Value-Based Cancer Care February 2014

february 2014 VOL 5 NO 1

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

ASCO Proposes New Reimbursement Model by Medicare for Cancer Care

By Neil Canavan

T

By Phoebe Starr

Clifford A. Hudis, MD

on ideas for moving away from the fee-for-service (FFS) model, and on the proposal itself.

The proposal, as put forth by ASCO’s Payment Reform Working Group, began with a (seemingly) Continued on page 21

Enzalutamide Extends Survival in Previously Untreated Metastatic Prostate Cancer Delays need for chemotherapy in some patients

By Phoebe Starr San Francisco, CA—Enzalutamide (Xtandi) prolonged survival and delayed radiographic progression of disease in men who had not received chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). The complete results of the

©2014 Engage Healthcare Communications, LLC

James N. Kochenderfer, MD

New Orleans, LA—Mounting evidence from several research centers shows that autologous T-cells genetically engineered with a chimeric antigen receptor-T (CAR-T; also called CTL019) achieve dramatic responses in patients with advanced leukemia and lymphoma who have exhausted all treatment options.

At the 2013 American Society of Photo courtesy of ASCO

he American Society of Clinical Oncology (ASCO) has proposed a radical new model for the reimbursement of oncology services under Medicare, with the new paradigm consisting of incentives for oncologists to emphasize quality rather than quantity of care as the greater good to the bottom line.

“This payment reform proposal represents a real shift in the way oncologists would be reimbursed,” said ASCO President Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York. “ASCO is offering a new and different perspective on how oncologists should be compensated that recognizes their expertise as well as the care and services they are providing to patients.”

The proposed reform is part 5 of a 5-part series of ASCO communications intended to educate its membership on how Medicare reimbursement is currently configured,

Novel CAR-T Therapy Shows Impressive Results in Aggressive Leukemia, Lymphoma

phase 3 PREVAIL trial were presented at the 2014 Genitourinary Cancers Symposium.

An interim analysis in 2013 was so favorable that the trial was halted prematurely, and all patients receiving placebo were offered enzalutamide.

Continued on page 17

Hematology meeting, many oral sessions and posters focused on the use of CAR-T cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma.

The centers doing this research use varying protocols, but the principle approach is the same.

The patient’s own T-cells are extracted and genetically engineered ex

Continued on page 26

Hematologic Drug Pipeline Boasts Novel Approaches

By Wayne Kuznar

New Orleans, LA—Novel options for the treatment of patients with hematologic conditions are in the pharmaceutical pipeline, with many drugs showing promising results. Here is a look at key studies presented at the 2013 American Society of Hematology annual meeting.

Chronic Lymphocytic Leukemia Phase 3 studies of idelalisib demonstrated impressive progression-free survival (PFS) in previously treated patients with chronic lymphocytic leukemia (CLL).

An orally bioavailable selective inhibitor of the Bcl-2 protein, known as Continued on page 34

inside FROM THE EDITOR . . . . . . . . . . . . . . 4 Innovating cancer care to improve value

ECONOMICS OF CANCER CARE . . .21 Rituximab more costly in the hospital

IN THE LITERATURE . . . . . . . . . . . . . 6 Obinutuzumab outperforms rituximab in CLL

PERSONALIZED MEDICINE . . . . . . 26 I-SPY 2: First genetic-based results in breast cancer

VALUE PROPOSITIONS . . . . . . . . . . 8 NCI investigates genetic-sequencing value for improving patient outcomes

GI CANCER SYMPOSIUM . . . . . . . . 35 Dual vaccine for pancreatic cancer

9

DRUG UPDATE . . . . . . . . . . . . . . . . 40 Abraxane for metastatic pancreatic cancer

FDA UPDATE . . . . . . . . . . . . . . . . . . 15 First combination for melanoma Ibrutinib approved for CLL

CONTINUING EDUCATION . . . . . . . 42 Optimal use of biologics in delivering value-based care

BREAST CANCER SYMPOSIUM . . . . . .

Anastrozole halves incidence by 5 yrs

Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

In This Issue FROM THE EDITOR

GENITOURINARY CANCERS

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com

Innovating cancer care to improve value

Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com

VALUE PROPOSITIONS

Radiation plus hormone therapy extends survival in high-risk prostate cancer More…

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 Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz

NCI assesses value of genetic sequencing

IN THE LITERATURE Obinutuzumab outperforms rituximab in CLL AEs underreported in oncology publications More…

BREAST CANCER SYMPOSIUM

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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I-SPY 2: biomarkers/genetics in breast cancer More…

FDA UPDATE

DRUG UPDATE

First combination for metastatic melanoma Ibrutinib approved for CLL More…

Abraxane indicated for metastatic pancreatic cancer

CANCER SCREENING

CONTINUING EDUCATION Optimal use of biologics in delivering value-based care

VBCC Editorial Board

Quality Control Assistant Theresa Salerno

Creative & Design Assistant Lora LaRocca

PERSONALIZED MEDICINE

Annual lung cancer screening recommended

Director, Quality Control Barbara Marino

Director, Creative & Design Robyn Jacobs

Rituximab more costly in the hospital More…

Exercise regimen cuts aromatase inhibitor– related pain More…

Associate Editorial Director, Projects Division Terri Moore

Director, Production & Manufacturing Alaina Pede

ECONOMICS OF CANCER CARE

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 Manager, 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.

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From the Editor

Innovating Cancer Care to Improve Value: Health Care Innovation Awards Round Two

By Craig Deligdish, MD

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

T

he Patient Protection and Af­ fordable Care Act (ACA) has been a major topic in the news of late. In addition to providing better healthcare and allowing the uninsured to obtain affordable insurance coverage, the ACA has provided funding for outcomes research and healthcare innovation. Established by the ACA, the Patient-Centered Outcomes Research Institute (PCORI) to date has approved more than 275 awards, totaling more than $464 million, to fund patient-centered comparative clinical effectiveness research projects.1 In addition, the Center for Medicare & Medicaid Innovation (CMMI) has already awarded more than $1 billion in grants to more than 50 organizations for the projects that propose improving quality, reducing cost, and improving value in healthcare.1 PCORI was created to fund research that will allow providers to adopt and utilize evidence-based information, allowing patients and providers to make better healthcare decisions. In addition, PCORI has set up a National Patient-Centered Clinical Research Network to facilitate clinical comparative effectiveness research, and has invested more than $100 million in this effort.2 In May 2013, CMMI announced Round Two of the Health Care Innovation Awards.3 The purpose of Round Two is to test new payment and service delivery models to improve health and to lower costs through improved quality for Medicare, Medicaid, and Children’s Health Insurance Program enrollees.

In Round One, the Innovation Center supported projects that transformed care through a variety of initiatives, also with a focus on improving quality and reducing cost.

Round Two proposals, however, looked to test models that focus on new payment and service delivery models, with a specific focus on populations with specialized needs, such as patients with cancer and those receiving high-cost physician-administered drugs, therapeutic services (eg, radiation therapy), and other outpatient services. The funds being provided are specifically targeted to approaches that transform financial and clinical models, focusing on high-cost subspecialties, such as oncology and cardiol-

4

ogy. The grants also look to support models that test patient engagement and shared decision-making tools.

In this regard, more than 20 grants were submitted by organizations that focus on treating patients with cancer to include academic medical centers, provider collaboratives, large oncology practices, state governments, and others. Examples of grants that were submitted include proposals by Oncology Resource Networks, a clinically integrated network model representing oncologists in New York, Michigan, Pennsylvania, California, Florida, Montana, and Nevada. Recently, Oncology Resource Networks submitted 3 proposals, each

The program rewards providers who implement a web-based decision support tool for chemotherapy and radiation therapy, and who adopt fee schedule adjustments for chemotherapy that incentivize cost-effective treatment.

of which proposed novel payment methodologies while transforming financial and clinical models for payers and providers. One of the models, “Transforming Cancer Care with Technology, Payment Engagement and Novel Payment Methodologies,” proposes equipping physicians with the electronic infrastructure and upto-date information needed to deliver cost-effective, evidence-based oncology, radiation, and palliative cancer care. This approach is designed to move beyond data and infrastructure to provide financial incentives for providers who embrace the proposed models and technology.

The program rewards providers who implement a web-based decision support tool for chemotherapy and radiation therapy, and who adopt fee schedule adjustments for chemotherapy that incentivize cost-effective treatment. The use of an electronic

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portal allows efficient communication between providers and patients, and is designed to enhance patient engagement and shared decision-making.

Practice enhancements that allow for the adoption of medical home concepts and accountable care contribute to a design that has been demonstrated to reduce the cost of care while improving outcomes. The model seeks to test how these approaches can result in better care coordination. The adoption of advanced illness programs and a shared-savings model allows physicians, patients, and payers to work together to encourage the use of costeffective, evidence-based treatment that improves quality in a very vulnerable patient population.

Payers, including Florida’s Medicaid program, Blue Cross Blue Shield of California, Blue Cross Blue Shield of Michigan, Priority Health, WellPoint, Florida Blue, Empire BlueCross BlueShield, BlueCross BlueShield of Western New York, and oncology providers in community, hospital, and comprehensive cancer centers, agreed to partner in this collaborative proposal to test these programs in more than 10,000 patients.

Other models that were proposed

by Oncology Resource Networks to CMMI include an integrated network model that suggests managing the costs of radiation therapy through episodes and bundled payments. Again, incentivizing patients and engaging patients, providers, and health plans were core components of this proposal. Requiring physicians to be accountable to evidence-based guidelines is an important feature of this proposal. A third proposal by Oncology Resource Networks described a model regarding high-cost drugs that resembled approaches taken in the Medicare Modernization Act, a law that resulted in the creation and implementation of Medicare Part D. A recent article published in the New York Times examined some of the efforts by the Health Care Innovation Center to transform healthcare and examine new models that will potentially improve outcomes.4 The article focused to a large degree on medicine’s historical approach to proving concepts such as randomized clinical trials. PCORI and the Health Care Innovation Center have examined

other approaches to include comparative effectiveness research and models that do not always include control groups. The article quoted a number of researchers who were critical of the approaches taken by the Innovation Center, whereas Patrick Conway, MD, MSc, the acting director of the center and Chief Medical Officer for the Centers for Medicare & Medicaid Services, defended the Health Care Innovation Center’s philosophy regarding its investments and the demonstration projects that have been funded by the center thus far.

Nearly all of the oncology professional organizations, including the American Society of Clinical Oncology (ASCO), Community Oncology Alliance, and the National Comprehensive Cancer Network, have taken positions on value-based cancer care. In 2007, ASCO established the Cost of Cancer Task Force, and more recently changed its name to the Value in Cancer Task Force, to address cost, quality, and value as they relate to cancer treatment.

It is frequently accepted that tremendous progress has been made in the treatment of cancer, yet there is also agreement that the costs are accelerating to a point where they are no longer sustainable for many patients and payers. The funding provided by CMMI as part of Round Two of the Health Care Innovation Awards will hopefully allow patients to continue to benefit from new and innovative treatments, and provide greater value and better outcomes for patients and payers. n References

1. Patient-Centered Outcomes Research Institute.

PCORI offers $206 million in research support through latest funding announcements. February 5, 2014. www.pcori.org/2014/pcori-offers-206-millionin-research-support-through-latest-fundingannouncements/. Accessed February 12, 2014.

2. Patient-Centered Outcomes Research Institute.

PCORnet: The National Patient-Centered Clinical Research Network. www.pcori.org/funding-oppor tunities/pcornet-national-patient-centered-clinicalresearch-network/. Accessed February 12, 2014.

3. US Department of Health and Human Services.

Health Care Innovation Awards. Catalog of Federal Domestic Assistance. Number 93610. www.cfda.gov/ ?s=program&mode=form&tab=step1&id=5cb9e 018d023ac884a 95a265aa11e623. Accessed February 12, 2014.

4. Kolata G. Method of study is criticized in group’s health policy tests. The New York Times. February 2, 2014. www.nytimes.com/2014/02/03/health/ effort-to-test-health-policies-is-criticized-for-studytactics.html?hpw&rref=us. Accessed February 10, 2014.

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NOW APPROVED FOR PREVIOUSLY TREATED MCL

INDICATION - IMBRUVICA™ (ibrutinib) 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 - 5% of patients with MCL had ≥ Grade 3 bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies and the benefit-risk of withholding ibrutinib 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. At least 25% of patients with MCL had infections ≥ Grade 3, according to 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.

These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2013 © Janssen Biotech, Inc. 2013 11/13

K08BR13037C

Renal Toxicity - Fatal and serious cases of renal failure have occurred. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients.

Periodically monitor creatinine levels. Maintain hydration.

*Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (7%), Second Primary Malignancies - Other malignancies abdominal pain (5%), atrial fibrillation, diarrhea (5%), (5%) have occurred in patients with MCL who have been fatigue (5%), and skin infections (5%). Treatmenttreated with IMBRUVICA™, including skin cancers (4%) emergent Grade 3 or 4 cytopenias were reported in 41% and other carcinomas (1%). of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111).

Embryo-Fetal Toxicity - Based on findings in animals, ™ IMBRUVICA can cause fetal harm when administered The most frequent adverse reaction leading to treatment to a pregnant woman. Advise women to avoid becoming discontinuation was subdural hematoma (1.8%). pregnant while taking IMBRUVICA™. If this drug is used Adverse reactions leading to dose reduction occurred in during pregnancy or if the patient becomes pregnant 14% of patients. while taking this drug, the patient should be apprised of DRUG INTERACTIONS the potential hazard to a fetus.

CYP3A Inhibitors - Avoid concomitant administration ADVERSE REACTIONS - The most commonly occurring with strong or moderate inhibitors of CYP3A. If a adverse reactions (≥ 20%) in the clinical trial were moderate CYP3A inhibitor must be used, reduce the thrombocytopenia*, diarrhea (51%), neutropenia*, IMBRUVICA™ dose. anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

(34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), SPECIAL POPULATIONS - Hepatic Impairment - Avoid vomiting (23%) and decreased appetite (21%). use in patients with baseline hepatic impairment.

In the Literature

B:10.75” T:10.5” S:9.5”

Obinutuzumab Outperforms Rituximab in Older Patients with CLL

The anti-CD20 antibody rituximab (Rituxan), combined with chemotherapy agents, had been shown to prolong overall survival (OS) in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL), but not in those with comorbidities.

In a recent head-to-head, randomized, phase 3 trial of older patients, researchers investigated the benefit of the anti-CD20 antibody obinutuz­ umab (Gazyva) plus chlorambucil (Leukeran) compared with rituximab plus chlorambucil in patients with previously untreated CLL and coexisting conditions (Goede V, et al. N Engl J Med. 2014 Jan 8. [Epub ahead of print]).

In this open-label study, 781 patients were randomized in a 2:1:2 ratio to receive six 28-day cycles of obinutuzumab plus chlorambucil (N = 333), chlorambucil alone (N = 118), or to rituximab plus chlorambucil (N = 330). Patients were required to have a Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of 30 mL/min to 69 mL/

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information 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 had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily.

The mechanism for the bleeding events is not well understood.

Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding ibrutinib 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 (14.1) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL 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. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). 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 and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies: Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers (4%), and other carcinomas (1%).

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 receiving the ibrutinib dose of 560 mg per day. 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.

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 TableTables 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.

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min. The obinutuzumab and rituximab groups were well balanced. The patients had a median age of 73 years, a CrCl of 62 mL/min, and a CIRS score of 8 at baseline. Most of the patients (83%) had 3 or more coexisting conditions, such as hypertension, coronary artery disease, and diabetes.

Chlorambucil was administered orally at 5 mg/kg of body weight on days 1

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

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis General disorders and Fatigue Peripheral edema administrative site Pyrexia conditions Asthenia Bruising Skin and subcutaneous tissue Rash Petechiae disorders Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea Cough and mediastinal Epistaxis disorders Metabolism and Decreased appetite nutritional disorders Dehydration Nervous system Dizziness disorders Headache

Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 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)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) 57 17 47 29 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.

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).

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.

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B:10.75” T:10.5” S:9.5”

and 15 of each cycle. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 to 6.

Rituximab was administered intravenously at a dose of 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 to 6.

Patients in the obinutuzumab plus chlorambucil group had a significant

increase in median prolonged progression-free survival (PFS) and a higher response rate than the rituximab plus chlorambucil group. The median PFS was 26.7 months in the obinutuzumab group and 15.2 months in the rituximab group (hazard ratio [HR], 0.39; 95% confidence interval (CI), 0.310.49; P <.001). The complete response rates were 20.7% and 7%, respectively.

The median PFS in patients receiving chlorambucil monotherapy was 11.1 months, which was shorter than the obinutuzumab plus chlorambucil group (HR, 0.18) or the rituximab plus chlorambucil group (HR, 0.44).

Grades 3 to 5 adverse events (AEs) ranged from 11% to 14% and did not differ significantly among treatment groups. The main difference was in

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].

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 administered the dose of 560 mg daily. 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.

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].

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 with MCL 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.

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 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2013

Issued: November 2013

Transparent and comprehensive reporting of AEs in published results of oncology-related clinical trials is crucial for the treatment of patients with cancer. In efforts to improve reporting of clinical trials results, the Consolidated Standards of Reporting Trials (CONSORT) extension group developed 10 recommendations in 2003 for reporting AEs. A new study of 175 publications assessed the degree to which the publication of phase 3 trials in oncology adhered with CONSORT recommendations (Sivendran S, et al.

J Clin Oncol. 2014;32:83-89).

The findings from this analysis showed that the reporting of AEs is suboptimal in published studies and is characterized by significant selectivity of the data. The researchers reviewed PubMed, Medline, and EMBASE citations to identify randomized, phase 3 trials in metastatic solid malignancies published between January 2009 and December 2011. Publications were assessed for 14 AE reporting elements taken from the CONSORT harms extension statement, with a completeness score of 0 to 14 being calculated. Data on 96,125 patients were included in the analysis. The median completeness score was 8 (range, 3-12). The majority of publications (96%) only reported AEs occurring above a particular threshold rate or severity. Overall, 37% did not specify the criteria for determining which AEs were reported, and 88% grouped AEs of varying severity.

The findings showed that 91% of the articles analyzed had a title or an abstract stating whether AEs were addressed, and 58% had introductions S:13”

K08BR13131B

Adverse Events Reporting Suboptimal in Oncology Publications

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IMBRUVICATM (ibrutinib) capsules

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IMBRUVICATM (ibrutinib) capsules

infusion-related AEs. In the obi­ nutuzumab plus chlorambucil group, 20% of the patients experienced infusion-related reactions compared with 4% of patients in the rituximab plus chlorambucil group. In the obinutuz­ umab plus chlorambucil group, the researchers noted that the reaction occurred during the first infusion, and no deaths were associated with infusion-related AEs. The researchers concluded that the combination of obinutuzumab or ri­ tuximab with chlorambucil improves outcomes in patients with previously untreated CLL and coexisting conditions. In this patient population, obinutuzumab plus chlorambucil showed an OS advantage over chlor­ ambucil monotherapy. Furthermore, obinutuzumab plus chlorambucil induced prolonged PFS and a higher complete response rate than rituximab plus chlorambucil.

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Advance Care Planning

VALUE PROPOSITIONS NCI Pilot Trial to Assess Value of Genetic Sequencing for Improving Patient Outcomes

The National Cancer Institute (NCI) has launched a clinical trial to determine whether selecting therapies based on genetic mutations can improve outcomes in patients with metastatic solid tumors. Molecular Profiling based Assignment of Cancer Therapeutics (M-PACT) is one of the first randomized trials to assess if using genetic mutation as the basis for treatment selection can improve the rate and duration of response in patients with advanced-stage solid tumors.

A second goal is to see if the use of genetic sequencing can identify a subpopulation of patients who could benefit from specific targeted treatment, which would help to expedite drug development for these patients based on their genetic profile, and could lead to smaller clinical trials and reduce cost and time of drug development.

“Patients will have their tumors genetically screened and if a predefined mutation is found, they will receive treatment with targeted agents,” said Shivaani Kummar, MD, head of NCI’s Developmental Therapeutics Clinic and the trial’s principal investigator. “What we don’t know, however, is whether using this approach to assign targeted treatments is really effective at providing clinical benefit to patients, as most tumors have multiple mutations and it’s not always clear which mutation to target, and which agent is most likely to provide maximal benefit.”

The M-PACT trial is designed to determine whether patients with mutations that have been shown in the laboratory to affect drug effectiveness will benefit from a specific targeted therapy, and if this approach results in better outcomes.

The NCI is now screening hundreds of people to select 180 patients with advanced refractory solid tumors based on their genetic profile.

National Cancer Institute Press Release; January 30, 2014

ASCO Launches Value in Cancer Care Initiative

Responding to the relentless economic pressures on patients and oncologists and the ever-escalating costs of cancer care delivery, the American Society of Clinical Oncology (ASCO), in collaboration with the Value in Cancer Care Task Force, is developing a working definition of “value” in oncology, as well as identifying how to incorporate the implications of that approach into clinical decision-making in patient care.

