Value-Based Cancer Care March 2014

MARCH 2014 VOL 5 NO 2

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com

Large Study Supports Early Oophorectomy for BRCA Mutation Carriers

An 80% risk reduction for ovarian or breast cancer

Photo by Carol and Mike Werner / Science Source

By Alice Goodman

Virtual Patients Help Identify Opportunities for Cost-Savings

By Charles Bankhead San Diego, CA—The use of virtual patient vignettes to improve adherence to a breast cancer clinical pathway identified correctable variances from a breast cancer clinical pathway with the potential to reduce the cost of care by several million dollars, according to the results of a pilot study reported at the 2013 American Society of Clinical Oncology Quality Care Symposium.

Eliminating a portion of unnecessary diagnostic tests and improving adherence to a chemotherapy pathway resulted in potential savings of $4.4 million. The vignettes helped improve provider awareness of clinical standards and identified areas for quality improvement.

The H. Lee Moffitt Cancer Center “prioritized value for its breast cancer patients by measuring quality and Continued on page 9

Genetic Test for Breast Cancer Screening Cost-Effective for Women at Intermediate Risk

W

omen who carry the BRCA1 or BRCA2 mutation had an 80% reduction in risk for ovarian, fallopian tube, or breast cancer if they underwent preventive oophorectomy, according to

a large prospective study, and a 77% reduction in all-cause mortality (Finch AP, et al. J Clin Oncol. 2014 February 24 [Epub ahead of print]).

The majority of the risk reduction was among carriers of the more

Continued on page 18

7SNP model adds value to the Gail risk test

By Eileen Koutnik-Fotopoulos

T

he American Cancer Society has recommended annual magnetic resonance imaging (MRI) as an adjunct to mammography for breast cancer screening in women who have a lifetime risk of breast cancer of approximately 25% to ≥50%, as determined by models such as the Gail risk test.

A new simulated clinical trial evaluated the cost-effectiveness of using 7 single-nucleotide polymorphisms (7SNPs) in combination with the Gail test to assess the cost-benefit of annual MRI screening in women at risk for breast cancer (Folse HJ, et al. Cancer Prev Res [Phila]. 2013;6:1328-1336).

Continued on page 16

HEAD AND NECK CANCER

Outpatient Chemoradiation Regimen Matches Inpatient Care Outcomes, at Lower Costs

FROM THE EDITOR . . . . . . . . . . . . . .

This year at HIMSS

By Charles Bankhead

CLINICAL PATHWAYS . . . . . . . . . . . .

New pathways for hepatocellular carcinoma

Delivering value to patients with head and neck cancer Scottsdale, AZ—Definitive chemoradiation with single-agent outpatient chemotherapy for head and neck cancer led to disease control and survival equivalent to that of inpatient multiagent therapy, at an annualized sav-

©2014 Engage Healthcare Communications, LLC

ings of almost $650,000, according to results of a small randomized trial presented at the 2014 Multidisciplinary Head and Neck Cancer Symposium.

The net revenue did not differ materially between the 2 strategies in the

Continued on page 11

inside 4

VALUE PROPOSITIONS . . . . . . . . . . 8 Value of yoga for women with breast cancer

9

HEAD AND NECK CANCER . . . . . . 10 Systemic therapy in head/neck cancer ECONOMICS OF CANCER CARE . . .16 Switching from IV to SC rituximab saves costs

VBCC PERSPECTIVE . . . . . . . . . . . 20 Prophylactic oophorectomy in women with BRCA mutations PROSTATE CANCER . . . . . . . . . . . . 21 Previous docetaxel thwarts enzalutamide activity PERSONALIZED MEDICINE . . . . . . 23 Understanding molecular subtypes IN THE LITERATURE . . . . . . . . . . . . 29 Nintedanib + docetaxel effective in NSCLC IMMUNOTHERAPY . . . . . . . . . . . . . 30 Immunotherapy key in GI cancer

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In This Issue Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon

FROM THE EDITOR

VBCC PERSPECTIVE

Is the promise of HIT more than a hope and a prayer?

Prophylactic oophorectomy in women with BRCA mutations

VALUE PROPOSITIONS

BREAST CANCER

Value of yoga for women with breast cancer More…

Promising new therapies in the pipeline More…

CLINICAL PATHWAYS

PROSTATE CANCER

New pathways, therapies explored in hepatocellular carcinoma More…

Long-term safety data for radium-223 More…

PERSONALIZED MEDICINE

Production Manager Melissa Lawlor

HEAD AND NECK CANCER

The Lynx Group

Outpatient chemoradiation as effective as inpatient, at lower costs More…

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly

Understanding molecular subtypes More…

DRUG UPDATE Gazyva for chronic lymphocytic leukemia

Human Resources Jennine Leale

ECONOMICS OF CANCER CARE

Associate Director, Content Strategy & Development John Welz

Genetic test for intermediate-risk breast cancer screening cost-effective More…

Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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No. 2

Advances in the treatment of hematologic malignancies

VBCC Editorial Board

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

CONTINUING EDUCATION

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy, Aetna, Hartford, CT

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Ted Okon, BS, MBA Executive Director Community Oncology Alliance, Washington, DC

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments.

This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com • Telephone: 732-992-1536 • Fax: 732-992-1881.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

march 2014

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From the Editor

Is the Promise of Health Information Technology More than a Hope and a Prayer? This Year at HIMSS

By Craig Deligdish, MD

Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL, and Editor-in-Chief, Value-Based Cancer Care

A

t the end of February, I had the opportunity to attend the Healthcare Information and Management Systems Society (HIMSS)14 Annual Conference, which was held in Orlando, FL. Attended by more than 30,000 committed vendors, healthcare administrators, providers, politicians, scientists, and others, the meeting provided a great deal of insight into the health information community’s past accomplishments, the present state of the art, and expectations for the future.

This year’s HIMSS conference focused on innovation, impact, and outcomes, and addressed a number of issues important to patients, providers, and payers. For those who are unfamiliar with HIMSS, it was founded in 1961, and it encompasses more than 52,000 individuals representing healthcare providers, government, and notfor-profit organizations, as well as corporations, worldwide. With a mission of leading endeavors that optimize health engagement and healthcare outcomes through information technology (IT), HIMSS is committed to better health through IT.

This year, HIMSS showcased Beacon Communities, which have made improvements using health information technology (HIT) as a foundation for care coordination and innovation.

Other foci of this year’s annual conference included organizations and companies focused on patient e-engagement and technology tools that allow for interoperability between different HIT systems.

Unfortunately, the “promise” of HIT has at times had its shortcomings.

Challenges have included the failure of many systems to interface with each other and the inefficiencies that providers frequently encounter when utilizing electronic medical records. Despite advances in HIT, many healthcare providers and payers have failed to see a positive impact on the cost of healthcare, or a clear improvement in quality care or outcomes that can directly be attributed to HIT. That being said, keynote addresses by Karen B. DeSalvo, MD, MPH, MSc, National Coordinator for HIT at the US Department of Health and Human Services (HHS); Marilyn Tavenner, Administrator for the Centers for Medicare &

Medicaid Services (CMS); and former Secretary of State and US Senator Hillary Rodham Clinton focused on a number of accomplishments and hope for the future.

Dr DeSalvo focused on efforts by the HHS and the CMS to partner with the HIT community and the private sector. She reviewed the federal government’s commitment to developing a national health information network for the purpose of improving care and transparency. She stated that the government’s commitment to investing in HIT for the public good lets providers access information that allows them to provide better care leading to improved outcomes. She described the government’s strategy, which is focused on harmonizing standards and encouraging interoperability, with meaningful use being one tool to encourage these goals.

Ms Tavenner stressed the federal government’s commitment to rewarding quality over quantity, stating that the trends that the CMS is seeing in healthcare include a reduction in adverse events and hospital readmission rates. She referenced a number of pilot

programs and other initiatives that link quality data to reimbursement.

Ms Clinton spoke briefly, addressing her commitment to innovation, improving outcomes, care coordination, and quality healthcare, stating that these initiatives are best when they come from the provider community. She stated the government’s role is to reward value over volume while supporting evidence-based care that reduces costs.

All of the keynote speakers at this year’s HIMSS conference spoke to the importance of value-based initiatives, value-based purchasing, and recognizing and incentivizing better health outcomes, with the overall goal of reducing the cost of care and improving quality.

All in all, it was refreshing to see the commitment and the investments that have been made by both the government and the private sector HIT community toward value-based care, although it is also clear that these investments have yet to generate the returns that both the provider community and patients so desperately need. n

Visit Value-Based Cancer Care online Read the most recent articles just published in Value-Based Cancer Care, the journal dedicated to questions of value, costs, and quality of care in oncology, as well as clinical updates, multidisciplinary care, drug updates, and reviews of key new studies published in oncology.

Submit a Letter to the Editor Coming Soon: Questions and answers from the journal’s editorial board members

www.valuebasedcancer.com 4

Value-Based Cancer Care

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march 2014

Vol. 5

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No. 2

1st oral kinase inhibitor for previously treated CLL

NOW APPROVED NEW

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

1 daily dose

FOR PREVIOUSLY TREATED CLL

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE).

Monitor patients for fever and infections and evaluate promptly.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels.

Maintain hydration.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 02/14

PRC-00287

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%). *Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), ADVERSE REACTIONS – atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), MCL: The most commonly occurring adverse reactions dehydration (6.4%), and musculoskeletal pain (6%). (≥20%) in the clinical trial were thrombocytopenia*, diarrhea Treatment-emergent Grade 3 or 4 cytopenias were reported (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal in 35% of patients. pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), Five patients (10%) discontinued treatment due to adverse constipation (25%), rash (25%), abdominal pain (24%), vomiting reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

(23%), and decreased appetite (21%).

Adverse reactions leading to dose reduction occurred in 13% *Treatment-emergent decreases (all grades) of platelets (57%), of patients. neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS The most common Grade 3 or 4 non-hematological adverse CYP3A Inhibitors - Avoid concomitant administration with reactions (≥5%) were pneumonia (7%), abdominal pain (5%), strong or moderate inhibitors of CYP3A. If a moderate CYP3A atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin inhibitor must be used, reduce the IMBRUVICA™ dose. infections (5%). Treatment-emergent Grade 3 or 4 cytopenias CYP3A Inducers - Avoid co-administration with strong CYP3A were reported in 41% of patients. Ten patients (9%) discontinued inducers. treatment due to adverse reactions in the trial (N=111).

SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in The most frequent adverse reaction leading to treatment patients with baseline hepatic impairment. discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICATM (ibrutinib) capsules

INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Gastrointestinal disorders

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

57

17

Neutrophils Decreased

47

29

Hemoglobin Decreased

41

9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 System Organ Class Preferred Term (%) (%) 4 63 Gastrointestinal disorders Diarrhea 2 23 Constipation 2 21 Nausea 0 21 Stomatitis 2 19 Vomiting 0 15 Abdominal pain 0 13 Dyspepsia Infections and infestations Upper respiratory 2 48 tract infection 6 21 Sinusitis 6 17 Skin infection 8 10 Pneumonia 0 10 Urinary tract infection 4 31 General disorders and administrative Fatigue 2 25 site conditions Pyrexia 0 23 Peripheral edema 4 13 Asthenia 0 13 Chills 2 54 Skin and subcutaneous tissue disorders Bruising 0 27 Rash 0 17 Petechiae 0 19 Respiratory, thoracic and mediastinal Cough 0 15 disorders Oropharyngeal pain 0 10 Dyspnea 6 27 Musculoskeletal and connective tissue Musculoskeletal pain 0 23 disorders Arthralgia 2 19 Muscle spasms 0 21 Nervous system disorders Dizziness 2 19 Headache 0 10 Peripheral neuropathy Metabolism and nutrition disorders Decreased appetite 17 2 Neoplasms benign, malignant, Second 10* 0 unspecified malignancies* Injury, poisoning and procedural Laceration 10 2 complications Psychiatric disorders Anxiety 10 0 Insomnia 10 0 Vascular disorders Hypertension 17 8 *One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

71

10

Neutrophils Decreased

54

27

Hemoglobin Decreased

44

0

* Based on laboratory measurements per IWCLL criteria and adverse reactions Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules

Meetings

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Oncology/Hematology Meetings 2014 March 26-28 HOPA 10th Annual Conference New Orleans, LA Tel: 877-467-2791 or info@hoparx.org March 31-April 2 ACCC 40th Annual National Meeting Arlington, VA Tel: 301-984-9496 or ksmith@accc-cancer.org

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, 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 IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients).

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

April 5-9 AACR Annual Meeting San Diego, CA Tel: 215-440-9300 or jeff.ruben@aacr.org May 6-9 AVBCC Annual Meeting Los Angeles, CA Tel: 732-992-1897 or association@avbcconline.org May 30-June 3 ASCO Annual Meeting Chicago, IL Tel: 877-457-4822 or meetings@asco.org June 26-28 MASCC International Symposium Miami, FL Tel: +41 22 908 0488 or mascc@kenes.com

October 17-18 ASCO Quality Care Symposium Boston, MA Tel: 888-651-3038 or meetings@asco.org October 29-31 3rd Annual World Cutaneous Malignancies Congress San Francisco, CA Tel: 732-992-1539 or conferences@the-lynx-group.com October 31-November 1 3rd Annual Global Biomarkers Consortium San Francisco, CA Tel: 732-992-1538 or conferences@the-lynx-group.com December 6-9 56th ASH Annual Meeting and Exposition San Francisco, CA Tel: 202-776-0544

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044

December 9-13 2014 San Antonio Breast Cancer Symposium San Antonio, TX Tel: 210-450-1550 or sabcs@uthscsa.edu

Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc.

PRC-00339

Issued: February 2014

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T:14”

September 26-30 ESMO 39th Congress Madrid, Spain Tel: +41 (0) 91 973 19 39 or esmo@esmo.org

B:14.25”

September 14-17 ASTRO’s 56th Annual Meeting San Francisco, CA Tel: 800-962-7876 or education@astro.org

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions].

• Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists.

©Pharmacyclics, Inc. 2014

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September 4-6 ASCO Breast Cancer Symposium 2014 San Francisco, CA Tel: 888-651-3038 or meetings@asco.org

Advance Care Planning

VALUE PROPOSITIONS New Evidence Confirms Value of Yoga for Women with Breast Cancer

A new study from M.D. Anderson has shown that patients with breast cancer who participated in yoga exercises that incorporated controlled breathing, meditation, and relaxation techniques into their treatment plan had significant improvement in their ability to manage their daily activities and had better regulation of the stress hormone cortisol. The patients who practiced yoga had the steepest reduction in their cortisol levels throughout the day. Increased levels of the stress hormone during the day (ie, blunted cortisol circadian rhythm) have been linked to worse outcomes in patients with breast cancer.

“Combining mind and body practices that are part of yoga clearly have tremendous potential to help patients manage the psychosocial and physical difficulties associated with treatment and life after cancer, beyond the benefits of simple stretching,” said Lorenzo Cohen, PhD, Director of the Integrative Medicine Program at M.D. Anderson, and lead author of the study that included 191 women with breast cancer (stage 0-III) that was recently published in the Journal of Clinical Oncology.

In addition, after completing radiation treatment, only the women in the yoga and stretching groups reported a reduction in fatigue. At 1, 3, and 6 months after radiation therapy, women who practiced yoga during treatment reported greater benefits to physical functioning and general health.

“The transition from active therapy back to everyday life can be very stressful as patients no longer receive the same level of medical care and attention. Teaching patients a mind-body technique like yoga as a coping skill can make the transition less difficult,” said Dr Cohen. M.D. Anderson News Release; March 3, 2014

Immunotherapy an Expanded Focus of the University of Pennsylvania–Novartis Cancer Research Program

Increasing evidence suggests that the human immune system plays a role in fighting cancer. Various research and development companies are increasing their investment in incorporating immunotherapy research into their drug development programs with the goal of creating new targeted anticancer therapies that will stimulate the patient’s immune response to such therapies to maximize outcomes.

Novartis is collaborating with the University of Pennsylvania on the investigative chimeric antigen receptor (CAR) technology to develop effective targeted immunotherapies. Novartis has announced its recent acquisition of CoStim Pharmaceuticals, a Cambridge, MA–based biotechnology company focused on harnessing the immune system to eliminate immune-blocking signals from cancer. This new acquisition will enhance the CAR program and expand the scope of its focus on immunotherapies directed at several targets, including the PD-1. The goal of this program is to develop medicines that will use the body’s immune system to prevent the patient’s cancer from developing drug resistance to therapeutic anticancer medicines.

“Therapy for many types of cancers is expected to increasingly rely upon rational combinations of agents,” said Mark C. Fishman, MD, President, Novartis Institutes for BioMedical Research. “Immunotherapy agents provide additional arrows in our quiver for such combinations. They com­ plement our extensive portfolio of drugs that hit genetically defined cancer-causing pathways, and also may be relevant to expansion of CAR therapies.” Novartis Press Release; February 17, 2014

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Rates of New Lung Cancer Cases Drop in the United States, CDC Reports

A new report from the Centers for Disease Control and Prevention (CDC) indicates that new cases of lung cancer were going down and had been decreasing between 2005 and 2009 for men and for women in the United States (see Figure on page 17). Lung cancer is the leading cause of cancer death in the United States and the second most often diagnosed cancer among US men and women. The majority of the cases are attributable to cigarette smoking and secondhand smoke.

Based on this report, the incidence rates were reduced from 87 to 78 cases per 100,000 men, an annual reduction of 2.6%, and from 57 to 54 cases per 100,000 women, an annual decrease of 1.1%. The fastest reductions were seen in people aged 35 to 44 years, decreasing by 6.5% annually for men and 5.8% for women. Overall, lung cancer incidence rates decreased faster in men than in women.

“These dramatic declines in the number of young adults with lung cancer show that tobacco prevention and control programs work—when they are applied,” said CDC Director Tom Frieden, MD, MPH. “While it is encouraging that lung cancer incidence rates are dropping in the United States, one preventable cancer is one too many,” Dr Frieden said. “Implementation of tobacco control strategies is needed to reduce smoking prevalence and the lung cancer it causes among men and women.”

The incidence of lung cancer decreased among men in all geographic regions in the United States, as well as in 23 states; among women, the incidence decreased in the South and West, as well as in 7 states. Lung cancer rates were stable in all other states. These declines reflect the successes of past tobacco prevention and control efforts, according to the CDC. The study indicates that continued attention to local, state, and national population-based tobacco prevention and control strategies are needed to achieve further reductions in smoking prevalence among both men and women of all ages to reduce subsequent lung cancer in the United States.

Millions of Americans are living with a smoking-related disease, and each day more than 2100 youth and young adults become daily smokers.

For assistance with stopping to smoke, call 1-800-QUIT-NOW (1-800-7848669) or visit www.smokefree.gov. For information on quitting and on preventing children from using tobacco, visit www.BeTobaccoFree.gov.

CDC; January 9, 2014

ASCO Is Asking Oncologists to Help Their Patients to Quit Smoking

After the report from the Centers for Disease Control and Prevention (CDC) about the reduction in the new cases of lung cancer in the United States, the American Society of Clinical Oncology (ASCO) issued a statement emphasizing that it has a role in educating patients with cancer on the need to stop smoking in an effort to control lung cancer. “Eliminating tobacco use is the most important thing we can do to prevent lung and other cancers, as well as the many other diseases its use causes,” said ASCO President Clifford A. Hudis, MD, FACP. “This new CDC report shows how far we’ve come in the United States as we approach the 50th anniversaries of both the Surgeon General’s first report on tobacco and ASCO’s founding. Having shown that we can make substantial progress, we must continue to do everything possible to expand tobacco control programs in the United States and especially overseas, where tobacco use is taking an even greater toll.”

Suggesting that oncologists have a responsibility as “cancer doctors” to help their patients quit smoking and oppose tobacco use in any form, Dr Hudis noted that ASCO officials are “deeply committed to proactive tobacco control globally and have set an aggressive agenda for slashing tobacco use, deploying every public health, policy and legal approach available.”

ASCO News Alert; January 9, 2014

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Clinical Pathways

Virtual Patients Help Identify Opportunities... pathway adherence,” said Karen K. Fields, MD, Medical Director, Strategic Alliances, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. “Continuous measurement and feedback with [virtual patient] vignettes can improve compliance with clinical pathways.”

“Measuring compliance can improve provider awareness and compliance with clinical standards, creating opportunities for savings,” she added.

The breast cancer pathway is one of more than 40 that the H. Lee Moffitt Cancer Center has developed, each of which has an adherence target of 80%.

Monitoring adherence to the pathways by reviewing patient records proved to be problematic and prohibitively expensive because of the large number of patients and decision points involved in the process, said Dr Fields.

Investigation of more efficient ways to monitor adherence to clinical pathways led the H. Lee Moffitt Cancer Center to partner with QURE Healthcare to use the company’s Clinical Performance and Value virtual patient vignettes. The Moffitt-QURE project evolved as a means to gather feedback regarding adherence, to improve health outcomes,

and to lower the cost of care.

Clinical Performance and Value vignettes are disease-specific online cases (or virtual patients), and have been validated as a means to measure the understanding of and the adher-

“Continuous measurement and feedback with [virtual patient] vignettes can improve compliance with clinical pathways. Measuring compliance can improve provider awareness and compliance with clinical standards, creating opportunities for savings.”

—Karen K. Fields, MD

ence to clinical pathways. Dr Fields reported the findings from a pilot study to evaluate the vignettes’ effect on providers’ understanding of clinical pathways related to breast cancer.

The pilot study involved 15 provid-

ers, including medical oncologists, surgeons, and advanced-practice providers in breast cancer. Participants completed 2 Clinical Performance and Value vignettes every 4 months, and they received individualized feedback regarding their performance. Dr Fields and colleagues applied utilization trends and cost data to the Clinical Performance and Value results to project savings.

The results showed a wide range of variance from pathways in several areas of care. The compliance rates included 83% for radiation therapy, 79% for hormonal therapy, and 69% for surgery. Two areas, in particular, stood out: unnecessary diagnostic tests (50% compliance with standards) and adherence to chemotherapy pathways (40% compliance).

Dr Fields and colleagues determined that providers ordered 1.6 additional diagnostic tests per patient, at an average cost of $2500 per test. During 2012, the H. Lee Moffitt Cancer Center provided care for 2055 patients with breast cancer. Putting the numbers together showed that a 30% decrease in unnecessary tests would reduce the cost of care by $1.6 million.

During 2012, charges for chemothera-

Continued from the cover

at a glance ➤ The H. Lee Moffitt Cancer Center has developed more than 40 oncology pathways with adherence rates of 80% ➤ The use of virtual patient vignettes can improve adherence and potentially reduce the cost of care by several million dollars ➤ The vignettes improved provider awareness of clinical standards and identified areas for quality improvement ➤ Appropriate diagnostic testing and compliance with chemotherapy pathways can lead to significant cost-savings of $4.4 million py related to breast cancer were approximately $20 million. A 30% improvement in compliance with che­­mo­­therapy pathways would reduce charges by $2.8 million.

Dr Fields said that the pilot study will be expanded to include other clinical pathways developed at the H. Lee Moffitt Cancer Center. n

New Pathways, Targeted Therapies Being Explored in Hepatocellular Carcinoma

See also Personalized Medicine, pages 23-28

By Wayne Kuznar

San Francisco, CA—Many molecularly targeted agents that inhibit different pathways of hepatocarcinogenesis are under development, and novel targets are being assessed in hepatocellular carcinoma (HCC), said Andrew X. Zhu, MD, PhD, Director, Liver Cancer Research, Massachusetts General Hospital, Boston, at the 2014 Gastro­ intestinal Cancers Symposium.

Sorafenib (Nexavar) remains the only systemic agent that improves the survival of patients with advanced HCC. It improves median overall survival (OS) in HCC, but median survival is still only approximately 10 months. Many more potent or selective antiangiogenic agents have failed to improve on this outcome.

“While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with

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safe, effective therapies,” said Dr Zhu. Surpassing sorafenib may require a combination of antiangiogenic agents with cytotoxic chemotherapy or with other molecularly targeted therapies to allow for synergy or additive effects. “Alternatively, it might require moving beyond the antiangiogenesis approach and targeting cell autonomous pathways involved in hepatocarcinogenesis, such as the hepatocyte growth factor [HGF]/c-MET, PI3K/ AKT/mTOR, or FGF [fibroblast growth factor]/FGF receptor pathways,” Dr Zhu said.

