val-ues 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 pri-mary cancers seems likely to be a statistical artifact,” stated Dr. Tannock.

“Based on the one-sided P value, I question whether there is sufficient evi-dence to recommend docetaxel and androgen-deprivation therapy routinely to men with M0 [nonmetastatic] disease. If there is no effect on survival, che-motherapy 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 DeathDr. 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.

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

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Relapsed multiple myeloma: A COMPLEX AND CHALLENGING DISEASEToday, 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 benefi t decreases with each subsequent line of therapy.3

Relapsed multiple myeloma: AIMING FOR LONG-TERM SUCCESSDeep 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 confi rmed 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

Improving long-term outcomes is a primary goal of relapsed MM treatment.3

As the treatment landscape evolves, both deep and durable responses should be the expectation for relapsed multiple myeloma.

In relapsed multiple myeloma,

IS DEPTH THE ANSWER? TO DISRUPT THE CYCLE OF DIMINISHING RESPONSES,

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 benefi ts of long-term treatment. Ann Hematol. 2014;93(12):1993-1999.

Onyx, Onyx Pharmaceuticals, and Onyx Pharmaceuticals logo are all trademarks of Onyx Pharmaceuticals, Inc.©2015 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-ONYX-101576 March 2015 Printed in USA

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Direct From ASCO

Registration Open for 2015 Community Research Forum Annual Meeting

Registration 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 pro-pose 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-

searchforum to register for the Meeting, and for information about the Forum and the stipend application process. n

© 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Releases Updated, Expanded Set of Survivorship Care Planning Templates

A SCO has issued an updated and expanded set of treatment and

survivorship care plan templates for on-cology care professionals and patients with cancer. The templates serve to en-hance ASCO’s existing suite of tools to help providers and patients fully plan a course of cancer treatment, from diag-nosis 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 treat-ment plan, which is intended to be given at the time of diagnosis, and sets the stage for the development of the treatment summary and follow-up care plan included in a survivor-ship care plan.

All told, the six ASCO disease-spe-cific survivorship care plan templates cover more than 50% of all cancer diagnoses.

The ASCO templates were devel-oped 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 com-ponents of a survivorship care plan, as

defined through a multidisciplinary consensus process, and has been en-dorsed by the Commission on Cancer of the American College of Surgeons.

The templates are available as part of ASCO’s Cancer Survivorship Com-pendium at www.asco.org/practice- research/asco-cancer-survivorship-compendium. n


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

ASCO released a proposal to sig-nificantly improve the quality and

affordability of care for cancer patients. ASCO’s Patient-Centered Oncology Pay-ment: Payment Reform to Support Higher Quality, More Affordable Cancer Care

(PCOP) proposal is designed to simul-taneously improve services to patients and reduce spending for Medicare and other payers.

“ASCO has developed a payment reform proposal that addresses the seri-ous financial challenges facing today’s oncology practices, addresses the prob-lems 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

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-

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 al-ternatives to the current Medicare fee-for-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 sys-tem, 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 prac-tice 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 im-portant that payment systems provide medical practices with the flexibility needed to be compensated fairly and adequately—preventing disruption to the care we provide patients, allow-ing 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 Patient-Centered 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, Con-solidated 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 devel-op 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


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


Direct From ASCO

New Resources Developed by ASCO’s Community Research Forum

The ASCO Community Research Forum (CRF) is a solution-oriented

venue for community research sites to overcome barriers to conducting clinical trials. Each year, the CRF council, com-prising ASCO member volunteers, selects topic areas and specific solution-oriented projects for working groups to make the projects a reality. These projects address challenges related to conducting clinical research in the community setting. Ulti-mately, the CRF and its initiatives facili-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. Re-sources include:• ASCO Clinical Trial Workload As-

sessment Tool: A free, user-friendly online resource to help research ad-ministrators assess clinical-trial asso-ciated workload of staff, based on the complexity of research protocols and the number of patients assigned to each staff member. The tool enables admin-istrators to more effectively monitor and manage staff capacity, productivity, and needs. Results from the tool can be used in a variety of ways, including budgeting and new staff justifications. The tool provides site-specific, individ-ual staff–specific, and protocol-specific reports. Findings from a national study using this tool are expected to be pub-lished later this year.

• The ASCO Research Program Quality-Assessment Tool: Basics for a Quality Community-Based Re-search Site is a free, downloadable tool designed to help community-based research sites develop an in-ternal quality assurance program and exceed the minimum standards of conducting clinical research. The tool also provides an overview of ASCO’s recommendations for the compo-nents needed for an internal quality-assessment program. A checklist is in-cluded to help researchers conduct an assessment to see how their research program measures up to these key quality standards. The CRF recently received a Conquer Cancer Founda-tion of the American Society of Clini-cal Oncology Mission Endowment grant to develop an online version of this tool, which is expected to be re-leased in early 2016.

• Resources for Researchers: Avail-able on the CRF’s website, resources include comprehensive materials related to conducting and manag-ing clinical trials. It includes links to

existing resources covering a range of topics, including tips for getting started as a research site, minimum standards and exemplary attributes of clinical trial sites, standard op-erating procedures, good clinical research practices, general research

program administration, budget management, study start up, project management, management of trial participants, and data management.These tools and resources can be

found at asco.org/practice-research/community-research-forum.

ASCO’s 2015 Community Research Forum Annual Meeting

The need for specific resources is typically identified through feed-back received from participants at the CRF’s Annual Meeting. This year’s


BIO741015-01 © 2015 Pfi zer Inc. All rights reserved. April 2015

REFLECTIONS–a clinical trial program created by Pfi zer to investigate the potential biosimilarity of several products

This information is current as of April 2015.HER2=human epidermal growth factor receptor 2; NSCLC=non-small cell lung cancer. Herceptin® is a registered US trademark of Genentech Inc. Rituxan® is a registered US trademark of Biogen Idec Inc. MabThera is a trademark of F. Hoffman-La Roche AG. Avastin® is a registered US trademark of Genentech, Inc.

For more information about these trials, including secondary endpoints and eligibility criteria, please visit:www.pfi zercancertrials.com and www.clinicaltrials.govor call the Pfi zer clinical trial call center at 1-800-718-1021.

PF-05280014, PF-05280586, and PF-06439535 are investigational compounds.

trastuzumab rituximab adalimumab bevacizumabinfliximab

B73910-03 ADVANCED NON-SQUAMOUS NSCLC

1:1 randomizationdouble-blind

PF-06439535 + paclitaxel and carboplatin vs Avastin® (bevacizumab) + paclitaxel and carboplatin in the fi rst-line treatment of patients with advanced non-squamous NSCLC

A global, phase 3, comparative clinical trial evaluating the effi cacy, safety, PK, and immunogenicity of PF-06439535, an investigational compound being studied as a potential biosimilar to Avastin.

• Primary endpoint: ORR• NCT02364999

Eligible patients with advanced non-squamous NSCLC who have not received prior therapy in the fi rst-line treatment setting and who are eligible to receive carboplatin/paclitaxel/bevacizumab

Target enrollment: 798 patients

PF-06439535 + paclitaxeland carboplatin

bevacizumab + paclitaxeland carboplatin


Patients with LTB-FL who have not received prior therapy in the fi rst-line setting


PF-05280586 rituximab

FOLLICULAR LYMPHOMA


B328-06

PF-05280586 vs Rituxan®/MabThera (rituximab) for the fi rst-line treatment of patients with CD20-positive, low tumor burden follicular lymphoma (LTB-FL)

A global, phase 3, comparative clinical trial evaluating the effi cacy, safety, PK, and immunogenicity of PF-05280586, an investigational compound being studied as a potential biosimilar to Rituxan/MabThera.

• Primary endpoint: ORR• NCT02213263

B327-02

PF-05280014 + paclitaxel vs Herceptin® (trastuzumab) + paclitaxel in the fi rst-line treatment of patients with HER2+ metastatic breast cancer (mBC)

A global, phase 3, comparative clinical trial evaluating the effi cacy, safety, pharmacokinetics (PK), and immunogenicity of PF-05280014, an investigational compound being studied as a potential biosimilar to Herceptin.

• Primary endpoint: objective response rate (ORR)• NCT01989676

METASTATIC BREAST CANCER

Patients with HER2+ mBC who have not received prior therapy in the fi rst-line setting with the exception of endocrine therapy



PF-05280014 + paclitaxel trastuzumab + paclitaxel

STUDY DESIGNCLINICAL TRIALS

NOW ENROLLING


PEBS15CDNY9158_A_Reflections_Clinical_Trial_Jrnl_Ad_A-Size_r4.indd 1 4/15/15 3:11 PM

http://www.pfizercancertrials.com/

http://www.pfizercancertrials.com/

https://www.clinicaltrials.gov/


Direct From ASCO

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.

Together, we’re taking it down.

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.

2015 ASCO Annual Meeting Planning Committees

Cancer Education CommitteeThe Cancer Education Committee,

comprising 24 tracks, assesses the need for, plans, develops, and initiates the edu-cation programs of the Society, with spe-cial emphasis on the Annual Meeting.