“In oncology, we face the fascinating challenge of determining the value of today’s cancer treatments,” said ASCO President Clifford A. Hudis, MD, FACP. “What is the worth, for example, of an average of three or four more weeks of time—be it freedom from progression, or life itself—relative to the cost and side effects of the treatment? What if a few benefit greatly and many not at all? The answers to these kinds of questions may vary widely among different patients, families, healthcare providers, and communities, but we must confront these difficult issues with courage, compassion, and integrity.”

ASCO’s initiative is centered on 3 goals: oncologists’ skill levels and tools to deliver value-based care, patients’ access to information that will enhance their ability to select high-value therapeutic options, and cost algorithms for payers to help them define value-based therapies.

“As the organization representing the nation’s cancer doctors, we have a responsibility to speak out on behalf of our patients against the unsustainable rising cost of cancer care—and to work with government agencies, insurance companies, pharmaceutical companies, patient groups, and policymakers to help limit its future growth,” said Dr Hudis in response to the launch of this new initiative.

“Through fostering a dialogue within the ASCO community of what value means to patients, providers, and the overall health-care system,

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we as oncologists have an opportunity to help shape the larger national debate on health-care spending,” said Lowell E. Schnipper, MD, Chair of the Value in Cancer Care Task Force. “We have an obligation to our patients to lead the way in identifying solutions that promote high-value, high-quality cancer care.” ASCO Press Release; January 21, 2014

M.D. Anderson’s Scientists Collaborate with Pfizer to Enhance Immunotherapy in Oncology

Researchers at the University of Texas M.D. Anderson Cancer Center have announces a new collaboration with Pfizer to develop immunebased approaches to new therapies for cancer. This new effort is based on M.D. Anderson’s Moon Shots Program that aims to reduce cancer deaths significantly in the future, using the 6 moon shots that target 8 types of difficult-to-treat cancer.

“Cancer immunotherapy is the most exciting and promising advance in the cancer field today,” said M.D. Anderson President Ronald DePinho, MD. “Pfizer’s strong experience in immunology and cancer therapeutics is an outstanding match for the talent and capabilities available through M.D. Anderson’s immunotherapy platform,” Dr DePinho added.

This 3-year agreement is designed to accelerate the development of immunotherapies in cancer and to further investigate promising combination therapies, as well as the use of new biomarkers to guide and monitor therapy.

“This collaboration offers a unique opportunity to work directly with recognized pioneers in the rapidly advancing field of cancer immunotherapy,” said Jaume Pons, PhD, Chief Scientific Officer of the Rinat biotechnology unit at Pfizer, which is a leading research effort on antibody drug development. “We look forward to partnering with the researchers and clinicians in the Moon Shots Program to potentially bring new treatment approaches to cancer patients,” Dr Pons noted.

Last October, M.D. Anderson’s Moon Shots Program received an additional $50-million gift, bringing the total gifts of the program to $139 million, providing a strong foundation for this effort to advance cancer research. M.D. Anderson Cancer Center Press Release; January 6, 2014

Aetna Announced First Patient-Centered Medical Home in Oncology

Late last year, Aetna, together with Consultants in Medical Oncology and Hematology, launched the first patient-centered medical home for oncology. This collaborative program is based on evidence-based decision support in cancer care, using personalized medicine and realigning payment structure with the goal of increasing patient treatment coordination, improving quality outcomes, and reducing overall costs of cancer care.

“Given the frequency of contact, oncologists are in a prime position to help their patients navigate the health care system to get appropriate and aligned treatment for all of their conditions. Helping a patient coordinate care for an underlying heart condition while being treated for prostate cancer is the right thing to do,” said Michael Kolodziej, MD, FACP, National Medical Director for Oncology Strategies at Aetna, and ValueBased Cancer Care editorial board member. Because the majority (>50%) of all new patients diagnosed with cancer are aged ≥65 years, many of them have comorbid conditions that are not related to their cancer. Therefore, coordinating the care for all their medical needs, not only cancer, can improve their overall outcomes. Aetna Press Release; November 14, 2013

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Anastrozole Cuts the Incidence of Breast Cancer by 50% in High-Risk Women

See also Personalized Medicine, pages 26-27

The 7-year risk reduction of recurrence greater than with tamoxifen

By Phoebe Starr London, United Kingdom, at the 2013 San Antonio Breast Cancer Sympo­ sium and published simultaneously online (Cuzick J, et al. Lancet. 2013 Dec 12 [Epub ahead of print]).

The magnitude of the reduction in risk of recurrence at 7 years is greater than that recorded with tamoxifen. “The effect of tamoxifen has been shown to persist for at least 10 years, and further follow-up is needed to establish whether anastrozole has such a sustained effect,” wrote Dr Cuzick and colleagues. “Our results strongly support the use of anastrozole for preventive treatment of high-risk postmenopausal women.”

Study Parameters Between February 2, 2003, and January 31, 2012, IBIS-II enrolled 3864 postmenopausal women with an increased risk for breast cancer related to family history or other factors (median age, 59 years). Women were randomized to 5 years of treatment with anastrozole (N = 1920) or to placebo (N = 1944). Approximately 47% of patients used previous hormone replacement therapy, and 33% had a hysterectomy.

Approximately 50% of the patients had 2 or more first-degree relatives with breast or ovarian cancer, and 35% had 1 first-degree relative with breast cancer under age 50.

Approximately 9% of patients had previous lobular carcinoma in situ or atypical hyperplasia.

at a glance ➤ Breast cancer risk was halved with 5 years of anastrozole in postmenopausal women at high risk for breast cancer ➤ At 5 years, 2.8% of patients receiving anastrozole developed breast cancer versus 5.6% with placebo ➤ The 7-year reduction in risk of breast cancer recurrence is greater than with tamoxifen ➤ However, tamoxifenʼs effect has been established for at least 10 years

The full 5-year adherence rate was estimated to be 72% in the placebo group and 68% in the anastrozole group. Treatment discontinuations as

Photo by © SABCS/Todd Buchanan 2013

San Antonio, TX—Five years of treatment with the aromatase inhibitor anastrozole (Arimidex) cut the risk of breast cancer by 50% in high-risk postmenopausal women who had not developed a first cancer. At a median follow-up of 5 years, only 2% of 1920 women taking anastrozole and 4% of 1944 women using placebo developed breast cancer.

Thus far, anastrozole has had no impact on survival, according to the results of the International Breast Cancer Intervention Study (IBIS)-II, which were presented by Jack Cuzick, PhD, Head, Centre for Cancer Prevention, Wolfson Institute of Preventive Med­ icine, Queen Mary University of

“Our results strongly support the use of anastrozole for preventive treatment of high-risk postmenopausal women.”

—Jack Cuzick, PhD, and colleagues a result of adverse events were reported in 15% of patients receiving placebo and in 20% of patients receiving anastrozole.

Risk Cut by Half At 5 years, 5.6% of patients receiving placebo and 2.8% of patients receiving anastrozole developed breast cancer. Of these, 3.3% and 1.4% of patients, respectively, developed an invasive estrogen receptor–positive breast cancer. The predicted cumulative incidence of all breast cancers after 7 years was 5.6% in the placebo group and 2.8% in the anastrozole group.

There were 17 deaths in the placebo group and 18 in the anastrozole group, but no pattern of causes was apparent in either group.

Musculoskeletal complaints were reported by 64% of the women taking anastrozole versus in 58% of those assigned to placebo (P = .001). The number of fractures and sites of fracture did not differ between the 2 groups.

Carpal tunnel syndrome and joint stiffness were more common in the anastrozole group.

In an accompanying editorial in the Lancet (Cameron DA. Lancet. 2013 Dec 12 [Epub ahead of print]), David A. Cameron, MD, MSc, Clinical Director, Edinburgh Cancer Centre, Western General Hospital, United Kingdom, was less enthusiastic about the use of anastrozole for chemoprevention than Dr Cuzick. Dr Cameron noted that without a proven survival benefit, women may be reluctant to take 5 years of an antiestrogen therapy with all of its perceived and actual toxicities. n

Aromatase Inhibitor–Related Pain Reduced with Exercise Regimen San Antonio, TX—Breast cancer survivors obtained significant relief from aromatase inhibitor–associated joint pain with a prescribed exercise program, the results of a randomized clinical trial showed.

At the end of 1 year, the patients in the exercise group reported 20% to 30% less pain compared with a control group that was randomized to usual care. The benefits were consistent across subgroups, irrespective of age, disease stage, treatment regimen, or duration of aromatase inhibi­­t­or therapy.

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By Charles Bankhead

“These results are a promising first step in developing clinical interventions that can improve aromatase inhibitor–associated joint pain.”

—Melinda L. Irwin, PhD, MPH

The magnitude of pain reduction in­­ creased with better adherence to the regimen, Melinda L. Irwin, PhD,

MPH, Associate Professor of Epi­ demiology (Chronic Diseases), Yale University, New Haven, CT, reported

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at the 2013 San Antonio Breast Cancer Symposium.

“These results are a promising first step in developing clinical interventions that can improve aromatase inhibitor–associated joint pain and, in turn, adherence to aromatase inhibitor therapy, breast cancer survival, and quality of life,” said Dr Irwin.

Although they are a standard of care for hormone receptor–positive breast cancer, aromatase inhibitors cause arthralgias in a substantial proportion of patients, with the estimated frequency ranging as high as 50%. Known colContinued on page 14

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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

San Antonio Breast Cancer Symposium

Adjuvant Bisphosphonates: Winner in Postmenopausal Breast Cancer Practice-changing results

By Phoebe Starr phonates were receiving zoledronic acid [Zometa]).

Bisphosphonates are thought to work by embedding in bone and interrupting the vicious cycle leading

phonate. Overall, 7 trials included oral clodronate and 29 included zoledronic acid.

Data were available for 22,982 patients with breast cancer (17,791 re-

“Adjuvant bisphosphonates had no significant effect on distant recurrences outside the bone, but the risk reductions in bone recurrence and breast cancer death were similar, regardless of estrogen receptor status, node status, and use/nonuse of chemotherapy.”

Photo by © SABCS/Todd Buchanan 2013

San Antonio, TX—Adjuvant bisphosphonates reduce the risk of bone metastases by approximately 33% and improve breast cancer–related survival by 17% in postmenopausal women with early breast cancer, according to a large meta-analysis reported at the 2013 San Antonio Breast Cancer Symposium (SABCS). Bisphosphonates had no effect on premenopausal women in the adjuvant setting.

“Adjuvant bisphosphonates had no significant effect on distant recurrences outside the bone, but the risk reductions in bone recurrence and breast cancer death were similar, regardless of estrogen receptor status, node status, and use/nonuse of chemotherapy,” stated Robert E. Coleman, MD, MBBS, Yorkshire Cancer Research Professor of Medical Oncology, University of Sheffield, United Kingdom, who presented the results on behalf of the Early Breast Cancer Trialists’ Collaborative Group.

Dr Coleman emphasized that the results were similar with clodronate and the aminobisphosphonates (65% of patients taking bisphos-

—Robert E. Coleman, MD, MBBS

to bone breakdown, Dr Coleman told attendees at the meeting.

The meta-analysis included 36 randomized trials conducted in the past 15 years comparing adjuvant bisphosphonates to placebo or to no bisphos-

ceived clodronate or an aminobis­ phosphonate); 11,036 women were postmenopausal.

With 10 years of follow-up, adjuvant bisphosphonates had no significant effect on disease recurrences of any type

Aromatase Inhibitor–Related Pain Reduced... lectively as aromatase inhibitor musculoskeletal syndrome, the arthralgias cause some patients to stop taking their medication. The current clinical guidelines specify 5 years of treatment

at a glance ➤ Breast cancer survivors with a prescribed exercise program reported 20% to 30% less pain than controls randomized to usual care ➤ Exercise improved aromatase inhibitor–associated joint pain ➤ The magnitude of pain reduction increased with adherence to the exercise regimen ➤ Positive results were seen regardless of age, disease stage, treatment regimen, or duration of aromatase inhibitor therapy

14

with an aromatase inhibitor after surgery for early breast cancer.

Dr Irwin and colleagues conducted a 12-month randomized trial involving 121 patients (mean age, approximately 60 years) with stage I to II hormone receptor–positive breast cancer and investigated the extent to which regular exercise can reduce the musculoskeletal pain caused by aromatase inhibitors, thereby improving adherence.

All study participants had been taking an aromatase inhibitor for at least 6 months, and all reported moderately painful arthralgias. Patients were randomized to a multimodality exercise regimen or to usual care, consisting primarily of education and advice about physical activity and monthly follow-up by telephone.

The exercise regimen consisted of twice-weekly supervised resistance and strength training and a weekly minimum of 150 minutes of at least moderate-intensity aerobic exercise (eg, brisk walking). Study participants randomized to the experimental arm

Value-Based Cancer Care

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february 2014

in the overall analysis of all women.

Among postmenopausal women, adjuvant bisphosphonates significantly reduced the risk for distant recurrence (21.9%) versus no bisphosphonate (18.4%) at 10 years (P = .003). This difference was mainly driven by the 10-year reduction in bone recurrence (8.8% vs 5.9%, respectively; P <.001).

Adjuvant bisphosphonates had no effect on mortality; however, among postmenopausal women at 10 years, an absolute reduction of 3.1% was seen in breast cancer mortality, and an absolute reduction of 2.3% in allcause mortality.

Peter M. Ravdin, MD, PhD, Codirec­ tor of the SABCS, and Director, Breast Cancer Program, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, called these results “practice changing.” Dr Ravdin said that the impact of bisphosphonates in the adjuvant setting is comparable to that of chemotherapy and trastuzumab (Herceptin) in HER2-positive women. He was not involved in any of the trials included in the meta-analysis. n

Continued from page 9

also received free memberships to health clubs. The primary outcome was a change in pain scores, as assessed by the Brief Pain InventoryShort Form.

Pain relief occurred in a dose-response manner: patients who attended at least 80% of the supervised sessions had greater improvement in pain outcomes compared with participants who attended the sessions less frequently.

Participants were well educated, overweight, and sedentary. The duration of aromatase inhibitor therapy at enrollment averaged 1.5 years.

When the trial ended, the data

showed that the exercise group had significantly lower scores on all major pain parameters. Average worst pain decreased by 20% versus <1% in the control group (P = .017); average pain severity by 21% versus no change, respectively (P = .025); and pain-related interference with daily activities by 29% versus <1%, respectively (P = .005).

As a group, the patients randomized to the exercise program lost more weight and improved their exercise capacity compared with the control group. Moreover, pain relief occurred in a dose-response manner: patients who attended at least 80% of the supervised sessions had greater improvement in pain outcomes compared with participants who attended the sessions less frequently.

The trial’s primary objectives were related to the effect of physical activity on joint pain. Although a potential to improve adherence to aromatase inhibitor therapy was implied, that outcome was not specifically investigated, said Dr Irwin. n

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No. 1

FDA Update First Drug Combination Approved for Unresectable or Metastatic Melanoma

The US Food and Drug Admin­ istration (FDA) approved the use of dabrafenib (Tafinlar; GlaxoSmith­ Kline) plus trametinib (Mekinist; GlaxoSmithKline) as a new combination therapy for the treatment of patients with advanced melanoma that is unresectable or metastatic. The 2 drugs were individually approved by the FDA in 2013 for melanoma.

Each of the 2 drugs blocks molecular signaling in different sites of the same pathway that promotes cancer-cell growth. Dabrafenib was initially approved for patients with melanoma whose tumors express the BRAF V600E mutation. The dabrafenib-trametinib combination is indicated for patients with melanoma who also have the BRAF V600E or BRAF V600K mutation. Approximately 50% of skin melanomas have a BRAF mutation.

“Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. This approval illustrates the value of continuing to study drugs in combination for clinical development.”

The FDA approval was based on results of a clinical trial of 162 patients with unresectable or metastatic melanoma with the BRAF V600E or BRAF V600K mutation; the majority of the patients were treatment-naïve.

They received dabrafenib as a single agent until their disease progressed or their side effects became intolerable, at which point they began using the combination. Overall, 76% of patients receiving the combination had an objective response for an average of 10.5 months compared with 54% of patients receiving dabrafenib alone who had an objective response lasting 5.6 months. Clinical trials are ongoing to determine whether this combination will also result in improved survival.

The side effects reported with the combination are similar to those reported with each individual drug.

Specifically, the combination was associated with an increase in the incidence and severity of fever.

The FDA approved this combination under its accelerated program, and also reviewed it under its priority review. (January 8, 2014)

Dabrafenib Receives Breakthrough Therapy Designation for Lung Cancer

A few days after the approval of the combination of the 2 melanoma drugs, the FDA approved dabrafenib (Tafinlar) as a breakthrough therapy

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designation for lung cancer based on interim results from an ongoing phase 2 clinical trial. (January 13, 2014)

Ibrutinib Approved for Chronic Lymphocytic Leukemia

The FDA approved a new indication for ibrutinib (Imbruvica;

Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least 1therapy before. The approval was granted under the FDA’s accelerated approval process to expedite access to patients with CLL to this promising new medication.

In November 2013, the FDA granted accelerated approval to ibrutinib for the treatment of patients with mantle-cell lymphoma (MCL), a rare and aggressive type of hematologic cancer; this approval, too, was for patients who had received at least 1 therapy before.

“Today’s approval provides an imContinued on page 16

First- and every-cycle Neulasta achieved: ■

94% relative reduction in febrile neutropenia (17% placebo vs 1% Neulasta; P < .001)1,2

■

93% relative reduction in febrile neutropenia–related hospitalization (14% placebo vs 1% Neulasta; P < .001)1,2

■

80% relative reduction in febrile neutropenia–related IV anti-infective use (10% placebo vs 2% Neulasta; P < .001)1,2

Phase 3 study in patients with breast cancer receiving 100 mg/m2 docetaxel for up to 4 cycles given placebo (n = 465) or Neulasta (n = 463); primary endpoint: incidence of febrile neutropenia.1 Febrile neutropenia = absolute neutrophil count (ANC) < 0.5 × 109/L and temperature ≥ 38.2°C.

Support through every cycle Help reduce the incidence of infection and protect your patients receiving myelosuppressive chemotherapy* from febrile neutropenia.

*Myelosuppressive chemotherapy regimens associated with a clinically significant risk of febrile neutropenia.

Neulasta® (pegfilgrastim) is administered by subcutaneous injection.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta for ARDS. Discontinue Neulasta in patients with ARDS.

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment.

Permanently discontinue Neulasta in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Please see brief summary of Neulasta Prescribing Information on the adjacent page.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta (pegfilgrastim) Prescribing Information. Thousand Oaks, CA: Amgen; 2011. © 2012 Amgen Inc. All rights reserved.

71679-R1-V1

Every appropriate patient.

Every cycle.

www.neulastahcp.com

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In the Literature Adverse Events Reporting...

Continued from page 7

stating whether AEs were addressed in the study. For methods, 93% specified an instrument or scale used to categorize AEs, 65% specified whether the reported AEs encompassed all recorded events or a select sample,

and 62% specified a surveillance time frame. For the results, 77% of articles reported absolute numbers of AEs, 75% reported if there were deaths related to AEs, 71% reported whether patients were evaluable for toxicity, and 65% reported reasons for treatment discontinuation.

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Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

71678-R1-V1

LASERS PRINTED AT

Value-Based Cancer Care

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

AMGNL10681 New Campaign Journal Ad PI Composite Master -04 Incremental Ad Insertions Colors: K + live/trim_DO NOT PRINT Bleed: NA Trim: 7.63"w x 10.75"h Live: 7"w x 9.625"h Output @ 100% Giant Creative Strategy

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In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

tions. The researchers cited potential factors for the observed variability in AE reporting and poor adherence with the recommendations, including the authors’ awareness of these recommendations and a lack of compliance with guidelines imposed by journals as a prerequisite.

This study further illustrates the importance of developing oncologyspecific standards for AE reporting to ensure consistency of reporting of AEs to provide oncologists with the information required to determine treatment recommendations, and to facilitate shared decision-making.

100%

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence malignancies receiving myelosuppressive anticancer drugs in Neulasta-treated patients as compared with placebo-treated patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation.

System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim.

Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim.

The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading.

Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta.

• Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] Blood and lymphatic system disorder: Sickle cell crisis • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity.

Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice.

Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

Regression analysis revealed that trials without a specified funding source and with an earlier year of publication were associated with significantly lower completeness scores.

This analysis shows substantial selectivity and heterogeneity in the reporting of AEs in oncology publica-

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FDA Update Ibrutinib Approved for Chronic Lymphocytic...

Continued from page 15

portant new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most.”

The approval of ibrutinib for the treatment of patients with CLL was also done under the priority review process of the FDA, based on the demonstration of the drug to have a significant improvement on the safety or efficacy of patients with this serious condition. Ibrutinib also received an orphan drug designation by the FDA. The new FDA indication for ibrutinib for CLL is based on the results of a clinical trial with 48 previously treated patients with CLL. Patients were diagnosed with CLL, on average, 6.7 years before enrolling in the study and had received 4 previous therapies. Patients received oral ibrutinib until disease progression or unacceptable toxicity.

Overall response was seen in nearly 58% of the patients, with a response duration of 5.6 months to 24.2 during the study.

The most common side effects reported with ibrutinib include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper-respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, mouth sores, sinusitis, and dizziness.

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Genitourinary Cancers Symposium

Enzalutamide Extends Survival in Previously Untreated Patients...