Antiangiogenic Strategies Antiangiogenic agents, including pazopanib (Votrient), lenvatinib, axit­ inib (Inlyta), and ramucirumab, are in development for the treatment of patients with HCC. Based on phase 2 clinical data, lenvatinib and ramucirumab have advanced to phase 3 trials.

Although HCCs are highly vascular tumors with increased levels of vascular endothelial growth factor (VEGF), several VEGF receptor (VEGFR) inhibitors have failed to improve OS in HCC. This failure has prompted reconsideration of targeting VEGFR in HCC, said Dr Zhu. Future efforts should focus on developing surrogate and predictive markers to identify patients likely to benefit from antiangiogenic treatment.

Antiangiogenics are being combined with chemotherapy (sorafenib plus doxorubicin [Doxil]) in late-stage clinical trials, and with targeted therapies (ie, bevacizumab [Avastin]) in early-phase trials. mTOR Inhibitors mTOR regulates protein translation, angiogenesis, and cell-cycle progression in patients with HCC. mTOR inhibitors have been shown to inhibit

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cell growth and tumor vascularity in HCC cell lines and HCC tumor models. The mTOR inhibitor everolimus (Afinitor) failed to extend OS compared with best supportive care in the multicenter EVOLVE-1 trial of 546 patients with advanced HCC. Nevertheless, the preclinical promise of inhibiting the mTOR pathway has led to the development of other mTOR inhibitors, such as temsirolimus (Torisel), sirolimus (Rapamune), and CC-223, which is a dual inhibitor of TORC1/ TORC2.

Immune-Based Therapy In the realm of immune-based therapy for HCC, “perhaps the most excitement comes from the inhibitors targeting the checkpoint pathway,” said Dr Zhu. A phase 1 trial has been conducted with tremelimumab, a fully human immunoglobulin G2 monoclonal antiContinued on page 10

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Head and Neck Cancer

Systemic Therapy Wins One, Loses One in Head and Neck Cancer

By Charles Bankhead

Scottsdale, AZ—The addition of chemotherapy to irradiation proved superior to accelerated radiotherapy without systemic therapy in a randomized trial of patients with advanced head and neck cancer.

Chemoradiation led to better overall survival (OS) at 2 years and to improved disease-free survival (DFS) in patients with mid-level disease status.

Among patients whose human papillomavirus (HPV) status was known, chemotherapy improved 2-year survival by more than 30% in the HPV-negative subgroup, which had a less favorable prognosis, according to a report presented at the 2014 Multidisciplinary Head and Neck Cancer Symposium.

“Early results of the Polish HN08 trial have proven that concurrent chemoradiation takes an advantage over accelerated radiotherapy in patients with marginally advanced head and neck squamous-cell carcinoma,” said Krzysztof Skladowski, MD, PhD, Head of Radiation Oncology, Institute of Oncology–Maria SklodowskaCurie Memorial Cancer Center, Gliwice, Poland.

“For these patients, concurrent

chemoradiation with conventional 7 weeks of fractionation and, at least, 2 courses of cisplatin is more effective than 6 weeks of accelerated radiation therapy. Perhaps the target for accelerated radiation therapy could be now limited for the population of patients

gional control compared with chemoradiation and placebo.

Several meta-analyses have suggested that patients with advanced head and neck cancer derive the most benefit from concurrent chemoradiation. As a result, accelerated radio-

“Early results of the Polish HN08 trial have proven that concurrent chemoradiation takes an advantage over accelerated radiotherapy in patients with marginally advanced head and neck squamous-cell carcinoma.”

—Krzysztof Skladowski, MD, PhD

with T2 head and neck squamous-cell carcinoma or to HPV-positive oropharyngeal cancer patients.”

Another study reported at the meeting showed that the addition of an epidermal growth factor receptor (EGFR) inhibitor to chemoradiation did not significantly improve locore-

therapy without chemotherapy has been considered an acceptable standard for patients with less advanced disease, said Dr Skladowski. However, the 2 strategies had not been compared directly in a randomized trial involving patients with less advanced forms of head and neck cancer.

Investigators at the Gliwice cancer center enrolled 101 patients with T2N1-2 to T4AN0-2 squamous-cell head and neck cancer. Patients received accelerated radiation therapy at a dose of 72 Gy delivered in 40 fractions over 40 days, or radiation therapy at a dose of 70 Gy in 35 fractions over 49 days plus cisplatin 100 mg/m2 on days 1, 22, and 43.

After a median follow-up of 30 months, the chemoradiation group had a 2-year survival of 81% versus 62% for the patients who received accelerated radiotherapy (P = .02). DFS was 75% with chemoradiation and 60% with accelerated radiation therapy (P = .05).

The patients treated with radiation therapy alone had a primary failure rate of 23% compared with 14% for the chemoradiation arm. The patients treated with accelerated radiation therapy also had higher rates of neck failure and distant metastasis.

Overall, HPV status was known in 46 patients. The 2-year survival in 11 patients with HPV-positive cancer was similar with either treatment. In 35 patients with HPV-negative cancer, 2-year survival was 80% with chemoContinued on page 11

Clinical Pathways

New Pathways, Targeted Therapies Being Explored...

HGF/c-MET Inhibitors The HGF/c-MET pathway has a significant role in promoting angiogenesis, proliferation, and metastasis in patients with HCC. Some c-MET inhibitors have shown early evidence of modest efficacy.

Compared with placebo, tivantinib, a selective, non–ATP-competitive inhibitor of c-MET, improved the time to

10

progression, particularly in patients with tumors with a high MET signa-

3.8 months with placebo. “If you enrich the right population, you may

“While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with safe, effective therapies.”

Photo by © ASCO/Todd Buchanan 2014

body that blocks cytotoxic T-lymphocyte–associated antigen 4, in patients with HCC associated with hepatitis C virus infection. It generated a modest response rate of 17% and a progression-free survival (PFS) of approximately 6 months in 17 evaluable patients. It also modulated hepatitis C viral load. The PD-1 inhibitor nivolu­ mab is also entering clinical trials.

—Andrew X. Zhu, MD, PhD

ture, in a phase 2 study. The median OS in patients with MET-high tumors was 7.2 months with tivantinib versus

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achieve the clinical benefit,” Dr Zhu told the audience.

Cabozantinib (Cometriq), an RTK

Continued from page 9

inhibitor of c-MET/VEGFR2, is also in phase 3 clinical trials for patients with HCC in whom sorafenib has failed or could not be tolerated. It demonstrated antitumor activity in a randomized discontinuation phase 2 study, with a median PFS of 4.2 months.

Cancer Stem Cells Novel approaches to targeting cancer stem cells (CSCs) are being explored in multiple cancers, including in advanced HCC. Hepatocarcinogenesis and the regulation of CSCs have both been shown to involve the Wnt pathway. OMP-54F28 targets CSCs, bulk tumor cells, and tumor stromal cells. A phase 1/2 study combining OMP-54F28 and sorafenib for the firstline treatment of advanced HCC is under way. n

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Head and Neck Cancer

Outpatient Chemoradiation Regimen Matches Inpatient Care Outcomes, at Lower...

Continued from the cover

overall analysis, but calculations based on a Medicare perspective yielded a $2600 loss per patient treated with the inpatient regimen. The estimated cost-savings for 2013 reached almost $900,000, reported John Greskovich, Jr, MD, Radiation Oncologist, Cleveland Clinic, OH. “Using a value-based framework, we determined that outpatient cisplatin delivered more value to our patients than inpatient cisplatin–5-FU [fluorouracil] chemotherapy, when combined with definitive radiation therapy for locally advanced head and neck cancer,” said Dr Greskovich.

at a glance ➤ An analysis of healthcare costs for 388 patients with head and neck cancer showed large cost differentials, with similar efficacy results ➤ The single-agent outpatient chemotherapy regimen led to disease control and survival that was equal to multiagent inpatient therapy ➤ However, the cost was almost $650,000 greater annually with the inpatient than the outpatient regimen ➤ In addition, a Medicare-based analysis yielded a $2600 loss per patient receiving the inpatient regimen ➤ The 2013 cost-savings with the outpatient regimen was almost $900,000 for this patient population

“Using a value-based framework, we determined that outpatient cisplatin delivered more value to our patients than inpatient cisplatin–5-FU chemotherapy, when combined with definitive radiation therapy for locally advanced head and neck cancer. The clinical outcomes were statistically the same.”

—John Greskovich, Jr, MD

“The clinical outcomes were statistically the same.”

“Financially, net income per patient was not materially different between the 2 arms, but the total cost of care was approximately $18,000 less per patient with the outpatient regimen.”

Study Details The results came from a randomized trial involving 69 patients with

grade 3 to grade 4 squamous-cell head and neck cancer. More than 80% of the patients had oropharyngeal cancer, and 75% tested positive for the human papillomavirus.

The investigators tested the hypothesis that inpatient administration of a 5-FU–cisplatin chemotherapy regimen in addition to radiation therapy would lead to an absolute 20% improvement in relapse-free survival compared with outpatient administration of cisplatin plus radiotherapy (ie, 55% vs 75%).

As reported at the 2013 American Society of Clinical Oncology annual meeting, both regimens exceeded expectations with respect to disease control. After a median follow-up of 29 months, relapse-free survival was 94% with the cisplatin regimen and 85% with the 5-FU–cisplatin regimen. Local control, regional control, distant control, and overall survival did not differ significantly between groups, but all of the end points favored the outpatient regimen.

Cost Analysis At the head and neck cancer symposium, Dr Greskovich presented data from an analysis of healthcare value comprising 388 patient encounters with 21 patients (11 inpatient, 10 outpatient).

The results showed that hospitalization (planned or unplanned) was the primary driver of costs, and that toxicity was the principal cause of hospitalization, as all but 1 hospitalization occurred during the treatment period.

The net income per patient was similar between the 2 treatment groups, but the inpatient regimen generated $19,338 higher net revenue per patient, most of which was offset by $18,664 higher per-patient cost.

Systemic Therapy Wins One, Loses One... radiation and 60% with accelerated radiation therapy.

Investigators in a multicenter Scandinavian trial found that adding the EGFR inhibitor zalutumumab to chemoradiation did not improve 3-year locoregional control compared with chemoradiation therapy by itself. OS and disease-specific survival also did not differ significantly between the groups, but were nu­ merically higher in the chemoradiation group.

“If anything, there was a slight ten-

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dency for the zalutumumab group to do not as well as the control arm,” said Jens Overgaard, MD, DMSc, Professor of Clinical Medicine and of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.

Investigators in Denmark and Norway enrolled 619 patients with squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx.

All patients received accelerated radiation therapy (66-68 Gy, 2 Gy/fraction, over 6 weeks) plus the radiosensitizer nimorazole. All patients (89%)

Different Toxicity Profiles Not surprising, the 2 chemotherapy regimens had different toxicity profiles. The outpatient cisplatin regimen was associated with more nephrotoxicity (26% vs 3%; P = .007) and ototoxicity (11% vs 0%; P = .042). The inpatient 5-FU–cisplatin combination was associated with more grade 2+ radiation toxicity (68% vs 43%; P = .038), neutropenia (65% vs 34%; P = .012), and unplanned hospitalization (68% vs 43%; P = .038).

“Financially, net income per patient was not materially different between the 2 arms, but the total cost of care was approximately $18,000 less per patient with the outpatient regimen.”

—John Greskovich, Jr, MD

Medicare Perspective Dr Greskovich and colleagues then analyzed revenue, cost, and income from a Medicare reimbursement perspective. The cost per patient remained $18,664 for the inpatient regimen, but the revenue per patient decreased to $16,035, resulting in a loss of $2629 per patient. After factoring in an estimated cost shift of $624 per patient in the outpatient group, the inpatient regimen resulted in a net loss per patient.

The use of the outpatient regimen resulted in a cost-savings of $643,838 from 2011 to 2012. The estimated savings for 2013 was $884,000. n

Continued from page 10

“We found no patient subgroup that seemed to do better with zalutumumab, including HPV status.”

—Jens Overgaard, MD, DMSc

with stage III to IV disease also received concurrent weekly cisplatin 40 mg/m2. The patients were random-

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ized to receive zalutumumab or no additional therapy.

The primary end point was locoregional control. After a median follow-up of 36 months, the 3-year locoregional control rates were 77% in the control arm and 76% in the zalu­ tumumab group. Disease-specific survival (85% vs 82%) and OS (79% vs 72%) also favored the control arm.

“We found no patient subgroup that seemed to do better with zalutumu­ mab, including HPV status,” said Dr Overgaard. n

www.ValueBasedCancerCare.com

11

FOR YOUR ONCOLOGY PRACTICE NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer recommendations for abiraterone acetate (ZYTIGA®) plus prednisone1: Category 1* Asymptomatic pre-docetaxel mCRPC Symptomatic post-docetaxel mCRPC

FOR PATIENTS WITH mCRPC WHO HAVE PROGRESSED ON ADT† LOCAL‡

THERAPY

ADT

§

ZYTIGA PLUS PREDNISONE

®

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

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women.

ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia,

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ZYTIGA Next ®

5.2 5 .

2 Months 5.2-month difference in median overall survival vs placebo plus prednisone (median OS: 35.3 months vs 30.1 months, respectively)

57% reduction in risk of radiographic progression or death vs placebo plus prednisone (median rPFS not reached vs 8.28 months, respectively)

Significantly increased median time to initiation of chemotherapy vs placebo plus prednisone (25.2 months vs 16.8 months, respectively)¶

Significantly increased median time to opiate use for prostate cancer pain vs placebo plus prednisone (not reached vs 23.7 months, respectively)¶

Hazard ratio (HR) = 0.792; 95% CI: 0.655, 0.956; P = 0.0151; prespecified value for statistical significance not reached.

HR = 0.425; 95% CI: 0.347, 0.522; P < 0.0001.

HR = 0.580; 95% CI: 0.487, 0.691; P < 0.0001.

HR = 0.686; 95% CI: 0.566, 0.833; P = 0.0001.

*Evidence and consensus level rating. †Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a Phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N = 1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH)

agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. ‡Local therapy = radiation and/or surgery. § For many patients with mCRPC, gonadotropin-releasing hormone (GnRH)agonist therapy typically continues throughout the disease course, and is used concomitantly with other mCRPC treatments, including ZYTIGA®. This illustration is not intended to suggest that ZYTIGA® is the only treatment option following androgen-deprivation therapy (ADT).

Primary endpoint. ¶ Secondary endpoint.

Reference: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed August 2, 2013. For the detailed recommendations, view the most recent and complete version of the Guideline on NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 003307-130924

hypercholesterolemia,hyperglycemia,elevatedAST,hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the coadministration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8.

Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Please see brief summary of full Prescribing Information on adjacent pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 10/13 003686-131001

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency.

Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

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 clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot flush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) All Grades1 Grade 3-4 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

0

7.6

0

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

0

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal

discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema all fractures with the exception of pathological fracture terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

4 Includes 5 Includes 6 Includes

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) All Grades Grade 3-4 Laboratory Abnormality (%) (%) Hypertriglyceridemia 62.5 0.4 High AST 30.6 2.1 Hypokalemia 28.3 5.3 Hypophosphatemia 23.8 7.2 High ALT 11.1 1.4 High Total Bilirubin 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N = 542) Placebo (N = 540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo.

There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms.

There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves.

Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: September 2013 003185-130920

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Genetic Test for Breast Cancer Screening Cost-Effective for Women at...

Continued from the cover

“For questions of screening in particular, there is often a lack of hard clinical trial data on the benefits and costs of screening due to the high costs and long-time horizons needed for such studies,” Henry J. Folse, PhD, scientist at Evidera (previously Archimedes), told Value-Based Cancer Care.

Folse and colleagues used the Archimedes simulation model of breast cancer risk factors, disease progression, and healthcare processes to estimate the cost-effectiveness of using genetic testing to assess the risk for breast cancer in women at risk and to identify those who would benefit from MRI screening.

“Models such as the Archimedes Model serve a valuable role in that they integrate a large amount of data from many different sources, including clinical trials and observational studies, to make specific predictions

at a glance ➤ Using the 7SNPs with the Gail test improves the cost-benefit assessment of annual MRI in women at risk for breast cancer ➤ For women with a lifetime breast cancer risk of ≥10%, adding the 7SNP test resulted in a 2.7% reduction in cancer deaths versus the Gail test alone ➤ The 7SNP test saved 0.005 QALYs per person, at a cost of $163,264 per QALY

that can help guideline authors make decisions based on the best available evidence,” Dr Folse said.

This model enables researchers and decision makers to make better informed decisions that could influence clinical and economic outcomes.

“By identifying patients who are actually at high risk of cancer, but who were not identified by the commonly used Gail risk test, we can prevent additional cancer deaths compared with using the Gail test alone.”

—Henry J. Folse, PhD

The Gail risk model, which is widely used by the National Cancer Institute, estimates a patient’s breast cancer risk using age, race, family history, age at menarche, first live birth, and number

of biopsies. The 7SNP genetic test uses the genotype of the patient to refine the estimate of the Gail test.

“Our study shows that by identifying patients who are actually at high risk of cancer, but who were not identified by the commonly used Gail risk test, we can prevent additional cancer deaths compared with using the Gail test alone,” Dr Folse said. “Specifically, for patients with a lifetime risk of at least 10%, the model showed that the 7SNP test results in a 2.7% reduction in cancer death relative to the Gail test alone.”

Study Details Data from the Surveillance, Epi­ demiology, and End Results database were used for the cancer incidence.

Average-risk patients (<20% risk) had an annual mammogram, and high-risk patients (>20% risk) had an annual MRI. The primary outputs of the Archimedes Model were total breast cancer deaths, total (discounted) costs, and total (discounted) quality-adjusted life-years (QALYs). The cohort consisted of 100,000 non-Hispanic white women (aged ≥40 years), with no history of cancer and a lifetime Gail risk of breast cancer of at least 10%.

Cost-Effective and Quality-of-Life Benefits For patients with a lifetime breast cancer risk of at least 10%, adding the 7SNP test resulted in a 2.7% reduction in cancer deaths compared with the Gail test alone. “Furthermore, we identified a subpopulation at an intermediate risk (16%-28%) as optimally cost-effective [for MRI]. For

this group, the cost per QALY was $163,264, as estimated by our model,” said Dr Folse. That is, the 7SNP test saved 0.005 QALYs per person, at a cost of $163,264 per QALY.

“We identified a subpopulation at an intermediate risk (16%-28%) as optimally cost-effective [for MRI]. For this group, the cost per QALY was $163,264.”

—Henry J. Folse, PhD

The cost-effectiveness of the 7SNP test for patients with intermediate Gail risk is similar to that of other recommended strategies, including the American Cancer Society guidelines that recommend annual MRI screening for patients with a lifetime risk greater than 20% or with BRCA1/BRCA2 mutations, for which the model estimated a cost of $141,415 per QALY, relative to a mammogram. The results were sensitive to the age of the patient at which the test was administered, the discount rate, and the expenditures of the genetic test and MRI, which can vary considerably.

Based on these findings, the 7SNP genetic test for breast cancer is most cost-effective when used to guide MRI screenings in patients at intermediate risk for breast cancer. n

Switching from Intravenous to Subcutaneous Rituximab Saves Staff Time and Money

By Wayne Kuznar

New Orleans, LA—The efficiency of rituximab (Rituxan) and the associated cost can be improved by switching from intravenous (IV) to subcutaneous (SC) administration. Such a switch led to a substantial reduction in patient chair time and in active healthcare professional time, said Christof Wiesner, PhD, MPH, of the Market Access Department, Genentech, San Francisco, CA, at the ASH 2013 meeting.

Rituximab is the standard treatment for indolent non-Hodgkin lymphoma

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“We found time-savings from the patient’s perspective in the range of 50% to 80%, which is pretty impressive, but we also have savings in the active healthcare professional time…in the range of 40% going up to 50%.”

—Christof Wiesner, PhD, MPH

and is currently administered by IV infusion. Results from studies of follic-

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ular lymphoma showed that a fixeddose SC formulation of rituximab

shortened administration time, without compromising the drug’s efficacy or safety.

Dr Wiesner and colleagues conducted a multinational, prospective, observational study to assess the possible resource benefits of switching from IV rituximab to SC administration. The data for rituximab SC injections were collected alongside a phase 3b trial, whereas the data for IV rituximab infusions were collected in a real-world setting in 23 international centers.

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Economics of Cancer Care

ACA Heralds Modest Increase in Healthcare Utilization for Testicular Seminoma

By Alice Goodman

evidence to suggest that when these people become insured, there will only be a modest increase in treatment considered discretionary” (ie, adjuvant therapy for stage IA/B seminoma).

The NCCN’s guidelines recommend active surveillance for stage IA/B seminoma. “The older approach was chemotherapy-lite or radiation and orchiectomy for 1 testicle. With that

“Under the ACA, insurance coverage will expand for the uninsured category, and they will become more like the Medicaid population. We found evidence to suggest that when these people become insured, there will only be a modest increase in treatment considered discretionary.”

—Jonathan J. Paly, MD

approach, patients may feel more reassured than with active surveillance, and once insurance is available, they could opt for that,” Dr Paly explained.

The National Cancer Data Base was used to identify Medicaid or underin-

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➤ This new study suggests that under the ACA, only a moderate increase in adjuvant therapy for patients with stage IA/B seminoma is expected ➤ These findings may have implications for other patient populations under the ACA ➤ No increase in the use of the NCCN-recommended adjuvant therapy is expected for patients with stage II disease ➤ Underinsured patients with stage IA/B disease were 14% less likely than Medicaid patients to receive adjuvant therapy or chemotherapy ➤ Hispanic patients aged ≥50 years (and diagnosed in 20062010) who were treated in lowvolume facilities or had tumors <4 cm were less likely to receive adjuvant therapy ➤ Patients with stage IA/B seminoma should be counseled on the benefits of postorchiectomy surveillance for early-stage disease that they will follow national recommendations,” Dr Paly stated. n

CDC report: rates of new lung cancer cases are dropping (See article, page 8)

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nance sessions), the estimated reduction in total healthcare professional time associated with the switch from IV to SC rituximab ranged from 1.2 hours in Austria to 5.1 hours in the United Kingdom.

The estimated chair time saved per patient for the first year of treatment ranged from a low of 31 minutes to a high of 60 minutes.

The estimated healthcare professional cost-savings per patient in the first year of treatment ranged from 25% in Spain to 52% in Russia. The healthcare professional opportunity cost-savings were driven mainly by a reduction in pharmacy staff time in Spain and in the United Kingdom, and by a reduction in physician and nurse time in other countries. n

90

2.6% annually

78

cases per 100,000

80

54

70 60

1.1% annually

cases per 100,000

➞

“We found time-savings from the patient’s perspective in the range of 50% to 80%, which is pretty impressive, but we also have savings in the active healthcare professional time…pharmacists and nurses, in the range of 40% going up to 50%,” said Dr Wiesner.

The difference in the mean active healthcare professional time saved by switching from IV rituximab to SC ri­ tuximab ranged from 7.3 minutes (Austria) to 30.9 minutes (United Kingdom). The proportionate reduction in mean healthcare professional time ranged from 28% (Spain) to 59% (Russia).

The mean time saved in the treatment room ranged from 28% to 59%.

Over the course of the first year of treatment (8 induction and 3 mainte-

at a glance

➞

Switching from...

sured patients diagnosed with seminoma between 1998 and 2010. Of 41,745 patients with seminoma, 5895 (14%) fell into these categories. Compared with Medicaid patients, uninsured patients were more likely to be younger (aged <29 years), Hispanic, live in the South, treated in community hospitals, reside in areas with higher education levels, and present with stage IA/B disease (66.5% vs 59.4%, respectively; P <.01).

A multivariate analysis adjusted for sociodemographic and clinical characteristics showed that underinsured patients with stage IA/B disease were 14% less likely than Medicaid patients to receive adjuvant therapy or chemotherapy. “People who are uninsured are more in line with the NCCN recommendations than those insured by Medicaid,” Dr Paly said.

In addition, patients with stage IA/B seminoma who were Hispanic, aged ≥50 years, diagnosed between 2006 and 2010, treated in low-volume facilities, or had tumors <4 cm were less likely than their counterparts to receive adjuvant therapy. No treatment differences by insurance were observed in patients with stage IIA/B disease.

“These findings suggest that it will be extremely important to counsel patients with stage IA/B seminoma about the benefits for postorchiectomy surveillance for early-stage disease, so

New lung cancer cases per 100,000

San Francisco, CA—Concerns that healthcare utilization will increase dramatically once more patients are insured under the Affordable Care Act (ACA) may be overblown, based on results of a large study of Medicaid and underinsured patients with seminoma, the most common type of tes­ ticular cancer.