John V. Cox, DO, MBA, FASCO, ChairApar Kishor Ganti, MD, MBBS, Chair-ElectGini F. Fleming, MD, Immediate Past ChairLillian L. Siu, MD, Board Liaison

Breast CancerMaxine S. Jochelson, MD, Track LeaderJennifer A. Brown, MDAngela DeMichele, MDCharles E. Geyer Jr, MD, FACPRaquel Nunes, MDDebra A. Patt, MD, MPH, MBAHope S. Rugo, MDJulia R. White, MDCancer Prevention, Genetics, and EpidemiologyJoshua David Schiffman, MD, Track LeaderMonique A. De Bruin, MDJeri Kim, MDP. Kelly Marcom, MDHoward L. McLeod, PharmD

Electra D. Paskett, PhDMing Tai-Seale, PhDDonald Lawrence Wickerham, MDCare Delivery and Practice ManagementDavid G. Pfister, MD, Track LeaderAditya Bardia, MBBS, MPHKelly Bugos, RNJohn Emmett Hennessy, MBA, CMPEThomas H. Openshaw, MDJeffery C. Ward, MDCentral Nervous System TumorsManmeet Singh Ahluwalia, MD, Track LeaderJaishri O’Neill Blakeley, MDRoger Stupp, MDClinical TrialsJanet Dancey, MDSumithra J. Mandrekar, PhDBhupinder Singh Mann, MBBSApostolia Maria Tsimberidou, MD, PhDDevelopmental Therapeutics and Translational ResearchRoisin M. Connolly, MBBS, Track LeaderHoward A. Burris, MDFrancisco J. Esteva, MD, PhDJohn Charles Morris, MDEthicsJon C. Tilburt, MDBeverly Moy, MDGastrointestinal (Colorectal) CancerMartin R.Weiser, MD, Track LeaderChris R. Garrett, MDDonald A. Richards, MD, PhDHenry Q. Xiong, MDGastrointestinal (Noncolorectal) Cancer Matthew H. G. Katz, MD, FACS, Track LeaderTanios S. Bekaii-Saab, MDJimmy J. Hwang, MDSe Hoon Park, MDVincent J. Picozzi, MDManish A. Shah, MDGenitourinary Cancer Andrea Borghese Apolo, MD,

Track LeaderThomas E. Hutson, DO, PharmD, FACPJose A. Karam, MDJohn Ward McClean, MDStephen Boyd Riggs, MDNicholas J. Vogelzang, MD, FASCOGeriatric Oncology Andrew S. Artz, MD, MSWilliam P. Tew, MDWilliam W. Tse, MDGynecologic Cancer Linda R. Duska, MD, Track LeaderHelen Mackay, MDMatthew A. Powell, MDHead and Neck Cancer Anthony Cmelak, MD, Track LeaderMatthew G. Fury, MDApar Kishor Ganti, MD, MBBSJohn Truelson, MDHealth Services Research and Quality of CareJennifer W. Mack, MD, Track LeaderDaniel J. Becker, MDNina A. Bickell, MD, MPHDawn L. Hershman, MDBruce Lee Jacobs, MDNicole Kuderer, MDLeukemia, Myelodysplasia, and TransplantationDavid Leibowitz, MD, Track LeaderJonathan Michael Gerber, MDJeffrey E. Lancet, MDLung CancerLaura Quan Man Chow, MD, Track LeaderMartin J. Edelman, MDCraig H. Reynolds, MDDavid R. Spigel, MDGlen J. Weiss, MDMauro Zukin, MDLymphoma and Plasma Cell DisordersGrzegorz S. Nowakowski, MD, Track LeaderJeffrey Matous, MDJohn M. Pagel, MD, PhD

Donna Ellen Reece, MDMichael A. Thompson, MD, PhDMelanoma/Skin CancersSuraj S. Venna, MD, Track LeaderSanjiv S. Agarwala, MDJason John Luke, MD, FACPJanice M. Mehnert, MDAhmad A. Tarhini, MD, PhDPatient and Survivor CareKaren L. Smith, MD, Track LeaderDeborah Mayer, PhD, AOCN, ANP-BCBarbara J. Miller, MS, PA-CMaria Alma Rodriguez, MDNagendra Tirumali, MDPediatric OncologyGregory T. Armstrong, MD, MSCE, Track LeaderNajat C. Daw, MDStewart Goldman, MDJoel A. Weinthal, MDProfessional DevelopmentAnne S. Tsao, MD, Track LeaderKristin Anderson, MD, MPHKelly J. Cooke, DOLaura Williams Goff, MDLee M. Krug, MDJason Michael Samuelian, MDSarcomaGary K. Schwartz, MD, Track LeaderL. Johnetta Blakely, MDRobert Mikael Henshaw, MDMin S. Park, MD, MSTumor BiologyElizabeth A. Maher, MD, PhD, Track LeaderElise C. Kohn, MDKimryn Rathmell, MD, PhDEliezer Mendel Van Allen, MD

Scientific Program CommitteeThe Scientific Program Committee,

made up of 22 tracks and a biostatisti-cal core, reviews and selects abstracts for presentation at the Annual Meeting and publication in the Programs/Pro-ceedings. Members serve a 3-year term

The ASCO Annual Meeting highlights the latest research

and treatment advances in oncol-ogy, with more than 28,000 oncol-ogy 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 devel-oping the Annual Meeting educa-tional and scientific programs.

meeting, scheduled for September 20 to 21, 2015, will host presenta-tions and panels geared toward health care professionals who conduct can-cer clinical trials in a community setting.

This meeting provides a unique fo-rum for community-based researchers and research staff to discuss barriers and propose solutions to common chal-lenges in conducting research, as well as provide input on ASCO programs and policy issues affecting clinical research. It also provides an exclusive opportuni-

ty for participants to network and col-laborate 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/practice- research/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-resources- developed-asco’s-community-research-forum. All rights reserved.

Community Research Forumcontinued from page 27

http://conquer.org/

http://conquer.org/


Direct From ASCO

on the committee to plan, develop, and initiate the scientific sessions at the An-nual Meeting.

Alan P. Venook, MD, ChairLynn Mara Schuchter, Chair-ElectJedd D. Wolchok, MD, PhD, Immediate Past Chair

BiostatisticsKatherine Panageas, PhD, Track LeaderUrania Dafni, ScDSusan G. Hilsenbeck, PhDWendy B. London, PhDYing Lu, PhDSumithra J. Mandrekar, PhDDonna Niedzwiecki, PhDBreast Cancer—HER2/ERPriya Rastogi, MD, Track LeaderCarey K. Anders, MDTufia C. Haddad, MDCornelia Liedtke, MDShanu Modi, MDPatrick Glyn Morris, MDAlexandra Thomas, MDBreast Cancer—Triple-Negative/Cytotoxics/Local TherapySteven J. Isakoff, MD, PhD, Track LeaderEleanor Elizabeth Harris, MDTari A. King, MDPamela N. Munster, MDDeborah Toppmeyer, MDTiffany A. Traina, MDJanice Maria Walshe, MDCancer Prevention, Genetics, and EpidemiologyJames M. Foran MD, FRCPC, Track LeaderHabibul Ahsan, MBBS, MScEric Andrew Collisson, MDAdam J. Olszewski, MDBrian M. Wolpin, MDCentral Nervous System TumorsAndrew B. Lassman, MD, Track LeaderEric L. Chang, MDHoward Alan Fine, MDDaphne A. Haas-Kogan, MDDevelopmental Therapeutics—

Clinical Pharmacology and Experimental TherapeuticsMiguel Angel Villalona-Calero, MD, Track LeaderEmiliano Calvo, MD, PhDRyan Bruce Corcoran, MD, PhDGerald Steven Falchook, MDHerbert Hurwitz, MDRobin Kate Kelley, MDScott Kopetz, MDTimothy Anthony Yap, PhD, MBBS, BSc, MRCPDevelopmental Therapeutics— ImmunotherapyNeil Howard Segal, MD, PhD, Track LeaderCharlotte Eielson Ariyan, MD, PhDGregory Lawrence Beatty, MD, PhDJonathan S. Cebon, MD, PhDLawrence Fong, MDZihai Li, MD, PhDAndrew Parsa, MD, PhDGastrointestinal (Colorectal) CancerEdward Chu, MD, Track LeaderChloe Evelyn Atreya, MD, PhDNancy N. Baxter, MDGong Chen, MD, PhDSteven J. Cohen, MDGunnar Folprecht, MDKimmie Ng, MD, MPHBert H. O’Neil, MDThomas John Semrad, MD, FACPRichard H. Wilson, MDZhen Zhang, MD, PhDGastrointestinal (Noncolorectal) CancerAndrew H. Ko, MD, Track LeaderGhassan K. Abou-Alfa, MDWaddah B. Al-Refaie, MDKaryn A. Goodman, MDSyma Iqbal, MDMilind M. Javle, MDLisa A. Kachnic, MDGeoffrey Yuyat Ku, MD, MBAEmil Lou, MD, PhDNipun B. Merchant, MDJames Posey, MDGenitourinary Cancer

Michael J. Morris, MD, Track LeaderPeter Albers, MDKathleen A. Cooney, MDRobert Dreicer, MDTerence W. Friedlander, MDNoah M. Hahn, MDJonathan E. Rosenberg, MDMark N. Stein, MDCora N. Sternberg, MDScott T. Tagawa, MD, MSNeha Vapiwala, MDGynecologic CancerDavid R. Spriggs, MD, Track LeaderJohn K. Chan, MDLevi S. Downs Jr., MDPaul Haluska, MD, PhDRebecca Sophie Kristeleit, MD, PhDKunle Odunsi, MDHead and Neck CancerQuynh-Thu Le, MD, Track LeaderJohn F. Deeken, MDRobert L. Ferris, MD, PhD, FACSRobert I. Haddad, MDVassiliki Papadimitrakopoulou, MDHealth Services Research and Quality of CareHelen M. Parsons, PhD, Track LeaderGeorge J. Chang, MD, MSShawn Dana Glisson, MD, FACPMonika K. Krzyzanowska, MD, MPHRebecca A. Miksad, MDArden M. Morris, MDCraig Evan Pollack, MDLeukemia, Myelodysplasia, and TransplantationMichael Russell Bishop MD, FACP, Track LeaderCharalambos Andreadis, MD, MSCERavi Bhatia, MDJoseph G. Jurcic, MDCelalettin Ustun, MDLung Cancer—Non–Small Cell Local-Regional/Small Cell/ Other Thoracic CancersGregory J. Riely, MD, PhD, Track LeaderEdward B. Garon, MDScott N. Gettinger, MDThomas A. Hensing, MDChuong D. Hoang, MDTom John, PhD, FRACP, MBBSFeng Ming Kong, MDLung Cancer—Non–Small Cell MetastaticGrace K. Dy, MD, Track Leader