Continued from the cover

The drug was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of patients with mCRPC who had received previous therapy.

“Enzalutamide provides clinically meaningful benefit for men with mCRPC. It is approved by the FDA in men previously treated with docetaxel, but not yet approved for use prior to docetaxel. If it does get expanded approval for this indication, it is likely to become an important standard option for use in patients with asymp­ tomatic or minimally symptomatic advanced prostate cancer,” said lead investigator Tomasz M. Beer, MD, Deputy Director, Knight Cancer Institute, Oregon Health & Science University, Portland.

Between September 2010 and September 2012, the PREVAIL trial included 1717 patients with asymptomatic or mildly symptomatic mCRPC who had not received previous chemotherapy. They were randomized to enzalutamide or to placebo plus standard hormone therapy between September 2010 and September 2012.

Improved Survival For the coprimary end points of the trial—reduced mortality and radiographic disease progression—enzalutamide reduced the risk of death (ie, improved survival) by 29% (hazard ratio [HR], 0.76; P <.001) and the risk for radiographic disease progression by 81% (HR, 0.86; P <.001).

Enzalutamide slowed or halted

“Enzalutamide provides clinically meaningful benefit for men with metastatic CRPC. It is approved by the FDA in men previously treated with docetaxel, but not yet approved for use prior to docetaxel. If it does get expanded approval… it is likely to become an important standard option.”

—Tomasz M. Beer, MD

tumor growth in 59% of the patients, based on the overall response rate (using imaging of soft-tissue disease), totally 20% complete responses and 39% partial responses compared with

5% response in the placebo group (P <.001).

Of note, enzalutamide delayed the need for chemotherapy by a median of 17 months: the median time to chemotherapy was 28 months in the enzalutamide group versus 10.8 months in the placebo arm (HR, 0.35; P <.001).

“This is important from a pragmatic perspective. Many men don’t want to take chemotherapy, especially if they are asymptomatic or mildly symptomatic,” Dr Beer emphasized.

Charles J. Ryan, MD, Associate Clinical Professor, Department of Medicine (Hematology/Oncology), University of California, San Francisco, the moderator of the press cast, emphasized that this study breaks new ground for enzalutamide in chemotherapy-naïve patients with mCRPC. “The interim analysis showed benefit in this patient group, and this is an important study in our field, to be sure,” Dr Ryan said.

Dr Beer said that abiraterone (Zytiga) and enzalutamide have shown benefit in docetaxel-naïve patients with meta­ static disease, but at present there are no head-to-head comparisons to guide treatment selection. Decisions should be made on an individual patient basis, he advised.

Safety The safety observation was 3 times longer with enzalutamide, reflecting longer duration of treatment in this arm, he continued. Enzalutamide was well tolerated after 17 months of treat-

at a glance ➤ Enzalutamide improved survival and delayed radiographic disease progression in chemotherapy-naïve men with mCRPC ➤ In the PREVAIL trial, the drug reduced the risk of death by 29% and of radiographic disease progression by 81% ➤ Enzalutamide also delayed the need for chemotherapy by a median of 17 months and was well tolerated overall ➤ In addition to improving survival, enzalutamide offers a subset of men with mCRPC an important clinical benefit of avoiding chemotherapy for a significant period of time

ment, with the most common adverse events (AEs; seen in ≥20% of patients) including fatigue (36% with enzalutamide vs 26% with placebo), constipation (22% vs 27%, respectively), back pain (27% vs 22%, respectively), and joint pain (20% vs 16%, respectively).

Grade ≥3 AEs were reported in 43% of the enzalutamide group versus 37% of the placebo group. In both arms, 6% of patients discontinued treatment because of AEs. Further studies comparing these treatments and sequencing them are needed, as well as studies earlier in the disease process, Dr Beer noted. n

Angiotensin System Inhibitors Extend Survival in Patients with Metastatic Renal-Cell Carcinoma

By Phoebe Starr

San Francisco, CA—The use of angiotensin system inhibitors (ASIs) improved survival in patients with metastatic renal-cell carcinoma (mRCC) by 9 months, according to a retrospective pooled analysis of several clinical trials presented at the 2014 Genitourinary Cancers Symposium. Survival was further improved if patients were also taking vascular endothelial growth factor (VEGF) receptor–targeted agents.

“Based on results of this study, an ASI should be considered for patients with metastatic renal-cell carcinoma who need an antihypertensive therapy

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“An ASI should be considered for patients with metastatic renal-cell carcinoma who need an antihypertensive therapy and do not have any contraindications that preclude their use, especially in patients receiving VEGF-targeted treatments.”

—Rana R. McKay, MD and do not have any contraindications that preclude their use, especially in patients receiving VEGF-targeted treatments,” stated lead investigator Rana R. McKay, MD, Clinical Oncology

Fellow, Dana-Farber Cancer Institute, Boston. “However, it is too early to determine if ASIs should be used for patients with metastatic renal-cell carcinoma who do not have coexisting

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hypertension or another medical condition to warrant ASI treatment.”

VEGF is an established target in mRCC, Dr McKay said. ASIs include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which act on the renin-angiotensin system and are used to treat hypertension (as well as other conditions).

Recent research suggests that the peptide hormone angiotensin II modulates VEGF-depending angiogenesis.

These data are intriguing and need confirmation in a larger prospective study, stated the investigators.

Continued on page 18

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Genitourinary Cancers Symposium

Adding Radiation to Antiandrogen Hormone Therapy Extends Survival in Patients with High-Risk Prostate Cancer

By Phoebe Starr

San Francisco, CA—Radiation added to hormone therapy with antiandrogens extended cancer-specific survival, as well as overall survival, when used as the primary treatment of patients with locally advanced or high-risk prostate cancer. In the Scandinavian Prostate Cancer Group VII study, 10- and 15year survival improved by more than 50% in patients who received radiation plus hormone therapy versus hormone therapy alone, according to an updated analysis presented at the 2014 Genitourinary Cancers Symposium.

Over time, the survival difference between the 2 arms grew larger. A 2009 analysis of this study showed that at 8 years, prostate cancer–specific mortality was reduced by 12% in the group receiving radiation plus hormonal therapy versus hormonal therapy alone.

Lead investigator Sophie D. Fosså, MD, PhD, Professor and Senior Researcher, Department of Oncology, Oslo University Hospital, Norway, explained that the study was initiated in 1996, when the standard therapy for locally advanced or high-risk prostate cancer was lifelong hormonal therapy alone; it is still standard in Scandinavia. “Lifelong therapy with antiandrogens improves survival,” Dr Fosså said.

At the time the study was initiated in 1996, prostate cancer that extended through the prostatic capsule was

considered inoperable, she continued, and although surgical techniques have improved since then, surgery is not typically used in Scandinavia for these patients.

“The combination of radiotherapy and hormone therapy more than doubled the 10-year and 15-year survival rate and confirms that this approach should be a standard curative option for men with this type of prostate cancer who have at least another 10-year life expectancy,” Dr Fosså told listeners at a press cast.

Updated, Long-Term Results The updated analysis was based on 11 years of observation of mortality data from the Norwegian and Swedish death registries. The 875 patients enrolled in the trial (aged <75 years) had locally advanced or high-risk prostate cancer, and a prostate-specific antigen level ≤70 mg/L. Patients were all in relatively good health, Dr Fosså said.

Both arms received medical castration alone for 3 months, and patients were then randomized to standard treatment with lifelong antiandrogens or to the same hormonal treatment plus radiation, consisting of 70 Gy to 74 Gy, to the prostate. That dose is considered high compared with doses used in the United States.

The 10-year prostate cancer–specific

“The combination of radiotherapy and hormone therapy more than doubled the 10-year and 15-year survival rate and confirms that this approach should be a standard curative option for men with this type of prostate cancer who have at least another 10-year life expectancy.”

—Sophie D. Fosså, MD, PhD

mortality was reduced by more than 50% when radiation was added—19% for antiandrogens alone versus 8% for

antiandrogens plus radiation. The difference between the 2 arms was even greater at 15 years—31% mortality rate with antiandrogens alone versus 12% with the combination of radiation plus antiandrogens.

Looking at overall mortality, hormones plus radiation achieved superior results, but the gap between the 2 arms was narrower than for prostate cancer–specific mortality, because many patients died from other diseases, Dr Fosså added. The 10-year overall mortality rates were 35% for antiandrogens and 26% for the combination; the 15-year overall mortality rates were 57% and 43%, respectively.

Safety Both treatment arms were associated with the adverse events that would be expected with these therapies, including impaired sexual function and bowel problems.

Press cast moderator Charles J. Ryan, MD, Associate Clinical Pro­ fessor, Department of Medicine (He­ matol­ ogy/Oncology), University of California, San Francisco, said that this study was interesting, because the outcomes continued to improve over time, which is different from many other randomized trials. Dr Ryan emphasized that the men in this study received antiandrogens—not lifelong medical castration. n

Angiotensin System Inhibitors Extend Survival...

Study Details The study—the largest retrospective analysis to date evaluating the role of ASIs on outcomes in patients with cancer—was based on a database of 4736 patients with mRCC participating in phase 2 and 3 clinical trials conducted between 2003 and 2013. ASI use was defined as taking an ASI within days 0 to 30 of cancer treatment initiation.

Baseline hypertension was present in approximately 48% of all patients; 1487 patients were taking an ASI, and 783 were taking other antihypertensive agents.

Treatments for patients with mRCC included VEGF-targeted agents (such as sunitinib [Sutent], sorafenib

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[Nexavar], axitinib [Inlyta], bevaciz­ umab [Avastin]), or an mTOR in­ hibitor (temsirolimus [Torisel]), and interferon.

Overall survival (OS) for patients receiving ASI treatment was 26.68 months versus 17 months for nonASI users (hazard ratio [HR], 1.213; P <.009). In patients taking VEGF agents for mRCC, ASI use significantly prolonged OS: 31 months for ASI users versus 21.94 months for nonusers (HR, 1.38; P = .003).

Moreover, tumor shrinkage was more likely in patients receiving ASIs. The median progression-free survival was 8.3 months for ASI users versus 6.5 months for nonusers (P = .042).

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february 2014

Concomitant Use of VEGF and ASI Agents A subgroup analysis of type of an-

at a glance ➤ The use of ASIs in patients with mRCC improved OS to 26.68 months compared with 17 months for non-ASI users ➤ Survival was further and significantly improved if patients were concomitantly taking VEGF receptor–targeted agents

Continued from page 17

ticancer therapy showed that only concomitant VEGF and ASI use was associated with a significant survival benefit. This association was not seen with mTOR inhibitors or interferon, and it persisted in a multivariate analysis adjusted for a number of cofactors, including age, sex, type of mRCC therapy, the presence of bone metastases, and risk groups.

“The effect of ASIs on renal-cell carcinoma needs to be studied further. For now, results suggest that in patients with metastatic renal-cell carcinoma who are hypertensive at baseline, ASIs may be the best choice of antihypertensive therapy,” Dr McKay said. n

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Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

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

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40178 February 2014.

Genitourinary Cancers Symposium

1 in 5 US Clinical Trials Fails to Complete

By Phoebe Starr San Francisco, CA—The early termination of clinical trials is a tremendous waste of resources and can leave patients with cancer with no improved treatment options. For the first time,

a comprehensive study of the clinical trial enterprise in the United States has shown that 20% of 7776 adult phase 2 and 3 clinical trials registered on ClinicalTrials.gov were terminat-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

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ed early. Furthermore, early terminations occurred across all cancer types, according to this retrospective study presented at the 2014 Genitourinary Cancers Symposium.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

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

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

february 2014

Factors associated with the likelihood of early termination included being conducted at a single site, industry sponsorship, and trials conducted exclusively within the United States.

The investigators were alerted to the problem after noticing that a series of bladder cancer trials failed to complete, “leaving little evidence to guide clinical decision-making in bladder cancer,” said lead investigator Matthew D. Galsky, MD, Director, Genitourinary Medical Oncology, Tisch Cancer Institute, Mount Sinai, New York.

A 2010 Institute of Medicine report showed that approximately 40% of all trials initiated by the National Cancer Institute (NCI) Clinical Trials Cooperative Group Program were not completed. NCI-sponsored trials account for only approximately 15% of all clinical trials in the United States.

Dr Galsky and colleagues looked at the full scope of the problem of early termination within the larger clinical trial enterprise, which he said had not been done before.

“Clinical trials that fail to complete waste financial resources and human capital. The results of this study further highlight the wide-ranging impact of poor accrual to cancer clinical trials in the United States. The fact that a large proportion of clinical trials are not completed at all is a major barrier to progress in cancer care,” Dr Galsky stated.

Of 7776 phase 2 and 3 adult cancer clinical trials registered at Clinicaltrials. gov between 2005 and 2011, approximately 20% failed to complete. The most common reasons for early termination were: • Poor accrual, 38.7% • Toxicity/efficacy, approximately 20% • Logistics, approximately 20% • Other, including sponsor cancellation (10.6%) and lack of funding (5.6%).

Dr Galsky said that trials sponsored by industry and trials conducted at a single site in the United States were twice more likely to be terminated early than those conducted in multicenters; those conducted outside the United States were 33% less likely to fail than trials conducted in this country.

“These results suggest that approximately 48,000 cancer patients were enrolled in failed trials. Poor accrual was the most common reason. These failed trials impact all cancer types, waste resources, increase expenditures, and prevent us from getting answers about optimal treatment more quickly,” Dr Galsky stated. n

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Economics of Cancer Care

ASCO Proposes New Reimbursement Model...

For this nontreatment month, 2 levels of payment are proposed—(1) a higher amount for months immediately after the end of treatment, and (2) a lower amount for patients undergoing long-term monitoring.

Transition of treatment payment.

This payment is made when a patient begins a new line of therapy or ends treatment without an intention to continue. The idea is to compensate (in a lump sum) for the additional time involved in treatment planning and patient education.

Photo courtesy of ASCO

simple question: “If we could build a logical Medicare model for oncology reimbursement from scratch, what would it look like?” The simple answer is, in brief, put quality of care first. How to do that requires a few more details, with 5 recommendations in particular: New patient payment. A single reimbursement is proposed for the time required to evaluate a new patient. This would eliminate Current Procedural Terminology (CPT)-based evaluation and management payments, but would retain payment for FFS diagnostic testing.

Treatment month payment. After the patient begins treatment, the practice would receive a single monthly payment for all treatment-related activities (eg, chemotherapy administration, therapeutic injections and infusions, hydration services, etc). This compensation would replace all current CPT-based payments.

Four different levels of payment are proposed for the monthly reimbursement. This would account for the differing treatment needs of individuals within a practice population resulting from comorbidities, performance status, complications related to the proposed treatment plan, and so on.

Nontreatment month payment. This payment is proposed for circumstances in which a patient does not receive treatment during a particular month because of treatment complication or other medical circumstance.

“This payment reform proposal represents a real shift in the way oncologists would be reimbursed.”

—Clifford A. Hudis, MD

Again, 2 payment levels are recommended, with higher payments for a patient who has a recurrence while off treatment.

Continued FFS payment for some CPT codes. Some activities would retain current CPT code–based payments, such as laboratory tests, bone

marrow biopsies, and the use of portable pumps.

The criteria for determining payment levels within each component of the proposal would be standardized

by Medicare.

“The appeal of this proposed model,” said ASCO Clinical Practice Committee Chair Anupama Kurup Acheson, MD, Medical Oncologist, Providence Cancer Center Oncology and Hematology Care Clinic, Portland, OR, “is that by incentivizing high-quality, high-value patient care—patients win, oncologists win, and ultimately the American people will win with a stable, sensible, sustainable health care system.”

Improving the State of the Art: Whatever It Takes Under the proposed model, oncology practices will receive additional payments for participation in improvement of care initiatives. The initiatives include performance on instruments measuring quality of care, adherence to value-based treatment pathways, conservation of resources (ie, minimizing emergency department visits and avoidable hospitalizations resulting from complications of treatment), and participation in clinical trials.

“Oncologists are already integrating many of these best practices in their day-to-day work,” said ASCO Clinical Practice Committee Past Chair Jeffery C. Ward, MD, Medical Oncologist, Swedish Cancer Institute, Seattle, WA. “However, the current system does

Continued from cover

not recognize, incentivize, or reimburse for these critical components to high-quality cancer care.”

That said, Dr Ward and colleagues are not married to any single approach to payment reform. For example, just days after the above proposal went public, ASCO, in collaboration with

“The appeal of this proposed model is that by incentivizing high-quality, high-value patient care—patients win, oncologists win, and ultimately the American people will win with a stable, sensible, sustainable health care system.”

—Anupama Kurup Acheson, MD the Community Oncology Alliance, announced that they had achieved “a unified set of principles” intended to guide the organizations’ respective efforts to achieve payment reform in oncology.

Going forward, such intraorganizational cooperation is key, stated Dr Acheson. “If we do not work together to develop a solution for oncology reimbursement, then it will be forced upon us. We’ve seen the consequences that can bring—let’s get this done.” n

Higher Copays for Imatinib Lead to Medication Nonadherence in Patients with CML

By Neil Canavan

P

atients with chronic myeloid leukemia (CML) and high out-ofpocket (OOP) costs for treating their disease have a 70% chance of discontinuing treatment and a 42% chance of nonadherence to treatment compared with patients with lesser copays. These conclusions, which were recently published online (Dusetzina SB, et al. J Clin Oncol. 2014;32:306-311), have dire implications for a growing population of patients with CML. “Our findings highlight the potentially harmful effects of high copayment requirements on patients with CML,” wrote lead investigator Stacie B. Dusetzina, PhD, Research Assistant Professor of Medicine, University of

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North Carolina at Chapel Hill, and colleagues.

The treatment in question, imatinib (Gleevec), a tyrosine kinase inhibitor (TKI), is one of the most effective anti­ cancer drugs ever developed. Before its development, the median survival for patients with CML was 5 to 6 years.

With the advent of imatinib, treatment-adherent patients with CML can now expect to live a nearly normal life span.

However, nonadherence to imatinib (a once-daily oral medication) can result in treatment failure as a result of the rise of imatinib-resistant CML clones. Although overcoming resistance with recently developed sec-

“Our findings highlight the potentially harmful effects of high copayment requirements on patients with CML.” —Stacie B. Dusetzina, PhD, and colleagues ond-generation TKIs is possible, the cost for these newer agents is as high as, if not higher than, that of imatinib.

In their cost-sharing versus adherence analysis, Dr Dusetzina and colleagues looked at health plan claims

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from 2002 to 2011 for patients with CML initiating treatment with imatinib (N = 1541). Treatment discontinuation was defined as a gap of 60 days or more in prescription refills after the number of pills previously received were exhausted. Adherence was defined as drug coverage for 80% or more of the treatment period.

The primary independent variable was the OOP cost for a 30-day supply of imatinib.

“Although we selected our cohort on the basis of imatinib initiation,” Dr Dusetzina and colleagues stated, “our outcome measure included adherence to any TKI used during our study period since patients may have been Continued on page 22

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Higher Copays for Imatinib Lead to Medication Nonadherence... Continued from page 21 switched to another TKI (dasatinib or nilotinib) because of intolerance or failure to respond to imatinib.” (Previous studies have shown that nonadherence in CML is common in ≥33% of patients, and 100% adherence is rare.)

A Price Sometimes Hard to Swallow The results of the analysis showed that the mean copayment required for a 30-day supply of imatinib was $108—although there was a wide

at a glance ➤ Overall, 21% of patients with CML and lower copays were nonadherent to their TKI therapy compared with 30% of patients with the higher copays ➤ Patients with a higher copay were 42% more likely to be nonadherent to their prescribed treatment ➤ Among those with coinsurance requirements, the mean spending on a 30-day supply of imatinib was $286

➤ The costs of imatinib varied substantially, with 6.4% of the patients paying more than $500 for a 30-day supply ➤ These data establish a negative correlation between treatment adherence and OOP expense for CML drugs ➤ The investigators question the motivation for the recent tripling of the price for this drug

range of payments, with patients in the lowest 25th percentile paying $17 and those in the upper 75th percentile paying $53.

Treatment continuation and discontinuation were often related to the patients’ cost-sharing for the drug: only 10% of patients with relatively lower copay requirements discontinued their TKI compared with 17% of patients with higher copayments who discontinued therapy during the first 180 days of treatment. This translates into a 70% increase in the risk of discontinuing TKIs among patients with higher copays.

For treatment adherence, 21% of patients with CML and lower copays were nonadherent to their TKI therapy compared with 30% of patients with the higher financial burden. These patients with a higher copay were 42% more likely to be nonadherent to their prescribed treatment.

Copayments for imatinib were

largely related to OOP payments by the patient rather than coinsurance.

“Only 6.4% of our sample paid any coinsurance for imatinib versus 88.5% paying any copayments. Among those with coinsurance requirements, the mean spending on a 30-day supply of imatinib was $286….Costs varied substantially among individuals in our sample, with 6.4% of the sample paying more than $500 for a 30-day supply of imatinib.”

These data, establishing a negative correlation between treatment adherence and OOP expense for CML drugs, are being published at a time when the price for imatinib has steeply risen.