The study, which was reported at the 2014 Genitourinary Cancers Symposium, suggests that there will only be a moderate increase in adjuvant therapy for patients with stage IA/B seminoma, an approach that is considered discretionary, and no increase in the use of the National Comprehensive Cancer Network (NCCN)-recommended adjuvant therapy for patients with stage II disease.

These results, the investigators suggest, may have implications for other patients under the ACA. “Once the ACA is in use, the question is whether cancer treatment utilization will skyrocket or will stay the same and follow NCCN guidelines. Our study sought to provide some insight into this question,” said lead investigator Jonathan J. Paly, MD, Department of Radiation Oncology, Massachusetts General Hospital, Boston.

“Under the ACA, insurance coverage will expand for the uninsured category, and they will become more like the Medicaid population. We found

50 40

n Men n Women 0 2005

2006

2007

2008

2009

Year Sources: CDC’s National Program of Cancer Registries; National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

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Breast Cancer

Large Study Supports Early Oophorectomy for BRCA Mutation...

Continued from the cover

common BRCA1 mutation. Furthermore, the study results suggest that prophylactic oophorectomy should be done by age 35 years in all BRCA1 carriers, because waiting for a later age increases the risk for cancer.

“To me, waiting to have oophorectomy until age 35 is too much of a chance to take. These data are so striking that we believe prophylactic oophorectomy by age 35 should become a universal standard for women with BRCA1 mutations,” said study coinvestigator Steven A. Narod, MD, Professor of Epidemiology, University of Toronto, Ontario, Canada, in a statement commenting on the study.

“Women with BRCA2 mutations, on the other hand, can safely delay oophorectomy until their 40s, since their ovarian cancer risk is not as strong,” Dr Narod added.

Current recommendations state that women with a BRCA mutation should consider prophylactic oophorectomy between the ages of 35 and 40 years.

The study results, as Dr Narod noted, were “striking.” Among women who were cancer free at baseline, preventive oophorectomy reduced the risk for death from any cause by 77%. Dr Narod noted that noncancer deaths would be rare in the study cohort, with an average age of 46 years at study enrollment. Over time, it is possible that the reduction in all-cause mortality associated with oophorectomy would be attenuated, because other causes of age-related death occur.

at a glance ➤ Women with BRCA1 or BRCA2 mutations have an 80% risk reduction for ovarian, fallopian tube, or breast cancer if they underwent preventive oophorectomy ➤ Prophylactic oophorectomy also reduces the all-cause mortality risk by 77% ➤ This procedure should be performed by age 35 years in all BRCA1 carriers to decrease their risk for cancer ➤ Women with BRCA2 mutations can delay oophorectomy until their 40s

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Study Details This prospective study was based on a cohort of 5783 women who were carriers of the BRCA1 or BRCA2 mutation; of these, 2270 did not undergo oophorectomy and had intact ovaries,

“These data are so striking that we believe prophylactic oophorectomy by age 35 should become a universal standard for women with BRCA1 mutations. Women with BRCA2 mutations, on the other hand, can safely delay oophorectomy until their 40s, since their ovarian cancer risk is not as strong.”

—Steven A. Narod, MD

2123 had undergone oophorectomy at baseline, and 1390 had the surgery after study enrollment. All women were identified from an international registry and completed a baseline questionnaire plus at least 1 follow-up questionnaire.

The mean age at enrollment was 46 years (range, 40.2 years for the no oophorectomy group and 50.5 years for those who had oophorectomy at baseline). Overall, 77.4% of the women were BRCA1 carriers, and 22.6% were BRCA2 carriers. Women who carried both mutations were excluded from the study.

At a mean follow-up of 5.6 years, 132 women developed ovarian cancer, 22 developed fallopian tube cancer, and 32 developed peritoneal (ie, breast) cancer; a total of 68 of these women died.

Among the women with intact ova-

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See also VBCC Perspective, page 20

ries, 98 cancers were diagnosed in BRCA1 mutation carriers and 10 cancers in BRCA2 mutation carriers. These cancers occurred approximately a decade earlier in BRCA1 mutation carriers, with the highest incidence between the ages of 50 and 59 years; for BRCA2 mutation carriers, the highest incidence was observed between the ages of 60 and 69 years.

At oophorectomy, 46 occult cancers were identified through pathology examinations: 27 ovarian cancers, 18 fallopian tube cancers, and 1 breast cancer. Of 44 cancers found in BRCA1 mutation carriers, 3 were in women aged ≤40 years, and an additional 19 cancers were diagnosed between the ages of 40 and 49 years.

The 2 BRCA2-related cancers identified at oophorectomy were in women aged >60 years.

The remaining 32 cases were primary peritoneal cancers (28 in BRCA1 carriers and 4 in BRCA2 carriers); in these women, the mean age at diagnosis was 51.6 years (range, 36-69 years).

The 5-year survival rate was higher in women with occult ovarian cancer compared with those who had clinically detected ovarian cancer (91.6% vs 54.4%, respectively; P <.01). The 5-year survival rate for women with peritoneal cancer was 38.4%.

An adjusted analysis was performed to estimate the extent to which prophylactic oophorectomy reduced the risk for ovarian, fallopian tube, or peritoneal cancers in BRCA1 and BRCA2 carriers combined. The adjusted hazard ratio associated with oophorectomy was 0.20 (95% confidence interval, 0.13-0.30; P <.001).

Dissenting Opinion “These data do not warrant changing the current recommendations regarding surgery for women who are BRCA1 and BRCA2 mutation carriers,” stated Noah D. Kauff, MD, Director, Ovarian Cancer Screening and Prevention Program, Memorial Sloan-Kettering Cancer Center, New York. “The study confirms prior data we have regarding the risk of ovarian cancer in women who are mutation carriers,” Dr Kauff said.

He pointed out that the actual rate of ovarian cancer in the study before age 40 years in women with BRCA1 mutations was 2.3%, as opposed to the 4% rate the investigators quoted in the Discussion section of the article.

“In women with intact ovaries, 8 of 979 women [0.8%] developed ovarian cancer by age 40; in an additional 202 women who had prophylactic oophorectomy prior to age 40, 3 had occult ovarian cancer [1.5%]. The 4% figure calculated by the authors was based on an assumption that the rate of ovarian cancer is constant from age 30-40, but that is not correct. The risk goes up after age 35,” Dr Kauff explained.

“These data do not warrant changing the current recommendations regarding surgery for women who are BRCA1 and BRCA2 mutation carriers.”

—Noah D. Kauff, MD

In his opinion, the evidence to date, including this study, supports current recommendations. The American Congress of Obstetricians and Gynecologists recommends that BRCA carriers have oophorectomy by age 40 years, or when childbearing is completed; the National Comprehensive Cancer Network guidelines recommend oophorectomy between the ages of 35 and 40 years, and when childbearing is completed.

“Oophorectomy 5 years earlier can be traumatic, especially in the US, where women are marrying later and often deferring childbearing until the late 30s. It is not clear to me that this study provides sufficient evidence to change current recommendations,” he said.

“Discussions with women who are BRCA1 or BRCA2 carriers should balance the risks versus benefits of preventive oophorectomy on cancer risks with its substantial costs on fertility, timing of menopause, and other symptoms that can markedly impact quality of life,” Dr Kauff said. n Genetic Testing for Breast Cancer Approximately 5% to 10% of all breast cancers are hereditary, although many women have a family history of this disease. The risk is 2- to 3-fold greater in women with a first-degree relative who has had breast cancer. Those women should consider genetic testing.

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VBCC Perspective: Breast Cancer

Considering Prophylactic Salpingo-Oophorectomy in Women with BRCA Mutations

By Allison W. Kurian, MD, MSc, and Jonathan S. Berek, MD, MMS

T

he study “Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation” that was recently published in the Journal of Clinical Oncology (Finch AP, et al. 2014 February 24 [Epub ahead of print]) provides an update of previous work by the same investigators on a similar population (see article, page 1).

For several years now we have known that removing the ovaries and the fallopian tubes (prophylactic bilateral salpingo-oophorectomy [BSO]) substantially reduces a woman’s risk for developing ovarian or fallopian cancers, as well as for breast cancer, if

the surgery is done before menopause.

Earlier studies (including several by the authors of the current study) have proved that BSO saves lives among high-risk women, particularly those with an inherited mutation in the BRCA1 or BRCA2 (BRCA1/2) cancer susceptibility genes. This study, therefore, builds on a robust body of existing work.

The novel aspects of this study are the size of the benefit from BSO, and the age-specific ovarian cancer risk estimates for BRCA1/2 mutation carriers.

The 77% to 80% estimated improvement in survival as a result of BSO is dramatic, and larger than reported in

Dr Kurian is Assistant Professor, Medicine (Oncology) and Health Research and Policy, Stanford University School of Medicine, and Associate Director, Stanford Program in Clinical Cancer Genetics, Stanford Women’s Cancer Center, CA. Dr Berek is Laurie Kraus Lacob Professor, Director, Stanford Women’s Cancer Center, Stanford Cancer Institute, and Chair, Department of Obstetrics and Gynecology, Stanford University School of Medicine, CA.

previous studies. The investigators also estimate that a BRCA1 mutation carrier has approximately a 4% probability of developing ovarian cancer between ages 35 and 40 years, and approximately a 14% probability of developing ovarian cancer between ages 35 and 50 years.

For BRCA2 mutation carriers, these risks are smaller and occur later. The authors conclude that for BRCA1 mutation carriers, BSO should be performed at age 35 years rather than waiting until age 40 years.

How should patients and their physicians interpret this new information?

Rather than representing a substantial change in our knowledge, this study

risk reduction is very personal. We recommend that women who may have a high inherited risk of breast and/or ovarian cancer seek expert advice from a cancer-genetics professional.

Resources The Stanford Women’s Cancer Center offers this service by way of the Stanford Women’s Cancer Genetics Clinic (appointments can be scheduled by calling 650-498-6004; further information is available at http://cancer. stanford.edu/cancergenetics/). Additional resources include the National Comprehensive Cancer Network (www.nccn.org), which provides evidence-based practice guidelines for

For each woman, the decision to undergo prophylactic surgery for cancer risk reduction is very personal. We recommend that women who may have a high inherited risk of breast and/or ovarian cancer seek expert advice from a cancer-genetics professional. confirms and expands on what we already know—that high-risk women with BRCA1/2 mutations should undergo BSO by age 40 years, and that BRCA1 mutation carriers may wish to consider earlier BSO, depending on their childbearing plans, family history, and other health issues.

For each woman, the decision to undergo prophylactic surgery for cancer

the care of patients with BRCA1/2 mutations; FORCE (www.facingourrisk. org), an online support group for BRCA1/2 mutation carriers; and an online decision tool developed by Stanford investigators (http://brca tool.stanford.edu), which allows women with BRCA1/2 mutations to compare different options for managing their cancer-related risks. n

Promising New Therapies in the Breast Cancer Pipeline

By Phoebe Starr

San Antonio, TX—Many new drugs are currently in development for the treatment of patients with breast cancer. The following is a selection of drugs featured at the 2013 San Antonio Breast Cancer Symposium.

Veliparib, a poly (ADP-ribose) polymerase inhibitor, showed promise in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 trial for the neoadjuvant treatment of patients with triple-negative breast cancer in combination with carboplatin (Paraplatin). This combination will move to phase 3 testing in patients with triple-negative breast cancer. Ve-

20

liparib is also being studied in patients with advanced breast cancer, cervical cancer, and ovarian cancer.

Ridaforolimus, an mTOR inhibitor, is a nonprodrug analog of rapamycin, and dalotuzumab is a monoclonal antibody targeted to insulin-like growth factor 1. These 2 drugs are being studied as a new combination therapy; the scientific rationale for the combination of ridaforolimus and dalotuzumab is upstream and downstream inhibition of molecular targets on the PIK3 pathway. In a phase 2 trial of ridaforolimus plus dalotuzumab in patients with metastatic estrogen receptor–positive breast cancer that progressed with pre-

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vious treatments, the median progression-free survival (PFS) was similar to that of exemestane (Aromasin), but no survival advantage was shown for the combination. The trial was stopped because of the toxicity level at the doses used, but the investigators concluded that further study is warranted.

Lower doses of ridaforolimus will be studied in a new phase 2 clinical trial for high-proliferation estrogen receptor–positive breast cancer that is progressing with previous hormonal therapies. The study will compare the combination of ridaforolimus plus dalotuzumab with ridaforolimus, dalotuzumab, and exemestane alone

in this patient population.

Ganetespib, a heat shock protein 90 (hsp90) inhibitor, is now in phase 2 clinical trials as frontline therapy for women with metastatic HER2-positive or triple-negative breast cancer in the ENCHANT-1 trial. Hsp90 inhibitors block multiple oncogenic pathways that play key roles in various breast cancer subtypes. ENCHANT-1 showed that treatment with ganetes­ pib was well tolerated, with an acceptable safety profile; diarrhea is the most common side effect. Ganetespib demonstrated promising antitumor activity in the HER2-positive and triple-negative breast cancer subgroups of paContinued on page 21

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Prostate Cancer

Previous Docetaxel Therapy Thwarts Enzalutamide Activity in CRPC Optimal sequencing of these therapies identified

By Charles Bankhead San Francisco, CA—Men with castration-resistant prostate cancer (CRPC) had inferior time duration to prostate-specific antigen (PSA) progression and of progression-free survival (PFS) if they received the androgen receptor agonist enzalutamide (Xtandi) after the taxane docetaxel (Taxotere) rather than before, according to data from a retrospective study presented at the 2014 Genitourinary Cancers Symposium.

The odds for time to PSA progression and of PFS were reduced by 60% when patients received the taxane before the androgen receptor antagonist compared with receiving enzalutamide before docetaxel.

These findings inform a key issue in the era of expanded treatment options for CRPC—the optimal sequencing of specific agents.

“The effect of enzalutamide predocetaxel on time to PSA progression and progression-free survival was maintained after adjusting for baseline prognostic factors,” according to a poster presented by Rosa Nadal, MD, Urologic Oncology Fellow, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, and colleagues. “The lower activity of enzalutamide observed postdocetaxel might be due to taxane-induced androgen receptor signaling changes, supporting the hypothesis of cross-resistance between enzalut-

amide and docetaxel.”

Enzalutamide is approved by the US Food and Drug Administration for the treatment of patients with CRPC that has proved refractory to docetaxel.

However, these agents’ overlapping mechanisms of action and evidence of interaction have raised questions about the most appropriate sequence for the use of these 2 drugs.

“The effect of enzalutamide pre-docetaxel on time to PSA progression and progressionfree survival was maintained after adjusting for baseline prognostic factors. The lower activity of enzalutamide observed post-docetaxel might be due to taxaneinduced androgen receptor signaling changes.”

—Rosa Nadal, MD, and colleagues

Study Details To examine the effect of sequence on antitumor activity, Dr Nadal and colleagues identified 90 patients with CRPC who were treated with enzalut-

amide—33 patients had no previous exposure to docetaxel and 57 had received the taxane before initiating treatment with enzalutamide. In addition, 81% of the patients had been treated with abiraterone (Zytiga), and 35.5% with ketoconazole.

PSA response was defined as a ≥50% decline from baseline, and PSA progression as a ≥25% increase from baseline. Time to PSA progression was defined as the interval from the initiation of treatment with enzalutamide to the first documentation of PSA progression. The investigators defined PFS as the time from the initiation of enzalutamide to the first documentation of PSA progression or death from any cause.

Analysis of prognostic factors associated with time to PSA progression identified baseline alkaline phosphatase, baseline albumin, baseline hemoglobin, no previous hormonal therapy, extent of disease, and previous docetaxel treatment as having significant associations. The same 6 factors were significantly associated with PFS. By multivariate analysis, previous docetaxel exposure remained significantly and inversely associated with time to PSA progression and PFS duration. Comparison of patients with and without previous docetaxel treatment resulted in hazard ratios of 0.39 for time to PSA progression (P = .021),

at a glance ➤ The sequence of drug use can have a significant impact on disease progression in patients with CRPC ➤ Using enzalutamide before rather than after docetaxel improves time to PSA progression and PFS duration in this patient population ➤ The lower activity of enzalutamide after docetaxel may relate to taxane-induced androgen receptor signaling changes ➤ The study findings support the hypothesis of cross-resistance between enzalutamide and docetaxel and 0.41 for PFS (P = .047).

The median follow-up from the initiation of enzalutamide was 6.8 months. The stratification of clinical outcomes by previous docetaxel exposure showed that patients who received enzalutamide before docetaxel had a higher PSA response rate (41.9% vs 25.5%), greater median time to PSA progression (9.0 vs 2.5 months; P <.001), and longer PFS duration (not reached vs 3.2 months; P = .006). n

Breast Cancer

Promising New Therapies... tients, with durable responses. En­ rollment is continuing in the phase 2 trial. Future strategies that will be studied include combinations with other treatments in early- and advanced-stage breast cancer, and biomarker studies will be conducted to try to determine which patients would benefit from this treatment.

Palbociclib, an oral selective cyclin-dependent kinase 4/6 inhibitor, passed the phase 2 clinical trials hurdle and has been designated a breakthrough therapy by the US Food and Drug Administration (FDA). In the phase 2 trial, palbociclib plus letrozole (Femara) improved PFS versus letrozole alone in advanced or metastatic

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estrogen receptor–positive, HER2-positive breast cancer: the median PFS was 26.1 months versus 7.5 months with letrozole alone.

Palbociclib is now in phase 3 clinical trials in the PENELOPEB trial as adjuvant therapy for patients with hormone receptor–positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy. After neoadjuvant chemotherapy and surgery, with or without radiation therapy, approximately 800 patients will be randomized to once-daily oral palbociclib versus placebo for 13 cycles. Patients will receive concomitant endocrine therapy according to local standards. The patients will be followed until progres-

sion, secondary malignancy, unacceptable toxicity, or withdrawal of consent.

Ramucirumab, a novel monoclonal angiogenesis inhibitor targeted to vascular endothelial growth factor receptor 2, failed to meet its primary end point of PFS in the Ramucirumab Overall Survival Evaluation/Translational Research in Oncology-12 trial when added to docetaxel (Taxotere) in patients with metastatic breast cancer.

These findings are disappointing and may put another nail in the coffin of antiangiogenic agents for breast cancer; however, investigators say that they will search for a biomarker to identify subgroups of patients who could benefit from this strategy. Ra-

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mucirumab is moving ahead as second-line therapy for gastric cancer, and the FDA has granted ramuciru­ mab priority review in this setting.

Entinostat, a novel oral small-molecule inhibitor of benzamide histone deacetylase, was shown to extend PFS when added to exemestane versus exemestane alone in postmenopausal women with advanced estrogen receptor–positive breast cancer that is progressing with a nonsteroidal aromatase inhibitor in the phase 2 ENCORE 301 study. The median PFS was 4.28 months for the combination versus 2.27 months for exemestane alone. Entinostat is now being evaluated in phase 3 clinical trials. n

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Prostate Cancer

QOL Improved with 18 versus 36 Months of Hormonal Therapy in Patients with High-Risk Prostate Cancer, Confirming Earlier Efficacy Evidence San Francisco, CA—Longer-term follow-up of a large randomized phase 3 trial suggests that quality of life (QOL) is improved when patients with highrisk prostate cancer have a shorter versus longer course of androgendeprivation therapy (ADT) plus radiotherapy as primary treatment. In this follow-up study, 18 months of ADT were found to improve QOL versus 36 months of ADT when added to radiotherapy.

These results build on the efficacy results presented in 2013 showing identical 5- and 10-year disease-specific survival in patients with high-risk prostate cancer who received 18 months of ADT versus 36 months of ADT. In addition, the rates of overall survival and biochemical failure at 5 and 10 years were similar between the 2 groups.

When the efficacy results were presented last year, they generated much discussion among experts, who suggested that shorter courses are more desirable, but more definitive evidence was needed before changing the stan-

Photo © ASCO/Todd Buchanan 2014

By Alice Goodman

These QOL differences, together with the survival evidence, favor reducing the duration of ADT to 18 months in men with high-risk prostate cancer also treated with radiotherapy.

—Abdenour Nabid, MD dard from 2 or 3 years down to 18 months. Patients should be educated about their options and should be given the supportive evidence, they noted. Given the high rate of adverse events associated with ADT, reducing the duration of treatment down from the 24- to 36-month range is attractive, but the optimal threshold needs more definite evidence, they said.

At the 2014 Genitourinary Cancers Symposium, Abdenour Nabid, MD, of the Centre Hospitalier Universitaire de Sherbrooke, Québec, Canada, presented QOL data from the prospective follow-up study. This analysis included 630 men with high-risk prostate cancer who were randomized in a 1:1 ratio to 18 months versus 36 months of ADT. The median follow-up was 79 months.

Approximately 73% of patients completed QOL questionnaires. Domains that significantly favored shorter duration of ADT (P <.01 for all vs 36 months) were found in 6 of 21 scales (physical, emotional, and social functioning; fatigue; hormonal treatment– related symptoms; and sexual activity), as well as 14 of 55 items (including trouble with long walks, stay in bed during the day, weakness, tenseness, irritability, depressed, close to a toilet, blood in stools, hot flushes, enlarged breasts, interest in sex, sexually active, and enjoyable sex).

Dr Nabid said that these QOL differences, together with the improved sur-

at a glance ➤ QOL is improved when patients with high-risk prostate cancer receive ADT plus radiotherapy for 18 months instead of 36 months ➤ Given the high rate of adverse events associated with ADT, reducing the duration of treatment is beneficial ➤ In addition to the previous efficacy data that showed identical survival results with 18 and 36 months of therapy, these new QOL data may be sufficient to suggest 18 months of ADT as the new standard vival evidence, favor reducing the duration of ADT to 18 months in men with high-risk prostate cancer who are also receiving radiotherapy. He is convinced, he noted, by this study that 18 months is appropriate. n

Encouraging Long-Term Safety Data for Radium-223

By Phoebe Starr

San Francisco, CA—The safety and efficacy of radium Ra 223 dichloride (Xofigo, formerly Alpharadin) injection in men with castration-resistant prostate cancer (CRPC) and bone meta­stases have held up over the longerterm follow-up of the phase 3 Alpha­ radin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Results of a study reported at the 2014 Genitourinary Cancers Symposium showed that at 1.5 years after the last injection of this therapy, minimal myelosuppression and minimal nonhematologic adverse events were reported, and there were no reports of cancers of concern, including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and primary bone cancer.

Lead investigator of the safety report, Sten Nilsson, MD, PhD, of the Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden, said these data support further evaluation of radium-223 in combination with other agents in this setting.

22

Last year, the US Food and Drug Administration approved radium-223 for the treatment of patients with CRPC and bone metastases based on the results of ALSYMPCA, showing that the drug significantly improved overall survival by 3.6 months compared with placebo (P <.001), with good tolerability.

The data support further evaluation of radium-223 in combination with other agents in this setting.

—Sten Nilsson, MD, PhD

ALSYMPCA enrolled 921 patients with CRPC and at least 2 symptomatic bone metastases. Patients with visceral metastases were excluded. Patients had received docetaxel or were not candidates for treatment with

Value-Based Cancer Care

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march 2014

docetaxel, and were randomized in a 2:1 ratio to radium-223 (6 injections at 4-week intervals) or to placebo.

Of the 921 patients included, 574 entered 3-year follow-up (radium-223, N = 406; placebo, N = 168). Withdrawals from the 3-year follow-up included 322 (79%) patients in the radium-223 group and 144 (86%) patients in the placebo group. Death was the most common reason for withdrawal.

The median duration of follow-up was 10.4 months for radium-223 and 7.6 months for placebo. Only 20 patients (16 in the active group and 4 in the placebo group) completed the 3-year follow-up.

Only adverse events considered treatment-related were reported in this safety evaluation. The incidence of myelosuppression was <3% in patients receiving radium-223. No grade 3 or 4 nonhematologic treatment-related adverse events were reported with this agent, with the exception of 1 pathological fracture.

at a glance ➤ The safety and efficacy of radium-223 in men with CRPC and bone metastases have held up over the longer-term followup of the ALSYMPCA trial ➤ Radium-223 significantly improved overall survival by 3.6 months compared with placebo, with good tolerability ➤ At 1.5 years after the last injection of the radium-223, there was minimal myelosuppression, minimal nonhematologic adverse events, and no cancers of concern There were no reports of AML, MDS, or primary bone cancer. A total of 5 cancers in other organs were reported—2 in the active group and 3 in the placebo group. n

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Personalized Medicine

Understanding Molecular Subtypes Is Basis for Genomic Medicine in Prostate Cancer

By Wayne Kuznar

Boston, MA—Incorporating genomics into the practice of medicine requires the demonstration of the ability of biomarkers to impact clinical decision-making, and ensuring that patients receive the best therapy based on genomic findings. Scott A. Tomlins, MD, PhD, Assistant Professor of Pathology and Urology, University of Michigan Medical School, Ann Arbor, reviewed efforts to realize genomic medicine into prostate cancer diagnosis and management at the second Global Biomarkers Consortium annual conference.