Matthew A. Gubens, MDMark G. Kris, MDGeoffrey R. Oxnard, MDLuis Paz-Ares MD, PhDNathan A. Pennell, MD, PhDJonathan Riess, MDLecia V. Sequist, MD, MPHLymphoma and Plasma Cell DisordersSaad Zafar Usmani, MD, FACP, Track LeaderRanjana H. Advani, MDAlexander M. Lesokhin, MDSagar Lonial, MDThomas G. Martin III, MDOwen A. O’Connor, MD, PhDMelanoma/Skin CancersSvetomir Markovic, MD, PhD, Track LeaderPaul B. Chapman, MDAdil Daud, MDGeorgina V. Long, PhD, BSc, FRACP, MBBSPatient and Survivor CareShari Beth Goldfarb, MD, Track LeaderTessa Cigler, MD, MPHTara O. Henderson, MD, MPHMonica Alexandra Iriso, MDArif Kamal, MDKavitha Ramchandran, MDCharles L. Shapiro, MDKatherine Van Loon, MD, MPHPediatric OncologyLisa Diller, MD, Track LeaderSteven G. DuBois, MDJeffrey Toretsky, MDSarcomaJonathan C. Trent II, MD, PhD, Track LeaderVenkata Ramesh Bulusu, MD, FRCREric K. Nakakura, MD, PhDDennis A. Priebat, MDTumor BiologyVictoria Louise Seewaldt, MD, Track LeaderMichael J. Birrer, MD, PhDWolfgang Michael Korn, MDMark M. Moasser, MDAndrew B. Nixon, PhDDavid Potter, MD, PhDLawrence H. Schwartz, MD


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

Direct your patients to www.cancer.net/blog for pod-

casts 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 un-derstand how it affects them. These podcasts will continue throughout the summer, and will cover new research on several different types of cancer. n


Save the Date

Best of ASCO® BostonJuly 31 –August 1, 2015

Renaissance Boston Waterfront Hotel

Boston, Massachusetts

Best of ASCO® San FranciscoAugust 7–8, 2015

San Francisco Marriott Marquis

San Francisco, California

LAUNCH JOURNAL AD SPREAD KING SIZE4C

THIS ADVERTISEMENT PREPARED BY FCB

Job#: 10255534 ONYX_KYPROLIS_10255534Client: KeryxDate: December 12, 2014 7:01 PMProof: 3

Name: PrePress:Onyx:Kyprolis:10255534:10255534_JournalAd_KingSize_M3

Prod.: B. Iannizzotto x2419Colors: 4/CBleed: 22.25” X 14.25”Trim: 10.5” X 13.875” each pageLive: 9.5” X 13.0” each pageFonts: Helvetica Neue, Inter-

state, Minion, Septem-ber

AD: S. Grillo x2362AE: B. Kreider x2395Traffic: E. Naylor x2414QC: Artist: tp/BD Spellcheck:M1 by Mark Ameen

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results*n 22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

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

n 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.

IndicationKyprolis® (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 InformationCONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSThe 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

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

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 REACTIONSSerious 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 POPULATIONSSince 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.

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

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 WAY FORWARDSHAPINGTHE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

S:19.75”

S:13”

T:21”

T:13.875”

B:22.25”

B:14.25”

F:10.5”

FS:9.5”

F:10.5”

FS:9.5”

10255534_JournalAd_KingSize_M3.indd 1 12/12/14 7:08 PM

LAUNCH JOURNAL AD SPREAD KING SIZE4C



Name: PrePress:Onyx:Kyprolis:10255534:10255534_JournalAd_KingSize_M3

Prod.: B. Iannizzotto x2419Colors: 4/CBleed: 22.25” X 14.25”Trim: 10.5” X 13.875” each pageLive: 9.5” X 13.0” each pageFonts: Helvetica Neue, Inter-

state, Minion, Septem-ber

AD: S. Grillo x2362AE: B. Kreider x2395Traffic: E. Naylor x2414QC: Artist: tp/BD Spellcheck:M1 by Mark Ameen

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results*n 22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

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

n 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.

IndicationKyprolis® (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 InformationCONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSThe 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

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

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 REACTIONSSerious 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 POPULATIONSSince 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.

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

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 WAY FORWARDSHAPINGTHE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

S:19.75”

S:13”

T:21”

T:13.875”

B:22.25”

B:14.25”

F:10.5”

FS:9.5”

F:10.5”

FS:9.5”

10255534_JournalAd_KingSize_M3.indd 1 12/12/14 7:08 PM

http://www.kyprolis.com/


News

National Cancer Institute Pulls PSA Data From SEER By Ronald Piana

In a move that reverberated through much of the cancer research com-

munity, the National Cancer Institute (NCI) recently announced that it had removed all prostate-specific antigen

(PSA) data from its current Surveil-lance, Epidemiology, and End Results (SEER) data submission and associ-ated 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, cau-tioned, “Withdrawal of these data from SEER will have major impacts on the

Cancer Research

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KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two 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 [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):

Cycle 1Week 1 Week 2 Week 3 Week 4

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

20 20 20 20 NoDosing

20 20 NoDosing

NoDosing

Cycles 2 and Beyonda

Week 1 Week 2 Week 3 Week 4

Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

a If previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment

Hematologic Toxicity Recommended Action• Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• Withhold dose.• If fully recovered before next scheduled dose, continue

at same dose level.• If recovered to Grade 2 neutropenia or Grade 3

thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Non-Hematologic Toxicity Recommended ActionCardiac ToxicityGrade 3 or 4, new onset or worsening of:• congestive heart failure; • decreased left ventricular

function; • or myocardial ischemia [see Warnings and Precautions]

• Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS at

a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Pulmonary Hypertension[see Warnings and Precautions]

• Withhold until resolved or returned to baseline.• Restart at the dose used prior to the event or reduced

dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2

to 15 mg/m2), at the discretion of the physician.• If tolerated, the reduced dose may be escalated to the

previous dose at the discretion of the physician.Pulmonary Complications• Grade 3 or 4 [see Warnings and Precautions]

• Withhold until resolved or returned to baseline.• Consider restarting at the next scheduled treatment

with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).


Hepatic Toxicity• Grade 3 or 4 elevation of

transaminases, bilirubin or other liver abnormalities

[see Warnings and Precautions]

• Withhold until resolved or returned to baseline.• After resolution, consider if restarting KYPROLIS is

appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.


Renal Toxicity• Serum creatinine equal to or

greater than 2 × baseline[see Adverse Reactions]

• Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function.

• If attributable to KYPROLIS, restart at the next scheduled treatment at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.


Peripheral Neuropathy• Grade 3 or 4 [see Adverse Reactions]




previous dose at the discretion of the physician.Other • Grade 3 or 4 non‑hematological

toxicities




aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS

Storage Conditions of Reconstituted KYPROLIS

Stabilitya per Container

Vial SyringeIV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hoursaTotal time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: 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 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 [see Dosage and Administration]. 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 were not eligible for the clinical trials. These patients 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 [see Dosage and Administration]. 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 [see Dosage and Administration and Adverse Reactions]. 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 or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. 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 considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].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 [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued)

(continued)

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 [see Dosage and Administration and Adverse Reactions]. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [see Warnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions]

The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% 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). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Patients (N = 526) [n (%)]

EventAll

GradesaGrade 3 Events

Grade 4 Events

Fatigue 292 (55.5) 38 (7.2) 2 (0.4)Anemia 246 (46.8) 111 (21.1) 7 (1.3)Nausea 236 (44.9) 7 (1.3) 0Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3)Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b

Diarrhea 172 (32.7) 4 (0.8) 1 (0.2)Pyrexia 160 (30.4) 7 (1.3) 2 (0.4)Upper respiratory tract infection 149 (28.3) 17 (3.2) 0Headache 145 (27.6) 7 (1.3) 0Cough 137 (26.0) 1 (0.2) 0Blood creatinine increased 127 (24.1) 13 (2.5) 1 (0.2)Lymphopenia 126 (24.0) 84 (16.0) 11 (2.1)Edema peripheral 126 (24.0) 3 (0.6) 0Vomiting 117 (22.2) 5 (1.0) 0Constipation 110 (20.9) 1 (0.2) 0Neutropenia 109 (20.7) 50 (9.5) 4 (0.8)Back pain 106 (20.2) 15 (2.9) 0Insomnia 94 (17.9) 0 0Chills 84 (16.0) 1 (0.2) 0Arthralgia 83 (15.8) 7 (1.3) 0Muscle spasms 76 (14.4) 2 (0.4) 0Hypertension 75 (14.3) 15 (2.9) 2 (0.4)Asthenia 73 (13.9) 12 (2.3) 1 (0.2)Hypokalemia 72 (13.7) 14 (2.7) 3 (0.6)Hypomagnesemia 71 (13.5) 2 (0.4) 0Leukopenia 71 (13.5) 27 (5.1) 1 (0.2)Pain in extremity 70 (13.3) 7 (1.3) 0Pneumonia 67 (12.7) 52 (9.9) 3 (0.6)b

Aspartate aminotransferase increased 66 (12.5) 15 (2.9) 1 (0.2)Dizziness 66 (12.5) 5 (1.0) 1 (0.2)Hypoesthesia 64 (12.2) 3 (0.6) 0Anorexia 63 (12.0) 1 (0.2) 0Pain 63 (12.0) 12 (2.3) 0Hyperglycemia 62 (11.8) 16 (3.0) 3 (0.6)Chest wall pain 60 (11.4) 3 (0.6) 0Hypercalcemia 58 (11.0) 13 (2.5) 8 (1.5)Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6)Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6)

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.bOne event was Grade 5 severity.

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of KYPROLIS in pediatric patients have not been established. Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated. OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care. NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area. PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath. Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05‑1088‑00©2014 Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J November 2014

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10255534_JournalAd_Insert_M3.indd 2 12/12/14 7:06 PM








KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two 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 [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):


Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28


20 20 NoDosing

NoDosing



Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

a If previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment








• Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS at















appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.





• If attributable to KYPROLIS, restart at the next scheduled treatment at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).








toxicities





Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS






WARNINGS AND PRECAUTIONS: 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 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 [see Dosage and Administration]. 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 were not eligible for the clinical trials. These patients 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 [see Dosage and Administration]. 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 [see Dosage and Administration and Adverse Reactions]. 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 or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. 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 considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].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 [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been


(continued)




Patients (N = 526) [n (%)]

EventAll


Grade 4 Events







S:14.625”

S:10”

T:16.25”

T:10.875”

B:16.75”

B:11.25”

F:8.125”

FS:7”

F:8.125”

FS:7”



News

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 mandat-ed 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 analy-ses using SEER and SEER-Medicare programs, the data will have to be rede-signed 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 proto-cols to ensure the quality of the data in

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 treat-ments, 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.