“It is unclear how insurers will respond to recent price increases for imatinib,” wrote Dr Dusetzina and colleagues. “But the recent tripling of price raises questions about the decisions manufacturers make when determining prices.” n

Decitabine More Cost-Effective than Conventional Induction in Older Patients with AML FDA should consider for this patient population

By Wayne Kuznar New Orleans, LA—The use of decitabine (Dacogen) is more cost-effective than conventional induction therapy for patients aged >60 years with acute myeloid leukemia (AML), according to data from a recent economic analysis.

The accepted treatments for patients with AML include cytarabine (Cytosar-U) plus daunorubicin, as well as hypomethylating agents such as decitabine. Complete remission rates with either approach are approximately 50%, noted the investigators. Furthermore, the 1-year overall survival (OS) rates are approximately 50% with either approach; 30-day mortality is slightly lower in patients receiving decitabine, but decitabine is not approved by the US Food and Drug Administration (FDA) for the treatment of AML. Given the economic pressures in the US health system, the FDA should consider approving decitabine for patients aged >60 years with newly diagnosed AML, suggested Nicolas Batty, MD, a hematology/oncology fellow at Roswell Park Cancer Institute, Buffalo, NY, and lead investigator of this analysis.

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Dr Batty’s team compared the direct costs of decitabine and conventional induction therapy in patients with AML (aged >60 years) using a semi-Markov model compiling survival and cost data. Derived from the 2012 US market, the costs of the drugs were assumed to be $1637.94 for 50 mg of decitabine, $12.08 for 2 g of cytarabine, and $58.62 for 20 mg/4 mL of daunorubicin.

The hospital costs were evaluated in a diagnosis-related group system.

The estimated cost of a direct hospital stay of 1 day was $2104.75, and the cost of an infusion clinic visit was $524.07. The cost-effectiveness was assessed using an incremental cost-­ effectiveness ratio (ICER).

The cytarabine plus daunorubicin regimen consisted of cytarabine 100 mg/m2 continuous infusion for 7 days, and daunorubicin 60 mg/ m2 for 3 days. Consolidation therapy with high-dose cytarabine followed the cytarabine plus daunorubicin regimen. The decitabine dosage used in the model was 20 mg/m2 daily as a 1-hour infusion for 10 days until remission, and then 5 days every 4 weeks until progression.

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The survival probabilities were taken from published literature. Data accounted for reinduction therapy with IDA-FLAG (idarubicin, fludar­ abine, cytarabine, and granulocyte

Decitabine was effective and more cost-effective than cytarabine or daunorubicin.

Given the economic pressures in the US health system, the FDA should consider approving decitabine for patients aged >60 years with newly diagnosed AML, the investigators suggest.

colony-stimulating factor) and consolidation therapy with high-dose cytarabine (HiDAC). The model assumed a maximum of 4 cycles of HiDAC and continuing decitabine until loss of benefit.

At 3 months, the OS rates were

98% with decitabine and 63.6% with cytarabine plus daunorubicin, and at 6 months, the OS rates were 59% and 50.4%, respectively. The survival rate at the end of 12 months was 47% in the cytarabine plus daunorubicin group and 52.6% in the decitabine group.

Life expectancy was 0.16 years long­­ er with decitabine versus with cytarabine plus daunorubicin (0.77 vs 0.61 years), and the quality-adjusted life-year (QALY) was 0.46 in the cytarabine plus daunorubicin group and 0.54 in the decitabine group.

The expected cost was nearly the same in both groups, with $88,325 for patients receiving cytarabine plus daunorubicin versus $91,312 with decitabine. The ICER per QALY with decitabine was $38,839.

Decitabine was the most costef­fective therapy. Decitabine was dom­inant in the model when the cost of cytarabine plus daunorubicin in­ creased by 10%, when the cost of decitabine decreased by 10%, and when the time horizon (the period for which the costs and treatment benefits were accounted) was 3 months or 6 months. n

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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

VIEW THE SERIES ONLINE AT:

www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127cs_Ksize13114

Economics of Cancer Care

Physicians Must Consider the Financial Burden Associated with Allogeneic Transplants Economically vulnerable patients may need financial counseling

By Wayne Kuznar New Orleans, LA—Recipients of allogeneic hematopoietic cell transplant are at high risk for financial burden, according to survey-based data collected by Nandita Khera, MD, MPH, a medical oncologist from the Blood and Marrow Transplant Program, Mayo Clinic Arizona, Phoenix, and colleagues.

The reasons include prolonged hospital stays, living away from home, high out-of-pocket (OOP) costs, ex­ tended duration of work loss for the patient and caregiver, and the occurrence of chronic medical problems, including complications from the transplant.

“One of the implications from the study is that, as healthcare providers, we need to be aware of the financial burden of allogeneic transplant, which is an important nonmedical complication of the transplant,” said Dr Khera.

To measure the financial toll on patients, Dr Khera and colleagues conducted a cross-sectional survey-­based study with 268 (of 482) eligible patients responding. The team used a

25-item questionnaire to measure sociodemographic information, as well as OOP expenses and medication copays, financial burden, and impact on medical care.

The median age of respondents was 55 years, and 51% of the total respondents were male. The study population was 95% white and 97% non-Hispanic, and 51% had unrelated donor transplants, 58% had reduced-inten­ sity conditioning regimens, and 49% had acute leukemia. The median follow-up time was 2.3 years.

Some 29% of patients reported working full time or going to school, in contrast to 69% of patients who had reported being a full-time worker or student before the transplant. A total of 31% of patients reported being on medical disability, and 72% had a monthly median household income of >$2000.

Of the 255 patients with available financial information, all were insured: 59% had private insurance, 4% Med­i­caid, 4% miscellaneous, and 33% had

Medicare with supplemental coverage.

Overall, 73% of patients said that being sick had hurt them financially.

In addition, 33% of patients believed that they did not have enough money

“We also need to be able to offer potential interventions like early and frequent financial counseling or connecting them to appropriate services for health.”

—Nandita Khera, MD, MPH

to take care of healthcare needs, or that their medicines were too expensive, and 22% reported being unable to pay their medical bills.

As a result of their medical bills, 13% of patients reported having had to

sell stocks or other investments; 25% had to withdraw money from a retirement account; 9% had to refinance a mortgage, take a second mortgage, or sell their house; and 3% had to declare bankruptcy.

The OOP costs for 3 months were >$2000 for 38% of patients and >$5000 for 12% of patients. The median monthly medication copayments were $100 (range, $0-$3000).

Of the patients, 19% reported cutting back on or not purchasing their prescription medications, 21% reported not making a physician appointment or having a medical test performed, and 28% deferred the use of a medical service (eg, physical therapy).

“We need to recognize the vulnerable patients who are at risk for catastrophic economic outcomes for self and their families. We also need to be able to offer potential interventions like early and frequent financial counseling or connecting them to appro­ priate services for health,” Dr Khera suggested. n

Rituximab Infusions Costlier When Given in the Hospital than in the Office Setting Careful selection of site of care can help to curb waste, save expenditures New Orleans, LA—More patients with diffuse large B-cell lymphoma (DLBCL) are receiving rituximab infusions in the hospital setting, incurring greater costs than those receiving infusions in the office or clinic, an examination of medical and pharmacy claims has shown.

Rituximab in combination with CHOP (cyclophosphamide, doxorubi­ cin, vincristine, and prednisone) is the recommended first-line therapy for DLBCL, improving overall survival compared with CHOP alone.

In a retrospective study, Carolina Reyes, PhD, of Genentech, South San Francisco, CA, examined differences in treatment patterns, healthcare resource use, and costs among patients with DLBCL receiving rituximab plus chemotherapy in the office or clinic versus in the hospital outpatient setting.

Medical and pharmacy claims from a large, geographically diverse US commercial health plan were used to identify 491 adults with DLBCL with 2

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or more claims for rituximab, 65% of whom received infusions in the office or clinic, and 35% of whom received them in the hospital. To be eligible for the analysis, patients were required to be enrolled in the health plan for ≥6 months before and after the date of the first rituximab claim (index date).

“Higher infusion-day costs contributed to higher unadjusted mean per-patient per-month costs among the hospital cohort.”

—Carolina Reyes, PhD

The follow-up extended through the episode of care: the date of the first rituximab infusion through 30 days after the last infusion, before a gap in

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rituximab administration of at least 7 months.

Of the 491 patients, 140 were covered under Medicare Advantage, and 351 were commercially insured. The percentage of patients receiving infusions in the hospital increased from 32% in 2007 to 43% in 2011/2012.

The mean length of episode of care was not significantly different by the site of service: 187 days in the office or clinic versus 178 days in the hospital.

The mean number of rituximab infusions was less in the hospital compared with in the office or clinic (4.92 vs 6.52, respectively), as was the mean number of infusions per month (1.01 vs 1.17, respectively).

Of the patients receiving infusions in the office or clinic setting, 93% had evidence of the receipt of combination therapy (rituximab plus chemotherapy) compared with 85% of those receiving treatment in the hospital. The receipt of granulocyte colony-stimulating factor

was 87% in patients treated in the office or clinic versus 77% in those treated in the hospital.

The total mean costs during the episode of care, as well as administration costs incurred on days of rituximab infusions, were significantly higher among the hospital cohort compared with the office/clinic cohort.

The unadjusted mean infusion-day costs were higher in the hospital cohort compared with the office/clinic cohort ($12,481 vs $5834, respectively).

“Higher infusion-day costs contributed to higher unadjusted mean per-patient per-month [PPPM] costs among the hospital cohort,” noted Dr Reyes.

Total unadjusted PPPM costs in the hospital cohort were significantly higher compared with the office/clinic cohort ($22,325 vs $15,541, respectively).

“These results warrant further investigation to assess the impact of these differences on clinical outcomes by site of care,” according to Dr Reyes.­—WK n

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Economics of Cancer Care

Significant Hospital Costs Tied to 30-Day Readmissions for Allogeneic Transplants

By Wayne Kuznar

New Orleans, LA—New research has confirmed that 30-day readmission for reduced-toxicity conditioning allogeneic hematopoietic-cell transplantation (allo-HCT) is linked to greater 100-day posttransplant hospital charges.

The finding justifies 30-day readmission as a significant marker of quality of care, said lead investigator Sherri Rauenzahn, MD, a palliative care fellow at West Virginia University in Morgantown, who presented her data at ASH 2013.

The criteria that impact 30-day readmission were examined for 91 patients who had reduced-toxicity conditioning allo-HCT with fludar­abine (Fludara; total dose, 150-160 mg/m2) and busulfan (Myleran; total dose, 6.4 mg/kg or 12.8 mg/kg). The researchers also measured the impact of 30-day readmission on mortality and healthcare costs of allo-HCT recipients. Of the 91 patients, 35 (38%) required readmission, at a median time of 14 days and a median length of stay of 3 days.

“The only variable on multivariate analysis that predicted readmission was an infection during the transplant admission,” said Dr Rauenzahn.

“There was no difference [between groups] as far as cause of readmission. Those readmitted within 7 days usually had either a fever or infectious process, but it wasn’t statistically significant.”

The caregiver type and the number of caregivers did not influence the readmission rate.

After an 18-month median follow-up for surviving patients, the approximate 2-year overall survival rates were 49% in readmitted patients and 58% in those not readmitted. The 1-year nonrelapse mortality rates were 18% in the patients who were readmitted and 13% in patients who were not readmitted.

“Other studies have found that the conditioning regimen used might impact the readmission rate, but we used only a single conditioning regimen to try to eliminate it as one of the confounders,” she said.

“The cost of readmission made a significant difference in the total cost in the 100-day period posttransplant,” Dr Rauenzahn noted. “There was no

“The cost of readmission made a significant difference in the total cost in the 100day period posttransplant.

There was no difference in outpatient charges between groups,…it was just the readmission rate.”

—Sherri Rauenzahn, MD

difference in outpatient charges between groups,…it was just the re­ admission rate.”

The respective median and mean hospital charges were: • Inpatient: $25,698 and $45,982 for readmitted patients versus $0 and

$24,292, respectively, for patients not readmitted (P <.001) • Outpatient: $43,280 and $47,942 for readmitted patients versus $37,834 and $42,421, respectively, for patients not readmitted (P = .22) • Total: $85,115 and $93,925 for readmitted patients versus $45,083 and $69,142, respectively, for patients not readmitted (P = .002).

“In this specific allo-transplant population, a 30-day readmission is an indicator of increased costs,” Dr Rauenzahn pointed out. “What we can do to lessen that readmission rate is going to be challenging, because in the transplant population you already have a fairly good follow-up system, with a lot of attention to detail. Do we keep patients who have an infection during their transplant admission for a few days longer to try to prevent readmissions down the road? Or do we continue to practice the way we currently have and discharge when we think the acute condition has resolved and the [blood] counts have recovered, and see what happens?” n

Peripheral T-Cell Lymphoma Associated with High Clinical Burden, Resource Utilization, and Costs New Orleans, LA—Peripheral T-cell lymphoma (PTCL) is associated with high resource utilization rates and high overall costs, according to a multicenter study presented at ASH 2013.

Hospitalizations, in particular, represent a major clinical and economic burden, indicating the need for treatments requiring lower resource utilization with better PTCL management.

Michele H. Potashman, PhD, of Millennium Pharmaceuticals, Cam­ bridge, MA, and colleagues, studied 1000 patients with PTCL identified by International Classification of Diseases, Ninth Revision (ICD-9) codes over a period from October 1, 2007, to June 30, 2011. Truven Health Analytics Market­Scan data for commercially insured and Medicare supplemental pa­­ tients were used to retrospectively identify patients with PTCL. This database comprises medical and pharmaceutical claims for more than 100 million unique patients across the United States.

To be included in the study, patients had to have at least 6 months of con-

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tinuous enrollment before their index date and 12 months of continuous enrollment after their index date.

The mean patient age was 56 years, 58% of the patients were male, and all patients had a high rate of comorbidi-

The average annual costs were $75,934.08 for patients with PTCL compared with $4660.64 for the matched controls, driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). ties (mean Charlson Comorbidity Index of 1.72 vs 0.39 for the control group).

The control group included 5000 randomly selected patients without PTCL, and was considered the average insured patient population.

Monthly healthcare costs were measured and annualized to provide average annual costs. Healthcare costs included hospitalizations; pharmacy services; office visits; emergency department visits; hospice stays; stem-cell transplant; and other patient-related costs, such as laboratory procedures, blood transfusions, and radiology procedures.

The cost estimates were based on net payments received by the providers, and healthcare costs included hospitalizations, pharmacy services, office visits, emergency department visits, and hospice stays.

High Annual Costs “On an average annual basis, PTCL patients were hospitalized more often and experienced a longer length of stay compared with matched controls,” noted Dr Potashman. “In addition, PTCL patients had higher utilization of office visits, pharmacy services, emergency room visits, and hospice care.”

Overall, the average annual costs were $75,934.08 for patients with

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PTCL compared with $4660.64 for the matched controls, driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs).

A total of 50% of the patients with PTCL compared with 13.8% of the controls had hospitalizations. Emergency department visits were almost twice as frequent in patients with PTCL as in the control group—47% versus 25%, respectively.

The mean cost of hospitalization per patient was $24,427 for the patients with PTCL versus $1058 for the controls (P <.001).

Some 11.4% of patients with PTCL had stem-cell transplant compared with none of the controls. The mean cost per patient undergoing transplant in the PTCL cohort for a first stem-cell transplant was $126,093.58.

The most common diagnoses associated with hospitalization (based on ICD-9 codes) among the patients with PTCL were fever, fatigue, dizziness, dyspnea, chest pain, cough, and other chest symptoms.–—WK n

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Personalized Medicine

Novel CAR-T Therapy Shows Impressive Results...

Acute Lymphoblastic Leukemia A total of 22 pediatric patients and 5 adult patients with relapsed, treatment-resistant ALL have been treated with CTL019 at the University of

at a glance ➤ A new approach in which the patient’s own T-cells are extracted and genetically engineered ex vivo to target the CD19 antigen in cancer cells has shown unprecedented results ➤ These CAR-T cells (or CTL019 cells) have led to complete or partial remissions lasting >3 years in patients with aggressive ALL, CLL, or B-cell lymphoma ➤ The responses were particularly encouraging in patients who had exhausted all other treatment options ➤ In some cases, “the disease has disappeared after a single infusion of these engineered T-cells” ➤ Experts expect that CTL019 will be available as a treatment option between 2016 and 2020

Pennsylvania, said Stephan A. Grupp, MD, PhD, Director, Translational Research, Center for Childhood Can­ cer Research, Children’s Hospital of Philadelphia, PA. Of these patients, 19 achieved complete remission (CR), 14 of them still ongoing; 5 patients relapsed. The first patient treated with the protocol is now 8 years old and has been in CR for 20 months.

Of the 5 adults, 4 achieved CR, the longest of which has been 6 months.

One patient subsequently underwent bone marrow transplant and remained in remission. One patient relapsed after being 3 months in CR, and his disease tested negative for the engineered cell target.

A separate report from the Uni­ versity of Pennsylvania described the fate of the CTL019 cells after they were reinfused into the population that was discussed by Dr Grupp above. The lead investigator was Michael Kalos, PhD, Adjunct Associate Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Patients with the greatest magnitude of in vivo expansion of the reengineered T-cells (above 5% of the total of all their T-cells) were most likely to achieve CR, patients with a lesser response but detectable levels of cell expansion were partial responders, and those with no detectable T-cell expansion were nonresponders. The reinfused T-cells remained in the body several months postinfusion and were viable.

Chronic Lymphocytic Leukemia CTL019 cells have been used to treat 32 adults with CLL by David L. Porter, MD, Director, Blood and Marrow Transplantation, Abramson Cancer Center, University of Pennsylvania, and colleagues. The overall response rate is

47% (15/32), including 7 CRs (still on­ going) and 15 partial responses (PRs).

These 32 patients included 14 patients in a pilot trial and the first 18 in a phase 2, dose-optimization trial.

Some of the remissions have lasted

Photo © American Society of Hematology

vivo to target the CD19 antigen present on cancer cells; a viral vector is inserted, and the cells are reinfused into the patient via a single infusion where they are designed to expand and attack cancer cells like a “smart bomb.”

Currently, it takes approximately 10 days to engineer the cells.

“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” reported James N. Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).

“It looks like the disease has disappeared after a single infusion of these engineered T-cells. This is the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable and have a very poor prognosis.

The novel finding is that CTL019 can eradicate solid tumor mass.”

—James N. Kochenderfer, MD for >3 years, suggesting that the T-cells continue to do their work over time.

Some PRs converted to CRs over time, Dr Porter said.

B-Cell Lymphoma: First Report Dr Kochenderfer presented results from the NCI’s study of 15 patients (age, 30-68 years) with B-cell lymphomas, including 9 with chemo-

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therapy-refractory disease (some up to 10 previous cycles of treatment) and 6 had a variety of indolent B-cell lymphomas.

“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options,” Dr Kochenderfer said.

Overall, 7 patients achieved CR and 5 achieved PR; 1 patient died from cardiac arrhythmias, and 1 patient was lost to follow-up.

Acute toxicities included fever, low blood pressure, focal neurological deficits, and delirium, all of which resolved in less than 3 weeks.

“This is the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable and have a very poor prognosis. The novel finding is that CTL019 can eradicate solid tumor mass,” Dr Kochenderfer said at a press conference. This approach could be used for patients who are not suitable for transplant, he noted.

Industry Buy-In These exciting, often dramatic responses have attracted industry partnerships. For example, the Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and the Seattle Children’s Re­ search Institute collectively launched Juno Therapeutics Inc, a new biotechnology company to develop CTL019 cells. The NCI has licensed their CTL019 cells to Kite Pharmaceuticals.

The University of Pennsylvania has partnered with Novartis to develop CTL019 cells, and Novartis is building a manufacturing facility at the University of Pennsylvania.

Experts estimate that CTL019 will be available as a treatment option between 2016 and 2020. n

PIK3CA Mutation Thwarts Neoadjuvant Anti-HER2 Therapy in Breast Cancer

By Charles Bankhead San Antonio, TX—Patients with HER2-­ positive breast cancer harboring a PIK3CA mutation had a significantly lower likelihood of achieving a pathologic complete response (pCR) to neoadjuvant anti-HER2 therapy, the results of 2 large clinical trials presented at the 2013 San Antonio Breast

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Cancer Symposium (SABCS) showed.

Patients without the mutation had a pCR rate of 37% versus 17% for those with a mutation. The pCR rate for mutated tumors was 17% to 18%, whether patients received a single anti-HER2 agent or a combination.

The findings also demonstrated

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how the mutation, which is traditionally associated with treatment resistance in advanced and metastatic breast cancer, has transitioned into the role of an obstacle in the treatment of patients with earlier-stage disease.

“We observed similar pCR rates for the different anti-HER2 treatments

in PIK3CA-mutant HER2-positive tumors,” Sibylle Loibl, MD, Professor, German Breast Group, Neu-Isenburg, Germany, said during a press briefing.

“Clearly, new treatment options need to be investigated in these cancers, such as PIK3CA-targeting agents.”

The findings have implications for Continued on page 27 Vol. 5

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Personalized Medicine

a substantial number of patients, Dr Loibl noted, because a PIK3CA mutation occurs in approximately 20% of breast cancers.