“We have things in prostate cancer that we know are potentially targetable, but there hasn’t been the momentum to do what’s been done in lung cancer where we looked for these patients to find them.”

—Scott A. Tomlins, MD, PhD

See also Prostate Cancer, pages 21-22 Point mutations have been found in several genes, including TP53, SPOP, PTEN, FOXA1, and MED12, each with

a prevalence of <10%.

“We have things in prostate cancer that we know are potentially target­

able, but there hasn’t been the momentum to do what’s been done in lung cancer where we looked for these paContinued on page 26

NEW FOR 2014

Principles in Value and Market Access

An educational session for product managers, reimbursement specialists, account managers, and marketers focusing on access, reimbursement, proving product value, and international markets.

CO-CHAIRS

MAY 6, 2014 Loews Hollywood Hotel Los Angeles, CA

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Gary M. Owens, MD

President Gary Owens Associates

AGENDA Genomic medicine starts with understanding basic molecular subtypes.

Numerous microarray studies, array comparative genomic hybridization studies, and the characterization of the prostate cancer transcriptome and genome have identified common alterations. “As in lung cancer, we can define prostate cancer molecular subtypes,” said Dr Tomlins. “The easiest way to do this is to look for the presence of ETS gene fusions. Like an ALK [anaplastic lymphoma kinase] rearrangement, these are chromosomal rearrangements that occur in prostate cancer, but they occur in about 50% of prostate cancers.”

More than 50% of prostate-specific antigen (PSA)-screened prostate cancers harbor fusions between the transmembrane protease serine 2 (TMPRSS2) and the v-ets erythroblastosis virus E26 oncogene homolog (avian [ERG]) genes.

No clear individual driver has been identified in patients with prostate cancer without an ETS fusion.

Exome sequencing of prostate tumor and normal pairs has discovered focal loss in common tumor-suppressor genes such as PTEN, TP53, and RB1.

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10:45am – 11:00am

Introductions and Opening Remarks Grant Lawless, RPh, MD, FACP; Gary M. Owens, MD

11:00am – 11:40am

Changing Access and Payer Challenges in Oncology - Medicare and Commercial Speaker TBD

11:40am – 12:20pm

Proving the Value for Oncology Therapy Using Comparative Effectiveness Research Dan Malone, PhD, Professor, University of Arizona College of Pharmacy

12:20pm – 1:30pm

Lunch

1:30pm – 2:10pm

Methods and Tools for Optimal Reimbursement Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead

2:10pm – 2:50pm

Impact of Healthcare Reform, Affordable Care Act, and Accountable Care Organizations on the Coverage of Cancer Treatments Speaker TBD

2:50pm – 3:30pm

Impact of New Risk Models on Traditional Pharmaceutical Relationships Ken Schaecher, MD, FACP, CPC, Medical Director, SelectHealth

3:30pm – 4:00pm

Break

4:00pm – 4:40pm

Using Competitive Intelligence to Maintain Coverage and Access Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting

4:40pm – 5:20pm

Panel Discussion - Will improvements in clinical outcomes and efficacy come from new products or a more thoughtful use of existing products using new adaptations?

Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE) AVBCC2014May6agenda Asize_20714

REGISTER TODAY! www.regonline.com/avbcc2014 march 2014

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www.ValueBasedCancerCare.com

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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Personalized Medicine

Understanding Molecular Subtypes Is Basis for Genomic Medicine in Prostate...

Continued from page 23

tients to find them,” Dr Tomlins said.

“Interestingly, there are almost no high-level focal amplifications in prostate cancer until the posttreatment set-

ting. There is a high level of genomic aberrations, and we’re seeing these as you start to do whole-genome studies.”

A TMPRSS2:ERG fusion serves as a

urine biomarker for prostate cancer. It has been shown to improve on serum PSA for predicting cancer in men undergoing diagnostic biopsy. “It is as

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Brief Summary

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VELC3X0043_A_Velcade_BS_7x10_r3.indd 1 Value-Based Cancer Care march NEPA14CDNY2145_PayerAd_Q1_Updte_KING_BS_Asize_r4.indd 1

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Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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 VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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Mutational Landscape Integrative profiling of lethal castration-resistant prostate cancer (CRPC) has been conducted at the University of Michigan in an effort to characterize the mutations that are present. The exomes of 50 lethal heavily pretreated metastatic CRPCs obtained at rapid autopsy were sequenced.

“Prostate cancer has a low mutational burden, but you do see patients with high numbers of mutations,” Dr Tomlins said. The exome data revealed 9 genes that were significantly mutated, 6 of which are recurrently mutated in prostate cancer—TP53, AR, ZFHX3, RB1, PTEN, and APC. Of the mutated genes, 3 did not have roles in prostate cancer—MLL2, OR5L1, and CDK12.

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INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

specific for prostate cancer as we can get,” Dr Tomlins said. A urine-based test developed at the University of Michigan uses quantification of TMPRSS2:ERG and PCA3, along with PSA, to calculate the risk of prostate cancer on needle biopsy.

Rather than provide a positive or negative value, the test will provide the risk of having cancer and highgrade cancer, with estimates of what constitutes low, intermediate, and high risk, said Dr Tomlins.

Clinical Sequencing Program: Finding What Is Actionable To translate these findings into potentially targetable actions for individual patients, a clinical sequencing program for advanced cancers was started at the University of Michigan’s Michigan Oncology Sequencing Center.

“We do profiling of the normal germline as well. We do full exome and transcriptome studies, and we do the exome of the normal sample, run it through pipelines, and we present the results to a sequencing tumor board [now called a precision medicine tumor board],” said Dr Tomlins. The board discusses actionable results and sends a report to the genetic counselor and the referring physician. A multidisciplinary tumor board determines which biomarkers are actionable.

The University of Michigan has recently initiated one of the first genetically stratified clinical trials (a multi-institution, randomized phase 2 trial) in which ETS gene fusions are assessed (ERG by immunohistochemistry, and ETV1 by fluorescence in situ hybridization), and patients are stratified to treatment with an antiandrogen alone or a poly (ADP-ribose) polymerase inhibitor plus an antiandrogen. n

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Personalized Medicine

Biomarker Development and Validation Crucial to Appropriate Use of Emerging Treatments in Oncology

By Wayne Kuznar

Boston, MA—Biomarker development and validation are essential for the rational use of emerging cancer treatments, said presenters at the second Global Biomarkers Consortium annual conference.

“If we don’t identify biomarkers, we’re likely to miss a therapeutic effect,” said Rob Coleman, MD, MBBS, Director, Sheffield Cancer Research Centre, United Kingdom. “We want to

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separate our patients into those that express the biomarker and those that do not, with the expectation that those that do will be enriched, and it will be easier to show benefit.”

The 3 phases in the development of a clinically useful biomarker are discovery, validation, and application. Clinical and biological validity of a potential biomarker is common, analytic validity is less common, and proving clinical

“If we don’t identify biomarkers, we’re likely to miss a therapeutic effect.”

—Rob Coleman, MD, MBBS

utility, whether prognostic or predictive, is rare, said Dr Coleman.

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“To be accepted as clinically useful, a biomarker needs to have gone through prospective clinical trial testing, or at least have been subjected to a meta-analysis,” he said. “Relatively few achieve that.”

Showing the value of a new biomarker requires complete publication of the methodology used in its evaluation, according to the Reporting Recommendations for Tumor Marker Continued on page 28

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Personalized Medicine

Biomarker Development and Validation Crucial to Appropriate Use...

Continued from page 27

Prognostic Studies (REMARK) criteria.

These include patient characteristics; the type of biologic material used and its collection, preservation, and storage; study design and case selection; a list of candidate variables examined or considered; and the handling of marker values and cut point determination.

The REMARK criteria are among several guidelines that have been established for reporting and evaluating biomarker studies.

“We want to separate our patients into those that express the biomarker and those that do not, with the expectation that those that do will be enriched, and it will be easier to show benefit.”

—Rob Coleman, MD, MBBS

Biomarker trial design relies on the availability of adequate archived specimens for analysis to have acceptable statistical power, said Dr Coleman.

The marker-based test should be analytically and preanalytically validated for use with the archived specimens.

Searching for Bone Metastases Marker in Breast Cancer The use of adjuvant bisphosphonates in early breast cancer is being studied in more than 3000 patients with metastatic breast cancer in the randomized Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) study, with the rationale that such treatment may enhance endocrine therapy and prevent metastasis.

Although disease-free survival was similar between the zoledronic acid

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(Zometa) arm and the controls, there was a 23% reduction (P <.05) in invasive disease events in postmenopausal women who received the bisphosphonate. The agent may be working to prevent bone metastases, but to use the bisphosphonate in the most appropriate and cost-effective manner, “you need to pull out a group of patients who are more likely to develop bone metastases,” he said, “and there’s no tool for doing that. We don’t have any biomarkers that do this.”

As an example of biomarker discovery and validation, his group has used a proteomic discovery platform to identify 2 candidate proteins for the prediction of bone metastases, which are being evaluated using tissue microarray samples from the AZURE study population.

When both proteins were expressed (in 15% of the study patients), the risk for bone metastases plus metastases at other sites was increased by more than 3-fold in the control group, and the risk of bone metastases only was increased by more than 4-fold in the controls. No such increase was found in the groups that were randomized to the bisphosphonate.

Markers in Hematologic Malignancies In the case of biomarkers for hematologic malignancies, chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome– positive (Ph+) status, creating the fusion gene BCR-ABL. The Ph+ chromosome is not only pathogenic for CML but is also a tumor marker. The tyrosine kinase inhibitors (TKIs) block excess tyrosine kinase activity caused by the BCR-ABL gene, changing the natural history of the disease.

“As good as the treatment is, the testing for the presence of molecular abnormalities at the BCR level is poorly homogenized,” said Jorgé E. Cortes, MD, Deputy Department Chair, Department of Leukemia, M.D. Anderson Cancer Center, Houston. Standardization of the test is lacking, resulting in large differences between laboratories in the measurement of the number of leukemic cells.

An undetectable molecular abnormality achieved with targeted therapy has been associated with excellent long-term survival. Not every BCRABL rearrangement is the same, however, and the response to therapy is different between patients with typical

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and atypical rearrangements, said Dr Cortes. The e1a2 transcript is rare in patients with CML, and patients with this transcript have inferior outcomes compared with those with more common transcripts.

“Knowing which mutation is more likely to respond to which drug helps you individualize treatment for that patient.”

—Jorgé E. Cortes, MD

Another marker of response in CML is the human organic cation transporter (hOCT1). Patients with an active hOCT1 experience cytogenetic and molecular responses to a standard dose of a TKI, whereas those with a less active transporter require higher doses of the drug.

In patients with CML, BCR-ABL can mutate to confer resistance to a TKI. “There are more than 100 mutations that can occur, and they create different levels of resistance to imatinib [Gleevec],” Dr Cortes said. Secondand third-generation TKIs have been developed to overcome resistance caused by specific mutations, “and they overcome some mutations better than others,” he said. “Knowing which mutation is more likely to respond to which drug helps you individualize treatment for that patient.”

Patients with CML and the T315I mutation currently have no treatment options. Ponatinib (Iclusig) is a potent pan–BCR-ABL inhibitor that is active against all tested resistant mutations, including the T315I mutation. In a phase 1 study of 403 patients resistant to or intolerant of dasatinib (Sprycel) or nilotinib (Tasigna), or those who

at a glance ➤ Biomarker development and validation are essential for the rational use of emerging cancer treatments ➤ Biomarkers can match treatments and patients to achieve best efficacy ➤ To be clinically useful, biomarkers must undergo prospective clinical trial testing or a meta-analysis ➤ Testing for molecular abnormalities at the BCR level is poorly homogenized ➤ Test standardization is lacking for hematologic malignancies, resulting in large differences in leukemic cell measurements between laboratories had the T315I mutation, early complete cytogenetic responses were achieved in 58% of patients who received ponatinib, said Dr Cortes.

In acute myelogenous leukemia (AML), a mutation in FLT3 is associated with frequent and rapid relapse and worse overall survival. In a retrospective study of patients with myelodysplastic syndrome or AML, 23 patients received an FLT3 inhibitor as part of their induction, and 9 achieved a complete remission or a complete remission with incomplete platelet recovery. A secondary tyrosine kinase domain mutation can arise after the use of FLT3 inhibitors in patients with single FLT3-internal tandem duplication–mutated AML, conferring resistance and a poor prognosis.

A molecular mechanism of AML is the process of farnesylation, which is required for the activation of reninangiotensin system proteins. The farnesyltransferase inhibitor tipifarnib (Zarnestra) has been evaluated in untreated elderly patients with AML, producing a complete remission in 18% to 20%.

A genetic predictor of response to tipifarnib is the ratio of RASGRP1/ APTX gene expression. The utility of this classifier for predicting response to tipifarnib was validated in a set of 58 samples from patients with relapsed or refractory AML, and was found to predict improved survival in patients with newly diagnosed and refractory or relapsed AML. n

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In the Literature Bortezomib plus Thalidomide Maintenance Therapy Improves Overall Survival in Transplant-Ineligible Patients with Newly Diagnosed Myeloma

Patients with multiple myeloma (MM) who are not fit to undergo stemcell transplantation (SCT), typically receive melphalan (Alkeran) plus prednisone in combination with either thalidomide (Thalomid) or bortezomib (Velcade). Recent studies are exploring the clinical benefit of the 4-drug induction regimen of melphalan, prednisone, bortezomib, and thalidomide, followed by maintenance with bortezomib plus thalidomide (VMPT-VT).

In a recent phase 3 clinical trial, a total of 511 patients with newly diagnosed MM who were not candidates for SCT were randomized to receive VMPT-VT (N = 254) or bortezomib, melphalan, and prednisone (VMP; N = 257). The patients’ median age was 71 years, and 27% of the patients were aged >75 years (Palumbo A, et al. J Clin Oncol.

2014;32:634-640).

After a median follow-up of 54 months, the progression-free survival (PFS) was 35.3 months with VMPT-VT and 24.8 months with VMP (hazard ratio [HR], 0.58; P <.001). Of note, the overall survival (OS) rates were significantly prolonged with VMPT-VT compared with VMP; the 5-year OS rates were 61% with VMPT-VT and 51% with VMP (HR, 0.7; P = .01). A multivariable analysis revealed that treatment with VMPT-VT, age <75 years, female sex, and disease stages I and II were associated with significantly longer OS. In addition, the difference between median PFS and time to next therapy was approximately 1 year with VMPT-VT, but only 3 months with VMP. The investigators suggested that the significant tumor reduction and ongoing treatment with maintenance therapy delayed disease progression in patients receiving VMPT-VT. The most common adverse events (AEs) were hematologic and included grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia; neutropenia was reported in 38% of patients in the VMPT-VT arm and in 28% of patients in the VMP arm, whereas grade 3 or 4 thrombocytopenia was reported in 22% of patients in the VMPT-VT arm and in 20% of patients in the VMP arm. The most common nonhematologic AEs in both treatment arms included infections, cardiologic events, and peripheral neuropathy. Overall, 28% of patients in the VMPT-VT arm and 16% of patients in the VMP arm discontinued treatment and required dose reduction because of AEs.

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The researchers concluded that the VMPT-VT regimen was superior to the VMP regimen in terms of PFS, OS, and time to next therapy in patients with newly diagnosed MM who are not eligible for SCT. Although these follow-up results are encouraging, an important question remains whether the clinical benefit observed with

VMPT-VT is attributed to the 4-drug induction combination or to maintenance treatment with bortezomib and thalidomide. In addition, the investigators believe that these results provide the foundation for newer, less-toxic combinations of immunomodulatory agents and proteasome inhibitors.

Nintedanib plus Docetaxel an Effective Combination in Patients with Advanced Non–Small-Cell Lung Cancer

Currently, the US Food and Drug Administration–approved second-line treatments for non–small-cell lung cancer (NSCLC) include monotherapy with docetaxel (Taxotere), erlotinib

Continued on page 31

NeW foR 2014

Government and Employers An educational session for policymakers and employers focusing on healthcare reform, benefit design, insurance, and coverage trends.

Co-Chairs

May 7, 2014 Loews Hollywood Hotel Los angeles, Ca

Jayson Slotnik, JD, MPH

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

aGEnda

F. Randy Vogenberg, PhD, RPh

Principal Institute for Integrated Healthcare

8:30am – 8:40am

Introductions and Opening Remarks Jayson Slotnik, JD, MPH; F. Randy Vogenberg, PhD, RPh

8:40am – 9:25am

Session 1: Investor Community Views on Healthcare Market Winners and Losers Michael E. Meyers, MPH, Managing Director, Head of Investment Banking, T.R. Winston & Company

9:25am – 10:10am

Session 2: Insurance Innovation on Reinsurance and Benefit Design Trends Matthew Palmgren, PharmD, President, Healthcare Solutions in Int’Ovation Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC

10:10am – 10:15am

Break

10:15am – 11:00am

Session 3: Private Exchanges: Why Different from Public Exchange Trends for Oncology Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions

11:00am – 11:40am

Session 4: Diagnostics: Recent FDA and CMS Policies Impacting Access to Diagnostic and Oncology Drugs John Ridge, Senior Director, Managed Care and Reimbursement, Exact Sciences Timothy J. Thompson, Chief Executive Officer, Intervention Insights

11:40am – 12:00pm

Session 5: What’s Next with Healthcare Reform – Fixes or More Related to Oncology?

Denise Pierce, President and CEO, DK Pierce & Associates Jayson Slotnik, JD, MPH, Vice President of Reimbursement Strategy & Innovation, United BioSource Corporation F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare

12:00pm – 12:15pm

Break

12:15pm – 1:15pm

Lunch/Product Theater

1:15pm – 1:30pm

Break

1:30pm – 2:15pm

Session 6: Employer Onsite Clinic Trends from Wellness into Infusion and Emergent Care Larry Boress, President & CEO, Midwest Business Group on Health; Executive Director, National Association of Worksite Health Centers

2:15pm – 3:45pm

Meet the Experts Roundtables Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE)

3:45pm – 4:15pm

Poster Presentations

4:15pm – 5:00pm

Poster and Session Discussant

5:00pm – 7:00pm

Cocktail Reception in the Exhibit Hall

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Immunotherapy

Immunotherapy Holds Promise to Extend Survival in GI Cancers

By Wayne Kuznar

pancreatic cancer, Dr Jaffee said, but there is evidence that the immune system can be provoked in patients with pancreatic cancer.

Combining gemcitabine (Gemzar) with an agonist signal (CD40 agonist) was able to reverse an immunosuppressive tumor microenvironment and induce tumor regression, which means that “T-cells are likely getting in and are associated with the clinical response,” she pointed out.

A pancreatic tumor vaccine study at Johns Hopkins provides new evidence for antitumor immunity. The vaccine is administered 2 weeks before surgical resection of the tumor. A single dose of intravenous cyclophosphamide is given with the vaccine to enhance immune response. Cyclophosphamide allows trafficking of antigen-specific T-cells to the tumor. “In 85% of the patients studied, we found lymphoid aggregates coming into the tumors,” said Dr Jaffee. “They’re located throughout the tumor and they’re located around the tumor. When examined closely, they look like Germinal Centre-like structures; they stain for T-cells on the outside, B-cells on the inside.”

It is known that vaccines can induce tumor-infiltrating lymphocytes in traditionally “nonimmunogenic” tumors.

“But vaccine-induced infiltrating T-cells likely get downregulated by suppressive mechanisms within the tumor,” Dr Jaffee said. “Vaccines must be given with agents that modulate these suppressive mechanisms to acti-

vate the T-cell response.”

In mice, anti–PD-1 therapy enhances the infiltration of vaccine-induced tumor-specific infiltrating lymphocytes. In pancreatic cancer, regulatory pathways can be modulated to en-

Photo by © ASCO/Todd Buchanan 2014

San Francisco, CA—The use of immunotherapy for the treatment of gastrointestinal (GI) cancers should become a reality in the not-too-distant future.

Uncovering the signaling networks within the tumor microenvironment that regulate host immune responses is leading to strategies to alter these responses to treat GI malignancies.

Combinations of therapies that can induce T-cells into a tumor and activate the T-cell response will most likely be needed. Such combinations are already under investigation, said Elizabeth M. Jaffee, MD, Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, in her keynote address at the 2014 Gastrointestinal Cancers Symposium.

“The main goal of immunotherapy is to raise an army of T-cells to attack the tumor. These T-cells need to get into the tumor, but they also have to be activated,” said Dr Jaffee.

Achieving an anticancer response may require not only targeting a specific antigen, but also costimulation to present antigens in the right form so that an activated T-cell can be generated. Activated T-cells in combination with 1 or more immune checkpoint blockers will be necessary for a response.

Vaccines are especially needed for cancers, such as pancreatic cancer, that do not naturally induce intratumoral immune responses. Effector T-cell infiltration is not a natural response to

“The main goal of immunotherapy is to raise an army of T-cells to attack the tumor. These T-cells need to get into the tumor, but they also have to be activated.”

—Elizabeth M. Jaffee, MD

hance vaccine efficacy. Ipilimumab (Yervoy) plus a vaccine extended median overall survival (OS) compared with ipilimumab alone in a small pilot study of patients with metastatic pancreatic cancer in whom 2 or more che-

motherapies had failed.

Targeting more than 1 checkpoint pathway at a time appears to produce a synergistic response. Early data from patients with melanoma suggest that the combination of anti–PD-1 and ipilimumab produces more frequent and deeper responses, but with a significant increase in toxicity.

Several strategies to enhance response are being explored. Two vaccines may be better than 1, Dr Jaffee said. A vaccine platform based on live attenuated, double-deleted Listeria monocytogenes targeting mesothelin (GVAX/CRS-207 combination) improved median OS in patients with metastatic pancreatic cancer in whom chemotherapy was refused or failed.

“Listeria is an intracellular bacterium that induces a T-cell response against antigen targeting the tumor, but it also induces T-cell responses against helper T-cells that propagate that T-cell response,” said Dr Jaffee.

Combinations of immune checkpoint inhibitors given with vaccines is another possible strategy. Ipilimumab plus a GVAX vaccine or anti–PD-1 therapy plus a GVAX vaccine with a Listeria boost are potential options.

Combinations of immune-activating agents with methylation-targeting agents are another possibility, because hypomethylation uncovers inflammatory signals within the tumor microenvironment, Dr Jaffee said. Engineering T-cells that target GI cancer tumor antigens is also being explored. n

Emerging Therapies

Idelalisib Improves Outcomes in Heavily Pretreated Patients with CLL New Orleans, LA—A planned interim analysis of the first phase 3 clinical trial shows that idelalisib, a first-in-class selective oral kinase inhibitor, when combined with rituximab (Rituxan), is superior to rituximab alone in progression-free survival (PFS) in patients with heavily pretreated chronic lymphocytic leukemia (CLL).

The 24-week data from the randomized, placebo-controlled trial were presented by Richard R. Furman, MD, Richard A. Stratton Assistant Professor

30

in Hematology and Oncology, Weill Cornell Medical College, New York.

Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients,” said Dr Furman.

Idelalisib was granted Breakthrough Therapy status in 2013.

Idelalisib targets the delta isoform of the phosphoinositide-3-kinase en-

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zyme, which is critical for the activation and survival of CLL cells and other low-grade B-cell lymphomas.

It inhibits homing and retention of malignant B-cells in lymphoid tissues, reducing B-cell survival, and restrains proliferation and induces apoptosis in CLL cells.

Study Details Overall, 220 adult patients (median age, 71 years) with relapsed CLL who were deemed unfit for further

cytotoxic chemotherapy and who had measurable lymphadenopathy that had progressed after the completion of previous therapy, were randomized to a combination of idelalisib twice daily plus rituximab or to placebo twice daily and rituximab continuously until disease progression or death. Patients were eligible for the trial if they had received at least 1 anti-CD20 antibody-containing therapy or at least 2 cytotoxic therapies. Patients had a median of 3 previous therapies before en-

Continued on page 34

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In the Literature Nintedanib plus Docetaxel an Effective Combination...