Loss of Trust Needs to Be Addressed

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

largest insurers. Despite this recent dis-covery, he noted, the SEER databases of-fer valuable information when answering difficult clinical and health-care policy is-sues. “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


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. —David F. Penson, MD








KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two 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 [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenouslyover 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatmentcycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, thedose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequentcycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [seeDosage and Administration]. The dose is calculated using the patient’s actual body surface area atbaseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon abody surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less thanor equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):


Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28


20 20 NoDosing

NoDosing



Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

aIf previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment








• Withhold until resolved or returned to baseline.• After resolution, consider if restarting KYPROLIS at















appropriate; may be reinitiated at a reduced dose (from27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.





• If attributable to KYPROLIS, restart at the next scheduledtreatment at a reduced dose (from 27 mg/m2 to20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).








toxicities





Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mLSterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution,KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear,colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS






WARNINGS AND PRECAUTIONS: 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 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 [see Dosage and Administration]. 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 were not eligible for the clinical trials. These patients 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 [see Dosage and Administration]. 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 [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions werecharacterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facialflushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness,or angina. These reactions can occur immediately following or up to 24 hours after administration ofKYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity ofreactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contactphysician if symptoms of an infusion reaction occur [see Patient Counseling Information]. 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 considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].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 [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been


(continued)

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 [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to apregnant woman based on its mechanism of action and findings in animals. There are no adequate andwell‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity inpregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females ofreproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, thepatient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sectionsof the labeling:

• Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [seeWarnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions]

The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea,diarrhea, and pyrexia. Clinical Trials Safety 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myelomareceived KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest,cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure),infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% 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). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Patients (N = 526) [n (%)]

EventAll


Grade 4 Events





Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI].USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic atany dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in humanmilk. Since many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursingor to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of KYPROLIS in pediatric patients have not been established.Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safetyand efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond.The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renalimpairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrationshas not been studied, the drug should be administered after the dialysis procedure [see ClinicalPharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated.OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care.NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility.Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenicin the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mousebone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg(approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area)experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeatedbolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation)systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms:fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms.Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue,South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05‑1088‑00©2014 Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J November 2014

S:14.625”

S:10”

T:16.25”

T:10.875”

B:16.75”

B:11.25”

F:8.125”

FS:7”

F:8.125”

FS:7”









KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two 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 [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenouslyover 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatmentcycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, thedose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequentcycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [seeDosage and Administration]. The dose is calculated using the patient’s actual body surface area atbaseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon abody surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less thanor equal to 20%.Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma

KYPROLIS(20 mg/m2):

KYPROLIS(27 mg/m2):


Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28


20 20 NoDosing

NoDosing



Day15

Day1

Day2

Days3–7

Day8

Day9

Days10–14

Day16

Days17–21

Days22–28

Day15


NoDosing

NoDosing

27 27 NoDosing

NoDosing

aIf previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment








• Withhold until resolved or returned to baseline.• After resolution, consider if restarting KYPROLIS at















appropriate; may be reinitiated at a reduced dose (from27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.





• If attributable to KYPROLIS, restart at the next scheduledtreatment at a reduced dose (from 27 mg/m2 to20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).








toxicities





Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mLSterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution,KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear,colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS






WARNINGS AND PRECAUTIONS: 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 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 [see Dosage and Administration]. 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 were not eligible for the clinical trials. These patients 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 [see Dosage and Administration]. 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 [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions werecharacterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facialflushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness,or angina. These reactions can occur immediately following or up to 24 hours after administration ofKYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity ofreactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contactphysician if symptoms of an infusion reaction occur [see Patient Counseling Information]. 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 considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].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 [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been


(continued)




Patients (N = 526) [n (%)]

EventAll


Grade 4 Events







S:14.625”

S:10”

T:16.25”

T:10.875”

B:16.75”

B:11.25”

F:8.125”

FS:7”

F:8.125”

FS:7”



Expert’s Corner

Deciphering the Genetic Variability of Cancer to Advance Precision Oncology CareA Conversation With David B. Solit, MDBy Jo Cavallo

In 2014, Memorial Sloan Kettering Cancer Center (MSKCC) in New

York opened the Marie-Josée and Hen-ry R. Kravis Center for Molecular On-cology with the sole purpose of expedit-ing 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 multi-disciplinary team of clinicians, patholo-gists, cancer biologists, and bioinforma-ticians. 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 sequenc-ing a patient’s tumor for enrollment in

a clinical study or administration of a targeted therapy.

Currently, the Center for Molecular Oncology is limiting prospective ge-nomic sequencing to patients with meta-static 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 meta-static 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-

ically relevant mutations in each cancer type and determining the most likely ef-fective course of therapy, a primary goal of the Center for Molecular Oncology

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

colorectal, and lung cancers, but whose tumors carry a similar molecular signa-ture, all respond to a particular molecu-larly targeted therapy.

The ASCO Post talked with David B. Solit, MD, Director of MSKCC’s Cen-ter for Molecular Oncology, about how sequencing the DNA of cancer cells is resulting in improved patient out-comes, 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

Currently, the Center for Molecular Oncology is sequencing the tumors of patients with advanced cancer to deter-mine treatment and potentially enroll them in clinical studies. Will the center also analyze the tumors of all patients with cancer?

Our initial goal is to sequence pa-tients with recurrent or metastatic sol-id tumors, since these are the patients most in need of novel therapeutic ap-proaches. MSKCC is also in the pro-cess of developing a specific assay for patients with leukemia. As our capaci-

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 be-lieve that such testing could provide prognostic information that would help doctors counsel patients more ac-curately on their risk for tumor recur-rence and also help identify patients who would most benefit from adjuvant therapies, including chemotherapy.

Improving Patient CareDo you believe that sequencing the ge-

nome 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 con-sidered standard of care. Patients who have lung cancer with EGFR mutations

us by their size and sheer amount of in-formation. 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 indi-vidual sites by registrars, and I think that the administrative data on the utilization of tests is very good,” he said. “The prob-lem 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

necessary for payment, and the law does not mandate their collection.”

Primary Data NeededDr. Penson continued, “These large

administrative data sets have tremen-dous value for our field if we use them properly, and that is the key. We have to stop publishing secondary data analy-ses 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

out on a mandated task to study the inci-dence, prevalence, and general outcomes in cancer. But as a clinical research com-munity, we’ve taken these data and ex-pected them to answer tough clinical questions. And as time passed, we’ve ac-tually become quite glib about the data,” he commented.

“There are researchers in the com-munity 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 re-serve these data sets for research ques-

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 pri-mary 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.

Reference1. National Cancer Institute: PSA

values and SEER data: SEER data, 1973–2012 (November 2014 submission). Available at seer.cancer.gov/data/psa- values.html. Accessed June 8, 2015.

PSA Data From SEERcontinued from page 33

Molecular Oncology

David B. Solit, MD


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

Michael F. Berger, PhD


Expert’s Corner

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 pa-tients 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 particu-lar genetic profile. Thus, genomic profil-ing may accelerate the development of novel targeted agents.

‘Cure Is a High Bar to Reach’Will tailoring therapy based on the bi-

ology of patients’ tumors allow more pa-tients 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 my-elogenous leukemia (CML). Although imatinib can induce a remission that lasts for many, many years, these pa-tients are rarely cured, and if they stop taking the drug, the cancer usually re-turns. 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 exam-ple, when given in the adjuvant setting for breast cancer, trastuzumab (Her-ceptin) 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 OncogenesWhat 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 tu-mors more precisely in terms of their prognosis and etiology, and almost all new drug targets that are being devel-oped 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 ther-apies that target the underlying cause of individual tumors.

For example, recent genetic stud-ies allowed for the identification of ALK fusions in lung cancer, which then directly led to the testing of ALK in-hibitors in those patients. These ALK inhibitors have dramatic activity in pa-tients who have lung cancer with ALK fusions, a disease for which previously there were no effective systemic thera-pies. 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.

Developing Newer Targeted Agents

There are a few hundred known mu-tations linked to cancer, but only a few dozen U.S. Food and Drug Administra-tion (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 muta-tions 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 muta-tions 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 ef-fective therapeutic strategy. Without such drugs, the full potential of genetic sequencing will be difficult to achieve.

In summary, you cannot initiate a

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 com-panies to make newer targeted agents available to patients with particular mu-tation profiles using newer clinical trial designs, including basket studies.

Role of Basket StudiesPlease 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 half-dozen of these trials actively enrolling patients. Designing a trial that is fo-cused 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 par-ticular tumor type.

Is this how clinical trials will be de-signed 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 tradi-tional 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 can-cer 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 BiopsiesPlease talk about the promise of liquid

biopsies as a diagnostic tool to spot early

Precision Oncology Carecontinued from page 34

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

Flow cells: This particular flow cell contains eight lanes and allows researchers to sequence two differ-ent 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.



Expert’s Corner

cancers; treatment effectiveness and resis-tance; and cancer recurrence.

The liquid biopsy approach is show-ing great promise in its ability to pick up snippets of circulating cancer DNA in a patient’s blood, and the technique is in-credibly 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 tech-nology 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 hur-dles 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 ex-pensive, and easier to perform.

Liquid biopsy can be used to ac-complish two separate goals. First, liquid biopsies can be used to figure out what mutations a tumor harbors, which can then be used to guide treat-ment selection. Second, the liquid bi-opsy 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, quanti-tative measures of tumor DNA can be used as a surrogate biomarker of clini-cal benefit and may eliminate or reduce the need for computed tomography or magnetic resonance imaging to deter-mine the state of a patient’s cancer.

The Future of Genetic TestingHow 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 test-ing performed on their tumor, and this

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 inher-ited 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 technol-ogy 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.