“We need to integrate PIK3CA mutation analysis of breast tumors into routine practice so we can ensure that women receive the most appropriate neoadjuvant therapy for their specific tumor type,” Dr Loibl added.

Aberrations in the PI3K/AKT signaling pathway occur frequently in breast cancer, the most common being PIK3CA, which affects approximately 20% of patients with breast cancer.

Despite the relatively high prevalence of the mutation, data related to its prognostic and predictive value have been sparse and inconsistent, particularly in patients with HER2-positive and triple-negative tumors.

Two previous clinical trials of patients with HER2-positive breast cancer had helped clarify the role of anti-HER2 agents in neoadjuvant therapy. The phase 3 Neoadjuvant Lapatinib and/or Trastuzumab Treat­ ment Optimisation (NeoALTTO) trial showed that the combination of trastuzumab (Herceptin) and lapatinib (Tykerb) leads to a higher pCR rate than either agent alone. The phase 2 NeoSphere trial showed that the addition of pertuzumab (Perjeta) and trastuzumab to docetaxel (Taxotere) improved pCR compared with the addition of trastuzumab alone. Studies have shown that pCR correlates with survival in patients with breast cancer.

Photo by © SABCS/Todd Buchanan 2013

PIK3CA Mutation Thwarts Neoadjuvant Anti-HER2...

“New treatment options need to be investigated in these cancers, such as PIK3CA-targeting agents.

We need to integrate PIK3CA mutation analysis of breast tumors into routine practice.”

—Sibylle Loibl, MD Study Details Using data from 2 large trials of neoadjuvant chemotherapy in patients with newly diagnosed breast cancer, Dr Loibl and colleagues investigated the frequent and clinical consequences of the PIK3CA mutation in 737 patients with this mutation. They analyzed data from the German Breast Group’s GeparQuinto and GeparSixto studies, the former involving only patients with HER2-

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(hazard ratio [HR], 0.44; P = .006; HR, 0.29; P = .007, respectively).

Although PIK3CA mutation was associated with a lower rate of pCR, patients with mutant HER2-positive breast cancer have benefited from anti-HER2 therapy, at least in the metastatic setting, Carlos L. Arteaga, MD, Director, Breast Cancer Program,

positive breast cancer.

In GeparQuinto, investigators compared the anti-HER2 agents lapatinib and trastuzumab, each added to conventional neoadjuvant chemotherapy.

GeparSixto evaluated neoadjuvant chemotherapy with or without carboplatin (Paraplatin). Patients with HER2-positive tumors also received lapatinib and trastuzumab. In both trials, the primary outcome was pCR. Consistent with previous observations, 20.8% of the patients in the 2 trials had PIK3CA-mutated tumors.

The pCR rates in GeparQuinto were 17.9% in patients with PIK3CA mutations and 26.4% in patients with wildtype PIK3CA. In GeparSixto, the pCR rates were 22.4% for PIK3CA-mutated tumors and 41.6% for tumors with wild-type PIK3CA. “Patients who had HER2-positive tumors that also were hormone receptor–positive had the worst outcomes,” said Dr Loibl, “as the pCR rate was only 6.3% in that subgroup. In contrast, patients with HER2-positive/ hormone receptor–positive and no mutations had a pCR rate of 30.6%.”

“There was no difference in pCR rate by PIK3CA status in patients who had HER2-positive/hormone receptor–neg­ative breast cancer.”

The type of anti-HER2 therapy did not significantly affect the pCR rate in patients with PIK3CA-mutated tumors.

A multivariable analysis of Gepar­ Sixto showed that hormone receptor– positive tumors and PIK3CA mutations were negative predictors of pCR

“Clearly, we need new agents and combinations to overcome resistance to targeted agents.”

—Carlos L. Arteaga, MD Vanderbilt-Ingram Cancer Center, Nashville, TN, said during an SABCS press conference. Comparisons of patients with PIK3CA-mutated tumors have shown better outcomes in patients treated with anti-HER2 therapy, although the benefit was lower than that seen in patients without mutations.

No agents that specifically target PIK3CA are available, but mammalian target of rapamycin (mTOR) inhibitors offer a potential option.

“The problem with using an mTOR inhibitor is that mTOR inhibition has been shown to activate PI3K,” said Dr Arteaga.

Echoing Dr Loibl’s sentiments, Dr Arteaga said, “Clearly, we need new agents and combinations to overcome resistance to targeted agents.” n

I-SPY 2: First Results Based on Biomarkers/Genetic Signatures in Breast Cancer

By Phoebe Starr

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“Our goal is to accelerate the process of identifying drugs that are effective for specific breast cancer subtypes, and reduce the cost, time, and numbers of patients needed to get effective drugs to market.”

Photo by © SABCS/Todd Buchanan 2013

San Antonio, TX—Veliparib plus carboplatin was identified as a worthy combination to move forward in trials of patients with triple-negative breast cancer (TNBC; ie, estrogen receptor–negative, progesterone receptor–negative, HER2-negative), a subtype of breast cancer with a very poor prognosis.

This combination was a “winner” in the phase 2 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) 2 trial, a series of studies of novel agents and combinations of therapies in biomarker-identified subsets of patients. The trial has a unique adaptive design that allows

—Hope S. Rugo, MD

screening of a series of novel agents in combination with standard neoadjuvant therapy for high-risk patients with breast cancer in small numbers

of patients with a particular biomarker or signature.

These first efficacy results of I-SPY 2 showing that veliparib plus carboplatin

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“graduated” in TNBC were presented

by Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco, at the 2013 San Antonio Breast Cancer Symposium. I-SPY 2 has also identified neratinib as a “graduate,” but those data are not yet available.

“Our goal is to accelerate the process of identifying drugs that are effective for specific breast cancer subtypes, and reduce the cost, time, and numbers of patients needed to get effective drugs to market. Today’s report is on 1 of 7 current experimental arms of I-SPY 2,” Dr Rugo told listeners at the meeting.

The study pits 12 weekly cycles of

Continued on page 31

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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.

In the Literature New Gene Mutation Identified in Myeloproliferative Neoplasms

New research shows promise in deciphering the underlying mechanism of myeloproliferative neoplasms (MPNs), according to findings from a recently reported study (Klampfl T, et

al. N Engl J Med. 2013;369:2379-2390).

The Janus kinase 2 (JAK2) gene is present in approximately 50% to 60% of patients with essential thrombocythemia or primary myelofibrosis, and an additional 5% to 10% have activating mutations in the thrombopoietin receptor gene, MPL. However,

no specific molecular marker has been identified in the remaining 30% to 45% of patients.

In the study, Klampfl and colleagues performed whole-exome sequencing and identified somatically acquired mutations in 6 patients with primary myelofibrosis without JAK2 or MPL

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Brief Summary 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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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.

mutations. After confirming the presence of 2 to 12 somatic mutations per patient, the analysis revealed recurrent somatic insertions and deletions in exon 9 of CALR, encoding calreticulin. The researchers resequenced 1107 samples from patients with MPN and found that CALR mutations were absent in polycythemia vera; however, CALR mutations and JAK2 and MPL mutations were mutually exclusive in essential thrombocythemia and primary myelofibrosis. Among patients with essential thrombocythemia and primary myelofibrosis with wild-type JAK2 or MPL, the researchers identified CALR mutations in 67% and 88% of patients, respectively. The researchers detected 36 different types of mutations in CALR. The prevalent types were a 52-bp deletion and a 5-bp insertion (53% and 31.7%, respectively). The findings also showed that patients with mutated CALR had a lower risk of thrombosis and longer OS than patients with mutated JAK2.

Patients with primary myelofibrosis and a somatic mutation of CALR had longer OS than those with a JAK2 mutation (median, 21.4 years vs 11 years, respectively; P <.001). The OS rates at 10 years among patients with essential thrombocythemia were 96.9% in patients with a CALR mutation and 91.1% in patients with a JAK2 mutation (P = .04). Patients with a CALR exon 9 mutation had a lower cumulative incidence of thrombosis at 10 years than patients with the JAK2 mutation (11% vs 21%, respectively; P = .003).

From a practical point of view, the researchers suggested that different effects of mutated genes might be incorporated into existing prognostic scoring systems and guide therapeutic decision-making for patients with primary myelofibrosis and essential thrombocythemia. Furthermore, the CALR molecular characterization may become a critical component in the clinical management of these 2 types of MPN.

Statin Therapy Lowers Mortality in Patients with Prostate Cancer

Statin use has been shown to improve lipid profiles and to reduce cardiovascular morbidity and mortality.

A 2012 study found that statins may have antitumor effects in various cancer types, including prostate cancer.

Observational studies have investigated the association between statin use and different prostate cancer outcomes, but the findings were inconsistent.

Also, these studies did not specifically assess whether the use of statins before the diagnosis of prostate cancer modified the association regarding the use of

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Personalized Medicine

Second-Generation Genomic Sequencing Offers Opportunities, Poses Challenges

By Charles Bankhead

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proved,” Dr Collins and Dr Hamburg said in their editorial.

With the technology, clinical practitioners can search for a virtually unlimited number of genetic changes

Photo Courtesy of FDA

he quest for personalized medicine has come full circle with the US Food and Drug Administration (FDA)’s approval of the first high-throughput genomic sequencer, MiSeqDx, but challenges remain on several fronts before the technology’s full potential can be realized, according to the nation’s top health research administrator.

The first commercially available next-generation sequencer represents a key milestone. Continued progress in the personalization of healthcare requires collaborative efforts in the areas of research, healthcare policy, and patient rights, said National Institutes of Health Director Francis S. Collins, MD, PhD, in an editorial (N Engl J Med. Epub 2013 December 19) coauthored with FDA Commissioner Margaret A. Hamburg, MD. In their editorial, “First FDA Authorization for Next-Generation Sequencer,” Dr Collins and Dr Hamburg noted that the approval of the MiSeqDx sequencer will facilitate the widespread development and use of genomic tests. The high-throughput sequencer can perform wholegenome sequencing within 24 hours at a cost of less than $5000. Although not inexpensive, the technology contrasts with the global research effort that led to the first sequencing of an entire human genome, which required more than a decade and cost hundreds of millions of dollars.

“This is a rare example of technology development in which faster, cheaper, and better have coincided: as costs have plummeted and capacity has increased, the accuracy of sequencing has substantially im-

Margaret A. Hamburg

“This is a rare example of technology development in which faster, cheaper, and better have coincided: as costs have plummeted and capacity has increased, the accuracy of sequencing has substantially improved.”

—Francis S. Collins, MD, PhD, and Margaret A. Hamburg, MD

that may have significance for the care of an individual patient. Using oncology as one specialty that will benefit greatly from high-throughput sequencing, the authors noted that “recent work from the Cancer Genome Atlas demonstrates that the

tissue of origin of a particular cancer may be much less relevant to prognosis and response to therapy than the array of causative mutations.”

Rapid whole-genome sequencing paves the way to realizing the full potential of pharmacogenomics, “the use of genomic information to identify the right drug at the right dose for each patient,” said Dr Collins and Dr Hamburg. More than 120 approved therapies have labeling that includes pharmacogenomics information, which could provide essential guidance about genetic-related differences in response to a therapy, possibly indicating a need for genetic testing before prescribing the agent.

Until now, the clinical potential of pharmacogenomics had languished in limited use because of an inability to obtain necessary genomic information in a timely fashion.

“Placing genomic information in the electronic medical record would facilitate this kind of personalized medicine,” wrote Dr Collins and Dr Hamburg. “If the patient’s entire genome were part of his or her medical record, then the complexities of acquiring a DNA sample, shipping it, and performing laboratory work would be replaced by a quick electronic query.”

However, the top healthcare administrators continued, “even the most promising technologies cannot fully realize their potential if the relevant policy, legal, and regulatory issues are not adequately addressed.”

To some extent, concerns about the potential misuse of an individual patient’s genomic information have been addressed. The Health Insurance Portability and Accountability Act

and the Genetic Information Non­ discrimination Act prohibit health insurers from considering genetic information as a preexisting condition, as underwriting material, or as a basis for denying coverage.

Provisions of the Affordable Care Act offer additional protection against the indiscriminant use of genetic information, extending the prohibition on preexisting conditions (genetic or otherwise) to life insurance, long-term care insurance, and disability insurance.

The US Supreme Court eliminated another potential hindrance to the use of genomic information, ruling that naturally occurring DNA cannot be patented.

“Before the…[Supreme Court] decision, there were substantial concerns that in order to offer whole genome sequencing, clinical laboratories would have to pay royalties to a long list of gene patent holders,” noted Dr Collins and Dr Hamburg. “The decision has opened the creative doors to an as yet unimaginable set of products that may benefit the public health.”

The authors cited the necessity for an “appropriate risk-based regulatory framework…to ensure the validation and quality of tests…developed in-house by clinical laboratories.”

Reimbursement issues also require resolution before the potential of genomic testing can be realized.

“We need to work together to ensure that research progresses, that regulatory policies are developed, that patients’ rights and needs are addressed, and that clinical use of genomic information is based on rigorous evidence,” Dr Collins and Dr Hamburg concluded. n

I-SPY 2: First Results Based on Biomarkers/Genetic... standard paclitaxel against 12 cycles of weekly paclitaxel plus novel agent A versus 12 weekly cycles of paclitaxel plus novel agent B. This treatment is followed by doxorubicin-based chemotherapy. Response is determined by pathologic complete response (pCR), defined as no residual invasive cancers in the breast and lymph nodes, and by magnetic resonance imaging (MRI) assessment after definitive surgery.

“Adaptive randomization based on the performance of regimens within biomarker subtypes/MammaPrint

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genetic signatures is the key for enrolling patients. Random probabilities are updated as the study proceeds according to MammaPrint signature, and the threshold for success is based on response for each patient’s tumor based on MRI and pCR assessment over time,” Dr Rugo explained.

The response of each patient informs the randomization assignment for the next patient on study, she continued. Each new patient benefits from the information obtained from the previous patient with that same signature.

“This allows us to drop an agent that isn’t working,” Dr Rugo explained.

Randomization is assigned based on the performance of the experimental regimens within 8 biomarker subtypes (based on hormone receptor, HER2, and MammaPrint He-1 and Hi-2).

The results reported at the meeting included 71 evaluable patients, 44 of whom had TNBC. The estimated probabilities of pCR showed that the probability of success with veliparib plus carboplatin is 99%, mainly as a result of the success of this regimen

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in patients with TNBC. By contrast, veliparib plus carboplatin had little probability of succeeding in the HER2positive/hormone receptor–positive subset of patients.

The ultimate plan for drugs that “graduate” in I-SPY 2 is a 300-patient phase 3 trial that includes the subset of patients who will benefit from that drug. “The phase 3 trial will incorporate outcome data to correspond with pCR. We hope this will be a mechanism for accelerated approval,” Dr Rugo said. n

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Personalized Medicine

Genetics Providing New Insights into Signaling Pathways and Treatment Targets in ALL New Orleans, LA—Those frustrated with low long-term remission rates in adult patients with acute lymphocytic leukemia (ALL) can find hope in the superior outcomes associated with treatment for pediatric ALL. Overall survival (OS) with therapy reaches 85% in children but lags in adults at 45%. Targeting specific pathways and adding novel agents to standard therapy should improve outcomes in adult patients.

Identifying Cytogenetic Subgroups “To achieve the goal of curing all patients with ALL and reduc­ing toxicity, there is a need for new therapies to target the underlying molecular pathology of the disease, which forms the crux of leukemia research at this time,” said Christine J. Harrison, PhD, Pro­ fessor of Child­ hood Cancer Cyto­genetics, Newcastle University Leu­ k emia Research Cytogenetics Group, Newcastle upon Tyne, United Kingdom.

Advances in sequencing technology will identify genes and pathways that are consistently altered in high-risk patients with ALL, which should yield novel targets, Dr Harrison said.

“To achieve the goal of curing all patients with ALL and reducing toxicity, there is a need for new therapies to target the underlying molecular pathology of the disease, which forms the crux of leukemia research at this time.”

—Christine J. Harrison, PhD

Although virtually all chromosomal abnormalities occur in adult and in childhood ALL, there is a significant difference in the incidence rate of most cytogenetic subgroups according to age, Dr Harrison said. For example, the low-risk cytogenetic subgroups characterized by ETV6-RUNX1 and high hyperdiploidy are seen almost exclusively in children, whereas the incidence of BCR-ABL1 increases dramatically with age.

Gene-expression profiling has iden-

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Relapse of childhood ALL is unacceptably high for some subgroups. Inherited genomic variation contributes to the risk of relapse and to the adverse effect of therapy.

—Mary V. Relling, PharmD

tified a subgroup of BCR-ABL1–like ALL that accounts for 10% to 15% of childhood and 25% of adult B-cell precursor ALL, “and there is evidence for sensitivity to tyrosine kinase inhibitors when incorporated into therapy,” Dr Harrison said.

A recently identified abnormality is intrachromosomal amplification of chromosome 21. It defines a distinct cytogenetic subgroup of older children (median age, 9 years) with B-cell precursor ALL, and is “associated with a dismal outcome” and a high risk for early and late relapse. When standard therapy is used, the prognosis is poor, but modified treatment with high-risk regimens significantly improves outcomes.

The Promise of Pharmacogenomics Relapse of childhood ALL is unacceptably high for some subgroups.

Inherited genomic variation contributes to the risk of relapse and to the adverse effect of therapy, said Mary V. Relling, PharmD, Chair, Pharma­ ceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN. Dr Relling’s laboratory is using candidate gene interrogation and is ap-

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plying genome-wide approaches, such as gene-expression profiling, genome-wide single nucleotide polymorphism (SNP) analyses, and whole exome/genome sequencing of patients undergoing uniform treatment, to identify genes and genome variations that determine the disposition and effects of antileukemia agents.

The goal is to elucidate the genomic determinants of toxicity and efficacy of drugs to fight leukemia.

Overall, 6 of 18 SNPs that differed in frequency between the genomes of children with ALL and of controls were associated with 1 of the 4 main subtypes of ALL, and 2 SNPs were linked to the ARID5B gene.

Polymorphisms in ARID5B are highest among Hispanics and lowest in blacks, “which mimics the frequency of childhood ALL in these racial groups,” Dr Relling said. They could account for some of the racial disparities in outcome of ALL therapy because of the higher frequency of var­ iants associated with relapse in Hispanics, she said. Inherited variations in ARID5B were found to influence the response to methotrexate, and to be associated with enhanced accumulation in leukemia cells, allowing for lower doses.

There is also evidence that ALL subtypes differ in their responsiveness to asparaginase. Using a genome-wide approach, the investigators discovered that inherited and acquired genomic interindividual variation in the aspartate metabolic pathway contribute to resistance to asparaginase in ALL. At present, genetic testing of thiopurine methyltransferase (TPMT) is being conducted before the initiation of thiopurines to minimize acute myelosuppression, said Dr Relling. Acute myelosuppression can be prevented by adjusting the doses of thiopurines based on TPMT phenotype or genotype, without compromising these agents’ effectiveness.

Exciting New Antibody-Based Therapies New antibody therapies that target cell-surface antigens were reviewed

by Anjali S. Advani, MD, Staff Physician, Department of Hematolog­ ic Oncology and Blood Disorders, Cleveland Clinic, OH. The older agent rituximab, a naked antibody, targets CD20. Although

Credit: Biology Pics / Science Source

By Wayne Kuznar

only half of the cases of pre–B-cell ALL express CD20 on 20% or more lymphoblasts, CD20 expression is associated with a shorter duration of remission and worse OS in adult patients with ALL, making CD20 an attractive target to combine with chemotherapy.

Epratuzumab is a humanized monoclonal antibody that targets CD22, a regulator of B-cell activation and the interaction of B-cells with T-cells, said Dr Advani. In a phase 1 clinical trial, surface CD22 was not detected on flow cytometry on peripheral blood leukemic blasts within 24 hours of epratuzumab administration.

Later-phase clinical trials showed a higher rate of complete molecular remission when epratuzumab was combined with backbone chemotherapy compared with chemotherapy alone.

Bispecific single-chain T-cell engaging (BiTE) antibodies retarget cytotoxic T-cell lymphocytes at preselected surface antigens on tumor cells.

Blinatumomab is the first member of the new class of BiTE antibodies; it combines a CD3-binding site for T-cells and a CD19-binding site for B-cells, thereby creating the opportunity for T-cells to destroy B-cells. In a small, 4-week study, infusions with blinatumomab led to B-cell depletion, an 80% complete molecular remission, and a relapse-free survival rate of 61% by 3 months of follow-up.

Inotuzumab ozogamicin is a promising monoclonal anti-CD22 antibody that is bound to calicheamicin for the treatment of patients with relapsed or refractory ALL. A response rate of 57% was obtained in a phase 1/2 clini­ cal trial of heavily pretreated adult patients with refractory CD22-positive ALL. n

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Emerging Therapies

Hematologic Drug Pipeline Boasts Novel...

ABT-199, induced remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma in an early-phase, open-label dose-escalation trial. Overall, 88% of patients had at least a 50% reduction in their nodal masses, and 89% of patients had at least a 50% reduction in bone marrow infiltrate at week 25.