Continued from page 29

(Tarceva), or pemetrexed (Alimta). A recent phase 3 clinical trial explored the safety and efficacy of nintedanib (Vargatef)—a potent oral angiokinase inhibitor—in combination with do­ cetaxel, as a second-line treatment in patients with NSCLC (Reck M, et al.

Lancet Oncol. 2014;15:143-155).

In this phase 3 LUME-Lung 1 trial, 1314 patients were randomized to receive nintedanib and docetaxel (ie, treatment group) or docetaxel and placebo (ie, placebo group). The primary end point was PFS, as assessed by central independent review. The key secondary end point was OS. The OS was assessed in the following order: first, in patients with adenocarcinoma who progressed within 9 months of starting first-line therapy; second, in all patients with adenocarcinoma; and third, in all patients, regardless of histology.

After a median follow-up of 7.1 months, the median PFS was 3.4 months in the treatment group compared with 2.7 months in the placebo group (P = .001). After a median follow-up of 31.7 months, the OS of patients with adenocarcinoma histology who progressed within 9 months of starting first-line therapy was 10.9 months versus 7.9 months in the placebo group (P = .007). Furthermore, in all patients with adenocarcinoma, the median OS was 12.6 months in the treatment group and 10.3 months in the placebo group (P = .035).

Although treatment with ninteda­ nib plus docetaxel had a significant effect on OS in patients with adenocarcinoma histology who progressed within 9 months of first-line therapy and in all patients with adenocarcinoma, no difference in OS was found between the 2 groups when all patients were assessed independent of histology results.

AEs that were more common in the treatment group than in the placebo group included diarrhea, increases in alanine and in aspartate aminotransferase, nausea, decreased appetite, and vomiting. Most of these AEs were managed with supportive care or with dose reduction.

The authors concluded that ninteda­ nib plus docetaxel combination may be an appropriate second-line treatment option for all patients with NSCLC and is particularly effective in patients with adenocarcinoma histology.

Implications of the Affordable Care Act for Adult Survivors of Childhood Cancer

Among adult survivors of child-

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hood cancer, the lack of health insurance is a major obstacle to obtaining the recommended follow-up care. The goal of the Patient Protection and Affordable Care Act (ACA) enacted in 2010 was to broaden insurance coverage for all Americans. A new commentary by Mueller and several health policy experts addressed the questions

regarding how several provisions in the ACA could help adult survivors of childhood cancers overcome insurance-based barriers to receiving the recommended follow-up care for patients with cancer (Mueller EL, et al.

J Clin Oncol. 2014;32:615-617).

The first provision in the ACA mandates that insurance coverage cannot

be denied or canceled because of a preexisting condition; under this provision, survivors of childhood cancers can continue to receive the recommended follow-up care, even in remission. The second provision states that individuals can be covered by their parents’ insurance up to age 26 years.

Under the third provision, states may

Continued on page 35

NeW foR 2014

Personalized Medicine and Payers An educational session for payers focusing on cost efficiency, value, outcomes, and impacts on treatment of personalized medicine.

Co-ChAirs

May 8, 2014 Loews Hollywood Hotel Los angeles, Ca

AgendA 7:00am – 8:30am 8:30am – 8:40am 8:40am – 9:20am

9:20am – 10:00am

10:00am – 10:40am

10:40am – 11:20am

11:20am – 12:00pm

12:00pm – 12:15pm 12:15pm – 1:15pm 1:15pm – 2:45pm

2:45pm – 3:00pm 3:00pm – 4:00pm 4:00pm – 5:00pm 5:00pm – 7:00pm

Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Special Session: Value-Based Strategies for Patients with Multiple Myeloma Supported by funding from Millennium: The Takeda Oncology Company Introductions and Opening Remarks Michael A. Kolodziej, MD; Grant Lawless, RPh, MD, FACP Session 1: Personalized Medicine and Value Peter Bach, MD, MAPP, Memorial Sloan-Kettering Cancer Center Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna Session 2: Measuring the Value of Prognostic and Predictive Outcomes Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine Macey Johnson, Vice President of Managed Care and Reimbursement, BioTheranostics Session 3: Utilizing Big Data to ID Phenotypes and Predictive Outcomes Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint George W. Sledge, MD, FASCO, Chief of Oncology, Stanford University Department of Medicine Session 4: Value Paradigm in Drug Development Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Kevin Knopf, MD, MPH, California Pacific Medical Center Christiane Langer, MD, Lead Medical Director for CRC, GU, and GBM, Genentech Panel Discussion - How will personalized medicine impact future treatment and use existing therapy?

Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint Break Lunch/Product Theater Meet the Experts Roundtables Al Benson, MD, Professor of Medicine and Oncology, Northwestern University Medical School Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Break Poster Presentations Poster and Session Discussant Cocktail Reception in the Exhibit Hall AVBCC2014May8agenda Asize_20714

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Drug Update

Gazyva for Chronic Lymphocytic Leukemia: First FDA-Approved Breakthrough Therapy in Oncology

By Lisa A. Raedler, PhD, RPh, Medical Writer

C

hronic lymphocytic leukemia (CLL), a monoclonal disorder characterized by progressive accumulation and proliferation of functionally incompetent B-cells, is the most frequently diagnosed leukemia in the United States.1,2 The American Cancer Society has estimated that 4580 Americans will die from CLL in 2013, which represents approximately 19% of all leukemia deaths.2 Because it can have an insidious onset, CLL is often discovered incidentally after blood work is conducted for another reason.3 Between 25% and 50% of patients with CLL are asymptomatic at the time of presentation.3 Patients with CLL are typically receiving treatment when their disease becomes symptomatic or when the signs of rapid disease progression are detected.3 Drug combinations for patients with CLL who warrant treatment include cytotoxic agents, such as the purine nucleoside analog fludarabine (Fludara), and therapeutic antibodies.3,4 Rituximab (Rituxan), a CD20 antibody, is widely used in patients with previously untreated symptomatic CLL and in salvage regimens.4 Other antibodies with clinical activity in CLL include the anti-CD20 antibody ofatumumab (Arzerra) and the anti-CD52 antibody alemtuzumab (Campath).4 Researchers continue to explore multiple novel strategies for the treatment of patients with CLL, including small molecules and newer-generation monoclonal antibodies, such as RG7356 and veltuzumab.5,6 For patients with CLL who are fit enough to tolerate treatment-related toxicities, including bone marrow suppression, modern chemoimmunotherapy combinations have significantly improved clinical outcomes.7 However, none of these regimens is curative, and a significant number of patients with CLL succumb to their disease. The effective management of elderly patients with CLL represents a particular challenge, in part because older patients with multiple comorbidities have been underrepresented in clinical trials of novel agents and drug combinations.7 Because the majority of patients with CLL are older than 65 years at the time of their diagnosis, reimbursement for the treatment of CLL in the United States is typically provided by Medicare.7,8 An analysis of US Medicare data (1999-2007) has demonstrated that the cost burden associated

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with CLL is substantial.9 This study, which was published in 2012, analyzed the total lifetime cost of treatment for more than 7400 patients with CLL compared with matched controls who did not have cancer. The results demonstrated that patients with CLL incurred average treatment costs of more than $87,000 compared with approximately $47,600 for the matched controls, a very significant difference.9

monoclonal antibody directed against CD20.14 On binding to CD20, obinutuzumab mediates B-cell lysis in 3 ways: (1) the engagement of immune effector cells, whose mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, (2) direct activation of intracellular death signaling pathways, and (3) complement cascade activation.14

The trial’s primary end point was PFS as assessed by independent review.12 Secondary end points included response rate, complete response rate, duration of response, disease-free survival, OS, minimal residual disease, safety, adverse events, patient-reported outcomes, and symptom burden defined by the European Organisation for Research and Treatment of Cancer questionnaire.15

New Treatment Option for CLL: Obinutuzumab In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (Gazyva; Gen­ entech) for use in combination with chlorambucil in patients with previously untreated CLL.10 The approval was done under the FDA’s priority review. Obinutuzu­mab is the first cancer agent with the “breakthrough therapy” designation to receive FDA approval.10,11 The approval of obinutuzumab for the treatment of patients with CLL was based on the demonstration of significant improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial comparing obinutuzumab in combination with chlor­ambucil versus chlorambucil alone.10,12 The study included 356 patients with previously untreated CD20-positive CLL and coexisting medical conditions or reduced renal function.10,12 In this study, known as CLL11, patients received 1 of 3 treatment regimens: chlorambucil alone for 6 cycles, chlorambucil plus obinutuzumab for 6 cycles, or chlorambucil plus rituximab for 6 cycles.12 All cycles were 28 days.12 Data from the first portion of the CLL11 study—the comparison of obinutuzumab plus chlorambucil and chlorambucil alone—were initially presented at the 2013 American Society of Clinical Oncology annual meeting and served as the basis for the FDA’s approval of the drug.12 In an interview regarding the CLL11 study, lead investigator Valentin Goede, MD, of the German CLL Study Group, Department of Internal Medicine, University Hospital Cologne, Germany, stated, “This [significant PFS] finding suggests an 86% reduction in the risk for a progression, relapse, or death in the obinutuzumab arm.”13

Dosing and Administration For patients with newly diagnosed CLL, the dose of obinutuzumab is 100 mg intravenously on day 1 in cycle 1, 900 mg on day 2, and 1000 mg on days 8 and 15; in cycles 2 to 6, the dose is 1000 mg, administered intravenously every 28 days.14 Premedication before infusion with obinutuzumab is recommended to reduce the risk for infusion-related adverse reactions.14

Patient Population

Mechanism of Action Obinutuzumab is a humanized

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CLL11: Pivotal Phase 3 Clinical Trial In the first portion of the multicenter CLL11 trial, 356 previously untreated patients with CLL were randomly assigned to treatment with obinutuzumab plus chlorambucil or to chlorambucil alone.12 All patients had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) of <70 mL/min.12 The majority of the patients received 1000 mg of obinutuzumab on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg) for 45 patients in the CLL11 trial. Chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of all treatment cycles (1-6).12

In the phase 3 obinutuzumab trial, the patient demographics and clinical characteristics were balanced between the treatment arms.12 The patients’ median age was 73 years, 60% were male, and 95% were Caucasian.12,14 Overall, 68% of the patients had a CrCl of <70 mL/min and 76% had multiple comorbidities.14 The median estimated CrCl was 61 mL/min.12 Of the patients who received obinutuzumab plus chlorambucil, 81% received all 6 cycles compared with 67% of patients who received chlorambucil alone.14

Efficacy

The phase 3 study demonstrated that obinutuzumab is active and safe in patients with newly diagnosed CLL and comorbidities.12 At the time of data cutoff for primary end-point analysis, patients receiving chlorambucil alone and obinutuzumab plus chlorambucil had been followed for a median of 13.6 and 14.5 months, respectively.12 On assessment by independent reviewers, the median PFS was significantly prolonged for patients receiving obinutuzumab plus chlorambucil compared with patients receiving chlorambucil alone (23 vs 10.9 months, respectively; P <.001).12 This significant difference in median

Table 1 Phase 3 Clinical Trial CLL11: Efficacy Results Efficacy end point PFS Median PFS, months Hazard ratio Stratified log-rank test P value

Obinutuzumab plus chlorambucil (N = 238)

Chlorambucil (N = 118)

23

11.1

0.16 (95% CI, 0.11-0.24) <.001

Response rate Overall, % Complete, %

75.9 27.8

32.1 0.9

Median duration of response, mo

15.2

3.5

CI indicates confidence interval; PFS, progression-free survival.

Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013.

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Drug Update Table 2 P hase 3 Clinical Trial CLL11: Adverse Reactions in ≥5% of Patients and ≥2% More in the Obinutuzumab-Treated Arm Obinutuzumab plus chlorambucil (N = 240) Chlorambucil (N = 116) a Adverse reactions All grades, % Grade 3-4, % All grades, % Grade 3-4,a % Injury, poisoning, and procedural complications Infusion-related reactions

69

21

0

0

Neutropenia

40

34

18

16

Thrombocytopenia

15

11

7

3

Anemia

12

4

10

5

Leukopenia

7

5

0

0

10

<1

7

0

10

0

7

<1

Blood and lymphatic system disorders

b

General disorders and administration-site conditions Pyrexia Respiratory, thoracic, and mediastinal disorders Cough

No grade 5 adverse reactions have been observed with a difference of ≥2% between the treatment arms.

Clinically significant events.

Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013. a

b

PFS was maintained in a subsequent analysis.

After a median observation time of 23 months, the median PFS for patients receiving obinutuzumab plus chlorambucil was 23 months compared with 11.1 months in patients receiving chlorambucil alone (P <.001).14 The PFS and overall response findings from the CLL11 study are summarized in Table 1.14

Safety

Of the 240 patients included in the phase 3 trial, approximately 194 (81%) received all 6 cycles (28 days each) of obinutuzumab-based therapy.14 Among the patients who received obinutuzumab, the most common adverse reactions (incidence, ≥10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder (Table 2).14 Infusion reactions were noted in 69% of patients undergoing their first infusion of obinutuzumab.14 Severe (grade 3 or 4) infusion reactions were observed in 21% of patients receiving obinutuzumab, and 8% of patients discontinued therapy.14 The incidence of infusion reactions was significantly lower with subsequent infusions—3% with the second 1000-mg dose of obinutuzumab, and less than 1% thereafter. No severe infusion reactions were reported after the first 1000-mg infusion.14 After this initial experience with infusion reactions in the CLL11 trial, study protocol modifications were made to require premedication with a corticosteroid, an antihistamine, and acetaminophen.14 The first dose of obinutuzumab was also divided into 2 infusions—100 mg on day 1 and 900

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mg on day 2. Among the 45 patients for whom these measures were implemented, 21 (47%) had an infusion reaction with the first 1000 mg of obinutuzumab. Less than 2% of patients experienced an infusion reaction with subsequent doses of obinutuzumab.14 HBV infection reactivation. Hepatitis B virus (HBV) reactivation can occur in patients treated with anti-CD20 antibodies, including obinutuzumab.

Reactivation of HBV replication is often followed by hepatitis, manifesting as an increase in transaminase levels and, in severe cases, increases in bilirubin level, liver failure, and death.14 In some recipients of obinutuzumab, the reactivation of the HBV resulted in fulminant hepatitis, hepatic failure, and death. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive, as well as in patients who are HBsAg negative but are anti–hepatitis B core antibody (HBc) positive. Reactivation was also observed in patients who appeared to have resolved HBV infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody positive).14 Warnings and Precautions Boxed warning. The approval of obinutuzumab includes a boxed warning regarding HBV infection reactivation and progressive multifocal leukoencephalopathy (PML).10 Clinicians should advise patients of these warnings, and should assess patients for HBV and reactivation risk.10 All patients receiving obinutuzumab should be screened for HBV infection by measuring HBsAg and anti-HBc before treatment initiation.

Patients who show evidence of HBV infection should consult with physi-

cians experienced in HBV infection to discuss the potential use of HBV antiviral therapy.14 In patients who develop reactivation of the HBV while receiving obinutuzumab, obinutuzumab and any concomitant chemotherapy should be discontinued immediately. Appropriate treatment should be instituted. In patients whose HBV reactivation resolves, resumption of obinutuzumab can be discussed with physicians who are experienced in managing patients with HBV infection. There are insufficient data regarding the safety of resuming obinutuzumab in patients who develop reactivation of the HBV.14 Progressive multifocal leukoencephalopathy. JC virus infection resulting in PML, a potentially fatal condition, was observed in patients receiving obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset neurologic manifestations or with changes to preexisting neurologic manifestations. If PML is diagnosed, therapy with obinutuzumab should be discontinued.14 Consider the discontinuation or reduction of concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.14 Infusion reactions. Obinutuzumab can cause severe and life-threatening infusion reactions during initial and subsequent infusions. Symptoms include hypotension, tachycardia, dyspnea, and respiratory symptoms.

Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills.14 Patients should receive premedication with acetaminophen, an antihistamine, and a glucocorticoid. Patients should be closely monitored during

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the entire infusion; reactions within 24 hours of receiving obinutuzumab have occurred. If infusion reactions occur, institute medical management with glucocorticoids, epinephrine, bronchodilators, and/or oxygen as needed.14 Table 3 summarizes the recommendations for managing infusion reactions associated with obinutuzumab.14 Because patients with preexisting cardiac or pulmonary conditions may be at greater risk for experiencing more severe infusion reactions, they should be monitored more frequently throughout the obinutuzumab infusion and the postinfusion time frame.14 Hypotension may occur as part of the obinutuzumab infusion reaction.

Consider withholding antihypertensive treatments for 12 hours before the obinutuzumab infusion, during the infusion, and for the first hour after administration until blood pressure is stable. For patients who are at increased risk of hypertensive crisis, the benefits and risks of withholding their hypertensive medication should be deliberated.14 Tumor lysis syndrome. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia secondary to tumor lysis syndrome (TLS) can occur 12 to 24 hours after the first infusion of obinutuzumab.

Because patients with high tumor burden and/or high circulating lymphocyte count (>25 × 109/L) are at greater risk for TLS, appropriate prophylaxis with antihyperuricemics (eg, allopurinol) and hydration should begin 12 to 24 hours before the infusion.14 Infection. Serious bacterial, fungal, and new or reactivated viral infections can occur during and after obinutuzumab therapy. Obinutuzumab should not be given to patients with active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection while taking obinutuzumab.14 Neutropenia. Neutropenia associated with obinutuzumab can occur more than 28 days after the completion of treatment and can last more than 28 days. Patients with grade 3 or 4 neutropenia while taking obinutuzu­mab should be monitored frequently until resolution. Any symptoms or signs of infection should be addressed immediately. Patients with neutropenia should receive antimicrobial prophylaxis during the treatment and may consider antiviral and antifungal prophylaxis.14 Thrombocytopenia. In the CLL11 trial, 12% of patients receiving obinutuzumab plus chlorambucil had grade 3 or 4 thrombocytopenia. In 5% of patients, obinutuzumab caused an acute thrombocytopenia within 24 hours Continued on page 34

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Drug Update Continued from page 33

ecommended Management of Adverse Reactions to Obinutuzumab Infusion, Table 3 R

by Severity (Grade) Recommendations Infusion reaction severity Grade 4 reaction (life-threatening): includes, but not limited to, anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction

• Stop the obinutuzumab infusion and permanently discontinue obinutuzumab therapy • Manage symptoms

Grade 3 (severe)

• Interrupt obinutuzumab infusion • Manage symptoms • On resolution of symptoms, consider restarting obinutuzumab infusion at no more than 50% of the previous rate (used at the time that the infusion reaction occurred) • If no further infusion reaction symptoms occur, infusion rate escalation may be resumed at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling) • Permanently discontinue treatment if the patient has a grade 3 infusion-related symptom on rechallenge

Grade 1 or 2 infusion reactions (mild • Interrupt obinutuzumab therapy or reduce to moderate) the rate of the infusion • Manage symptoms • On resolution of symptoms, continue or resume infusion • If no further infusion reaction symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling) Source: Gazyva (obinutuzumab) injection [prescribing information]. Genentech; November 2013. after infusion. Platelet counts should be monitored frequently in patients with grade 3 or 4 thrombocytopenia until resolution. Platelet transfusions may be required.14 Immunization. Immunization with live virus vaccines is not recommended until the completion of obi­nutuzumab treatment and B-cell recovery.14

Special Populations Obinutuzumab has not been specifically studied in pregnant or nursing women. Women of childbearing age should use effective contraceptive when receiving this medication and for the 12 months after treatment.14 Nursing women should be carefully evaluated for the benefits of obinutu-

zumab for the woman versus potential risk for the infant.14 The combination of obinutuzumab and combination chlorambucil has resulted in serious adverse events in geriatric patients. Among 240 treatment-naïve patients who received obinutuzumab in combination with chlorambucil, 82% were aged ≥65 years and 45% were aged ≥75 years.

Of those aged ≥75 years, 45% had serious adverse events and 5% died.

Among those aged ≥65 years, adverse event rates were similar in the active treatment and the comparator arms.

The efficacy rates were not significantly different among patients of different ages.14 Conclusion Obinutuzumab is the first cancer drug with a designated breakthrough therapy to receive FDA approval. This third-generation anti-CD20 monoclonal antibody, which was approved for the initial treatment of patients with CLL in combination with chlorambucil, has demonstrated improved efficacy with manageable side effects compared with chlorambucil alone.11,16 For patients with CLL and coexisting medical conditions and/or reduced renal function, obinutuzumab plus chlorambucil represents an effective alternative to purine analog-based therapy and to the use of chlorambucil alone.

Obinutuzumab may also confer clinical benefit in other cancers that express CD20. Clinical studies are under way to evaluate the use of obinutuzumab combined with cytotoxic agents in indolent and aggressive subtypes of non-Hodgkin lymphoma (NHL), including follicular NHL, diffuse large B-cell lymphoma, and mantle-cell lymphoma.17 n

Idelalisib Improves Outcomes... rollment, with 90% previously treated with rituximab.

After 24 weeks, the PFS rate for patients receiving idelalisib plus rituximab was 93% compared with 46% for those receiving rituximab alone (P <.001). The median PFS has not yet been reached in the combination arm, but was 5.5 months in the rituximab plus placebo arm.

The patients receiving idelalisib plus rituximab had a significantly better overall response rate (81%) versus patients receiving rituximab alone (13%; P <.001), in addition to a higher lymph-node response rate (93% vs 4%, respectively). The patients who were randomized to idelalisib plus rituximab also had a 72% improvement in overall survival compared with the

34

control group (P = .018).

The combination of idelalisib plus

“Given the efficacy and low risk for long-term toxicities demonstrated, we believe this treatment could be applicable to all CLL patients, because it eliminates the need for chemotherapy.”

Value-Based Cancer Care

—Richard R. Furman, MD

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References

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352:804-815.

2. American Cancer Society. Cancer facts and figures 2013. 2013. www.cancer.org/acs/groups/content/@ epidemiologysurveilance/documents/document/ acspc-036845.pdf. Accessed November 27, 2013.

3. Mir MA, Liu D, Patel SC, Rasool HJ. Chronic lymphocytic leukemia. Medscape. Updated November 11, 2013. http://emedicine.medscape.com/article/199313overview. Accessed November 27, 2013.

4. Jaglowski SM, Alinari L, Lapalombella R, et al. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood. 2010;116:3705-3714.

5. Zhang S, Wu CC, Fecteau JF, et al. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci U S A. 2013;110:6127-6132.

6. OBR. OBR Pipeline Online: chronic lymphocytic leukemia (CLL). http://obr oncology.com/pipeline_ online.php. Accessed November 29, 2013.

7. Stephens DM, Byrd JC. Ask the hematologists.

Hematologist. 2012;9:4-5.

8. American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Revised November 14, 2013. www.cancer.org/cancer/leu kemia-chroniclymphocyticcll/detailedguide/leu kemia-chronic-lymphocytic-key-statistics. Accessed November 28, 2013.

9. Lafeuille MH, Vekeman F, Wang ST, et al. Lifetime costs to Medicare of providing care to patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1146-1154.

10. US Food and Drug Administration. Drugs: Gazyva (obinituzumab). Updated November 1, 2013. www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm373263.htm. Accessed November 29, 2013.

11. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm373209.htm.

Accessed November 29, 2013.

12. Goede V, Fischer K, Humphrey K, et al.

Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31(15 suppl). Abstract 7004.

13. McCall B. Obinutuzumab active in elderly chronic lymphocytic leukemia. Medscape Medical News. June 21, 2013. www.medscape.com/viewarticle/806700.

Accessed November 29, 2013.

14. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; November 2013.

15. ClinicalTrials.gov. CLL11: A Study of RO5072759 (GA101) with Chlorambucil in Patients with Previously Untreated Chronic Lymphocytic Leukemia. http:// clinicaltrials.gov/ct2/show/NCT01010061?term= obinutuzumab&rank=12. Accessed November 29, 2013.

16. Ingram I. FDA approves obinutuzumab (Gazyva) for chronic lymphocytic leukemia. Cancer Network.

November 1, 2013. www.cancernetwork.com/news/ fda-approves-obinutuzumab-gazyva-chronic-lympho cytic-leukemia. Accessed November 29, 2013.

17. ClinicalTrials.gov. Obinutuzumab. Search results. http://clinicaltrials.gov/ct2/results?term=obinutu zumab &Search=Search. Accessed November 29, 2013.