Precision Oncology Care continued from page 35

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The ASCO Post

We want to change the faceof EGFR-targeted therapy

Inhibition of wild-type and mutant EGFRin non–small cell lung cancer (NSCLC)Normal, or wild-type, EGFR is highly expressed onepithelial cells in the skin, liver, and gastrointestinaltract.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 tocutaneous toxicities including rash, stomatitis,and paronychia.1,2,6-8

90% of patients treated with approved EGFRTKIs experience rash7,8

The skin is dependent on wild-type EGFR signalingfor normal growth and differentiation.1,9,10 Drug-induced inhibition of wild-type EGFR disrupts itsnormal function and can cause cutaneousinflammation and injury. This accounts for the highincidence of cutaneous toxicities associated withEGFR TKIs.1,9

Cutaneous toxicities can bedose-limitingThe symptoms and psychosocial impact ofcutaneous toxicities can negatively affect bothpatient quality of life and patient compliance.11,12

In some studies, rash and paronychia were amongthe most frequent causes of dose modification,combining to cause dose reductions in as manyas 33% of patients.7,8

The future of EGFR inhibitionStrategies that eliminate inhibition of wild-typeEGFR may be most effective at mitigating cutaneoustoxicities and maintaining optimal dosing.9 At ClovisOncology, we’re committed to exploring newapproaches in EGFR therapy to advance thefight against NSCLC.

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. TheEGF 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 relatedto 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 epidermalgrowth 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.

Clovis Oncology is leading the fight

Cutaneous toxicities are caused by inhibition of wild-type epidermalgrowth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2015 Clovis Oncology. DARO-101(1) 3/15

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

31698_clovco_fa2_rash_ASCOPOST.indd 1 3/31/15 9:39 AM

http://t790m.com/?source=targetEGFR


Journal Spotlight

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

In a study reported in The Lancet, the Collaborative Group on Epide-

miological 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 pro-spective and 35 retrospective studies. The principal analyses involved prospective studies, with last hormone therapy use ex-trapolated forward for up to 4 years.

Risk in Current and Past UsersDuring prospective follow-up in the

principal analysis, 12,110 postmeno-pausal women developed ovarian can-cer, 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 sig-nificantly 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 stud-ies (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 dura-tion stopped < 5 years before diagno-sis) 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 stud-ies and for prospective studies involv-ing estrogen-only (RR = 1.37, 95% CI = 1.26–1.50) and estrogen- progestogen

Gynecologic Oncology


We want to change the faceof EGFR-targeted therapy

Inhibition of wild-type and mutant EGFRin non–small cell lung cancer (NSCLC)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

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

The skin is dependent on wild-type EGFR signalingfor normal growth and differentiation.1,9,10 Drug-induced 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

Cutaneous toxicities can bedose-limitingThe 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

The future of EGFR inhibitionStrategies 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.

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.

Clovis Oncology is leading the fight

Cutaneous toxicities are caused by inhibition of wild-type epidermalgrowth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2015 Clovis Oncology. DARO-101(1) 3/15

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

31698_clovco_fa2_rash_ASCOPOST.indd 1 3/31/15 9:39 AM

http://t790m.com/?source=targetEGFR


Journal Spotlight

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

Ovarian cancer is the second most common gynecologic ma-

lignancy 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 muta-tions 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 re-mains questionable.

In a study published by The Lancet, researchers in the Collabora-tive Group on Epidemiological Stud-ies of Ovarian Cancer demonstrated that use of menopausal hormone therapy was associated with an in-creased risk of ovarian cancer, with risk being highest among current us-ers.2 The study is summarized in this issue of The ASCO Post.

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

Risk in Current UsersDuring prospective follow-up in

the principal analysis, 12,110 post-menopausal women developed ovar-ian cancer, including 6,601 (55%) who had used hormone therapy. Compared with never-users, cur-rent 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 UseCompared with nonuse, current

use or recent use (defined as use of any duration stopped < 5 years be-fore 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 estro-gen-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 SubtypesThis increased risk of ovarian can-

cer 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 ther-apy use was associated with a reduced risk of clear cell tumors (RR = 0.75, 95% CI = 0.57–0.98).

Persistence of RiskAlthough risk declined with great-

er 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, com-pared 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 re-ported 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-

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-

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). Hor-mone therapy use was associated with a reduced risk of clear cell tumors (RR = 0.75, 95% CI = 0.57–0.98).

Persistence of RiskAlthough 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 signifi-cantly 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

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 stud-ies to age-specific ovarian cancer in-cidence and death rates in England

yielded the following excess inci-dence and excess death estimates: for 5 years while they are taking hormone therapy (from age 50 to 54), their ex-cess 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, estimat-ed 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 hor-mone therapy and the older they are when taking hormone therapy.

In total, there would be 1 addi-tional ovarian cancer per 1,000 users and 1 additional death per 1,700 us-ers. 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 ex-tra 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.

Reference1. Collaborative Group on Epidemio-

logical Studies of Ovarian Cancer: Meno-pausal hormone use and ovarian cancer risk: Individual participant meta-analysis of 52 epidemiological studies. Lancet 385:1835-1842, 2015.

Menopausal Hormone Therapycontinued from page 37

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

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.

Dr. Tergas is Clinical Instructor of Gyne-cologic Oncology, at Columbia University Medical Center, New York.


Perspective

mone therapy use, the absolute excess in ovarian cancer incidence per 1,000 users would be 0.52 (from the expect-ed incidence of 1.2 per 1,000 never-users 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 addi-tional death per 1,700 users among women of all ages.

Interpreting ResultsThis study is an important con-

tribution to the literature, with sev-eral strengths—particularly the large number of patients who were followed prospectively. As the au-thors point out, “the robustness of prospective data is demonstrated by the stability of the findings in vari-ous sensitivity analyses.” Their search strategy and analyses were compre-hensive and included the grey litera-ture in order to decrease the impact of publication bias.

However, their results must be interpreted with the study limita-tions 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 de-crease the risk of ovarian cancer,3 including these women would likely

have biased the effect measure toward the null. Perhaps a more prudent ap-proach 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

prospective data, which provide evi-dence of a temporal relationship be-tween the exposure and outcome of interest—thereby supporting their causal claim—there is little discus-sion about the proposed underlying mechanism by which hormonal ther-apy causes ovarian cancer.

Hormonal therapy as a cause of ovarian cancer is inconsistent with the well-established protective link be-tween oral contraceptive use and ovar-ian cancer. Further evidence against biologic plausibility is the differential

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 prob-lematic, and the authors offer no sub-stantive discussion on this issue.

The authors claim that they dem-onstrate a dose-response relationship by showing that current users are at greatest risk of ovarian cancer, there-

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 in-sufficient to provide strong evidence of a dose-response relationship.

Closing ThoughtsAll in all, the study provides com-

pelling evidence of a possible associa-tion between menopausal hormonal therapy use and serous and endome-trioid 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 bene-fits of hormonal therapy. Women who are taking or are considering start-ing 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.

References1. American Cancer Society: Cancer

Facts & Figures 2015. Atlanta, American Cancer Society, 2015.

2. Collaborative Group on Epidemio-logical Studies of Ovarian Cancer: Meno-pausal 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 salpingec-tomy: A nationwide population-based study. J Natl Cancer Inst 107:dju410, 2015.

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.

—Ana I. Tergas, MD, MPH

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

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

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

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

Visit The ASCO Post online at ASCOPost.com

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

PV

plus low-dose aspirin

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

Hydroxyurea (HU) or interferon-alpha as �rst-line cytoreductive therapy at any agea

Unmet need exists for a subset of patients not managed appropriately by current treatment

strategies (alone or in combination)

• Patients are intolerant of or resistant to HU

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

Phlebotomy to maintain Hct at <45%Polycythemia Vera: Are Some Patients at Increased Risk?

OverviewWhat Is Polycythemia Vera?Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by an overproduction of normal red blood cells, white blood cells and platelets that leads to an increased risk of thrombosis.1-4 Erythrocytosis (elevated red blood cell mass) is the most prominent clinical manifestation of PV, distinguishing it from other MPNs.5

PV may occur at any age but often presents later in life, with a median age at diagnosis of 60 years.6,7 Approximately 100,000 patients in the United States are living with PV.8

Clinical Presentation of PV Contributing to Its Diagnosis Janus kinases (JAKs) mediate cytokine signaling and growth factors.9,10 An important genetic discovery about a point mutation in the Janus kinase 2 (JAK2) gene has enhanced the understanding of PV.11

The speci� c JAK2V617F mutation is detected in >95% of patients with PV.5 Although the JAK2V617F mutation is the key driver of PV, an understanding of the clinical presentation of PV will help to facilitate a more accurate diagnosis.

PV is an elusive disease that may not be recognized for years. Diagnosis most frequently occurs by chance following a routine examination.12 Diagnosis may also occur after a thrombotic event or as a result of disease-related symptoms.12

The following important signs and symptoms warrant a prompt evaluation and suggest PV6,7:• Elevated hemoglobin or hematocrit levels• Thrombotic events • Splenomegaly (with or without thrombocytosis and/or leukocytosis)

Clinical Considerations in Managing PV Prognosis and Risk Factors In a large population-based study in more than 4,000 patients with PV, life expectancy was 36% lower than that of the general population.13

For some patients whose hematocrit levels remain elevated, and for those who continue to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remains uncontrolled.

Thrombotic and hemorrhagic complications are among the leading causes of morbidity and mortality associated with PV.14 Cancer and cardiovascular mortality are the frequent causes of deaths in PV.6,15

When assessing risks for morbidity and mortality in patients, consider the following3,14,16: • Elevated hematocrit levels • History of thrombosis • Advanced age (≥60 years) • Leukocytosis • Cardiovascular risk factors such as high cholesterol levels, hypertension, diabetes, obesity and smoking

According to data from a large, randomized, controlled clinical trial, the rate of death due to cardiovascular events or major thrombosis was four times higher in patients with elevated hematocrit levels of 45% to 50% compared with those who maintained a hematocrit target of <45%2 (Figure 1).

Thrombosis, Splenomegaly and Other Disease-related Symptoms In PV, a wide spectrum of thrombotic manifestations exists that may occur before the disease is diagnosed.14 Palpable splenomegaly is an important physical � nding because increased spleen size is present in 30% to 40% of patients with PV.12 Additional signs and symptoms of PV, which may contribute to a substantial quality-of-life burden in patients with PV, include17: • Fatigue• Pruritus • Night sweats

CI = con� dence interval; Hct = hematocrit.

Figure 1. Kaplan-Meier curve for total cardiovascular events.