The small molecule inhibitor IPI145, which blocks the activity of the enzyme phosphoinositide-3-kinase (that is responsible for CLL signaling), was investigated in an early-phase trial of 193 patients, including 52 patients with relapsed or treatment-resistant CLL and 15 patients with untreated CLL. IPI-145 demonstrated activity in approximately 50% of the patients with a p53 mutation. A 25-mg twice-daily dose of IPI-145 will be further evaluated in a randomized phase 3 clinical trial.

A phase 2 clinical trial of patients with relapsed CLL who received otlertuzumab in combination with bendamustine (Treanda) showed superior response rates compared with bendamustine alone. Among 65 patients with relapsed CLL who had received 1 to 3 previous regimens had overall response rates (ORRs) of 68% (International Workshop on CLL criteria) and 81% (National Cancer Institute Working Group response criteria) in the group receiving otlertuz­ umab plus bendamustine versus 32% and 64%, respectively, with bendamustine alone.

In patients with myelodysplastic syndrome refractory to hypomethylating agents, sapacitabine was associated with a 1-year survival rate of up to 38%.

Myelodysplastic Syndromes In patients with myelodysplastic syndrome (MDS) refractory to hypomethylating agents, sapacitabine was associated with a 1-year survival rate of up to 38%. Sapacitabine is an oral nucleoside analog prodrug that interferes with DNA synthesis by introducing single-strand DNA leading to the arrest of the cell division cycle at G2 phase. In a phase 2 clinical study, 63 patients with MDS refractory

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to azacitidine and/or decitabine were randomized to 1 of 3 dosage arms of sapacitabine. The 1-year overall survival (OS) rate was 32%, with greater survival seen in the 2 higher-dosage arms. Of the 63 patients in the study, 23 had stable disease at ≥16 weeks.

Oral rigosertib (Estybon) induced responses and transfusion independence in lower-risk patients with MDS in a phase 2 clinical trial. Rigosertib inhibits the cellular-signaling pathways PI3K and PLK. A combined response rate of 53% (International Working Group criteria) was observed in 36 evaluable patients receiving an intermittent dosing schedule. Overall, transfusion independence was seen in 39% of patients who received ≥8 weeks of intermittent rigosertib.

Non-Hodgkin Lymphoma Monotherapy with the selective oral PI3K-delta inhibitor idelalisib produced a high response rate in patients with indolent B-cell non-Hodg­ kin lymphoma (NHL) refractory to rituximab (Rituxan) and an alkylating agent, with responses persisting for 1 year in the average patient. Idelalisib was well tolerated, with the primary adverse event (AE) being diarrhea (13% grade ≥3).

After a median of 3 treatment cycles, copanlisib showed significant activity, including many complete responses (CRs), with weekly infusions of copanlisib in 67 patients with relapsed or refractory lymphoma. The ORRs were high in patients with follicular lymphoma (40%), chronic lymphocytic leukemia (43%), mantle-cell lymphoma (71%), peripheral T-cell lymphoma (50%), and diffuse large B-cell lymphoma (13%).

SAR245409 is a potent oral paninhibitor of PI3K that also inhibits mTORC1 and mTORC2. The multicenter phase 2 ARD12130 study evaluated the efficacy of SAR245409, given continuously as a single agent, in 28 patients with follicular lymphoma who had received a median of 3 previous regimens. In 27 efficacy-evaluable patients, the ORR was 44%, including CRs in 15%. All but 4 patients had a reduction in target lesions, which exceeded 50% in more than half of the patients. AEs were observed in 57% of patients and were most frequently diarrhea, although this was grade ≥3 in only 2 (7%) patients.

PNT2258 is a DNA “interference” molecule targeting the Bcl2 gene, which is in very early development. A total of 12 patients with various NHL subtypes and relapsed/refractory dis-

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ease received PNT2258 intravenously for 5 days every 3 weeks for 6 cycles.

PNT2258 exhibited antitumor effects, and 9 of 11 evaluable patients derived clinical benefit, including CRs in 2 patients and a partial response (PR) in 1 patient.

Multiple Myeloma In newly diagnosed patients with multiple myeloma (MM), the oral proteasome inhibitor ixazomib led to high response rates and increased depth of response with extended treatment duration when combined with lenalidomide (Revlimid) and dexamethasone.

A study of treatment-naïve patients included 14 patients in the dose-finding phase 1 trial and 57 patients in the phase 2 study who received ixazomib 3 mg every 21 days for up to 16 cycles.

The ORR was 94%, and CRs plus very good PRs (VGPRs) were achieved by 76% of patients. Drug-related serious AEs were seen in 28% of patients; grade 3 drug-related AEs were reported in 58%, and there were no grade 4 events.

ImMucin is a myeloma vaccine in development.

Most patients achieved vaccine-specific immune responses and significant reductions in MUC1 levels, and had stable disease lasting up to 29 months after study completion.

In another phase 2 study of ixazomib, 69 patients with relapsed MM who had not received bortezomib or who received <6 cycles of bortezomib had a PR or better without progression.

Patients who progressed or who had an inadequate response also received dexamethasone. For the 32 patients remaining on study, the ORR was 34%.

At 12 months, 77.5% of the surviving patients have not progressed and 59% are alive without progression.

The oral proteasome inhibitor, oproz­ omib, is also demonstrating promising activity. In an ongoing dose-finding study of 42 relapsed patients, approximately 1 of 4 patients is responding.

In the phase 2 PANORAMA 2 trial, which evaluated the oral HDAC inhibitor panobinostat paired with bortezomib (Velcade) and dexamethasone in 55 patients with relapsed

Continued from the cover

and bortezomib-refractory disease, patients received up to 8 cycles (21 days per cycle) of the combination. The ORR was 35%, the median PFS was 5.4 months, the median OS was 17.5 months, and the drug’s safety profile was manageable.

Another multicenter phase 2 study evaluated panobinostat in combination with carfilzomib (Kyprolis) in 44 patients with relapsed/refractory MM. The median PFS was 6.8 months, and the 12-month PFS rate was 41%.

There are more than 10 potential monoclonal antibodies in various stages of development for MM. In an evaluation of 11 patients who received dar­ atumumab, 8 patients achieved a PR or better after single-agent treatment (up to 16 mg/kg), including CRs in 3 patients, VGPRs in 2 patients, and PRs in 3 patients. Two patients achieved a minimal response, and 1 had stable disease; no patients progressed. The drug was generally well tolerated.

SAR650984 is another monoclonal antibody on the radar, although it is further behind in development.

In a phase 2 trial in heavily pretreated patients, the response rates were 16% for single-agent filanesib (ARRY-520), a highly selective, targeted kinesin spindle protein inhibitor, and 15% for patients who were dual refractory to bortezomib and lenalidomide and also received dexamethasone. In addition, the retrospective use of acute-phase protein alpha-1-acidic glycoprotein (AAG) levels as a biomarker improved response rates and OS. In AAG-low patients, the response rate was 24% with filanesib alone and 19% with filanesib plus dexamethasone. The incidence of nonhematologic AEs was low, including an absence of peripheral neuropathy.

Indatuximab ravtansine is a combination antibody and chemotherapy that helps deliver the drug to myeloma cells and other cancer cells. Among the 9 patients who are currently available for response, the ORR was 78%.

ImMucin is a myeloma vaccine in development that is based on the protein MUC1, which is found on the surface of cancer cells. A total of 15 patients with myeloma who had received a median of 2 previous lines of therapy and who had residual or progressive disease after stem-cell transplantation received 6 or 12 biweekly ImMucin injections plus growth factors. Most patients achieved vaccine-specific immune responses and significant reductions in MUC1 levels, and had stable disease lasting up to 29 months after study completion. n

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GI Cancers Symposium

Dual-Vaccine Combination Improves Survival in Patients with Metastatic Pancreatic Cancer

By Wayne Kuznar

San Francisco, CA—A dual-vaccine strategy improved survival more than single vaccination of patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Data from a randomized phase 2 trial were reported by Dung T. Le, MD, Assistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, at the 2014 Gastrointestinal Cancers Symposium.

“Using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system.”

—Dung T. Le, MD

said Dr Le. “The GM-CSF serves to attract dendritic cells to the vaccine site that will then pick up the antigens and present them to the immune

system, resulting in an activation of tumor-specific T-cells.” Low-dose intravenous cyclophosphamide is administered the day before GVAX to in-

hibit regulatory (suppressive) T-cells.

The second immunotherapy platform, CRS-207, is attenuated Listeria monocytogenes, engineered to express

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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

First Immunotherapy to Improve Survival It is the first randomized study to show improved overall survival (OS) for patients with metastatic pancreatic cancer who received immunotherapy.

“This study is just a first step, and we believe we’ll be able to take this approach further,” said Dr Le. The approach used in the study involves 2 distinct immunotherapy platforms. GVAX is an allogeneic wholecell vaccine created from 2 pancreatic cancer cell lines. These cells have been genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF).

“The advantage of this platform is that using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system,”

at a glance ➤ A dual-vaccine strategy with GVAX and CRS-207 improves survival more than a single vaccine in patients with metastatic pancreatic cancer ➤ The 1-year survival rate was doubled (24%) by giving dual immunotherapy compared with single GVAX (12%) ➤ The vaccine’s side effects were relatively mild and resolved quickly ➤ This approach spares patients the side effects of chemotherapy

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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 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

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GI Cancers Symposium

Adjuvant Chemotherapy Benefit in Stage II Colon Cancers Is Small, May Even Cause Harm, Depending on Prognostic Markers

By Wayne Kuznar

S

an Francisco, CA—The majority of patients with stage II colorectal cancer (CRC) have a good prognosis with surgery and gain little with adjuvant chemotherapy, said Richard M. Goldberg, MD, Physician-in-Chief, Ohio State University Comprehensive Cancer Center, Columbus, OH, at the 2014 Gastrointestinal Cancers Symposium.

Microsatellite instability (MSI) manifested by deficient mismatch repair (dMMR) carries a particularly favorable prognosis (compared with microsatellite stable tumors) for patients with colon cancer that does not warrant adjuvant treatment. “Available data…do not provide compelling evidence for treating patients with MSI/ dMMR stage II disease with chemotherapy, and have shown that treatment may be potentially harmful,” Dr Goldberg said.

In general, the recurrence rate in stage II colon cancer is 20% to 25%.

The risk of recurrence after surgery can be estimated based on anatomic and genomic factors. Only patients with high-risk features appear to derive benefit from adjuvant therapy, and even then only modestly, Dr Goldberg said.

Patients with stage II disease who are at high risk for recurrence include those with a T4 tumor, poorly differ-

entiated histology, lymphovascular invasion, bowel obstruction, less than 12 lymph nodes examined, perineural invasion, perforation, and positive margins. Patients exhibiting such features have an approximate 7% improvement in 3-year disease-free survival (DFS) when given adjuvant FOLFOX (5-fluorouracil [5-FU], leucovorin, and oxaliplatin [Eloxatin]) compared with 5-FU alone.

“Available data…do not provide compelling evidence for treating patients with MSI/dMMR stage II disease with chemotherapy, and have shown that treatment may be potentially harmful.”

—Richard M. Goldberg, MD

The Cancer and Leukemia Group B (CALGB) 9581 study investigators con­ firmed that low-risk patients with colon cancer have extremely favorable long-term survival in the absence of adjuvant treatment, said Dr Goldberg.

The CALGB 9581 trial enrolled lowrisk patients, excluding those with T4b

tumors, obstruction, perforation, or positive margins.

The 5-year overall survival (OS) rate was 93%, regardless of whether they received adjuvant treatment, and the OS was better than 90%, regardless of the subpopulation analyzed based on age, race, or ethnicity.

Low- or average-risk patients may even derive harm from adjuvant chemotherapy. “MSI high [MSI-H] phenotype is consistently a favorable prognostic marker,” said Dr Goldberg.

In a 2003 analysis, Ribic and colleagues showed worse outcomes in patients with stage II/III disease and MSI-H colon tumors who had received adjuvant chemotherapy: the 5-year DFS rate was 69.3% in patients with MSI-H tumors who received 5-FU plus leucovorin compared with 82.9% in patients with MSI-H tumors who did not receive adjuvant therapy.

Similarly, the 5-year OS was reduced with chemotherapy administration (70.7% vs 88%, respectively; P = .07).

A 2010 pooled analysis of adjuvant trials showed a detrimental effect of chemotherapy in patients with stage II disease, but not in patients with stage III disease. In the Quick and Simple and Reliable (QUASAR) trial, comparing 5-FU plus leucovorin with no chemotherapy for stage II disease, 11% of tumors were dMMR; although the risk of recurrence was more than dou-

ble in dMMR versus MMR-proficient tumors (pMMR), it was not predictive of a benefit to chemotherapy, said Dr Goldberg.

Tumors in patients with CRC and Lynch syndrome and in patients with sporadic MSI-H tumors are believed to develop by 2 distinct molecular pathways. Up to 70% of sporadic MSI-H tumors have mutations in the BRAF gene, whereas Lynch syndrome–associated tumors have virtually no mutations in BRAF. One study showed that 5-FU helped the patients who had Lynch syndrome and did not help the patients with acquired MSI, according to Dr Goldberg. “So it may not be as simple as we hoped…but it is certainly a provocative finding,” he said.

Dr Goldberg concluded by providing a suggested algorithm for stage II colon cancer. “Be sure patients are adequately staged, and do mismatch repair,” he suggested.

Patients with T3 and dMMR tumors are low risk, “and don’t even think about treatment.” In patients with T4 and pMMR tumors, “I would give FOLFOX without thinking about it very much, unless there is a contraindication,” Dr Goldberg said. The vast majority of stage II cancers are T3 and pMMR tumors, in which case gene-expression profiling may be useful, but treatment with 5-FU plus capecitabine is reasonable. n

Dual-Vaccine Combination Improves Survival... mesothelin. Mesothelin is a tumor-associated antigen expressed in a majority of pancreatic cancers. Previous studies have shown that the induction of mesothelin-specific T-cell responses is associated with improved survival.

“Listeria is unique in that it is able to stimulate both innate and adaptive immunity,” Dr Le said. “Because it is an intracellular organism, it has access to both class I and class II antigen-processing pathways and can deliver the encoded antigen directly to the encoded antigen-presenting cell.”

The investigators randomized 90 patients with previously treated, metastatic PDAC in a 2:1 ratio to 2 doses of GVAX and low-dose cyclophos-

36

“These are exciting results in a poor-prognosis cancer. This is…the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival.

This is accomplished without the side effects of chemotherapy.”

Value-Based Cancer Care

—Smitha S. Krishnamurthi, MD

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february 2014

phamide followed by 4 doses of CRS207, every 3 weeks, or to 6 doses of cyclophosphamide and GVAX every 3 weeks.

At a planned interim analysis, the median OS on an intent-to-treat basis was 6.1 months with the 2-vaccine therapy compared with 3.9 months with GVAX alone. The 1-year survival rate was doubled (24%) with the dual immunotherapy compared with single GVAX (12%). The study met the early stopping rule for efficacy at this interim analysis, said Dr Le. Among the patients who received at least 3 doses, the median OS was 9.7 months in the dual-vaccine group and 4.6 months in the single-vaccine group (P = .03).

Continued from page 35

Relatively Mild Side Effects The vaccine’s side effects were relatively mild and resolved quickly, Dr Le said. Toxicities included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207.

“These are exciting results in a poor-prognosis cancer. This is a phase 2 study, but it is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” said Smitha S. Krishnamurthi, MD, Associate Professor of Medicine, University Hospitals Case Western Reserve University Medical Center, Cleveland, OH. “This is accomplished without the side effects of chemotherapy.” n

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Lung Cancer

Task Force Recommends Annual Screening for Lung Cancer in High-Risk Populations

By Neil Canavan

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he US Preventive Services Task Force (USPSTF) is recommending that individuals aged >55 years who have a history of heavy smoking be screened annually for lung cancer.

If adopted, this initiative will bring an estimated 14% reduction in lung cancer–related mortality as a result of early disease detection, according to the USPSTF position paper, which was recently published online (Moyer VA. Ann Intern Med. 2014 January 14.

Epub ahead of print).

“It’s clear that the longer and the more a person smokes, the greater

ing cause of cancer-related death in the United States, with high rates of mortality that are attributed to the late stage at which most cases

are diagnosed—early detection of the disease is uncommon because of its largely asymptomatic progression.

Because of the later-stage diagno-

ses, the typical patient with lung cancer has an abysmal 5-year survival rate of 17%. Rates are much higher (52%) when the disease is detected

Continued on page 38

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

“When clinicians are determining who would most benefit from screening, they need to look at a person’s age, overall health, how much the person has smoked, and whether the person is still smoking.”

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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

—Michael L. LeFevre, MD, MSPH their risk is for developing lung cancer,” stated the task force’s co–vice chair Michael L. LeFevre, MD, MSPH, Vice Chair, Family and Community Medicine, University of Missouri, Columbia. “When clinicians are determining who would most benefit from screening, they need to look at a person’s age, overall health, how much the person has smoked, and whether the person is still smoking or how many years it has been since the person quit.”

The task force further suggests that screening be discontinued once a person has not smoked for 15 years or lacks the ability (because of medical reasons) or the willingness to have curative lung cancer surgery.

Currently, lung cancer is the lead-

F. Randy Vogenberg, PhD, RPh

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Lung Cancer

Task Force Recommends Annual Screening... early; however, only 15% of lung cancer cases are diagnosed early.

New Data, Updated Recommendations The current recommendations take into account new data that bolster the case for widespread screening

programs and that validate low-dose computed tomography (LDCT) as the screening method of choice.

Most of the information used to form the USPSTF’s opinion came from 2 sources: the National Lung Screening Trial (NLST)—the largest such trial ever performed—and a

modeling study performed by the Cancer Intervention and Surveillance Modeling Network, as commissioned by the USPSTF. In the NLST trial, 53,454 individuals aged 55 to 74 years who were current or former smokers (quit within the past 15 years) and had a 30–pack-

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

Continued from page 37

year smoking history were screened 3 times annually with LDCT or standard chest x-ray.

After a median follow-up of 6.5 years, participants receiving low-dose helical CT scans had a 20% lower risk of dying from lung cancer than participants who received standard chest x-rays; this translated into an LDCT tumor sensitivity of 93.8% and a specificity of 73.4%.

The current recommendations take into account new data that bolster the case for widespread screening programs and that validate low-dose computed tomography as the screening method of choice.

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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Using these data, as well as data from smaller randomized trials of lung cancer screening, the USPSTF arrived at its current recommendations of screening 30–pack-year smokers aged 55 to 80 years (older than the NLST cohort) once annually, with the preferred method of LDCT. That said, the USPSTF report is chock full of caveats, many of which power the argument against screening younger and/or less-frequent smokers. Those caveats, in descending order of concern, are: • False findings. In the NLST, 24.2% of screening test results were positive; 96.4% of these results were false-positives. Most false findings were invalidated by repeat imaging; however, roughly 2.5% of positive test results required additional invasive diagnostic procedures (ie, needle biopsy). Of 17,053 positive test results that were evaluated, additional tests resulted in 61 complications and 6 deaths • Overdiagnosis. Results from modeling studies suggest that up to 12% of actual cancer cases identified by screening would not have otherwise been detected in the patient’s lifetime, meaning that these slow-growing tumors posed less threat to the patient than the screening itself • Radiation exposure. LDCT studies incur approximately 1.5 mSv of radiation per scan—this is less than typical annual background radiation, but more than a standard mammography (ie, 0.7 mSv). The USPSTF considers the risk from radiation at this level to be negligible • Inadequate expertise. Although

Continued on page 39

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In the Literature Statin Therapy Lowers Mortality...Continued from page 30

statins after diagnosis. In a new study, researchers examined the correlation between the use of statins after a prostate cancer diagnosis and the risk of cancer-related and all-cause mortality (Yu O, et al. J Clin Oncol. 2014;32:5-11).

The results are based on a large, population-based electronic database of 11,772 men in the United Kingdom.

The cohort focused on patients newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, who were followed until October 1, 2012. The mean age at study entry was 71.3 years.

During a mean follow-up of 4.4 years, the researchers identified 3499 deaths, and 1791 (51%) of those were specific to prostate cancer. The postdiagnostic use of statin therapy was

associated with a 24% risk reduction in mortality (HR, 0.76; 95% CI, 0.660.88). The results also showed a 14% decreased risk of all-cause mortality (HR, 0.86; 95% CI, 0.78-0.95), with the HRs gradually decreasing with longer cumulative durations of use. For patients who used statins before their diagnosis, these decreased risks were more pronounced (HR, 0.55; 95% CI,

0.41-0.74; and HR, 0.66; 95% CI, 0.530.81, respectively). However, weaker effects were observed in patients who started statins after diagnosis.

Overall, these findings indicate that statin use after a diagnosis of prostate cancer is correlated with a reduced risk of cancer-related mortality and all-cause mortality. This effect, however, was stronger in patients who also

used statins before their diagnosis of prostate cancer, suggesting a possible effect of longer cumulative duration of use and higher cumulative doses.

The researchers cautioned that additional well-conducted, observational studies are needed to validate these findings before initiating randomized controlled trials evaluating the effects of statins in the adjuvant setting. 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.

Task Force...