Continued from page 30

rituximab had an acceptable adverse event (AE) profile, said Dr Furman.

Grade ≥3 AEs were reported in 56.4% of the patients in the combination arm compared with 47.7% of patients in the rituximab plus placebo arm. The most common AEs included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusion-related reactions.

Most study discontinuations were a result of disease progression, although 9 patients in the combination arm and 11 in the control arm discontinued treatment because of AEs. Promising Safety, Efficacy With several new agents on the horizon for the treatment of CLL, the optimal sequence of therapies will be ripe for exploration. Jennifer R.

Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, DanaFarber Cancer Institute, Boston, said, “That’s going to depend to some extent on emerging patterns of resistance and whether some agents may work better than others based on those emerging patterns of resistance. Certainly, combinations of these agents will be of great interest, and I think that’s what we’ll be evaluating over the next 5 years or so.” Dr Furman said that he sees idel­alisib being used beyond the heavily pretreated patient population with CLL. “Given the efficacy and low risk for long-term toxicities demonstrated, we believe this treatment could be applicable to all CLL patients, because it eliminates the need for chemotherapy,” he said. n

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In the Literature Implications of the Affordable Care Act...

Continued from page 31

choose to raise the Medicaid minimum eligibility requirement to 133% of the federal poverty level, allowing lowincome adults without children to be ensured Medicaid coverage without a federal waiver. The fourth provision states that insurance companies cannot set annual or lifetime coverage limits for medical services. To increase the affordability of health insurance, the fifth and final provision permits states to purchase health insurance with subsidies, for eligible individuals, based on income and family size.

Because the ACA supports insurance coverage (with no out-of-pocket costs) of only those procedures set forth by the US Preventive Services Task Force, Mueller and colleagues point out that some screening tests related to an individual’s previous cancer or cancer-related treatment history may not be covered by all plans. In these instances, clinicians should be aware of the potential respective health plan limitations.

Although the ACA may alleviate some of the financial burden associated with healthcare insurance, the authors contend that there are survivors of childhood cancers who may not opt for health insurance coverage. However, these individuals may end up paying a penalty, because the ACA now requires all individuals to maintain a minimum amount of health coverage monthly.

The authors suggest several topics related to adult survivors of childhood cancers that warrant further investigation, including the ability to obtain and maintain health insurance, measures of underinsurance, and evaluation of access to care. Furthermore, the authors stated that the success of the ACA is partly dependent on clinicians counseling and encouraging their patients to receive follow-up care, especially for patients with a history of cancer.

Bevacizumab Does Not Improve Survival in Patients with Newly Diagnosed Glioblastoma

In early clinical studies, bevacizu­ mab (Avastin) showed clinical activity in patients with recurrent glioblastoma. A new randomized, double-blind, placebo-controlled trial investigated whether the use of bevacizumab would improve the OS and PFS of patients with newly diagnosed glioblastoma (Gilbert MR, et al. N Engl J Med. 2014;370:699-708).

A total of 637 patients with newly diagnosed glioblastoma were random-

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ized to receive bevacizumab or placebo. All patients received temozolomide until the completion of radio­ therapy. At week 4 of radiotherapy, the patients received either intravenous bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression, severe AEs, or the completion of adjuvant therapy. Four weeks after

completing radiotherapy, the patients received maintenance treatment with temozolomide.

After a median follow-up of almost 21 months, 208 patients were evaluable for response. The median OS was 15.7 months in the bevacizumab group and 16.1 months in the placebo group.

Although PFS was longer in the beva-

cizumab group, it did not reach statistical significance.

As can be expected, the incidence of serious neutropenia and thrombocytopenia was more common in the bevacizumab group than in the placebo group. Serious AEs during maintenance treatment were more frequent in the bevacizumab group. n

NEW FOR 2014

Oncology Practice Management, Advocacy, and Navigation An educational session for practice managers and other care providers focusing on cancer care and innovative delivery techniques.

CO-CHAIRS

MAY 9, 2014 Loews Hollywood Hotel Los Angeles, CA

Linda Bosserman, MD, FACP President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AGENDA 8:30am – 8:45am

Introductions and Opening Remarks Linda Bosserman, MD, FACP; Vicki Kennedy, LCSW

8:45am – 9:15am

Session 1: Cancer Care in Crisis: An Imperative for Change Douglas Blayney, MD, Ann & John Doerr Medical Director, Cancer Center, Stanford University Medical Center; Professor of Medicine, Stanford University School of Medicine

9:15am – 10:30am

Session 2: Innovation in Practice Management and Care Delivery: A Progress Report on Value-Based Innovation Linda Bosserman, MD, FACP, President, Wilshire Oncology Medical Group John Fox, MD, Associate Vice President of Medical Affairs, Priority Health John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

10:30am – 10:45am

Break

10:45am – 11:45am

Session 3: Uniting the Patient, Provider, and Community Voice in Value-Based Cancer Care Terry Langbaum, Chief Administrative Officer, Kimmel Center, Johns Hopkins School of Medicine Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center Kim Thiboldeaux, President & CEO, Cancer Support Community

11:45am – 1:00pm

Lunch/Meet the Experts Roundtables John Fox, MD, Associate Vice President of Medical Affairs, Priority Health Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

1:00pm – 1:45pm

Keynote Address Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna

1:45pm – 2:00pm

Closing Remarks

AVBCC2014May9agenda Asize_20714

REGISTER TODAY! www.regonline.com/avbcc2014 march 2014

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CONTINUING EDUCATION

Faculty Perspectives

FEBRUARY 2014 • VOLUME 4 • NUMBER 4

™

ADVANCES IN THE TREATMENT OF HEMATOLOGIC MALIGNANCIES LETTER

PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndromes, myelofibrosis, and multiple myeloma has been presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will continue to feature highlights from these meetings, along with perspectives from highly respected thought leaders in the field, which will provide valuable practice implications for the management of your patients with hematologic malignancies.

Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly

Sincerely,

Human Resources Jennine Leale

Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

FACULTY

Creative & Design Assistant Lora LaRocca

Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/ Rush University Chicago, Illinois

Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen

Ruben A. Mesa, MD, FACP Professor and Chair Division of Hematology and Medical Oncology Deputy Director Mayo Clinic Cancer Center Professor of Medicine Scottsdale, Arizona

Susan M. O’Brien, MD Ashbel Smith Professor Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy

Supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Office Coordinator Robert Sorensen Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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FACULTY PERSPECTIVES Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Target Audience This educational program is designed for medical oncologists, hematologists, oncology nurses, advanced practice nurses, oncology/hematology nurse practitioners, physician assistants, and oncology/hematology pharmacists who participate in the management of patients with hematologic malignancies.

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of hematologic malignancies.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 2.0 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this applicationbased activity provides for 2.0 contact hours (0.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-14-001-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with hematologic malignancies, and integrate key findings into clinical practice

• Outline contemporary prognostic and predictive biomarkers and patient characteristics for MM, CLL, NHL, HL, MDS, and MF and apply the results to create an individualized approach to managing each patient Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss either non-FDA-approved or investigational use for the following products/devices: ofatumumab, ibrutinib, idelalisib, lenalidomide plus rituximab, brentuximab vedotin, 90Y ibritumomab tiuxetan, vorinostat, alemtuzumab, ruxolitinib, fedratinib, imetelstat, lenalidomide plus dexamethasone, MLN9708, carfilzomib/thalidomide/dexamethasone, and pomalidomide.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Stephanie A. Gregory, MD, is on the Speakers’ Bureau for Celgene Corporation and is Chair of the Data Safety Monitoring Board for Genentech (Protocol GAO4753g). She does intend to discuss either non–FDA-approved or investigational use for the following products/devices: brentuximab in DLBCL, lenalidomide as frontline therapy for MCL, and idelalisib for low-grade NHL. Ruben A. Mesa, MD, FACP, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

Susan M. O’Brien, MD, is a Consultant for Amgen, Celgene, Emergent, Genentech, Gilead Sciences, GlaxoSmithKline, Infinity, Pharmacyclics, and Spectrum; is on the Advisory Board for CLL

Global Research Foundation; and has received research support from Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, and Spectrum. She does intend to discuss either non–FDAapproved or investigational use for the following products/devices: ibrutinib, idelalisib, and bendamustine plus rituximab.

Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Genmab, Johnson & Johnson, Millennium: the Takeda Oncology Company, Novartis, and Triphase. He does intend to discuss non–FDA-approved or investigational use for the following products/devices: MLN9708, carfilzomib, and pomalidomide.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005D.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

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Estimated time to complete activity: 2.0 hours Date of initial release: February 18, 2014 Valid for CME/CPE/CE credit through: February 18, 2015

To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

Updates from ASH 2013 Introduction On December 7-10, 2013, researchers from around the world gathered in New Orleans, Louisiana, for the 55th American Society of Hematology Annual Meeting and Exposition (ASH 2013). After the meeting, Susan M. O’Brien, MD, from MD Anderson Cancer Center in Houston, Texas; Stephanie A. Gregory, MD, from Rush University Medical Center in Chicago, Illinois; Ruben A. Mesa, MD, FACP, from the Mayo Clinic Cancer Center in Scottsdale, Arizona; and Paul Richardson, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reviewed emerging data from abstracts and presentations on the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), myelodysplastic syndrome (MDS), myelofibrosis (MF), and multiple myeloma (MM). This supplement is designed to provide community oncology practices with key take-home messages from these experts.

CHRONIC LYMPHOCYTIC LEUKEMIA

According to the American Cancer Society (ACS), in 2013, an estimated 15,680 new cases of CLL (9720 men and 5960 women) were expected to be diagnosed in the United States, with 4580 patients (2750 men and 1830 women) dying from the disease.1 Although CLL remains incurable, over the past decade, major advances in the treatment of the disease have been realized in both the frontline and relapsed settings.2 At ASH 2013, investigators discussed promising new combination treatment regimens that incorporate both standard and investigational agents.

Ofatumumab Plus Chlorambucil versus Chlorambucil Alone Hillmen and colleagues presented the results of a phase 3 study (COMPLEMENT 1) of ofatumumab plus chlorambucil combination therapy in patients with untreated CLL considered inappropriate for treatment with fludarabine-based therapy because of age or comorbidities.3 In this study, 447 patients were randomized to receive ofatumumab plus chlorambucil or chlorambucil alone. Patients were treated for a minimum of 3 cycles until best re-

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sponse, up to a maximum of 12 cycles. Median age was 69 years; 82% of patients were ≥65 years of age and/or had ≥2 comorbidities. All modified Rai stages were represented: low, 8%; intermediate, 51%; high, 40%. Overall, 56% of patients had unmutated immunoglobulin VH (IgVH), 6% showed 17p deletions (del[17p]), and 75% had β-2-microglobulin levels ≥3500 µg/L.3 As assessed by an independent review committee, progression-free survival (PFS)—the primary end point—was 22.4 months (95% confidence interval [CI], 19.0-25.2 months) in the ofatumumab-plus-chlorambucil arm versus 13.1 months (95% CI, 10.6-13.8 months) in the chlorambucil-alone arm (hazard ratio [HR]=0.57; P<.001). Responses were higher in the ofatumumabplus-chlorambucil group compared with the group who received chlorambucil only (Figure 1).3 At a median follow-up of 28.9 months, median overall survival (OS) was not reached for patients in either arm (P=.666). OS rates at 2 years and 3 years were 88.7% and 85.1%, respectively, in the ofatumumab-plus-chlorambucil group versus 86.7% and 83.2%, respectively, in the chlorambucil-alone group.3 A total of 50% of patients in the ofatumumab-plus-chlorambucil arm and

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Figure 1. Response rates with ofatumumab plus chlorambucil vs chlorambucil alone.3 100

ORR CR PR

Patients Achieving Response (%)

82 80 68

69

67

Table 1. Grade ≥3 Adverse Events: Obinutuzumab Plus Chlorambucil vs Rituximab Plus Chlorambucil4 Grade ≥3 Adverse Events

Obinutuzumab + Chlorambucil (n=336), %

Rituximab + Chlorambucil (n=321), %

Any

70

55

Infusion reaction

20

4

Neutropenia

33

28

Infection

12

14

60

bucil versus 7% with rituximab plus chlorambucil. Infusion reactions and neutropenia were more common with obinutuzumab plus chlorambucil, and the rate of infections was similar in both groups (Table 1).4 The authors concluded that overall, obinutuzumab plus chlorambucil is superior to rituximab plus chlorambucil and is a highly active treatment in this typical, older CLL patient population with comorbidities.4

40

20

14 1

0 Ofatumumab + Chlorambucil (n=221)

Chlorambucil (n=226)

CR indicates complete response; ORR, overall response rate; PR, partial response.

43% of those in the chlorambucil-only arm experienced grade ≥3 adverse events (AEs). The most common AE was neutropenia (26% with ofatumumab plus chlorambucil vs 14% with chlorambucil alone). Grade ≥3 infusionreactions were reported in 10% of patients in the ofatumumab-plus-chlorambucil arm and in 0% of those in the chlorambucil arm. Grade ≥3 infections were reported in 9% of patients in the ofatumumab-plus-chlorambucil group versus 12% in the chlorambucil-only group. Four patients in the ofatumumabplus-chlorambucil arm and 3 patients in the chlorambucil-alone arm died.3 Perspective Although ofatumumab is approved in the United States, it is not frequently used because the original accelerated approval of this drug was for fludarabine- and alemtuzumab-refractory patients with CLL. In this trial, investigators assessed the safety and efficacy of ofatumumab when added to chlorambucil in the upfront setting for older, less fit patients. Results showed that this combination improved outcomes, including PFS, compared with chlorambucil alone. As is the case with other antibodies, use of this drug was associated with infusion reactions, and this needs to be considered. However, the overall results look promising and I think that this agent will eventually be approved for frontline use, which will further expand the treatment choices available for newly diagnosed patients who cannot tolerate more aggressive chemotherapy.

-Susan M. O’Brien, MD

Obinutuzumab Plus Chlorambucil versus Rituximab Plus Chlorambucil Goede and colleagues from the German CLL Study Group presented results of a phase 3 study (CLL11) that compared combination therapy with obinutuzumab plus chlorambucil versus rituximab plus chlorambucil in 781 previously untreated, older patients with comorbidities (Cumulative Illness Rating Scale [CIRS] total score >6 and/or estimated creatinine clearance [CrCl] <70 mL/min).4 PFS—the primary end point of the study—was significantly longer in the obinutuzumab-plus-chlorambucil group than in the rituximab-plus-chlorambucil group (median 26.7 months vs 15.2 months, respectively; HR=0.39; 95% CI, 0.31-0.49; P<.0001). Overall response rates (ORRs) were 78% with obinutuzumab plus chlorambucil versus 65% with rituximab plus chlorambucil; complete response (CR) rates were 21% with obinutuzumab plus chloram-

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Perspective In Europe, where clinicians generally cannot use drugs off-label, the standard of care for older or frail patients with CLL is chlorambucil. Here in the United States, however, there is a wider variety of drugs available, including rituximab. The CLL11 study compared the combination of either obinutuzumab or rituximab plus chlorambucil with chlorambucil alone in patients with advanced age and/or comorbidities, and found that the addition of either antibody produced better results. In a later analysis of this trial, investigators compared these antibodies head to head, and found that obinutuzumab plus chlorambucil was superior to rituximab plus chlorambucil.

Specifically, the CR rates were 3 times as high in the obinutuzumab arm as in the rituximab arm, and the PFS was significantly longer. There was even a trend toward prolonged OS with obinutuzumab. The investigators performed a minimal residual disease (MRD) assay in select patients in this study, which showed that approximately 20% of the obinutuzumab-treated patients were MRD-negative, which is a surprising result with a chlorambucil backbone.

Although toxicity rates were very similar overall, it is important to note the significantly higher rate of infusion reactions, including severe reactions associated with obinutuzumab. This is an important consideration in a frail population, and now that this agent is approved for use in the United States, clinicians need to be aware of this risk and have appropriate mechanisms and protocols in place to deal with it.

-Susan M. O’Brien, MD

Fludarabine, Cyclophosphamide, and Rituximab versus Bendamustine Plus Rituximab Eichhorst and colleagues from the German CLL Study Group presented planned interim analysis results of a phase 3 study (CLL10) that compared the combination of fludarabine, cyclophosphamide, and rituximab (FCR) with bendamustine plus rituximab (BR) in 561 previously untreated, physically fit patients (CIRS total score ≤6 and estimated CrCl >70 mL/min) with advanced CLL.5 Patients with del[17p] were excluded from the study.

After a median observation time of 27.9 months, all 561 patients were evaluable for PFS and OS, but only 547 patients were evaluable for response.

At 2 years, PFS was 85.0% in the FCR group and 78.2% in the BR group (HR=1.385; P=.041). No difference in OS rate was reported between the 2 groups (FCR, 94.2% vs BR, 95.8% at 2 years; HR=0.842; P=.593). The ORR was identical (97.8%) in both arms, but higher CR rates were observed with FCR versus BR therapy (Table 2).5 FCR-treated patients experienced significantly more frequent grade ≥3 AEs than did BR-treated patients (90.8% vs 78.5%, respectively; P<.001), including hematologic AEs (90.0% vs 66.9%, respectively; P<.001). The higher rate of severe neutropenia (81.7% vs 56.8%, respectively; P<.001) was associated with a significantly higher rate of severe infections (39.0% vs 25.4%, respectively; P=.001) in the FCR group, particularly in the elderly (FCR, 47.4% vs BR, 26.5%; P=.002). Treatment-related mortality was reported in 3.9% of pa-

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FACULTY PERSPECTIVES tients (n=11) in the FCR group and 2.1% of patients (n=6) in the BR group.5 The authors concluded that FCR seems more efficient than BR in the frontline treatment of physically fit patients with CLL, although a higher rate of severe AEs, including neutropenia and infections, was associated with FCR use.5

Table 2. Response Rates: Fludarabine, Cyclophosphamide, and Rituximab vs Bendamustine Plus Rituximab5 FCR (n=274)

BR (n=273)

ORR

97.8%

97.8%

CR

40.1%

36.3%

PR

50.4%

59.7%

Response

Perspective This was a follow-on trial to the CLL8 trial that evaluated FCR versus FC for newly diagnosed CLL. Results of this new trial showed that the ORR rates were similar in both arms, although FCR produced a higher CR rate and longer PFS than BR. However, the percentage of patients who had unmutated IgVH was higher in the BR arm than in the FCR arm. This is important to note because we know that patients who have mutated genes experience much longer PFS than those who do not. Because the mutation status was not balanced between the 2 arms, the investigators conducted a multivariate analysis for PFS and OS, which still showed that FCR was a more effective regimen than BR. FCR was shown to be more toxic, however, especially in terms of neutropenia and infection. One caveat to remember, though, is the fact that the German group did not administer growth factors to their patients. In the United States, we typically will use growth factor support with FCR, which allows more patients to complete all 6 cycles of therapy. I think that BR is a good frontline treatment option for older patients with CLL who cannot tolerate FCR. -Susan M. O’Brien, MD

Ibrutinib Plus Rituximab Burger and colleagues presented results of a single-center, nonrandomized, phase 2 study of the combination of ibrutinib plus rituximab in 40 patients with high-risk CLL (ie, presence of del[17p] or TP53 mutation; PFS <36 months after frontline chemoimmunotherapy; or relapsed CLL with del[11q]).6 At 18 months’ follow-up, median PFS was 78% for all patients (72% for those with del[17p] and 84% for those without del[17p]); median OS was 84% for all patients (78% for those with del[17p] and 89% for those without del[17p]).6 The responses at 12 months or best responses before study discontinuation were 95% ORR, including 4 patients (10%) who achieved a CR and 34 patients (85%) with a partial response (PR).6

The question that this trial asked is whether faster or deeper responses can be achieved when rituximab is added to ibrutinib for the treatment of CLL. Among the 8 patients who came off study, 3 died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possible ibrutinib-related toxicity (1 subdural hematoma, 1 grade 3 mucositis), 1 patient experienced progressive disease, and 1 proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common AE. Two grade 3, possibly related AEs were reported: mucositis in 1 patient and peripheral neuropathy in 1 patient.6 Perspective The question that this trial asked is whether faster or deeper responses can be achieved when rituximab is added to ibrutinib for the treatment of CLL. We know that there is a very dramatic and rapid reduction in lymphadenopathy with single-agent ibrutinib, but for the majority of patients, there will also be a rise in the lymphocyte count. Although many patients are asymptomatic despite these high counts, the reality is that a response, according to International Workshop on Chronic Lymphocytic Leukemia (WCLL) criteria, requires not only lymph node shrinkage but a 50% reduction in baseline lymphocyte count. The goal of combining rituximab and ibrutinib in this trial was to abrogate the lymphocytosis using a nonchemotherapeutic regimen that would not be myelosuppressive. In that respect, I think the trial was successful. Although the CR rates do not appear to be much higher than those

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BR indicates bendamustine plus rituximab; CR, complete response; FCR, fludarabine, cyclophosphamide, and rituximab; ORR, overall response rate; PR, partial response.

we have seen with ibrutinib alone, it is important to remember that CRs evolve over time. Therefore, it may be too early to see this potential benefit.

Another factor that should be considered is the fact that the rituximab was given only during the first 6 months of therapy, whereas the ibrutinib was given indefinitely. Since the follow-up for this trial is still relatively short, we do not yet know whether ibrutinib plus rituximab will lead to more durable responses than ibrutinib alone in CLL. -Susan M. O’Brien, MD

Idelalisib Plus Rituximab Furman and colleagues presented results from a prespecified interim analysis of a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of idelalisib plus rituximab in 220 previously treated patients with CLL. Patient characteristics included the following: median age, 71 years; CIRS total score >6 in 85% of subjects; median CrCl, 63.6 mL/min; anemia in 73% of patients; thrombocytopenia in 61% of subjects; neutropenia in 34% of patients.7 Median time since diagnosis was 8.5 years, median number of prior therapies was 3 (range, 1-12), and 44% of participants had del[17p] or TP53 mutation.7 PFS in the idelalisib-plus-rituximab group was superior to that in the control group, who received placebo plus rituximab alone (HR=0.15; 95% CI, 0.08-0.28; P<.001). The median PFS in patients treated with idelalisib plus rituximab was not reached and was 5.5 months in the control group. At 24 weeks, PFS rates in the idelalisib-plus-rituximab group and the control group were 93% and 46%, respectively. Compared with the control group, patients treated with idelalisib plus rituximab also experienced a significant improvement in OS: HR=0.28; 95% CI, 0.09-0.86; P=.018.7 Among 88 evaluable patients, idelalisib also significantly improved ORR (81% in the idelalisibplus-rituximab arm vs 13% in the control group; P<.0001). The combination of idelalisib plus rituximab had an acceptable safety profile, with grade ≥3 AEs reported in 56% of patients, compared with 48% in the rituximabplus-placebo group.7 The most common AEs included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusion-related reactions. Based on a review of interim efficacy and safety findings, the data monitoring committee recommended stopping this study early.

Perspective Although the eligibility criteria in this trial were a bit complicated, the bottom line is that these were patients for whom chemotherapy was not a good treatment option, due to serious comorbidities, poor performance status, and/or cytopenia. Not surprisingly, the results of this study showed that adding idelalisib to rituximab led to superior outcomes compared with rituximab alone, in terms of higher response rates and dramatically longer PFS. This trial has received some criticism, however, from those in the hematology/oncology community who feel that rituximab alone is not an adequate control arm. In an academic setting, where clinicians have other treatment options, this is true. However, in community centers, rituximab is often used for patients who cannot tolerate chemotherapy in the relapsed/refractory setting, due to the fact that it is not myelosuppressive. If you look at the AEs in the 2 arms of this study, you will notice that, with the exception of transaminases elevation, they are very similar. So perhaps a lot of these toxicities (eg, diarrhea, cough) are events that commonly occur in a frail population. This is exactly why you would not want to treat these patients with chemotherapy.

-Susan M. O’Brien, MD

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Table 3. Adverse Events With Idelalisib in Indolent NHL Refractory to Rituximab and to an Alkylating Agent9 Adverse Event

All Grades, %

Grade ≥3, %

Diarrhea

43

13

Fatigue

30

2

Nausea

30

2

Cough

29

0

Pyrexia

28

2

Dyspnea

18

3

Rash

13

2

Pneumonia

11

7

NHL indicates non-Hodgkin lymphoma.