From The New England Journal of Medicine. Marchioli R, Finazzi, G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. Copyright ©2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Learn more about understanding the burden of Polycythemia Vera

at www.MPNConnect.com

The rate of death due to cardiovascular

events or major thrombosis was four times higher

in patients with elevated hematocrit levels of 45% to 50% compared with those who maintained

a hematocrit target of <45%.2

Hct, hematocrit; Hgb, hemoglobin.

Modi� ed from Barosi et al.19

Table 1. Assessment of hydroxyurea (HU) resistance and intolerance

HU Resistance HU Intolerance

After 12 weeks of HU at a total dose of ≥2 g/day or at the maximum tolerated dose, if <2 g/day

• Need for phlebotomy to maintain Hct level at <45% or

• Elevated platelet and white blood cell counts or

• <50% reduction in splenomegaly

At least 1 of the following:• Neutropenia (absolute

neutrophil count of <1.0 x 109/L)

• Platelet count of <100 x 109/L

• Hgb level of <10 g/dL• Leg ulcers or other

unacceptable nonhematologic HU-related toxicity

Clinical Need in PVTherapeutic approaches to PV focus on3,11:• Controlling and maintaining hematocrit levels at <45%• Treating complications of thrombosis and hemorrhage • Reducing thrombotic risk and minimizing the risk of leukogenic transformation • Managing splenomegaly and other disease-related symptoms

Phlebotomy is usually the starting point of treatment in patients with PV, in addition to therapy with low-dose aspirin.2,11 Low-dose aspirin has been shown to prevent both arterial and venous thrombotic complications in patients with PV.18

Cytoreductive therapy with hydroxyurea or interferon-alpha may also be helpful in patients who have dif� culty with phlebotomy, who have symptomatic or progressive splenomegaly or who experience severe symptoms.11 Although treatment with hydroxyurea may be tolerated by most patients, it is important to consider that approximately 25% of patients with PV developresistance to or intolerance of hydroxyurea (Table 1).19, 20

Despite current approaches, including phlebotomy, low-dose aspirin, interferon-alpha or cytoreductive therapy with hydroxyurea, some patients will not be able to gain and maintain hematocrit levels of <45%19,20 (Figure 2).

For some patients whose hematocrit levels remain elevated, and for those who continue to experience clinical signs and symptoms such as fatigue, pruritus, night sweats or splenomegaly, PV remains uncontrolled.11,20 Recently, standardized criteria for monitoring and assessing response in PV have been developed for clinical research. Evaluation of response includes such parameters as resolution of splenomegaly and other disease-related signs, hematocrit of <45%, blood count remission, absence of thrombotic events and bone marrow histology.21

References

1. Vannucchi AM, Guglielmelli P, Tefferi A. CA Cancer J Clin. 2009;59:171-191. 2. Marchioli R, Finazzi G, Specchia G et al. N Engl J Med. 2013;368:22-33. 3. Tefferi A. Am J Hematol. 2013;88:507-516. 4. Spivak JL. Blood. 2002;100:4272-4290. 5. Spivak JL. Ann Intern Med. 2010;152:300-306. 6. Tefferi A, Rumi E, Finazzi G et al. Leukemia. 2013;27:1874-1881. 7. Gruppo Italiano Studio Policitemia. Ann Intern Med. 1995;123:656-664. 8. Data on � le. Incyte Corporation. 9. Verstovsek S. Postgrad Med. 2013;125:128-135.10. Staerk J, Kallin A, Demoulin JB et al. J Biol Chem. 2005;280:41893-41895.11. Barbui T, Barosi G, Birgegard G et al. J Clin Oncol. 2011;29:761-770.12. Passamonti F. Blood. 2012;120:275-284. 13. Hultcrantz M, Kristinsson SY, Andersson TML et al. J Clin Oncol.

2012;30:2995-3001.14. Falanga A, Marchetti M. Hematology Am Soc Hematol Educ Program.

2012;2012:571-581. 15. Marchioli R, Finazzi G, Landol� R et al. J Clin Oncol. 2005;23:2224-2232. 16. De Stefano V, Za T, Rossi E et al. Haematologica. 2008;93:372-380.17. Mesa RA, Niblack J, Wadleigh M et al. Cancer. 2007;109:68-76.18. Landol� R, Marchioli R, Kutti J et al. N Engl J Med. 2004;350:114-124.19. Barosi G, Birgegard G, Finazzi G et al. Br J Haematol. 2010;148:961-963.20. Alvarez-Larrán A, Pereira A, Cervantes F et al. Blood. 2012;119:1363-1369.21. Barosi G, Mesa R, Finazzi G et al. Blood. 2013;121:4778-4781.

Figure 2. A practical management algorithm.11

©2015, Incyte Corporation. All rights reserved. EDU-1118i 03/15

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32240_incjak_fa2_ascopst_advrt.indd All Pages 4/7/15 2:55 PM

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Expert’s Corner

Issues in Oncology

to the rising cost of cancer care.2 In 2013, ASCO developed another Top Five list of tests, procedures, and treat-ments that are not supported by avail-able 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 Frame-work 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 ap-proach to assist physicians and patients in assessing the value of a new drug treatment based on efficacy, toxicity, and cost compared with the prevail-ing standard of care to calculate a net health benefit. Because clinical con-cerns and decisions vary depending on disease prognosis, two versions of the preliminary framework have been de-veloped—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. Be-renson Professor in the Department of Medicine at Harvard Medical School, and Clinical Director of the Cancer Center and Chief of Hematology/On-cology at Beth Israel Deaconess Medi-cal Center, Boston, about the develop-ment 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 pro-jected to become astronomic, largely because there will be a lot more people with cancer due to an aging population and because cancer is increasingly be-coming a chronic illness for which very costly medications are being used for long periods of time.

This effort was borne out of the im-perative 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 compa-nies share more of the costs of these highly expensive agents with patients. Patients and their families often suf-fer 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 avail-able options for treating a specific can-cer and come up with a sense of how

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 sur-vival benefit or how long disease pro-gression 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 physician-guided tool for use in the clinical setting.

Consistent Treatment Evaluation

How is ASCO defining “value” in can-cer 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 ben-efit assessment in addition to informa-tion on cost.

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 every-thing else and it should. Using the al-gorithm, 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 de-gree of financial toxicity, which may be important to them.

Physician ReactionWhat has been the reaction from phy-

sicians about ASCO’s value framework concept?

Some physicians are quite forward-thinking on this issue and see the dis-cussion as a responsibility that is not to be shied away from, but rather, to be engaged in thoughtfully and empathet-ically. 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. Neverthe-less, 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 mo-tivating factor—it is important for pa-tients 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 do-ing so because ASCO is primarily a society of medical oncologists. How-ever, 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 hospi-talization costs and new surgical and radiologic interventions.

There is a tendency to make drug manufacturers the fall guys for the sky-rocketing 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 af-fects 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 web-site at jco.ascopubs.org. The period for public commentary on the framework will close on August 21, 2015. To pro-vide feedback, go to asco.org/value. n

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

References1. Mariotto AB, Yabroff KR, Shao Y, et

al: Projections of the cost of cancer care in the United States: 2010-2020. J Natl Can-cer Inst 103:117-128, 2011.

2. American Society of Clinical Oncol-ogy: 2012 Top Five list: Choosing Wise-ly—ASCO identifies five key opportuni-ties in oncology to improve value of patient care. Available at www.asco.org/practice-research/2012-top-five-list. Accessed June 9, 2015.

3. American Society of Clinical Oncol-ogy: ASCO’s 2013 Top Five list in oncol-ogy. Available at www.asco.org/practice-re-search/ascos-2013-top-five-list-oncology. Accessed June 9, 2015.

4. Schnipper LE, Davidson NE, Wol-lins DS, et al: American Society of Clinical Oncology statement: A framework to as-sess the value of cancer treatment options. J Clin Oncol. June 22, 2015 (early release online).

Value in Cancer Carecontinued from page 1

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


Through the Lens of Oncology History

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.

A Century of Progress

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

THE RADIUM Era: 1916–1945‘Frozen Sleep’ as Cancer Treatment, Springfield, Illinois, 1939

D 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 prepar-ing to restore the patient to consciousness.

The frustration with failure to improve survival rates for cancer patients resulted in the creation of numerous ad-ditions to already combined therapies. The medical com-munity 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.


Clinical Trials Resource Guide

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

PHASE I

Study Type: Phase I/interventional/single-group assignment

Study Title: A Phase I Trial of Vori-nostat in the Treatment of Advanced Laryngeal, Hypopharyngeal, Nasopha-ryngeal, and Oropharyngeal Squamous Cell Carcinoma of the Head And Neck.

Study Sponsor and Collaborators: The Ohio State University Comprehen-sive Cancer Center, National Compre-hensive 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 unre-sectable or borderline resectable

Primary Outcome Measures: Maxi-mum tolerated dose of vorinostat in com-bination with concurrent chemoradiation therapy, the toxic effects of the combina-tion of vorinostat and cisplatin using NCI CTCAE v. 40 [time frame: weekly dur-ing 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, [email protected]

ClinicalTrials.gov Identifier: NCT01064921

Study Type: Phase I/interventional/single-group assignment

Study Title: Evaluation of Diagnos-tic 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-

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]The information contained in

this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with oral cavity and oropharyngeal cancers. The trials are investigat-ing combination therapies, treat-ment toxicity, specialized adjuvant therapies, and proton therapy. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

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.

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.

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

79235ha_b.indd All Pages 5/19/15 4:31 PM

http://www.gene.com/


Clinical Trials Resource Guide

Principal Investigator: Ann M. Gillenwater, MD, BA, MD Anderson; 713-792-6920


Study Type: Phase I/II/Interven-tional/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 In-stitutes of Health Clinical Center

Purpose: To determine a safe number of white blood cells harvested from the respective patient modified with retrovi-rus 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 meta-static or recurrent/refractory HPV-16+ cancers treated with autologous T cells expressing the E6 TCR plus aldesleukin [time frame: 4 years]

Principal Investigator: Christian S. Hinrichs, MD, National Cancer In-stitute; 301-496-4164, [email protected]


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 Medi-cine, 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 pu-tative tumor-initiating cell populations as defined by cell surface CD44 and intracellular phospho-ERK1/2 stain-ing after treatment with GSK1120212 [time frame: baseline and day 15]

Principal Investigator: Ravindra Uppaluri, MD, PhD, Washington Uni-versity School of Medicine; 314-362-6599, [email protected]


PHASE III

Study Type: Phase III/interven-tional/parallel assignment

Study Title: Adjuvant De-escala-tion, Extracapsular Spread, P16+, Tran-soral (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 posi-tive oropharynx cancer patients, who have had all known disease removed surgically by a minimally invasive ap-proach, and who have extracapsular spread in their lymph nodes

Primary Outcome Measures: Dis-ease-free survival [time frame: 2 years]

Principal Investigator: Bruce Haughey, MBChB, Washington Uni-versity School of Medicine; 314-362-0365, [email protected]


Editor’s Note: The clinical trials pre-sented here do not represent all the trials listed on ClinicalTrials.gov. For the com-plete list, go to ClinicalTrials.gov. n

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.