CO-CHAIRS

Continued from page 38

difficult to quantify, the USPSTF panel members acknowledged that the conditions of the NLST screen may not be easily replicated in the community setting. Therefore, the panel recommends that quality standards for LDCT, as well as protocols for related follow-up for positive results, be established.

Cost of Screening Strikingly, the USPSTF recommendations mention nothing about cost beyond suggesting that smoking cessation programs are cheaper. However, a recent article published in a journal of the H. Lee Moffitt Cancer Center (Nanavaty P et al. Cancer Control. 2014; 21:9-14) addressed this issue.

In the Moffitt analysis, assuming an average cost of $300 per LDCT screen, and using outcomes from the NLST, lung cancer screening incurs costs of $126,000 to $169,000 per quality-adjusted life-year (QALY) for patients with a 20–pack-year habit, and $110,000 to $166,000 per QALY for a 40–pack-year individual.

By contrast, mammography was equal to $47,000 per QALY. (Although the cost-effectiveness ratios for the NLST are not yet available, some reports have estimated costs at $38,000 per QALY.) Of note, should these recommendations be adopted, effective prevention measures are covered under the Affordable Care Act without copayments or other barriers starting January 1, 2015. n

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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

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39

Drug Update

Abraxane Receives a New Indication for the Treatment of Patients with Metastatic Pancreatic Cancer

By Lisa A. Raedler, PhD, RPh

T

he American Cancer Society has estimated that approximately 45,220 new cases of pancreatic cancer would be diagnosed in the United States in 2013 and approximately 38,460 patients would die of pancreatic cancer in 2013.1 Despite being the tenth most common cancer, pancreatic cancer is the fourth most common cause of cancer deaths, in part because a large majority of patients present with nonresectable advanced disease.2,3 Although adjuvant chemotherapy with gemcitabine or with 5-fluorouracil (5-FU) confers a small survival advantage for patients with early-stage pancreatic cancer, the vast majority will relapse and die from their disease.3 Only approximately 4% of patients with pancreatic cancer will be alive and disease free at 5 years.3 With statistics like these, there is clearly an urgent unmet need for more effective therapies for patients with pancreatic cancer.4 Because pancreatic cancer results in substantial morbidity and mortality, the financial burden associated with patient management can be significant.

US researchers recently reported the direct medical costs of pancreatic cancer treatment based on an analysis of a population-based cohort of Medicare beneficiaries.5 Using the 2001 to 2007 Surveillance, Epidemiology, and End Results–Medicare database, more than 15,000 patients (aged ≥66 years) with pancreatic cancer were identified.5 The total mean direct medical cost was $65,500, with greater costs ($134,700) for patients with resectable locoregional pancreatic cancer compared with patients with unresectable locoregional or distant disease ($65,300 and $49,000, respectively).5 Hospitalizations and cancer-directed procedures were the largest cost drivers in this analysis.5 Demographic trends and the increasing use of targeted therapies are likely to affect treatment patterns, as well as increase the costs of managing pancreatic cancer in the future, the investigators suggest.5 Today, the only potentially curative technique for pancreatic cancer is surgical resection.6 Cytotoxic chemotherapy and radiation therapy are relevant options in the neoadjuvant and adjuvant settings, as well as in patients with unresectable and metastatic disease. The current National Comprehensive Cancer Network (NCCN) guidelines for patients with

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metastatic or locally advanced unresectable pancreatic cancer include several category 1 recommendations, including clinical trials, the 4-drug regimen FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin), the combination of gemcitabine and erlotinib, other gemcitabine-based combinations, and gemcitabine monotherapy.6 For patients whose performance status is poor (Eastern Cooperative Oncology Group 2 or higher), the NCCN suggests gemcitabine monotherapy or best supportive care.6 Abraxane a New Treatment Option In September 2013, the US Food and Drug Administration (FDA) approved the cytotoxic agent nab-paclitaxel (pac­ litaxel protein-bound particles for injectable suspension, albumin-bound; Abraxane; Celgene Corporation) for first-line treatment of patients with metastatic adenocarcinoma of the pancreas in combination with gemcita­bine.7 Nabpaclitaxel is also approved for first-line treatment of locally advanced or metastatic non–small-cell lung cancer in combination with carboplatin and for breast cancer after failure with combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.8 The FDA’s approval of nab-paclitaxel for advanced pancreatic cancer was based on the demonstration of a significant increase in overall survival (OS) in a phase 3 multicenter clinical trial of 861 patients with metastatic pancreatic cancer conducted in more than 150 centers throughout the world.9,10 “This large, randomized, international, phase 3 study showed that the nab-paclitaxel plus gemcitabine led to a significant improvement in survival at all time points,” said Daniel D. Von Hoff, MD, Physician-in-Chief, Translational Genomics Research Institute, Phoenix, AZ, and Chief Scientific Officer, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, AZ. “The rate of survival was significantly higher in the nab-paclitaxel-gemcitabine group than in the gemcitabine group,” he added. Dr Von Hoff served as the principal investigator of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), which included sites in North America, Europe, and Australia.10 Mechanism of Action Nab-paclitaxel is a cytotoxic agent that stabilizes microtubules in cancer

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cells and protects them from disassembly. This stability inhibits normal microtubule network functions that are essential for cell division.8 Compared with the original formulation of paclitaxel, nab-paclitaxel or albumin-bound paclitaxel is a solvent-free formulation that utilizes albumin to deliver the taxane, resulting in an advantageous pharmacokinetic profile.11 Dosing and Administration For patients with newly diagnosed metastatic pancreatic cancer, the recommended dose and schedule for nabpaclitaxel is 125 mg/m2 intravenously over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle.8 Gemcitabine should be administered on days 1, 8, and 15 of each 28-day cycle immediately after nab-paclitaxel.8 Phase 3 Clinical Trial The multicenter MPACT trial enrolled 861 patients with newly diagnosed advanced pancreatic cancer.

Patients were randomly assigned to nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks or to gemcitabine monotherapy 1000 mg/m2 weekly for 7 of 8 weeks (cycle 1), and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients were treated until disease progression.

Patients with pancreatic cancer who had received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting were excluded from study participation.9 The primary end point of this trial was OS duration. Secondary end points included progression-free survival (PFS), overall response rate (ORR), and safety.9 Tumor scans were assessed every 8 weeks by investigators, as well as by independent reviewers.9

Patient Population

The median age of patients enrolled in this phase 3 clinical trial was 63 years.9 Of the patients, 10% were aged ≥75 years.9 The majority of the patients were male (58%) and white (87%), with Karnofsky performance scores of 80 to 100 (92%).9 Overall, 46% of the patients had 3 or more metastatic sites, and most patients (84%) had liver metastasis.9 Demographic and clinical characteristics were well balanced between the 2 study arms at baseline.9

Efficacy

The OS benefit, the study’s primary

end point, was significant for patients receiving the combination of nab-pac­ litaxel and gemcitabine. In the intentto-treat population, the median OS was 8.5 months (95% confidence interval [CI], 7.89-9.53) for the nab-paclitaxel plus gemcitabine group compared with 6.7 months (95% CI, 6.01-7.23) for the gemcitabine monotherapy group (hazard ratio for death, 0.72; 95% CI, 0.620.83; P <.001).9 The Figure illustrates these significant OS advantage findings in the combination of nab-paclitaxel and gemcitabine using a Kaplan-Meier curve. Of note, these survival curves separated early, with a median improvement of 1.8 months and an improvement of 3.4 months at the time point when 25% of the patients were alive.9 In addition, survival rates were significantly higher in the nab-pac­ litaxel plus gemcitabine group than in the gemcitabine monotherapy group at 1 year (35% vs 22%, respectively) and 2 years (9% vs 4%, respectively).9 The secondary end points of PFS and ORR were also significantly improved in the nab-paclitaxel plus gemcitabine arm relative to the gemcitabine monotherapy arm. The median PFS was 5.5 months in patients receiving the nab-paclitaxel plus gemcitabine combination (95% CI, 4.5-5.9) versus 3.7 months for the patients receiving gemcitabine monotherapy (95% CI, 3.64).9 At 1 year, the PFS rate was 16% in the group receiving nab-paclitaxel plus gemcitabine compared with 9% in the group receiving gemcitabine.9 According to independent review, the ORR was also significantly improved with nab-paclitaxel combined with gemcitabine relative to gemcitabine alone (23% vs 7%; P <.001).9 The Table summarizes these data and relevant statistical analyses.

Safety and Serious Adverse Events

In the nab-paclitaxel plus gemci­tabine group, the median duration of treatment was 3.9 months (0.1-21.9 months) compared with 2.8 months (0.1-21.5 months) in the gemcitabine group.9 The median relative dose intensity rates, defined as the proportion of the administered cumulative dose relative to the planned cumulative dose, in the group receiving nab-pac­ litaxel plus gemcitabine were 81% for nab-paclitaxel and 75% for gemcita­ bine.9 In the gemci­ tabine monotherapy group, the median relative dose intensity was 85%.9 The most frequently reported nonhematologic adverse events (AEs) re-

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Drug Update Figure K aplan-Meier Curve for Overall Survival (ITT Population)

Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population)

Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population)

1.0

Abraxane plus gemcitabine Gemcitabine

0.9

Proportion of survival, %

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Time, months Patients at risk, N Nab-paclitaxel plus 431 357 269 169 108 67 40 27 16 9 4 1 1 0 gemcitabine Gemcitabine 430 340 220 124 69 40 26 15 7 3 1 0 0 0 15

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S.

ITT indicates intent-to-treat Department of Health and Humanpopulation.

Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

Reprinted 2.from Abraxane [prescribing information]. Summit, NJ; September 2013.

15 OSHA REFERENCES Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for

3. Occupational American Society Health-System (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Safetyofand Health, DHHSPharmacists.

(NIOSH) Publication No. 2004-165.

Pharm. 2006;63:1172-1193. elected Efficacy Results from the MPACT Study in Patients with 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, Table S 4. 1999.

Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html Adenocarcinoma of the Pancreas (ITT Population) practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs.

16 HOW SUPPLIED/STORAGE AND HANDLING Nab-paclitaxel 125 mg/m2 Am J Health-Syst Pharm. 2006;63:1172-1193.

16.1 How Supplied and gemcitabine Gemcitabine 4. Polovich, M., White, Product No.: 103450

J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh,100 PA:mg Oncology Nursing NDC No.: 68817-134-50 of paclitaxel in Society. a single-use vial, individually packaged in a carton.

Efficacy end point (N = 431) (N = 430) 16.2 16

Storage HOW SUPPLIED/STORAGE

ANDº HANDLING º º

Store the vials in original cartons at 20 C to 25 C (68 F to 77 F). Retain in the original package to protect from bright light.

Progression-free survival º

16.1 How Supplied 16.3 Handling and Disposal Product No.: 103450

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

Death or progression, N (%) 277 (64) 265 (62) been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

16.2 Storage Median progression-free survival, mo 5.5 3.7 Store the vials in original cartons at 20 C to 25 C (68 F to 77 F). Retain in the original package to protect from bright light. º

95% CI

º

º

º

4.5-5.9

3.6-4.0

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HR (95% CI)

Reference ID: 3369272

P value

0.69 (0.58-0.82) <.001

Overall response rate Confirmed complete or partial overall Reference ID: 3369272 response, N (%)

99 (23)

31 (7)

95% CI

19%-27%

5%-10%

P value

<.001

CI indicates confidence interval; HR, hazard ratio; ITT, intent-to-treat; MPACT, Metastatic Pancreatic Adenocarcinoma Clinical Trial.

Source: Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

lated to treatment with the nab-pac­ litaxel plus gemcitabine combination included fatigue (54%), alopecia (50%), and nausea (49%).9 Grade 3 or higher neutropenia, leukopenia, fatigue, and peripheral neuropathy were reported more often in the nab-paclitaxel plus gemcitabine group compared with the gemcitabine monotherapy group.9 The incidence rates of anemia (13% in the nab-paclitaxel plus gemcitabine group vs 12% in the gemcitabine monotherapy group) and thrombocytopenia (13% vs 9%) were similar in the 2 treatment arms.9 Febrile neutropenia was rare in both groups (3% vs 1%).9 Peripheral neuropathy was the most notable difference in AEs between the 2 treatment groups.9 It was cumulative and rapidly reversible in most patients after temporary discontinuation of nab-paclitaxel and subsequent dose reduction. None of the patients experienced grade 4 peripheral neuropathy. The rate of discontinuation

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of nab-paclitaxel secondary to peripheral neuropathy (all grades) was 8%.9 Overall, 10% of the patients had dose reduction of nab-paclitaxel as a result of peripheral neuropathy.9 In the MPACT trial, 50% of the patients receiving nab-paclitaxel plus gemcitabine and 43% of the gemci­ tabine recipients experienced serious AEs.9 Fatal events were reported for 4% of the patients in each treatment group.9 Patients in the nab-paclitaxel plus gemcitabine group were more likely to experience pneumonitis (4% vs 1%, respectively), as well as sepsis (5% vs 2%, respectively) compared with the gemcitabine group.9 A limitation of the MPACT study was that quality of life was not assessed.9 Warnings and Precautions Hematologic effects. Bone marrow suppression—primarily neutropenia —is a dose-dependent and dose-limiting toxicity associated with nab-pacl-

20

itaxel. In the phase 3 trial comparing nab-paclitaxel and gemcitabine with gemcitabine monotherapy in metastatic pancreatic cancer, grade 3 to 4 neutropenia occurred in 38% of patients receiving the combination.8,9 Patients with pancreatic cancer who receive nab-paclitaxel and gemcita­ bine should undergo frequent complete blood cell counts to monitor for myelotoxicity, including before drug dosing on days 1, 8, and 15.8 The combination of nab-paclitaxel and gemci­ tabine should not be given to patients with pancreatic cancer whose baseline absolute neutrophil count (ANC) is <500 cells/mm3 or whose platelets are <50,000 cells/mm3.8 Initiation of the next treatment cycle should be delayed if ANC is <1500 cells/mm3 or if the platelet count is <100,000 cells/ mm3 on day 1.8 Treatment can be resumed with appropriate dose reduction if recommended.8 Nervous system. Sensory neuropathy is also a dose-dependent and dose-limiting toxicity associated with nab-paclitaxel. Grade 1 or 2 sensory neuropathy typically does not require dose modification.8 If grade 3 or higher sensory neuropathy develops in a patient with pancreatic cancer, withhold nab-paclitaxel treatment until it 20 resolves to grade 1 or lower.8 The dose of nab-paclitaxel should be reduced in all subsequent treatment courses.8 Sepsis. Sepsis with or without neutropenia occurred in 5% of patients with pancreatic cancer who received nab-paclitaxel in combination with gemcitabine.8,9 Risk factors for severe or fatal sepsis included biliary obstruction and the presence of a biliary stent.8 Patients who become febrile regardless of ANC should receive treatment with broad spectrum antibiotics.8 If febrile neutropenia is detected, nab-paclitaxel and gemcitabine should be withheld until fever resolves and ANC increases to ≥1500 cells/mm3.8 Treatment with nab-paclitaxel can then be resumed at reduced dose levels.8 Pneumonitis. Of patients with pancreatic cancer, 4% receiving nab-paclitaxel in combination with gemcitabine experienced pneumonitis, including some fatal cases.8,9 Patients exhibiting signs and symptoms of pneumonitis should not receive nab-paclitaxel and gemcitabine during evaluation. If an infectious etiology is ruled out and pneumonitis is diagnosed, treatment with nab-paclitaxel and gemcitabine should be permanently discontinued.8 Hypersensitivity. Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with nab-paclitaxel.

Patients who experience a severe hypersensitivity reaction to nab-pacli-

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taxel should not be rechallenged.8 Hepatic impairment. Dose adjust­ ments are not necessary for patients with mild hepatic impairment.8 How­ ever, nab-paclitaxel should be withheld if aspartate aminotransferase is greater than 10 times the upper limit of normal (ULN) or if bilirubin is greater than 5 times the ULN.8 The starting dose of nab-paclitaxel should be reduced in patients with moderate-to-severe hepatic impairment.8 Dose reductions or discontinuation may be appropriate if severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities occur.8 Albumin (human). Because nab-pac­ litaxel contains human albumin, a derivative of human blood, it carries a re­ mote risk for viral disease transmission.8 Use in pregnancy. Based on animal studies, nab-paclitaxel can cause fetal harm when administered to a pregnant woman. Women of childbearing age should avoid becoming pregnant while receiving nab-paclitaxel.8 Conclusion For patients with advanced pancreatic cancer, the combination of nab-paclitaxel and gemcitabine offers clinically and significant efficacy benefits, with an acceptable tolerability profile. Experts suggest that this combination may represent an alternative to FOLFIRINOX in patients who are unlikely to tolerate the toxicities associated with this regimen.10 Studies are under way to elucidate the optimal dosing schedule of the nab-paclitaxel and gemcitabine combination for pancreatic cancer, as well as the efficacy and safety of triple-drug regimens combining these 2 cytotoxic drugs with novel targeted agents.12 n References

1. American Cancer Society. What are the key statistics about pancreatic cancer? Revised September 6, 2013. www.cancer. org/cancer/pancreaticcancer/detailed guide/pancreatic-can cer-key-statistics. Accessed October 16, 2013.

2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012.

CA Cancer J Clin. 2012;62:10-29.

3. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer.

Lancet. 2011;378:607-620.

4. Rosenberg JD, Sigal D. A path toward pancreatic cancer predictive biomarkers. Per Med Oncol. 2013;2:182-190.

5. O’Neill CB, Atoria CL, O’Reilly EM, et al. Costs and trends in pancreatic cancer treatment. Cancer. 2012;118: 5132-5139.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): pancreatic adenocarcinoma. Version 1.2013. April 9, 2013. www.nccn.org/professionals/physician_gls/pdf/pancreatic. pdf. Accessed October 21, 2013.

7. US Food and Drug Administration. Drugs: paclitaxel.

Updated September 9, 2013. www.fda.gov/Drugs/Infor mationOnDrugs/ApprovedDrugs/ucm367613.htm.

Accessed October 21, 2013.

8. Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) [prescribing information]. Summit, NJ: Celgene Corporation; September 2013.

9. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

N Engl J Med. 2013;369:1691-1703.

10. Translational Genomics Research Institute. Pancreatic cancer patient survival is ‘significantly higher’ with nab-pac­ litaxel, in study led by TGen and Scottsdale Healthcare.

Press release. October 16, 2013. www.tgen.org/news/2013media-releases/abraxane-improves-survival-of-pancreaticcancer-patients.aspx#.Ul-8NWTwJ4Y. Accessed October 21, 2013.

11. Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Control Release. 2013;170:365-372.

12. ClinicalTrials.gov. Nab-paclitaxel pancreatic cancer.

Search results. www.clinicaltrials.gov/ct2/results?term= nab-paclitaxel+pancreatic+cancer&Search=Search.

Accessed October 21, 2013.

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Continuing Education

Optimal Use of Biologics in Delivering Value-Based Care: Challenges for Managed Care Pharmacy Faculty Douglas Burgoyne, PharmD

John Fox, MD, MHA

President VRx Pharmacy Services, LLC Salt Lake City, UT

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 an educational grant from Genentech/ Biogen Idec.

Target Audience This activity was developed for managed care pharmacists and professionals who are involved in the care of patients with cancer or autoimmune disorders, and who manage insurance designs.

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 knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-028-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the current trends in the use of biologic therapies in oncology, rheumatology, inflammatory bowel disease, and multiple sclerosis • Discuss the challenges facing all stakeholders in optimizing value in the use of biologic therapies • Analyze issues around cost, quality, and access to care in the use of biologic therapies • Formulate biologic treatment options that maximize value by improving clinical outcomes and reducing disease burden on patients, families, and the healthcare system

Senior Medical Director Vice President of Medical Affairs Priority Health Associate Professor of Medicine Michigan State University College of Human Medicine Grand Rapids, MI

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 CPE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Sabeeha Muneer, PhD, Medical Writer, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Patricia Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Douglas Burgoyne, PharmD, has received consulting fees from Biogen Idec, Eli Lilly, Novo Nordisk, and Purdue. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

John Fox, MD, MHA, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Jeffrey D. Dunn, PharmD, MBA, has received honorarium from AbbVie, Biogen Idec, and Janssen. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Jeffrey D. Dunn, PharmD, MBA Senior Vice President VRx Pharmacy Services, LLC Salt Lake City, UT

Disclaimer The information provided in this CPE 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 toward 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 CPE 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/P13031E.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. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Estimated time to complete activity: 1 hour Date of initial release: February 11, 2014 Valid for CPE credit through: February 11, 2015.

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

Supported by an educational grant from Genentech/Biogen Idec.

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

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T

he advent of biologic therapies has revolutionized the management of patients with cancer and autoimmune diseases across the therapeutic spectrum. These advances reflect improved understanding of the pathobiology of different malignancies and immunologically mediated disorders, and identification of rational targets for therapeutic development. Current projections, however, indicate that spending related to specialty drugs, including biologic agents, will reach astronomical levels by the year 2018—amounting to an increase per member per year (PMPY) from $290 in 2012 to $845 PMPY in 2018 (Figure).1 Although the clinical drug pipeline historically has been dominated by biologic agents directed toward cancer-relevant antigens, a majority of biologic therapies are increasingly being developed for noncancerous indications, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). Consistent with this trend, inflammatory diseases, such as RA and MS, show the highest PMPY spending of specialty drugs (23.3% and 18.0%, respectively), followed by oncology at 14.3%.2 The concept of Triple Aim, which was first proposed in 2008, defines the simultaneous improvement of population health, patient experience of care, and per-capita cost reduction as the 3 dimensions needed to achieve optimal outcomes.3 Outcome measures for achieving these lofty goals have since been developed by the Institute for Healthcare Improvement, and they serve as the central tenet for public and private health organizations.4 As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal.