LYMPHOMAS

According to the ACS, in 2013, an estimated 79,030 new cases of lymphoma (69,740 cases of NHL and 9290 cases of HL) were expected to be diagnosed in the United States, with 20,200 patients dying from the disease (19,020 from NHL and 1180 from HL).1 At ASH 2013, investigators discussed new combination and single-agent therapies now being used to improve outcomes in patients with indolent and more aggressive forms of the disease.

Lenalidomide Plus Rituximab Ruan and colleagues presented results of a multicenter, phase 2 study of lenalidomide plus rituximab as frontline treatment in 31 patients with mantle cell lymphoma (MCL).8 At study entry, the median patient age was 65 years (range, 42-86 years). All patients had stage III/IV disease, 12 (39%) had elevated lactate dehydrogenase (LDH), and 27 (87%) had bone marrow involvement. Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were evenly distributed among low-, intermediate-, and high-risk groups (36%, 32%, and 32%, respectively). The Ki-67 proliferation index was <30% in 23 patients (74%). A total of 30 patients were evaluable for efficacy. The preliminary ORR for the evaluable patients was 77% (95% CI, 57%-89%), with 40% CR/unconfirmed complete response (CRu; 95% CI, 23%-59%). Median time to response was 2.8 months, with CR typically confirmed between 6 and 12 months. Median PFS and duration of response (DOR) were not reached.

Neither the MIPI score nor the Ki-67 index correlated with the response.8 Treatment was generally well tolerated, with expected AEs reported. Grade 3/4 hematologic toxicities included neutropenia (39%), thrombocytopenia (13%), and anemia (7%). Grade 3/4 nonhematologic toxicities included rash (23%), tumor flare (7%), and serum sickness associated with rituximab (7%).

One incidence each of deep vein thrombosis and pulmonary embolism was observed, both of which resolved with treatment. The authors concluded that this study provides the first demonstration that a chemotherapy-free, combination biologic approach is feasible as initial therapy for patients with MCL.8 Perspective This was a very impressive study of combining the monoclonal antibody rituximab with the immunomodulator lenalidomide for the treatment of patients with newly diagnosed MCL. It is important to note, however, that when we look at the types of patients enrolled in this trial, approximately one-third had low-risk disease. In addition, the Ki-67 index was <30% in 74% of patients, which may have contributed to the high response rates seen with the use of biologic agents such as these. Regardless, I still think the results are exciting and this regimen may be a useful addition to the treatment armamentarium for MCL, especially for older patients who may not be able to tolerate standard chemotherapy.

-Stephanie A. Gregory, MD

Idelalisib Gopal and colleagues presented results from a phase 2 study of idelalisib in 125 patients (median age, 64 years; range, 33-87 years) with indolent B-cell NHL refractory to both rituximab and to an alkylating agent.9 Indolent NHL

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subtypes included 58% (n=72) with follicular lymphoma (FL), 22% (n=28) with small lymphocytic lymphoma (SLL), 12% (n=15) with marginal zone lymphoma (MZL), and 8% (n=10) with lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM). The median number of prior therapies was 4 (range, 2-12). The most common treatment regimens included BR (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n=56).9 Overall, 14 patients (11%) had undergone autologous stem cell transplantation (ASCT). A total of 81 patients (65%) had received prior bendamustine, of whom 61 (75%) were refractory; 112 patients (90%) were refractory to their last treatment regimen, and 99 patients (79%) were refractory to ≥2 regimens. Median time since completion of the last treatment regimen was 3.9 months. At baseline, patients had elevated LDH (30%), bulky disease >7 cm (26%), anemia grade ≥1 (51%), neutropenia grade ≥1 (24%), and thrombocytopenia grade ≥1 (34%).9 At a median follow-up of 9.4 months, the ORR was 57% (95% CI, 47.665.6), including 7 CRs (6%) and 63 PRs (50%).9 Median time to response was 1.9 months (range, 1.6-8.3 months); median time to CR was 3.7 months (range, 1.9-12 months). ORRs for the various NHL subtypes were as follows: FL, 54%; SLL, 61%; LPL/WM, 80%; and MZL, 47%. ORRs were as follows: 59% among bendamustine-refractory patients; 50%/62% among those with <4/≥4 prior therapies; and 57%/57% among those with bulky disease <7 cm/≥7 cm. Among responders, median DOR was 12.5 months. Median PFS for all patients was 11.0 months, and median OS was 20.4 months. The most common AEs are shown in Table 3.9 Based on central laboratory measurements, grade ≥3 alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevations occurred in 16 patients (13%). The drug was held for these patients, and 11 of 14 patients (79%) were retreated without any recurrence of ALT/AST elevation. Grade ≥3 neutropenia occurred in 27% of patients, thrombocytopenia in 6%, and anemia in 2%.

Overall, 20% of patients have discontinued treatment due to AEs.9

The authors concluded that idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory, indolent NHL population.

The authors concluded that idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory, indolent NHL population, with an ORR of 57%. The ORR was consistent across all subgroups, regardless of disease histology, number of prior treatment regimens, refractoriness to bendamustine, or tumor bulk.9 Perspective This phase 2 trial enrolled heavily pretreated patients with indolent NHL who had become refractory to both rituximab and an alkylating agent; many of these individuals were refractory to bendamustine. Although the data presented reflect a rather short follow-up, the ORR rate of 57% and the median DOR of more than 1 year in patients treated with single-agent idelalisib look very promising. I think that a possible future direction may be to evaluate new combinations that include oral agents such as idelalisib at the time of first relapse. This is especially important given the high cost of standard chemotherapy, which typically includes numerous expenses related to monitoring for and managing treatment-related toxicities.

-Stephanie A. Gregory, MD

Brentuximab Vedotin in NHL Bartlett and colleagues presented interim results of an open-label, single-arm, phase 2 study of brentuximab vedotin in 68 evaluable patients with CD30-positive B-cell NHL (diffuse large B-cell lymphoma [DLBCL; n=50]; other B-cell lymphomas [n=18]) with variable CD30 expression who have relapsed or have been refractory to ≥1 prior systemic therapy.10 The median patient age was 63 years in the DLBCL cohort and 36 years in the B-cell lymphoma cohort. The median percentage of CD30-positive malignant cells was

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FACULTY PERSPECTIVES 25% in the DLBCL group and 45% in the group with other B-cell lymphomas.

Of the 50 patients with DLBCL, 42% achieved an ORR, including 16% CRs and 26% PRs. At the time of data analysis, the median DOR in patients with DLBCL was 5.8 months. In patients with DLBCL who achieved a CR, the median DOR was 11.5 months.10 The most common treatment-emergent AEs of any grade in patients with DLBCL and other B-cell lymphomas included fatigue (49%), neutropenia (40%), nausea (38%), diarrhea (37%), and fever (29%). The most common grade 3 treatment-emergent AEs in patients with DLBCL and other B-cell lymphomas were neutropenia and anemia. The only grade 4 treatment-emergent AE was neutropenia. Serious AEs that were considered treatment-related and occurred in >1 patient were pneumonia (n=3), anemia (n=2), febrile neutropenia (n=2), neutropenia (n=2), and thrombocytopenia (n=2).10 Perspective In this phase 2 study, 40% of the evaluable patients with DLBCL who were treated with brentuximab achieved an ORR; that is impressive since many of these individuals were heavily pretreated. The results of this trial have also shed new light on the significance of CD30 expression in this subset of patients. I think these are exciting new findings and it appears that there are patients with B-cell lymphomas who may respond to a drug that has traditionally been used for T-cell lymphomas and HL. What I would like to see reported is the correlation between CD30 expression and response to this therapy.

-Stephanie A. Gregory, MD

Yttrium-90 (90Y) Ibritumomab Tiuxetan Lopez-Guillermo and colleagues presented preliminary (36-month) results from a multicenter, randomized, phase 2 study (ZAR2007) that compared consolidation with a single dose of 90Y ibritumomab tiuxetan versus maintenance with rituximab in 146 patients (median age, 55 years) with newly diagnosed FL responding to R-CHOP.11 Based on Follicular Lymphoma International Prognostic Index scores, 14% of patients were low risk, 47% were intermediate risk, and 39% were high risk.11 After R-CHOP, 124 patients (56 in CR, 13 in CRu, and 55 in PR) were randomized in a 1:1 fashion (stratified by response) to receive consolidation with 90Y ibritumomab tiuxetan or rituximab maintenance. A total of 63 patients (51%) were assigned to group A (consolidation with 90Y ibritumomab tiuxetan) and 61 (49%) to group B (rituximab maintenance). There were 22 patients who were not randomized because of response <PR, low neutrophil or platelet counts, or personal decision.11

I think that the long-term follow-up data from this phase 2 study of brentuximab holds promise for patients with HL who have relapsed following transplant.

After a median follow-up of 37 months from randomization (range, 26-56 months), 31 patients eventually progressed/relapsed, with a 36-month PFS of 64% for patients in group A and 86% for patients in group B (HR=0.38; 95% CI, 0.17-0.83; P=.01). Overall, 50% (14 of 28) of patients in group A and 46% (12 of 26) of those in group B who were in PR after R-CHOP reached CR during maintenance. Two patients developed transformation to DLBCL at 8 months (arm A) and 39 months (arm B) after randomization.11 During the maintenance period, patients receiving 90Y ibritumomab tiuxetan exhibited grade 3/4 neutropenia in 6 of 63 cases and grade 3/4 thrombocytopenia in 5 of 63 cases, whereas these values were 1 of 61 cases and 0 of 61 cases, respectively, for patients in arm B (P=.05). No unexpected late toxicities were reported. Five patients died during the follow-up due to progression of lymphoma in all cases, with no differences between the arms (36-month OS, 98% vs 95% for arms A and B, respectively).11 The authors concluded that in patients with FL who responded after R-CHOP, maintenance with rituximab was superior to consolidation with 90Y ibritumomab tiuxetan in terms of PFS, with no differences in OS reported.11

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Table 4. Median Overall Survival by Best Clinical Response With Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma13 Best Clinical Response

n

Median OS

CR

34

Not yet reached

PR

42

31.6 months

SD

22

20.6 months

PD

3

10.2 months

CR indicates complete response; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease.

Perspective The results of this study were disappointing, especially in light of the impressive data that were reported in the earlier FIT trial,12 which compared 90Y ibritumomab tiuxetan versus observation in patients with FL who had achieved a CR or PR with standard frontline chemotherapy. In that trial, there was a conversion from PR to CR in 77% of patients who received 90Y ibritumomab. In this new study, investigators compared 90Y ibritumomab consolidation with rituximab maintenance in patients who had responded to R-CHOP. Interestingly, they reported shorter PFS with 90Y ibritumomab than with rituximab, and the conversion rate from PR to CR with radioimmunotherapy was lower than in the FIT trial. There also was no difference in terms of OS between the 2 therapies. However, a larger international trial is under way comparing 90Y ibritumomab consolidation with rituximab maintenance following frontline chemotherapy in patients with FL. It will be interesting to see results from that trial.

-Stephanie A. Gregory, MD

Brentuximab Vedotin in HL Gopal and colleagues presented 3-year follow-up data and characterization from an ongoing phase 2 study of brentuximab vedotin in 102 patients with relapsed or refractory HL following ASCT.13 In this high-risk population with a poor prognosis, the median time to relapse after ASCT was 6.7 months (range, 0-131 months). After a median of 9 cycles of brentuximab vedotin, the ORR was 75%, which included CRs in 33% of patients. The median OS was 40.5 months and the estimated 36-month survival rate was 54% (95% CI, 44%-64%). Median OS times by best clinical response are shown in Table 4.13 The most commonly reported (≥15%) brentuximab vedotin–related AEs of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Grade ≥3 AEs that occurred in ≥5% of patients included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.13 Of the 102 patients enrolled, 51 (50%) were alive at the time of last follow-up. Of the 51 patients who were alive at the time of this analysis, 14 remain in remission with no evidence of disease progression. Of these 14 patients, 11 had CRs and 3 had PRs following treatment with brentuximab vedotin; all 3 of the patients with PRs underwent subsequent allogeneic stem cell transplantation. The observation time for the 14 patients who remain in remission ranges from 31.5 months to 44.4 months, and their PFS ranges from 27.2+ months to 44.4+ months.13 Perspective I think that the long-term follow-up data from this phase 2 study of brentuximab holds promise for patients with HL who have relapsed following transplant; these individuals typically have a very poor prognosis and few treatment options left. What we are seeing with these data are a large number of patients who are in long-term remission who have not relapsed after 16 cycles of therapy. In addition, brentuximab tends to be very tolerable, with the most common toxicity being peripheral neuropathy. It was also impressive to see that 14 patients showed no evidence of disease progression and some of those who had PR were actually taken off the drug because they were able to go on to transplant.

-Stephanie A. Gregory, MD

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Group

Intermediate-1 Risk

Intermediate-2 Risk

High Risk

Unclassified

1

3

3

5

2

2

3

4

4

2

3

2

5

3

3

IPSS indicates International Prognostic Scoring System.

MYELODYSPLASTIC SYNDROME

The MDSs are a collection of myeloid malignancies characterized by ≥1 peripheral blood cytopenias and that progress to acute myeloid leukemia (AML) with myelodysplastic features when blood or bone marrow blasts reach or exceed 20%.14 Approximately 50% of patients with MDS have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromosome 5 or 7, or trisomy 8.14 In recent years, several therapies have been approved for the treatment of MDS, with a number of promising new agents also under investigation, as discussed by presenters at ASH 2013.

Vorinostat Plus Azacitidine Silverman and colleagues from the New York Cancer Consortium presented initial results of a phase 2 study of the combination of vorinostat plus azacitidine in 40 patients (median age, 67 years) with intermediate-1, intermediate-2, or high-risk MDS.15 Patients were treated with vorinostat plus azacitidine, using 1 of 3 different dosing schedules: • Group 1 (n=13) received azacitidine 55 mg/m2 once daily on days 1 to 7 plus vorinostat 200 mg twice daily on days 3 to 16 of a 28-day treatment cycle • Group 2 (n=13) received azacitidine 75 mg/m2 once daily on days 1 to 7 plus vorinostat 300 mg twice daily on days 3 to 9 of a 28-day treatment cycle • Group 3 (n=14) received azacitidine 55 mg/m2 once daily on days 1 to 7 plus vorinostat 200 mg twice daily on days 3 to 9 of a 28-day treatment cycle The distribution of patients by International Prognostic Scoring System classification is illustrated in Table 5.15 Among the 33 patients evaluable for response, ORR was 70% (23 of 33), including 10 patients who achieved a CR. Responses by group are shown in Figure 2. Median time to response was 2 cycles (8 weeks). Median DOR was 16 months overall, and 9.5 months, 23 months, and 27 months, respectively, for groups 1, 2, and 3.15

I think that in the end, it will be necessary to also compare azacitidine plus vorinostat with azacitidine alone in a randomized trial.

Median OS was 21.1 months; median OS by group was 10.1 months, 37.4 months, and 19 months for groups 1, 2, and 3, respectively.15 Grade 3 fatigue occurred during cycle 1, 2, or 3 in group 1 (8%), group 2 (16%), and group 3 (8%). Grade 3 gastrointestinal toxicity (vomiting, diarrhea, dehydration) was reported in 8% of patients in each of the 3 treatment groups.15 Perspective Azacitidine is clearly the standard treatment for the majority of patients with MDS, with the possible exception of lenalidomide, which has been approved as frontline therapy for patients with a deletion 5q cytogenetic mutation. Over the past several years, there has been increased interest in trying to build upon these treatments to improve patient outcomes. The results of this trial are important because investigators sought to determine whether there is a synergistic benefit when azacitidine is combined with vorinostat, an oral histone deacetylase inhibitor that has shown some activity as a single agent in MDS. Based on the data presented, it appears that the doses and schedules used in groups 2 and 3 appear to be safe and effective. The next step will be to move ahead with another clinical trial in which a large number of patients are treated with the approach used in this

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Figure 2. Responses to vorinostat plus azacitidine by treatment group.15 100

Patients Achieving Response (%)

Table 5. IPSS Classification of Patients by Group15

80 70

73 67

60

40

20

0 Group 1

Group 2

Group 3

study. I think that in the end, it will be necessary to also compare azacitidine plus vorinostat with azacitidine alone in a randomized trial to determine whether the 2-drug regimen can replace the 1-drug regimen. It will also be interesting to see the results from a parallel intergroup study that is comparing azacitidine alone versus azacitidine plus vorinostat versus azacitidine plus lenalidomide.16 -Ruben A. Mesa, MD

Alemtuzumab Ranpura and colleagues presented updated results from a phase 1/2 study of alemtuzumab in 40 patients with MDS (median age, 56 years; range, 23-71 years) who were deemed good candidates for immunosuppressive therapy.17 Median follow-up was 25 months (range, 3-64 months). Of 39 evaluable patients, 64% (25 of 39) achieved an ORR, including 21% (8 of 39) who achieved a CR. All responding patients who were previously transfusion-dependent became transfusion-independent following treatment with alemtuzumab. Overall, 73% (8 of 11) of patients who relapsed responded again with the addition of cyclosporine, another immunosuppressive therapy. The median OS was 34 months (range, 1-72 months), with a median OS of 36 months (range, 6-72 months) in patients who responded versus 16 months (range, 1-56 months) in those who did not respond (P<.001).17 Of 12 patients with abnormal cytogenetics at the start of treatment, 5 experienced a complete cytogenetic remission at 1 year. One patient with monosomy 7 and another with del[13] were in cytogenetic remission for 4.5 years and 4 years, respectively. Decline in those patients’ blood counts correlated with reemergence of the initial clone. Three patients with del[13], del[5q], and del[5] continue to remain in cytogenetic remission at 4 years, 2 years, and 1 year, respectively.17 Alemtuzumab was generally well tolerated, with most patients experiencing manageable infusion reactions with the first dose. Of the 39 evaluable patients, 16 became transiently positive for Epstein-Barr virus DNA and 6 of 29 cytomegalovirus-seropositive patients had reactivation, but no patient developed clinically significant viral disease.

Perspective In previous trials, immunosuppressive therapy with azacitidine and cyclosporine has shown some efficacy in patients with hypocellular MDS; this may be due to the degree of T-cell mediated suppressive hematopoiesis that occurs. This single-arm study was developed to assess whether alemtuzumab is a viable alternative for patients who are deemed good candidates for immunosuppressive therapy, based on a specific algorithm. Overall,

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FACULTY PERSPECTIVES despite the fact that this was not a randomized trial comparing alemtuzumab versus azacitidine or cyclosporine, the results look promising in terms of clinical activity and effectiveness for this subset of patients with MDS. -Ruben A. Mesa, MD

Table 6. Improvement in Spleen Volume (≥35% Reduction from Baseline) in the COMFORT-I and COMFORT-II Trials22 Ruxolitinib Weeks

MYELOFIBROSIS

MF, which belongs to the class of hematologic malignancies known as myeloproliferative neoplasms, may be primary, secondary to polycythemia vera, or secondary to essential thrombocythemia.18 Characterized by splenomegaly, burdensome symptoms, progressive bone marrow fibrosis, and shortened survival, MF has a poor prognosis and limited treatment options.19,20 Clinical trial results presented at ASH 2013 provided important safety and efficacy updates on novel and approved agents being evaluated for the disease.

Ruxolitinib In the 2 phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment (COMFORT) studies, ruxolitinib was shown to reduce spleen volume, ameliorate myelofibrosis-related symptoms, and improve quality of life and OS compared with placebo (COMFORT-I)21 and best available therapy (COMFORT-II), which included hydroxyurea, interferon-alpha, or various sequential therapies.22,23 The primary and key secondary end points were both met: proportion of patients achieving a response (defined as a ≥35% reduction in spleen volume) at week 48 (ruxolitinib, 28%; best available therapy, 0%; P<.0001) and at week 24 (41% and 0%; P <.0001), respectively (Table 6).22 At 2013 ASH, a 3-year update of the longer-term efficacy and safety findings of the COMFORT-I study was presented by Verstovsek and colleagues.24 After a median follow-up of 149 weeks, of 155 patients originally randomized to ruxolitinib, 77 remained on therapy. Of 154 patients originally randomized to placebo, 111 crossed over to ruxolitinib; the median time to crossover was 41.1 weeks (range, 5.1-65.4 weeks). At week 24, patients originally randomized to ruxolitinib had a mean spleen volume reduction of 31.6%; this was durable for patients who continued on ruxolitinib, with a mean spleen volume reduction at week 144 of 34.1%. Overall, 59% (91 of 155) of patients originally randomized to ruxolitinib achieved a ≥35% spleen volume reduction at any time during the study; for these patients, the probability of maintaining this response for >132 weeks from the time of their initial response was 0.53.24

It is encouraging to see that approximately half of the patients enrolled in the COMFORT-I study have remained on ruxolitinib therapy after 3 years.

OS favored ruxolitinib (HR=0.69; 95% CI, 0.46-1.03; P =.067), with 42 and 54 deaths among patients originally randomized to ruxolitinib and placebo, respectively. Modeling of the hazard function of death over time, in order to explore the effect of crossover to ruxolitinib in patients originally randomized to placebo, showed a decrease in hazard for these patients, which corresponded to an increased proportion of patients crossing over to ruxolitinib.24 In patients originally randomized to ruxolitinib who continued on therapy, no substantial change in the rate, distribution, or severity of nonhematologic AEs was reported with longer-term therapy; most nonhematologic AEs were grade 1 or grade 2. Mean/median hemoglobin levels and platelet counts remained stable with longer-term therapy. Consistent with this, the incidence of new-onset grade 3/4 anemia and thrombocytopenia observed after the first 6 months of ruxolitinib therapy decreased relative to that seen in the first 6 months of therapy. With approximately 1 year of additional follow-up, 4 new cases of AML were reported: 2 patients originally randomized to placebo (376 and 666 days after crossover to ruxolitinib) and 2 patients originally randomized to ruxolitinib (848 and 1143 days after starting ruxolitinib).24 The authors concluded that after a median follow-up of 149 weeks, the HR for OS favored patients originally randomized to ruxolitinib over those originally randomized to placebo, the majority of whom crossed over to ruxolitinib.

The hazard of death for patients originally randomized to placebo decreased as

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Week 24

Patients with spleen volume reduction ≥35% P Value

Placebo

41.9%

Placebo

Week 48 0.7%

<.0001

Ruxolitinib 28.5%

0% <.0001

patients crossed over to ruxolitinib. Spleen volume reductions were sustained with longer-term therapy. Additionally, the incidence of new-onset grade 3/4 anemia and thrombocytopenia decreased with longer-term therapy.24 Perspective It is encouraging to see that approximately half of the patients enrolled in the COMFORT-I study have remained on ruxolitinib therapy after 3 years, and that these patients continue to reap benefits in terms of reduced spleen volume and other symptoms. It is also important to note that an improvement in survival continues to be reported. I think that a significant key takeaway point regarding these long-term follow-up results is the fact that these patients do not seem to be experiencing late treatment-related AEs. In particular, there is no evidence of long-term neurologic toxicity. This is very important, as we have seen neurologic toxicities, such as Wernicke’s encephalopathy, with fedratinib (formerly SAR302503).