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.

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

79235ha_b.indd All Pages 5/19/15 4:31 PM

https://www.mapkpathwayinfo.com/?cid=cob_PR_00005108_1


Expert’s Corner

Redefining CancerA Conversation With Patrick Soon-Shiong, MD, FRCS(C), FACSBy Jo Cavallo

The ability to interrogate cancer cells at the genomic, proteomic, im-

munologic, and metabolomic levels will transform oncology care from one that relies mainly on trial-and-error treatment strategies based on the anatomy of the tu-mor to one that is more precisely based on the tumor’s molecular profile at the pro-teomic 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 Lon-don 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 chemo-therapeutic 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-through-put 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) next-generation sequencing technology to analyze genomic (DNA) and transcrip-tomic (RNA) sequencing data to iden-tify driver variants between somatic and germline DNA.1 Using this technology, Dr. Soon-Shiong and his colleagues de-termined expression of identified mu-tations in a cohort of 3,784 patients to establish therapeutic relevance of the mu-tated genes overcoming the limitations of the cancer gene panels. The study, which included sequencing on 19 anatomic tu-mor 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 find-ings from his study integrating whole-genome and RNA sequencing with quantitative proteomics to inform treat-ment selection.2 In this study, over 50 unique tumors from primary and meta-static 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 pa-tient’s cancer is independent of the ana-tomic tumor type and since many gene mutations were not expressed, the study authors again concluded that clinical treatment decisions need to be based

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 molecu-lar science, Dr. Soon-Shiong has es-tablished an omics network—an inter-national cadre of clinicians, scientists, pharmaceutical manufacturers, em-ployers, 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, pro-teomics, and immuno-oncology.”

Late last year, Dr. Soon-Shiong launched the Chan Soon-Shiong Insti-tute of Molecular Medicine, a nonprofit medical research organization designed to support and fund the delivery of per-sonalized, 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

has committed a $1 billion philanthrop-ic fund to make grants available to can-cer institutions throughout the United States and in countries around the world to provide the financial resources neces-sary for more patients with cancer to benefit from genomic sequencing.

The ASCO Post talked with Dr. Soon-Shiong about his vision for oncol-ogy care based on highly sophisticated molecular science.

Evolving Concept of CancerYou have said that the ability to se-

quence the cancer genome is turning ev-ery cancer into a rare disease. Please talk about the implications of that premise.

The commonly held belief that can-cer is a single clonal disease is a mis-placed assumption. With the advent of next-generation sequencing, the realiza-tion has emerged that patients with can-

cer face the enormous challenge of inter- and 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 struc-tural changes in the genome, dynamical-ly changing across time and space.

Having discovered multiple abnor-mal variants from a single patient, the critical question we have explored is, which of these variants transcribe down-stream and drive tumor growth or cell immortality? Thus, it’s not just about the identification of mutations and ge-nomic hotspots, some of which may be expressed while others remain dormant, but the protein products expressed downstream that are important to iden-tify in order to improve decision-making and optimize treatment options.

We have discovered that in many in-stances, 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 tran-scription of the mutated downstream molecules through RNA sequencing. This comprehensive test will thus pro-vide the necessary data to more accu-rately identify the protein pathway driv-ing tumor growth in that patient and finally match this comprehensive mo-lecular information to FDA-approved drugs or drugs in clinical trials.

Recognizing that practicing physi-cians 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 data-base 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 compa-nies such as Blue Cross to provide this actionable information at the point of care in the form of a downloadable de-cision support app called Eviti. This sys-tem is now available in all 50 states and will drive an adaptive learning system at scale, since we will now have the capabil-ity 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 real-ity 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 in-

Novel Therapies

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

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


ONCUS15UB00500-01-01 05/15© 2015 Bristol-Myers Squibb

Pediatric Oncology Research – Funding Available!

IntroductionThe 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.

Program GoalsIn 2015, the Pediatric Oncology Research Program seeks to:

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

» Support the development of future clinical researchers

Eligibility Criteria» M.D. pediatric oncology fellows or investigators

» Desire to enhance knowledge within the field of Pediatric Oncology

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

Enrollment and Funding» $50,000 per year will be funded to prioritized

proposals for up to 3 years. No indirect costs will be provided.

Application Process» To submit an application, visit:

www.bms.com/israpplications• Click on Pediatric Oncology Research Funding

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» To be considered, completed application must be submitted through the website by 5 P.M. EST on July 31st, 2015

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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.

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Expert’s Corner

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 pa-tients, and in order to achieve sufficiently high numbers of patients to test thera-pies 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 BeyondIf cancers are divided into many types

of rare diseases, how will drugs be discov-ered and tested for individual patients?

That is the issue we started address-ing in 2001, when we conceived [nab-paclitaxel] 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 nab-paclitaxel 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 forma-tion at the endothelial cell level to initiate transcytosis and drive the paclitaxel mol-ecule 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 occur-ring during the dynamic changes of met-astatic 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 to-day the drug is approved globally in all three indications. What is most gratify-ing is recent data from a head-to-head trial against weekly paclitaxel in neoad-juvant breast cancer, presented late last year at the San Antonio Breast Cancer Symposium.3 These data showed a re-markable and statistically significant improvement with nab-paclitaxel in triple-negative breast cancer.

This year marks the 10th anniversa-ry since [nab-paclitaxel] was approved, and the lesson I have learned is that we,

meaning the collective oncology com-munity and the pharmaceutical indus-try, 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 me-tabolism. 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 per-form genomic, proteomic, immunologic, and metabolomic interrogation at the cel-lular level. We spent almost a decade build-ing 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 recog-nition 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 administrat-ing 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

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 prolifera-tion and metabolism of the cancer cell, to attack both the stem and metastatic cancer cells, to recognize that the biol-ogy of these two cell types differ, and to use multiple drugs focused on mul-tiple points of attack, targeting the cell’s nucleus, DNA, cell signal pathways, and metabolism all simultaneously. We must pursue a path of combination therapy

and immunotherapy, which I term “quantum oncotherapeutics,” to address the need for combination therapies that will change over time in step with the in-evitable dynamic molecular changes that will occur in response to our treatment.

Through constant molecular interroga-tion and through the application of liquid biopsies, we can establish predictive mod-eling and be prepared for the almost inevi-table resistance. Furthermore, instead of using high-dose chemotherapy in the stan-dard 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 pa-tient 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 be-ing 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 en-ter phase I and phase II trials in multiple indications, in both blood and solid tu-mor 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 chang-ing the paradigm of how we manage cancer patients. Eventually, by more deeply un-derstanding 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 pa-tients with the method you described?

We will begin a phase II clinical trial very soon with low-dose metronomic nab-paclitaxel combined with 5-FU and com-bination regimens. We will be launching natural killer cells to enhance the innate immunity of patients receiving these low-dose combinations. We have supported a next-generation “basket” clinical trial, the PANGEA (Personalized Antibod-ies for Gastro-Esophageal Adenocarci-noma) 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 mo-lecular profile of patients to enter into the appropriate treatment arm based on this comprehensive molecular analysis.

Rethinking the ParadigmBased 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 ad-dress 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 strat-egy of ordering the maximum tolerated dose of single chemotherapy. Encourag-ing early results of this paradigm shift are seen in our current management of pa-tients 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 com-pletely 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 (Pancre-atic Genomic Abraxane).

Patrick Soon-Shiong, MD, FRCS(C), FACScontinued from page 46

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


Expert’s Corner

Liquid BiopsiesWill sophisticated genomic sequenc-

ing 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 nor-mal cells embedded in formalin-fixed par-affin sections and converting these laser-dissected cells into liquid lysate to allow us to measure the protein level in the tumor.

As an example of this early re-search 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 immunohisto-chemistry and even fluorescence in situ hybridization tests.

The second element of our liquid bi-opsy platform is our ability to analyze a cancer patient’s blood sample to detect circulating tumor cells and use this infor-mation to understand the disease biology, determine treatment, and anticipate the resistance factor that is going to be gener-ated 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-ge-nome, 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 dy-namic of quantum oncotherapeutics.

Major ChallengeWhat do you think is the greatest im-

pediment 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 im-pediment 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 shar-ing 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

contribute to this common cause. nDisclosure: Dr. Soon-Shiong is the majority

shareholder in NantWorks and its affiliated companies: NantHealth, NantOmics, and Conkwest, a natural killer cell immunotherapy company.

References1. Benz SC, Rabizadeh S, Sanborn JZ, et

al: Protein expression by genetic mutations

identified in gene panels (hotspots) and ef-ficacy 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 pro-teomics in the clinical setting. 2015 ASCO Annual Meeting. Abstract 11093. Presented May 31, 2015.