A live symposium was held on October 16, 2013, during meetings of the Academy of Managed Care Pharmacy, to educate managed care pharmacists, who are uniquely positioned to evaluate the value of biologic therapies, on recent treatment advances and practice management strategies. This review provides a synthesis of the proceedings of this meeting, including current trends in personalized biologic therapy–based management approaches in oncology and chronic inflammatory diseases, and cost-effective strategies for improving overall outcomes from the perspective of managed care pharmacists.

Review of Current and Emerging Biologic Agents for the Treatment of Cancer and Autoimmune Diseases Biologics in Oncology According to the most recent estimates from the Centers for Disease Control and Prevention, cancer is the second leading cause of death in the United States, Figure Exponential Growth of Specialty Drug Spending Traditional

surpassed only by cardiovascular diseases.5 Historically, standard treatment modalities in oncology have included a combination of surgery, radiation, and/or chemotherapy. Immunotherapy with biologic agents, however, is now considered an integral and indispensable component of the treatment arsenal for many different types of cancer.6,7 Cancer immunotherapy strategies are aimed at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms, and include monoclonal antibodies (mAbs), cytokines and growth factors, and vaccines.6,7 Indeed, the oncology arena has witnessed an unprecedented upswing in the use of biologic therapies. Currently, the US Food and Drug Administration (FDA) lists more than 50 medications with accompanying pharmacogenomic biomarkers that have been approved for clinical use.8 In many cancer types, antibody-based treatment has dramatically improved disease response while reducing the major concomitant toxicities typically associated with the use of chemotherapy. In the field of oncology, mAbs include the anti–human epidermal growth factor receptor 2 (HER2) mAb trastuzumab for breast cancer, the anti-CD20

As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal. mAb rituximab for non-Hodgkin’s lymphoma, the anti–vascular endothelial growth factor (VEGF) mAb bevacizumab for several different cancer types, the anti–epidermal growth factor receptor (EGFR) mAb panitumumab for colon cancer, and the anti-EGFR mAb cetuximab for colorectal cancer and head and neck cancer.9 These mAbs directly target the cancer antigen, resulting in blockade of growth factor–mediated signaling and inhibition of angiogenesis, which regulate key processes involved in cancer growth and progression.

Other types of biologic immunotherapy used in oncology include cytokines such as interleukin (IL)-2 and interferon (IFN)-alpha for various forms of cancer, and vaccines9 such as Bacillus Calmette-Guérin for the treatment of bladder cancer. In addition, biologic agents are used as supportive care in oncology, for the mitigation of treatment-related side effects. These treatments include the use of such hematopoietic growth factors as granulocyte colony-stimulating factor following cytotoxic chemotherapy, in order to promote neutrophil production and thus reduce the risk for infection.9

Biologics for Autoimmune Diseases Multiple sclerosis MS is a chronic autoimmune disease that is defined by the progressive destruction of axonal myelin sheaths in the central nervous system.10,11 The symptoms associated with MS are interrelated, having a major impact on quality of life

Specialty

$1800 $1600 $1400

Table 1 Biologics Currently Approved for the Treatment of Multiple Sclerosis

$1200 $612

$1000 $800

$290

$348

$425

$722

$845

$514

$600 $400

$665

$675

$694

$722

$751

$789

$836

$200 $0

2012

2013

2014

2015

2016

2017

2018

Year Reprinted with permission from Artemetrx. Specialty Drug Trend Across the Pharmacy and Medical Benefit. 2013. All rights reserved. www.artemetrx.com/docs/ARTEMETRX_Specialty_ Trend_Rpt.pdf.

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Generic name

Mechanism of action

Approval date

Interferon beta-1b

Immunomodulator

1993

Interferon beta-1a

Immunomodulator

1996

Glatiramer acetate

Immunomodulator

1996

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2006

Fingolimod

Immunomodulator

2010

Teriflunomide

Immunomodulator

2012

Dimethyl fumarate

Immunomodulator

2013

Source: Reference 12.

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Continuing Education

Table 2 Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Name of agent

Mechanism of action

Approval date

Infliximab

Anti–TNF-α

1998

Etanercept

Anti–TNF-α

1998

Anakinra

IL-1 receptor

2001

Adalimumab

Anti–TNF-α

2002

Abatacept

CD28

2005

Rituximab

CD20

2006

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2009

Tocilizumab

IL-6 receptor

2010

IL indicates interleukin; TNF, tumor necrosis factor.

Sources: References 18, 19.

Table 3 Expanding Therapeutic Pipeline for Inflammatory Bowel Disease Name of agent

Mechanism of action

Approval date

Adalimumab

Anti–TNF-α

2007

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2008

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2013

Tofacitinib

JAK inhibitor

2012

Vedolizumab

Adhesion molecule blocker (anti-integrin α-4/β-7)

In FDA review

PF-00547659

Mucosal adhesion blocker

In clinical testing

GSK-1605786

Oral chemokine antagonist

In clinical testing

Ustekinumab

Cytokine blocker

In clinical testing

FDA indicates US Food and Drug Administration; JAK, Janus kinase; TNF, tumor necrosis factor.

Source: Reference 25.

(QOL) and carrying a considerable economic burden.11 The current treatment armamentarium for MS includes IFN beta-1a, IFN beta-1b, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, and dimethyl fumarate— all of which are able to reduce relapse rates and the accumulated disability scores in patients with relapsing-remitting MS (RRMS) (Table 1).12 The overwhelming majority of these treatments, however, have been unable to prevent disease progression or demonstrate curative potential. Therefore, several novel therapies, including alemtuzumab, daclizumab, laquinimod, and neuroprotective agents, are currently under investigation for the treatment of MS.13 In the near future, biosimilars, generics, and novel formulations of current agents (eg, low-dose and generic fingolimod, glatiramer acetate injections 3 times weekly, and first-line intravenous natalizumab) should be available in the biologic MS space, which is expected to have a favorable impact on the treatment paradigm, as well as on the cost of therapy.14 Rheumatoid arthritis RA is a chronic, debilitating, systemic autoimmune disorder that is often characterized by swollen joints, pain, and decreased functional mobility.15,16 Little is understood about the many extraarticular manifestations of RA, including cardio-

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vascular disease, infections, depression, and gastrointestinal ulcers.16 Consequently, RA frequently leads to an increased risk for premature mortality, hospitalization, work disability, increased medical costs, and poor QOL.16 Historically, RA has been managed primarily with corticosteroids and nonsteroidal anti-inflammatory agents, followed by the use of conventional, nonbiologic disease-modifying antirheumatic drugs (DMARDs). These agents have been able to prevent or delay erosive changes that lead to disability, have demonstrated efficacy in reducing synovitis and systemic inflammation, and have improved functionality.16 Recently, the use of biologic agents has significantly altered the natural history of the disease. The latest RA treatment guidelines from the European League Against Rheumatism advocate that the key to optimizing patient outcomes is early diagnosis and early aggressive therapy with optimal doses of conventional DMARDs and, if active disease persists, early introduction of biologic agents.17 Biologic approaches include such tumor necrosis factor (TNF) alpha inhibitors as etanercept, infliximab, adalimumab, golimumab, and certolizumab; the anti–IL-6 agent tocilizumab; the anti–CD20-directed mAb rituximab; the small-molecule Janus kinase (JAK) 1/3 inhibitor tofacitinib; and the antiCTLA-4 fusion protein abatacept (Table 2).18,19 These agents all have demonstrated efficacy in limiting both symptomatic manifestations and radiographic progression of disease.18,19 Inflammatory bowel disease IBD broadly refers to conditions that are believed to be the result of immune dysregulation, impaired mucosal integrity, enteric bacterial dysbiosis, and genetic susceptibility factors.20 These debilitating diseases are characterized by intestinal inflammation, and are associated with such symptoms as persistent diarrhea, cramping abdominal pain, fever, rectal bleeding, loss of appetite, and weight loss.21-23 The 2 most common types of IBD are Crohn’s disease and ulcerative colitis.23-25 The expanding pipeline of drugs for IBD include the anti–TNF-alpha agents adalimumab and golimumab; the adhesion molecule blockers natalizumab, vedolizumab, and certolizumab; the mucosal adhesion blocker PF-00547659; the oral chemokine antagonist GSK-1605786; the JAK inhibitor tofacitinib; and the cytokine blocker ustekinumab (Table 3).25 Increased understanding of the pathogenesis of IBD has identified several other biologic targets for the disorder, including growth factors such as platelet-activating factor and transforming growth factor beta; inflammatory cytokines such as IL-1; immunoregulatory cytokines such as IL-2, IL-4, and IL-12; and chemokines such as intercellular adhesion molecule-1, all of which might further expand the biologic armamentarium for IBD.26

Personalized Management Approaches with Biologic Agents Our expanding knowledge regarding the role of genetic and molecular drivers of disease pathogenesis heralds an era of molecular disease classification and personalized treatment strategies. In basic terms, personalized medicine refers to tailoring treatment to address patient- and disease-related characteristics that are unique to each individual. At the core of practicing personalized medicine is the identification and validation of biomarkers that may be useful for diagnostic purposes, along with the prediction of disease course, prognosis, treatment response, and risk for adverse events associated with a particular therapy.

Personalized Medicine in Oncology The use of trastuzumab in breast cancer serves as a prototype for the successful application of personalized medicine.27 Trastuzumab, first approved in 1998 for the treatment of patients with HER2-positive breast cancer, relied on a molecular diagnostic test to identify individuals who overexpress HER2 and would therefore benefit from trastuzumab therapy.27 Prior to the approval of trastuzumab, patients with HER2-positive disease were resigned to a particularly poor prognosis.28 In addition to trastuzumab, several other HER2-targeted therapies are now available for this patient population, including pertuzumab, trastuzumab-DM1, and lapatinib, all with proven efficacy in significantly improving outcomes in both early and metastatic HER2-positive breast cancer settings.28 In a subset of lung adenocarcinomas, the identification of driver mutations in the EGFR gene is associated with response to the tyrosine kinase inhibitor (TKI) erlotinib, leading to the successful application of genetic profiling and rational use of targeted therapies directed toward these common mutations.29 Similarly, recent data demonstrate that response to the anti-EGFR mAb cetuximab in EGFR-

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expressing tumors in metastatic colorectal carcinoma is predicted not by EGFR expression, but rather by KRAS mutation status.30 In a non–small-cell lung cancer subset, the presence of mutations in the anaplastic lymphoma kinase (ALK) receptor has provided the opportunity for successful use of the ALK/Met TKI crizotinib in these patients.31 Therefore, current National Comprehensive Cancer Network (NCCN) guidelines recommend the first-line use of erlotinib and crizotinib in patients with EGFR and ALK mutations, respectively, and doublet chemotherapy or cisplatin plus pemetrexed in those without mutations.31 Unfortunately, acquired resistance to TKI therapy is a clinical challenge; a clearer understanding of drug-resistance mechanisms is critical to developing more effective personalized therapeutics.

Along the same line, activating mutations in BRAF, such as V600E and V600K, have been identified in metastatic melanoma. The selective BRAF V600E inhibitor vemurafenib has been FDA approved in this patient subset, and is associated with improved outcomes with respect to overall survival, progression-free survival, and clinical response rates.32 In patients with colorectal cancer, the same BRAF V600E mutation is also present in 5% to 15% of all tumors and in up to 80% of tumors with high microsatellite instability, and is associated with a poor prognosis.33 Unexpectedly, patients with colorectal cancer who harbor BRAF V600E mutations and are treated with vemurafenib exhibit suboptimal responses, highlighting the importance of disease-specific studies.33 These conflicting data emphasize the heterogeneous biology and pathogenesis underlying different malignancies, and caution against extrapolating results among different cancer types.

Although whole-genome sequencing is an attractive prospect in oncology, contradictory data, such as with the BRAF V600E mutation, undermine its universal applicability. Moreover, considerable intratumor heterogeneity exists, rendering biomarker assessment challenging. Gerlinger and colleagues found significant mutational microheterogeneity and corresponding protein expression, with discrepancies detected in different regions of the same tumor, and among molecular profiles of primary and metastatic lesions.34 Despite such limitations, however, it is clear that identification of genetic or molecular tumor abnormality profiles in oncology will allow more rational use of targeted agents and biologic therapies, leading to improved health outcomes, improved patient experience, better use of resources, and reduced costs through avoidance of ineffective therapies.

Personalized Medicine in Chronic Inflammatory Diseases Unlike in oncology, personalized management approaches are still in their infancy in chronic inflammatory diseases, with few biomarkers having made their way into clinical practice. Increasing evidence, however, suggests that this will be the way in which inflammatory or immunologically mediated diseases will be treated in the future.

Emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNF-alpha agent.

MS is a highly heterogeneous disorder with diverse etiology, pathologic features, clinical course, disease severity, and response to therapy, which presents obvious challenges when making treatment decisions.35 Treatment selection for MS has been largely empirical and not guided by validated molecular or genetic biomarkers. Existing treatments for RRMS have demonstrated limited efficacy, with disease activity persisting in the majority of patients despite therapy.

Treatment response has been based on preventing clinical relapses and progression of disability, and monitoring for new lesions on magnetic resonance imaging after 1 year of treatment.36 Established predictive biomarkers include neutralizing antibodies against such immunotherapies as IFN-beta and natalizumab.37 Detection of pathologic immune responses, primarily antibody responses, against putative autoantigens has also shown some promise in predicting patient response.35

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In RA, several matrices have been developed to predict the risk for rapid radiologic progression following treatment with either DMARD monotherapy or combination therapy.38 Predictive biomarkers have also been identified for response to biologic agents and for their successful discontinuation upon achievement of treatment goals. Moreover, emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNFalpha agent.39 In IBD, genomic assessments have identified approximately 100 loci whose gene products function as key transcription factors or are involved in several critical pathways, such as the IL-23 pathway, and in modulating functions that affect IBD pathogenesis, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense.40 Such profiles also reveal association patterns that are similar between Crohn’s disease and ulcerative colitis, such as those involving Th17 pathways, indicating significant overlap in pathophysiology, as well as distinct disease-specific pathways (eg, NOD2 and autophagy in Crohn’s disease; major histocompatibility complex and epithelial barrier genes in ulcerative colitis).41,42

Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.”

Despite these promising new avenues of research, only clinical markers of treatment response are being applied at the current time. Other tools, however, such as disease activity measures, are being used to assess remission and state of disease activity in patients with MS, RA, and IBD.43-46 In RA, the Simplified Disease Activity Index is a validated composite score of the tender joint count, swollen joint count, patient global assessment, physician global assessment, and C-reactive protein (CRP) level, which is associated with the highest sensitivity and specificity for treatment decisions.43,44 In spite of its limitations, the Kurtzke Expanded Disability Status Scale, which combines disability and neurologic impairment, remains the most widely used activity score in MS.45 Similar indices are available for patients with IBD, such as the Crohn’s Disease Activity Index and the HarveyBradshaw Index, as well as such surrogate markers as CRP and fecal calprotectin.46 Their reliability and sensitivity remain questionable, however. Taken together, these data suggest that a combination of clinical markers, response biomarkers, and disease activity or disability indices holds great promise for the use of personalized medicine in patients with chronic inflammatory diseases.

Cost-Effective Strategies for Improving Overall Outcomes from the Managed Care Perspective: Meeting the Challenges and Barriers to the Use of Biologic Agents Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.”2,47 Given that the “pursuit of the Triple Aim is an exercise in balance,”3 it is imperative that the clinical utility and “value” of biologic agents be balanced, and that appropriate utilization occurs—that is, the biologic is used in the right patient with the right disease at the right time. In this regard, numerous examples abound in clinical practice in which significantly less expensive, nonbiologic therapy can be used to obtain good clinical outcomes prior to the use of biologic agents.48 For example, a recent 2-year, randomized, double-blind study demonstrated that initial methotrexate monotherapy with the option to step up to combination therapy is associated with similar outcomes to the use of immediate combination therapy in patients with early, poor-prognosis RA.48 Managed care pharmacy, in particular, plays a key role in incorporating diagnosis, cost, and treatment information with pharmacy data. These efforts also

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Table 4 Clinical Pathways in Oncology Clinical pathways: Are an evidence-based approach to care Use the framework of tumor-specific guidelines Specify which interventions are performed and in what sequence Are intended to reduce practice variation, improve outcomes, and reduce costs Are typically developed by an individual provider team or national organization Source: References 50, 51.

improve appropriate utilization and optimal leveraging of pharmacy resources, thereby affecting benefit design, implementing management approaches for diseases that can be treated with biologic agents, and ensuring cost-effectiveness.

From a managed care perspective, cost-effectiveness of an intervention equates with “value” in terms of efficacy and cost.

A survey by The Zitter Group showed that most stakeholders are concerned about the inappropriate utilization of specialty drugs in oncology and consider waste reduction to be a primary cost-control strategy. The participants in this survey differed significantly, however, with respect to their estimation of the percentage of excess cost that could be eliminated from cancer treatment without negatively impacting overall outcomes.49 Payers were of the opinion that there was a 22.7% wastage in oncology, whereas oncologists and practice managers believed the wastage to be approximately 18% and 15.9%, respectively.49 Excessive end-of-life care, inappropriate drug use, and unwarranted diagnostic testing were considered to be key contributors to excess costs by payers and by oncologists.49 The costs of biologic agents and waste drive many of the value-based control mechanisms currently in place. Potential solutions, such as comparative effectiveness research (CER) and drug benefit designs, have been implemented by many managed care organizations.50 An important value initiative has been the recent efforts to define limited clinical pathways or evidence-based algorithms that describe the treatment selection, sequence, and timing of biologic therapies, and typically drive formulary decisions (Table 4).50,51

When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care.

In oncology, clinical pathways typically use tumor-specific guidelines from the NCCN and the American Society of Clinical Oncology, which are systematically developed, evidence-based best practices. The primary purposes of clinical pathways are to ensure proper utilization, reduce practice variation or standardize care, improve outcomes, and reduce cost variation. Preferred pathway options are often developed by individual teams or national organizations in collaboration with participating physicians. Oncologists may receive incentives to achieve a certain level of pathway compliance, whereas potential manufacturer rebates received for use of specific drugs in the preferred pathways can further lower net costs to payers.51 Additional data related to clinical pathways are warranted to substantiate improved outcomes and cost-savings, not only for oncology, but for inflammatory diseases as well.

In addition, a patient-focused, value-based benefit design has been developed that offers plan-based incentives, such as reduction or elimination of patient cost-sharing, to encourage patients to use preferred treatment pathways and fol-

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low healthy behaviors, in order to improve health outcomes and control costs.52 Alternatively, patients may be penalized with increased cost-sharing for services that are not associated with clinical benefit or that have marginal benefit improvements with significant price increases.

In inflammatory diseases, optimization of the use of specialty pharmaceuticals in a cost-effective manner is of primary interest. Several cost-containment management strategies for biologic agents are being implemented, including pharmacy prior authorization, clinical care management, 30-day supply limits, preferred products and formulary, pharmacy step therapies, cost-sharing tiers, restricted medical benefit coverage and closed pharmacy benefits, and tracking outcomes.53 Moreover, improving medication adherence in these chronic diseases is a major priority; increased out-of-pocket costs and adverse effects associated with biologic agents can limit patient adherence and result in reduced drug efficacy.54 Essentially, health plans want to realize the clinical benefits of their financial investment in biologics.

When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care.55 Rising healthcare costs and the introduction of novel, efficacious, and expensive biologic therapies have led to renewed emphasis on comparing the relative merits of one intervention versus competing interventions, particularly in the absence of head-to-head comparison data, in order to bridge knowledge gaps and drive informed clinical decisions and outcomes. Such efforts are known as CER, which is defined as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care.”56 CER consolidates evidence from multiple sources, including prospective observational studies and peer-reviewed, published, retrospective analyses of healthcare data, such as medical or pharmacy claims, electronic health records, registries, and systematic literature reviews or meta-analyses.

Conclusion Biologic agents have become the mainstay of treatment for several disease states, including several cancer types, MS, RA, and IBD, and are the cornerstone of personalized medicine in these disorders. In the face of ongoing innovation, rising utilization, and increased costs, important considerations related to cost, value, patient access, and clinical utility are warranted. Cost-effectiveness may be optimized by implementation of value-based initiatives, including the use of CER and clinical pathways to inform treatment decisions for payers and physicians.

Moreover, managed care pharmacists play a critical role in managing the use of biologics and in improving healthcare outcomes in their plan members. In this context, managed care pharmacists find themselves in the unique position of evaluating the clinical utility of biologic agents, affecting benefit design, optimizing current standards of personalized care, and helping providers and patients achieve optimal clinical outcomes. ◆ Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article.

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