-Ruben A. Mesa, MD

Fedratinib Pardanani and colleagues presented the results of a randomized, double-blind, placebo-controlled, phase 3 study (JAKARTA) of fedratinib (400 mg vs 500 mg) in 289 patients (median age, 65 years) with intermediate-2 or high-risk MF.25 Spleen response rate, defined as a ≥35% reduction in spleen volume from baseline as measured by magnetic resonance imaging or computed tomography at week 24 and confirmed 4 weeks later, was the primary end point. Secondary end points included symptom response rate and safety.25 Although dose reductions and treatment interruptions were higher with fedratinib, discontinuation rates up to 24 weeks were similar across the 3 arms (placebo, 36%; fedratinib 400 mg, 22%; fedratinib 500 mg, 32%). Spleen response (confirmed at 28 weeks) was reported in 1.0% of patients receiving placebo, 36% of those receiving fedratinib 400 mg, and 40% of those receiving fedratinib 500 mg (fedratinib vs placebo, P<.0001). Response differences were consistent across MF subtypes, risk status groups, mutational status, and platelet count groups. Analysis of symptom response (proportion of patients with ≥50% reduction in total symptom score) at week 24 revealed rates of 28% and 35% with fedratinib 400-mg and 500-mg doses, respectively, versus 7% with placebo (P<.0001).25 The most common nonhematologic treatment-emergent AE (all grades) was diarrhea (16%, 66%, and 56% of patients in the placebo, fedratinib 400mg, and fedratinib 500-mg groups, respectively). Grade 3/4 diarrhea was reported in 5% of patients in both the fedratinib 400-mg and fedratinib 500-mg dose groups. The most common hematologic treatment-emergent AE was anemia (any grade: 91%, 99%, and 98%; grade 3/4: 25%, 43%, and 60% in the placebo, fedratinib 400-mg, and fedratinib 500-mg groups, respectively).25 Rates of grade 3/4 thrombocytopenia were 9% (placebo), 17% (fedratinib 400 mg), and 27% (fedratinib 500 mg). Incidences of grade 3/4 liver function tests (placebo/fedratinib 400 mg/fedratinib 500 mg) were as follows: bilirubin, 2%/2%/1%; ALT, 0%/3%/3%; and AST, 1%/2%/2%. Overall discontinuation rates up to 24 weeks of treatment were 25% with placebo, 22% with fedratinib 400 mg, and 32% with fedratinib 500 mg. A total of 25 patients died during the study (10, 5, and 10 in the placebo, fedratinib 400-mg, and fedratinib 500-mg groups, respectively). The most common causes of death were disease progression (placebo, n=5; fedratinib 400 mg, n=3; and fedratinib 500 mg, n=4) and AEs (placebo, n=4; fedratinib 400 mg, n=1; and fedratinib 500 mg, n=4).25 The study met its primary and key secondary end points, with fedratinib associated with significant improvements in splenomegaly and constitutional

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CONTINUING EDUCATION

Table 7. Adverse Events in the FIRST Study27 Group

Continuous Rd

Rd18

MPT

Neutropenia

27.8

26.5

44.9

Anemia

18.2

15.7

18.9

Thrombocytopenia

8.3

8.0

11.1

Infections

28.9

21.9

17.2

Pneumonia

8.1

8.3

5.7

DVT and/or PE

7.9

5.6

5.4

PSN

1.1

0.4

9.4

Constipation

2.3

1.9

5.4

Cataract

5.8

2.6

0.6

Hematologic, %

Nonhematologic, %

Continuous Rd indicates low-dose dexamethasone plus continuous lenalidomide until disease progression; DVT, deep vein thrombosis; MPT, melphalan/prednisone/thalidomide; PE, pulmonary embolism; PSN, peripheral sensory neuropathy; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.

symptoms compared with placebo, but little change in the JAK2 mutant allele burden.25 Unfortunately, several patients developed serious neurologic AEs, most closely resembling Wernicke’s encephalopathy. Because of these toxicities, the manufacturer has halted all clinical studies and canceled plans for regulatory filings of the agent.

Perspective Fedratinib was the second agent to be evaluated in a rigorous phase 3 study for the treatment of MF. This clinical study was successful in the sense that it met its primary end point (ie, improvement in splenomegaly).

However, between the time that the investigators submitted their abstract and the actual ASH 2013 meeting, a small subset of patients treated with fedratinib developed Wernicke’s encephalopathy. As a result, all clinical trials of this agent have now been halted. I think this clearly illustrates the fact that we cannot assume that long-term toxicities are automatically benign and that they need to be considered carefully when evaluating the safety of novel therapies.

-Ruben A. Mesa, MD

Imetelstat Tefferi and colleagues from the Mayo Clinic in Rochester presented the results of an investigator-sponsored, single-center, phase 1 study of imetelstat in 18 patients with high- or intermediate-2–risk MF. Overall, 44% of patients had an ORR, including 22% (n=4) who achieved a CR.26 All 4 patients with a CR experienced a reversal of bone marrow fibrosis and recovery of normal megakaryocyte morphology. Two CR patients who were transfusion-dependent at baseline became transfusion-independent. Complete molecular responses were documented in 2 CR patients. Among 13 patients with leukocytosis, 10 (77%) normalized their leukocyte count or had a >50% reduction. A total of 11 patients (61%) experienced complete or partial resolution of leukoerythroblastosis.26 The authors concluded that telomerase-based treatment strategies, including studies with imetelstat, should be continued in MF. Perspective This phase 1 study, which enrolled patients with a variety of myeloid disorders, is of particular interest because it evaluated a drug with a completely different mechanism of action than those previously used in the treatment of MF. Imetelstat is the first in a class of new drugs known as telomerase inhibitors, and preclinical data suggest that the inhibition of this enzyme involved with the repair of telomeres at the end of chromosomes might be active against myeloid malignancies. The preliminary data from this study seem positive in terms of improvement in spleen and other symptoms. It is impor-

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tant to remember, however, that this is a very early study, and it is therefore not possible to make comparisons between imetelstat and JAK inhibitors in terms of depth of response.

-Ruben A. Mesa, MD

MULTIPLE MYELOMA

According to the ACS, in 2013, an estimated 22,350 new cases of MM (12,440 men and 9910 women) were expected to be diagnosed in the United States, with 10,710 patients (6070 men and 4640 women) dying from the disease.1 Novel and active combination regimens that are well tolerated as long-term therapy are required for elderly patients with MM, including many who are ineligible for stem cell transplantation. Presentations at ASH 2013 shed light on promising new treatments.

Lenalidomide Plus Dexamethasone versus Melphalan, Prednisone, and Thalidomide Facon and colleagues presented initial results from the multicenter, openlabel, phase 3 Frontline Investigation of Lenalidomide + Dexamethasone Versus Standard Thalidomide (FIRST) trial of the first-line use of lenalidomide plus low-dose dexamethasone (Rd) versus melphalan, prednisone, and thalidomide (MPT) in 1623 newly diagnosed patients with MM ineligible for ASCT.27 The patients were randomized to 1 of 3 treatment arms: • Continuous Rd group (n=535): low-dose dexamethasone 40 mg on days 1, 8, 15, 22, and 28 plus continuous lenalidomide 25 mg on days 1 to 21 in 28-day cycles until disease progression • Rd18 group (n=541): low-dose dexamethasone 40 mg on days 1, 8, 15, 22, and 28 plus lenalidomide 25 mg on days 1 to 21 in 28-day cycles for 72 weeks (18 cycles) • MPT group (n=547): MPT in 42-day cycles for 72 weeks (12 cycles)

The incidence of secondary primary malignancies was lower with Continuous Rd than with Rd18 and MPT (7.0%, 8.1%, and 8.7%, respectively).

Results for the primary end point, PFS, were as follows: 25.5 months in the Continuous Rd group (Continuous Rd vs MPT, P=.00006), 20.7 months in the Rd18 group (Continuous Rd vs Rd18, P=.00001), and 21.2 months in the MPT group (Rd18 vs MPT, P=.70349).27 An interim OS analysis at 4 years revealed a significant advantage for Continuous Rd over MPT (59.4% vs 51.4%; P=.0168), with Rd18 at 55.7% (P=.307 vs Continuous Rd and P=.184 vs MPT). The Continuous Rd group had an ORR of 75% and a median DOR of 35 months.27 The safety profile with continuous lenalidomide was manageable, with hematologic and nonhematologic AEs occurring as expected (Table 7).27 Neutropenia was higher in the MPT group than in the Continuous Rd group; infection was higher in the Continuous Rd group than in the MPT group.

The incidence of secondary primary malignancies was lower with Continuous Rd than with Rd18 and MPT (7.0%, 8.1%, and 8.7%, respectively). Study discontinuation rates due to AEs were similar among the 3 groups (11%, 13%, and 14% with Continuous Rd, Rd18, and MPT, respectively).25 Perspective It is important to note that this was an international multicenter trial, and the largest of its kind, enrolling over 1600 patients. Treatment with Continuous Rd significantly improved PFS compared with the standard treatment of MPT in this population and there was also an OS benefit demonstrated, as well as an advantage in terms of ORR. The toxicity profile was manageable and, interestingly, the investigators reported a reduced rate of hematologic secondary primary malignancies with Rd versus MPT, pointing to the genotoxic damage associated with melphalan and prednisone as an important culprit. Results of a PFS2 analysis also showed an advantage with continuous Rd. In summary, I think the results of this study are very impressive and practice-changing for nontransplant patients with MM. -Paul Richardson, MD

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FACULTY PERSPECTIVES Ixazomib Plus Lenalidomide and Dexamethasone At ASH 2013, Richardson and colleagues presented data from a phase 1/2 study of twice-weekly oral ixazomib (formerly MLN9708) plus lenalidomide and dexamethasone in 64 patients (median age, 64 years; range, 34-82 years; 31%, International Staging System [ISS] stage II; 16%, ISS stage III) with newly diagnosed MM.2 Responses over the course of treatment are shown in Table 8.28 Depth of response increased over the course of treatment; median DOR was 13.8 months, ranging up to 18.8+ months.28 Treatment-related AEs of all grades reported in >20% of patients included rash (50%), peripheral neuropathy (53%), fatigue (48%), peripheral edema (39%), dysgeusia (31%), diarrhea (30%), insomnia (30%), constipation (27%), nausea (27%), and dizziness (22%). Grade 3 AEs reported in >5% of patients included rash-related events (16%), hyperglycemia (8%), pneumonia (6%), and thrombocytopenia (6%). No grade 4 treatment-related AEs were observed. One patient death from cardiorespiratory arrest was deemed likely related to lenalidomide.28 Perspective This trial evaluated the all-oral triplet regimen of a novel proteasome inhibitor, an immunomodulator, and a steroid. Twice-weekly dosing of ixazomib, in combination with lenalidomide and dexamethasone, was shown to be feasible and very active in newly diagnosed patients. Not only did we observe strikingly high response rates, but these responses improved over time. In addition, in a subset analysis of patients achieving high-quality responses, MRD negativity was 80%, which for an all-oral regimen, is especially encouraging. However, the incidence of rash—and to some extent peripheral neuropathy with the need for dose reduction accordingly—was higher in this trial compared with our parallel study in which we administered ixazomib weekly. Although these toxicities were manageable, I think once-weekly dosing is in general proving to be the preferred approach.

-Paul Richardson, MD

Carfilzomib Plus Thalidomide and Low-Dose Dexamethasone Sonneveld and colleagues presented the results of an investigator-sponsored, phase 2, open-label, dose-escalation study of carfilzomib combined with thalidomide and low-dose dexamethasone in 70 newly diagnosed, transplant-eligible patients (median age, 58 years; ISS stage I, 27%; ISS stage II, 40%; ISS stage III, 27%) with measurable MM.29

In a subset analysis of patients achieving highquality responses, MRD negativity was 80%, which for an all-oral regimen, is especially encouraging.

CR rates were high at 55% in high-risk patients (defined as having t[4;14] and/or 17p deletions and/or 1q and/or ISS3) and 44% overall. Rates for achieving at least a very good partial response (≥VGPR) were observed in 90% of high-risk patients and in 84% of subjects overall. Rates for ≥PR were 95% in high-risk patients and 96% overall. Induction-phase response rates increased through the high-dose melphalan/ASCT and consolidation phases.

Premature discontinuation rates for carfilzomib, thalidomide, and dexamethasone were 8%, 16%, and 10%, respectively, in the induction phase, and 10%, 26%, and 26%, respectively, in the consolidation phase.29 Grade 3 toxicities included peripheral neuropathy (2%), azotemia (4%), gastrointestinal (6%), skin (12%), and cardiac (6%). No severe sensory neuropathy and no dose-limiting toxicities were observed.29 Perspective Data from this study show compelling activity for the combination of carfilzomib when partnered with thalidomide and a steroid, with an ORR of 96%, and a ≥VGPR rate of approximately 80%, which is especially encouraging. These rates are comparable to what we have seen with the regi-

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Table 8. Responses With Ixazomib Plus Lenalidomide and Dexamethasone28 ORR

sCR

CR

VGPR

PR

After 4 cycles

93%

9%

2%

50%

32%

After 8 cycles

95%

16%

7%

48%

24%

Overall

95%

21%

6%

48%

20%

CR indicates complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

mens of bortezomib, lenalidomide, and dexamethasone or carfilzomib, lenalidomide, and dexamethasone. Thus for settings in which thalidomide may be preferred, these results are highly favorable. Significant toxicities included both peripheral neuropathy and cardiac side effects, although these were uncommon and rates for discontinuation of carfilzomib were low at about 10%.

-Paul Richardson, MD

Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) versus High-Dose Dexamethasone (HiDEX) Dimopoulos and associates presented results from the final analysis of a phase 3 study (MM-003) that compared pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in 455 patients who were refractory to their prior therapy (progressive disease during treatment or within 60 days) and had exhausted bortezomib and lenalidomide alone or in combination.30 Patients were randomized in a 2:1 fashion to receive 28-day cycles of pomalidomide 4 mg on days 1 to 21 plus dexamethasone 40 mg (20 mg for patients >75 years of age) weekly or dexamethasone 40 mg (20 mg for patients >75 years of age) on days 1 to 4, 9 to 12, and 17 to 20. The primary end point of the study was PFS; secondary end points included OS, ORR, duration of treatment, and safety. These end points were further explored relative to patient characteristics, cytogenetics, and prior antimyeloma therapy. Modified high-risk cytogenetics were defined as the presence of del[17] and/or t[4;14].

It was previously reported that with a median follow-up of 10.0 months, POM + LoDEX significantly extended median PFS (4.0 months vs 1.9 months; HR=0.48; P<.0001) and median OS (12.7 months vs 8.1 months; HR=0.74; P=.0285) compared with HiDEX. The OS benefit was observed despite 50% of patients in the HiDEX group receiving subsequent pomalidomide. The ORR was 31% in the POM + LoDEX group versus 10% in the HiDEX group (P<.0001).31 In a retrospective analysis, the increases in ORR and median PFS were maintained for POM + LoDEX versus HiDEX regardless of modified high-risk cytogenetics (del[17p] or t[4;14]; ORR: 25% vs 9%, respectively; P=.071; median PFS: 3.8 months vs 1.1 months, respectively; HR=0.44; P<.001) or standard-risk cytogenetics (ORR: 35% vs 10%, respectively; P<.001; median PFS: 4.2 months vs 2.3 months, respectively; HR=0.55; P<.001). Numerical increases in median OS were observed regardless of cytogenetics (modified high-risk cytogenetics: 9.9 months vs 4.9 months, respectively; HR=0.67; P=.092; standard-risk cytogenetics: 14.1 months vs 9 months, respectively; HR=0.85; P=.38). Of note, 46% of patients who received HiDEX with highrisk cytogenetics and 64% of patients who received HiDEX with standard-risk cytogenetics were treated with subsequent pomalidomide.30,32 Perspective This is an exciting analysis from the MM-003 trial, because it not only confirms the significant PFS and OS benefit with POM + LoDEX, but it showed that high-risk cytogenetics did not impact median PFS for patients receiving POM + LoDex, which was also observed in the MM-002 trial. This is a remarkable finding for an immunomodulatory agent in this highly refractory population of patients. These data strongly support the recommendation that this regimen should be considered a standard treatment option in relapsed/ refractory patients who have been previously treated with bortezomib or lenalidomide.

-Paul Richardson, MD

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CONTINUING EDUCATION Pomalidomide, Bortezomib, and Dexamethasone Mikhael and colleagues presented results of a phase 1/2 trial of pomalidomide in combination with bortezomib (weekly) and dexamethasone in 19 patients with relapsed/refractory MM.33 Of 12 patients evaluable for response, 10 (83%) have responded, including 1 patient who achieved a stringent complete response, 3 participants who reached a CR, 3 patients with a VGPR, and 3 subjects with a PR.33 The most common AEs at least possibly attributable to the combination therapy were anemia, fatigue, leukopenia, and thrombocytopenia; however, the majority of these were grade 1/2. In 14 evaluable patients, grade ≥3 AEs included neutropenia (n=5), leukopenia (n=3), lung infection (n=1), lymphopenia (n=1), and atrial flutter (n=1). One dose-limiting toxicity has been reported (hospitalization for infection). All patients are alive and remain on therapy; no patients have progressed.33 The authors concluded that pomalidomide, bortezomib, and dexamethasone is a highly effective combination in patients who are refractory to lenalidomide, with the enhanced tolerability and convenience of weekly administration of bortezomib.33 Perspective The combination of pomalidomide, bortezomib, and dexamethasone in this trial was associated with minimal toxicity, mostly consisting of mild cytopenia, with no significant neurotoxicity or thrombosis, which is very relevant in the relapsed/refractory setting. The response rates were very encouraging and exceeded 80%. It is important to note, however, that the number of patients reported in this trial is still small and these remain early results from this trial, but the results from the study as a whole are awaited with great interest.

-Paul Richardson, MD

References

1. American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed February 3, 2014.

2. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol.

2011;29(5):544-550.

3. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study Complement 1 (OMB110911). Blood (ASH Annual Meeting Abstracts). 2013;122: Abstract 528.

4. Goede V, Fischer K, Busch R, et al. Head-to-head comparison of obinutuzumab (GA101) plus chlorambucil (Clb) versus rituximab plus Clb in patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions (comorbidities): final stage 2 results of the CLL11 trial. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 6.

5. Eichhorst B, Fink A-M, Busch R, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German CLL Study Group (GCLLSG). Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 526.

6. Burger JA, Keating MJ, Wierda WG, et al. Ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 675.

7. Furman RR, Sharman JP, Coutre SE, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib and rituximab for previously treated patients with chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract LBA-6.

8. Ruan J, Martin P, Shah BD, et al. Combination biologic therapy without chemotherapy as initial treatment for mantle cell lymphoma: multi-center phase II study of lenalidomide plus rituximab. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 247.

9. Gopal A, Kahl BS, de Vos S, et al. Mature response data from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (rituximab and alkylating agent)-refractory indolent B-cell non-Hodgkin lymphoma (iNHL). Blood (ASH Annual Meeting Abstracts). 2013;122: Abstract 85.

10. Bartlett NL, Sharman JP, Oki Y, et al. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas. Blood (ASH Annual Meeting Abstracts). 2013; 22:Abstract 848.

11. Lopez-Guillermo A, Canales MA, Dlouhy I, et al. A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan (Zevalin®) (Z) vs. maintenance

with rituximab (R) for two years in patients with newly diagnosed follicular lymphoma (FL) responding to R-CHOP. Preliminary results at 36 months from randomization. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 369.

12. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156-5164.

13. Gopal AK, Chen R, Smith SE, et al. Three-year follow-up data and characterization of longterm remissions from an ongoing phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts). 2013;122: Abstract 4382.

14. National Cancer Institute. Myelodysplastic Syndromes Treatment (PDQ®). http://www. cancer.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfessional/page1. Accessed January 30, 2014.

15. Silverman LR, Verma A, Odchimar-Reissig R, et al. A phase II trial of epigenetic modulators vorinostat in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS): initial results of Study 6898 of the New York Cancer Consortium. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 386.

16. Azaciditine with or without lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. http://clinicaltrials.gov/ct2/show/ NCT01522976?recr=Open&intr=Azacitidine&cntry1=NA:US&lup_s=02/19/2013&lup_ d=360.

17. Ranpura VN, Wu CO, Olnes MJ, et al. Alemtuzumab is safe and associated with high response rates in selected patients with myelodysplastic syndrome. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 593.

18. Mesa RA, Verstovsek S, Cervantes F, et al; on behalf of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Leuk Res. 2007;31(6):737-740.

19. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901.

20. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-397.

21. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

22. Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

23. Verstovsek S. Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med. 2013;125(1):128-135.

24. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 396.

25. Pardanani A, Harrison CN, Cortes JE. Results of a randomized, double-blind, placebo-controlled phase III study (JAKARTA) of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis (MF). Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 393.

26. Tefferi A, Begna K, Laborde RR, et al. Imetelstat, a telomerase inhibitor, induces morphologic and molecular remissions in myelofibrosis and reversal of bone marrow fibrosis. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 662.

27. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the first (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM020/IFM 07 01) in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 2.

28. Richardson PG, Hofmeister CC, Rosenbaum CA, et al. Twice-weekly oral MLN9708 (ixazomib citrate), an investigational proteasome inhibitor, in combination with lenalidomide (len) and dexamethasone (dex) in patients (pts) with newly diagnosed multiple myeloma (MM): final phase 1 results and phase 2 data. Blood (ASH Annual Meeting Abstracts). 2013;122: Abstract 535.

29. Sonneveld P, Asselberg-Hacker E, Zweegman S, et al. Dose escalation phase 2 trial of carfilzomib combined with thalidomide and low-dose dexamethasone in newly diagnosed, transplant eligible patients with multiple myeloma. A trial of the European Myeloma Network.

Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 688.

30. Dimopoulos MA, Weisel K, Song KW, et al. Final analysis, cytogenetics, long-term treatment, and long-term survival in MM-003, a phase 3 study comparing pomalidomide + lowdose dexamethasone (POM + LoDEX) vs high-dose dexamethasone (HiDEX) in relapsed/ refractory multiple myeloma (RRMM). Blood (ASH Annual Meeting Abstracts). 2013;122: Abstract 408.

31. Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055-1066.

32. Richardson PG, Schlossman RL, Alsina M, et al. Time to event analyses in PANORAMA 2: a phase 2 study of panobinostat, bortezomib, and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts).

2013;122:Abstract 1970.

33. Mikhael JR, Roy V, Richardson PG, et al. A phase I/II trial of pomalidomide, bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 1940.

COE104-4

46

Value-Based Cancer Care

I

march 2014

Vol. 5

I

No. 2

COMING SOON A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to discuss the most recent available data concerning improvements in cost of care, safety profiles, and patient preferences as they pertain to the use of emerging agents used in the treatment of patients with MM. IN MULTIPLE MYELOMA

Value-BasedCare

™

November 2013 u 8th IN A SERIES

Cost-Effective Use of Imaging Modalities for Diagnosis and Monitoring in Multiple Myeloma

Topics include: • Effective Treatment of Newly

Diagnosed and Relapsed/ Refractory Patients with MM: Utilizing Optimal Dosing Regimens • Appropriate Duration of Therapy

for MM in a Value-Based Care Plan • Improving the Standard of Care

in MM: Interpreting Overall Survival Data and Assessing the Cost of a Complete Response • Establishing a Value-Based

Paradigm for the Management of Patients with MM: A Pharmacoeconomic Analysis of Treatment Options

Introduction Identification, characterization, and management of osteolytic bone lesions are key aspects of care in multiple myeloma (MM).1 A comprehensive, chart-based study from the Mayo Clinic, published in 2003, revealed that 84% of patients with myeloma developed skeletal lesions at some time during the course of their disease.2 Based on conventional radiography at the time of diagnosis, 79% of patients presented with at least one type of skeletal abnormality (Figure 1).2 In the decade since the publication of this influential study, these high estimates of skeletal-related events have held constant.1 What has changed, however, are the options available to clinicians for imaging the skeleton. Although radiographic skeletal survey remains the fundamental imaging study at both the initial workup and follow-up of the patient with MM, additional newer technologies can be utilized. These include magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET) scan, which may be combined with CT scan (PET-CT). Bone densitometry is another imaging technology with application in the disease.3 These technologies may provide helpful diagnostic and follow-up information on the patient, but despite evidence-based guidelines on imaging in MM, there is currently no standard for their appropriate clinical use.3-7 Individual providers, institutions, and payers are tasked with the decision to deploy or to forego MRI, CT, and PET on a case-by-case basis. The choice to utilize these sophisticated imaging methods ultimately affects the value of myeloma care: overuse or inappropriate use of such technologies results in unnecessary utilization costs; failure to use the technologies when prudent may result in a lower quality of care.

This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients.

These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

The most recent of the guidelines, from the National Comprehensive Cancer Network (NCCN), recommends radiographic skeletal survey for all patients at initial workup and for the follow-up of every patient annually or when symptoms are present.3 The NCCN makes provisional recommendations for MRI, CT, and PET scans, which are described as “useful under some circumstances” in initial workup and may be used “as clinically indicated” for follow-up surveillance.3 When is additional testing “useful” and “indicated”? Different organizations and experts have given various answers to this question. According to the NCCN, PET-CT scanning and MRI scans provide greater sensitivity than did conventional radiography.3 Therefore, during an initial workup in a patient who presents with bone pain, weakness, or other symptoms in

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care.

Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

STAKEHOLDER’S PERSPECTIVE Assessing the Optimal Use of Imaging Modalities in Patients with Myeloma ...........................5

Imaging Options in MM: Evidence-Based Guidelines and Expert Consensus Since 2007, 5 different sets of clinical practice guidelines have been issued on the use of imaging technologies in MM (Table).3-7 These guidelines provide a good starting point for individual providers, institutions, and payers seeking to evaluate these modalities.

This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

James R. Berenson, MD Institute for Myeloma & Bone Cancer Research West Hollywood, CA

An official publication of

11/15/13 9:58 AM

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www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127cs_Ksize13114

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