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

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2015 Oncology Meetings 2015 JuneASCO Review 2015June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/courses/2015/ASCO15/default.asp

2nd EACR Special Conference on Cancer GenomicsJune 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org

IO360–Immuno-Oncology 360o

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

July7th World Congress on Gastrointestinal CancerJuly 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/WGIC2015/index.asp

Gynecologic Oncology GroupJuly 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

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

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

Palliative Medicine and Supportive Oncology 2015July 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-OncologyJuly 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-Lung-Cancer-Congress

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

AugustAdvances in Cancer ImmunotherapyTM

August 7 • Washington, DC For more information: www.sitcancer.org

Best of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://boa.asco.org/

World Congress on Cancer and Prevention MethodsAugust 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/oncology-2015/

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

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

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

September2015 World Molecular Imaging CongressSeptember 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/

International Palliative Care WorkshopSeptember 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 OncologistsSeptember 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

The International Liver Cancer Association’s 9th Annual ConferenceSeptember 4-6 • Paris, France For more information: www.ilca2015.org

16th World Conference on Lung CancerSeptember 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

25th World Congress of LymphologySeptember 7-11 • San Francisco, California For more information: www.lymphology2015.com

29th Annual Canadian Association of Radiation Oncology (CARO) Annual Scientific MeetingSeptember 9-12 • Kelowna, Canada For more information: www.caro-acro.ca

American Society of Head and Neck Radiology (ASHNR) Annual MeetingSeptember 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 MalignanciesSeptember 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/

ISEH 44th Annual Scientific MeetingSeptember 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting

HPV 2015–30th International Papillomavirus ConferenceSeptember 17-21 • Lisbon, Portugal For more information: www.hpv2015.org

3rd Annual Hematology/Oncology Pharmacy Association (HOPA) Oncology Pharmacy Practice Management ProgramSeptember 18-19 • Chicago, Illinois For more information: www.hoparx.org/education/2015-Practice-Management-Program/2015-practice-management-program-welcome.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 SymposiumSeptember 25-27 • San Francisco, California For more information: http://breastcasym.org

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Patient’s Corner

Carpe DiemBy Amir Steinberg, MD, FACP

My life as a cancer survivor and an oncologist has taught me the im-

portance of living every day to the fullest.Sometimes we all need a little re-

minding to appreciate life to the full-est. 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 lym-phoma. 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 Lym-phoma/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 un-dergoing therapy over 20 years ago, I have tried to do just that.

Along the way, I used my life experi-ence as a cancer survivor as motivation to pursue a career in medicine. Like Dr. Hagemeister, I wanted to be a lympho-ma specialist, working at a large hospi-tal, involved in research. And through the various stages of my medical train-ing, hematology-oncology fellowship, and bone marrow transplantation fel-lowship, that continued to be my goal. However, sometimes when one is so goal oriented, life becomes all about pursuing the next step and not appreci-ating the present. Although it is impor-tant to think about the future and plan for that future, one can lose sight of liv-ing 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 InterruptedI 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 de-veloped chest discomfort. An x-ray of his chest was performed and showed a mediastinal mass. He returned to Cali-fornia, 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

months of intense treatment, mainly inpatient. This precluded Marc from completing his last semester in col-lege. I remember Marc often challeng-ing 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 liv-ing his life to the fullest, just as he had done prior to his diagnosis.

After undergoing 8 months of in-tense chemotherapy, and getting ready to start his 2-year maintenance chemo-therapy, Marc began noticing blood in his urine and some discomfort on urination. A bladder mass was noted, and he was found to have recurrent

lymphoma. As a result, he needed to undergo an allogeneic stem cell trans-plant. Although his sister’s stem cells were not a match for his immune sys-tem, fortunately, a near-match was found from the National Marrow Do-nor 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

enough, to resume his education and complete his degree, and most impor-tantly 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 in-dicated 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

one-eyed man is king.” What was the meaning of this im-

age to Marc? Clearly, the face (per-haps subconsciously his face) de-picted 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 diffi-cult ordeal, we are blind to the mean-ing and the essence of life. And he is no longer completely blind to the es-sence and meaning of life because he’s been through a life-threatening situa-tion, 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 interpreta-tion of his print.

Patient/Physician/ Cancer Survivor Bond

A few months into my new job, I got an e-mail from Marc. He was driv-ing across the country in a truck. Dur-ing the drive, he explored the towns and cities he passed through and vis-ited national parks and other tourist attractions he passed along the way. He would surf when he had the op-portunity 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 wor-rying what the next day would bring, truly following the Latin maxim carpe

Perspective

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

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 in-formation 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

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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 en-joyable, 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 ex-periences I had shared with him re-garding 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 for-mer 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 diag-nosis by becoming an oncologist and helping provide Marc and other pa-tients 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 e-mail 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 surf-ing 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 PresentSome 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 per-spective 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 can-

cer stays in remission, he has his whole life ahead of him to do what he is “sup-posed 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 prompt-ed 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-pro-voking 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 Hematology-Oncology at Mount Sinai Hospital in New York.

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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/refrac-tory chronic lymphocytic leukemia (CLL) who discontinued ibrutinib (Im-bruvica) 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 sal-vage 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 progres-sive CLL or transform when receiving ibrutinib,” the researchers wrote.

The majority of patients discontinu-ing ibrutinib in the four trials “had high-risk features: 94% with unmutated im-munoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype,” the in-vestigators noted.

Causes of treatment discontinuation were adverse events in 11 patients and serious adverse events/deaths in 3 ad-ditional 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 en-rolled 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 me-dian duration of ibrutinib therapy be-fore treatment discontinuation was 13 months. The median overall survival after ibrutnib discontinuation was 3.1 months, and 25 patients (76%) died af-ter discontinuing ibrutinib.

The “foremost” take-home lesson from this study is “the very poor progno-sis and overall survival of CLL patients who discontinued the drug regardless of the reason,” according to an accompa-nying 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/re-fractory] CLL treatment and constitutes an important paradigm in the molecularly targeted approach of this disease, with ex-cellent efficacy and tolerability,” the com-mentators 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 ibru-tinib 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 fac-ing 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 re-ceive 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 Af-fairs Medical Center, San Francisco, and colleagues reported in JAMA Dermatol-ogy. Voice message and online patient portal were each preferred by 5.1% of pa-tients, e-mail was preferred by 2.7%, and text message was preferred by 0.3%.

“Experience with online portal deliv-ery 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 ques-tion about how patients preferred to be notified of the results.

Survey DetailsPatients 18 years or older were re-

cruited 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 Pennsylva-nia, 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 physi-cian 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 or-der of preference, why they chose a spe-cific method, and if they preferred differ-ent methods of notification for normal and abnormal results.

“The most important consideration for patients was a communication mo-dality that provided test results in the most rapid manner; 51.7% wanted a method that was rapid, and 7.8% pre-ferred 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 meth-od regardless of the biopsy results, 40.5% preferred different modes. For normal results, more of these patients would pre-fer 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 abnor-mal 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 meth-od of contacting patients aligned with patient preference for speaking by tele-phone (56.5%). However, for benign re-sults, 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.

©David Sipress/The New Yorker Collection/www.cartoonbank.com


Letters to the Editor

Response to May 10 Cartoon

As a medical writer specializing in oncology, an ASCO member,

and someone who tries to build sen-sitivity 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 car-toon 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 pro-mulgate? As a writer, I know that words

count; words shape attitudes, even if not consciously. I use empathetic ter-minology 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 rein-forces 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

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 cer-tainly 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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Perspective

myeloid leukemia (CML) with the BCR-ABL translocation. Other examples have followed, but they have had mixed suc-cess, and only a few of them have impact-ed the clinical management of patients.

With the announcement of a precision medicine initiative by the National Insti-tutes of Health, there will be renewed vig-or in this endeavor. However, in attempt-ing 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 evolu-tion in Science magazine in which he suggested “tumor progression results from acquired genetic variability within the original clone allowing se-quential 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 re-sults 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 progeni-tor to propagate disease relapse. There is perhaps no disease with greater evi-dence of this than CML.

The initiating event in CML is acqui-sition of the t(9;22)(q34;q11) translo-cation, which creates a fusion between the BCR and ABL1 genes. This altera-tion can be found in hematopoietic stem cells and traced through the lin-eage to CML cancer cells. Secondary genetic alterations, such as mutations of TP53, RB1, and CDKN2A, can be acquired after the BCR-ABL transloca-tion 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 ki-nases 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 thera-pies targeting other important “driver

mutations” in other diseases have failed to produce similar results? An important factor contributing to the success of ima-tinib 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 BCR-ABL translocation and are susceptible to the effects of imatinib. The efficacy of imatinib is confounded by stromal inter-actions that protect the tumor-initiating clone and prevent clearance of the dis-ease. 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 peri-ods, 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 muta-tions that play an active role in disease pathogenesis (ie, driver mutations)

and (2) those mutations that do not contribute to disease pathogenesis but undergo clonal expansion alongside one that does (ie, passenger muta-tions). 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 evolu-tion and play a role in disease genesis (early drivers), whereas others occur as later events during clonal evolu-tion and play a role in disease progres-sion (late drivers/accelerators). Early driver mutations that have a role in disease genesis, such as the BCR-ABL translocation, will therefore be pres-ent 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 understand-ing and measurement of the clonal origin of mutations, each driver mu-tation will confer a variable boost in evolutionary fitness, which will cause

them to overtake less-fit clones at dif-ferent 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 sig-nificant 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 frequen-cies (the representation of mutant al-leles as a proportion of all sequencing reads over that nucleotide), which in-dicate they are subclonal events.

Currently, the majority of cancer sub-types 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 per-ceived future of precision medicine is one in which patients will receive a re-port of “actionable” mutations matched to suggested therapeutics or clinical tri-als, which their oncologist can use in the formulation of their treatment strategy.

The question will then be is every “ac-tionable” 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 be-cause early mutations are more likely to reside with a tumor progenitor cell com-partment that propagates relapse, where-as 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 pro-vide 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 eradi-cate 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 po-tentially extend patient survival. However,

targeting a subclonal mutation may have little or no effect on tumor burden and could waste valuable time. Understand-ing the hierarchical order in which somatic mutations are acquired in each disease will therefore be an important consideration in ranking therapeutic targets for drug de-velopment, but this is a complex scientific undertaking. At the very least, the report-ing 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 RemarksClonal evolution and clonal domi-

nance will be important considerations in precision medicine as an increasing repertoire of mutations becomes “ac-tionable.” 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 prog-nostic value. This is because investiga-tors often do not discriminate between clonal and subclonal events when iden-tifying associations with prognosis. In addition, adverse mutations residing within a subclone are likely to be asso-ciated with inferior outcome because of their role in therapeutic resistance and/or increased clonal fitness, which are functions that can facilitate clonal ex-pansion and disease progression regard-less 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 es-timated 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 ap-proaches 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” muta-tions for clinical decision-making. n

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

Michael Green, PhDcontinued from page 1

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

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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. Internation-al 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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TAP Vol 6 Issue 11

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