Vbcc june 2013 by Value-Based Cancer Care

JUNE 2013 VOL 4 NO 5

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

Patient-Centered Oncology Medical Home in New Mexico Demonstrating Value Saving costs and increasing patient satisfaction By Caroline Helwick

Genomic Sequencing Assay Potentially a Game Changer By Caroline Helwick

Hollywood, FL—Genomic profiling of individual tumors represents a paradigm shift in oncology and holds great promise for patients, according to Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foun dation Medicine, who described this new genomic assay at the Third

Gary Palmer

Annual Conference of the Association for Value-Based Cancer Care. Before his position with Foundation Medicine, Dr Palmer led the development of the Oncotype DX Breast Cancer Assay for Genomic Health. In recent years, Foundation Medi cine has sequenced hundreds of breast Continued on page 9

ASCO Annual Meeting

Variations in Cancer Treatment Raise Average Cost of Care by $25,000 per Patient By Wayne Kuznar

Hollywood, FL— A community oncology medical home headed by Barbara L. McAneny, MD, Chief Executive Officer and Managing Partner of the New Mexico Cancer Center, Albuquerque, is a good example of how putting patients first can be good for patient care and good for the bottom line. Continued on page 8

ASCO Annual Meeting

Pazopanib: First Positive Maintenance Trial in Ovarian Cancer By Phoebe Starr

approximately 25% of the patients had treatment plans that did not conform to evidence-based standards. The finding “is an argument for decision support tools that are used at the point of care,” noted Dr Forastiere. “We can’t change this if we’re always at the back end.” Eviti is an independent health in for mation technology company that Continued on page 26

inside

A multikinase inhibitor delays relapse in advanced disease Chicago, IL—Previous trials of maintenance therapy for patients with ovarian cancer have failed to show improved survival. A study presented at the 2013 American Society of Clinical Oncology annual meeting is the first successful phase 3 trial in this setting, showing that the targeted therapy pazopanib (Votrient) extend-

Chicago, IL—Inappropriate deviation from evidence-based standards of care for cancer raises costs in excess of $25,000 per patient, stated Arlene A. Forastiere, MD, Senior Vice President of Medical Affairs at eviti, Inc, Philadelphia, PA, in a poster presented at the 2013 American Society of Clinical Oncology annual meeting. In Dr Forastiere’s review of oncology treatment plans for 2544 patients,

ed progression-free survival (PFS) by a median of 5.6 months in women with ovarian cancer. Women enrolled in the trial were free of disease after initial treatment with surgery and chemotherapy. “Pazopanib maintenance therapy prolongs the time the patient has

Continued on page 26

ASCO ANNUAL MEETING . . . . . . . 26 Sorafenib effective in metastatic differentiated thyroid cancer

VALUE PROPOSITIONS . . . . . . . . . 6 Genetic testing for endometrial cancer

HEALTH POLICY . . . . . . . . . . . . . . 36 Medicare committee rejects new genetic tests for cancer

FROM THE EDITOR . . . . . . . . . . . Popularizing cancer as a topic of public discourse

CONFERENCE . . 8, 16 Pathways creating increasing value Value and quality of life in cancer care The changing landscape of oncology FDA UPDATE . . . . . . . . . . . . . 14,15 Xofigo approved for metastatic CRPC Mekinist and dabrafenib for advanced melanoma with BRAF mutations

ECONOMICS OF CANCER CARE . 36 High-cost lung cancer surveillance testing Disparities in guideline-based breast cancer care DRUG UPDATE . . . . . . . . . . . . . . . 40 Kadcyla approved for HER2-positive metastatic breast cancer

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM * SUSTAIN IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION • For Autologous Use Only. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. • Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. • Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag. • Do Not Initiate Infusion of Expired Product. • Infuse PROVENGE intravenously over a period of approximately 60 minutes. Do Not Use a Cell Filter. • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction. (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use. • Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed. • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

PROF35855_Provenge_VBCC_DR.indd 2

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

3/12/13 4:00 PM

From the Editor

Popularizing Cancer as a Topic of Public Discourse By Craig Deligdish, MD

Chief Medical Officer, Oncology Resource Networks, and Editor-In-Chief, Value-Based Cancer Care

ith the Third Annual Con ference of the Associ ation for Value-Based Cancer Care (AVBCC) held in May in Florida

and the 2013 Annual Meeting of the American Society of Clinical Oncology concluding in June in Chicago, it is tempting to consider which of the

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

Value-Based Cancer Care PROF35855_Provenge_VBCC_DR.indd 3

many presentations, abstracts, and reports were most impactful or will have the greatest influence on how oncologists think about, diagnose, and treat patients with cancer. Nevertheless, cancer as a public topic has made its way into the main-

It is, however, Angelina Jolie’s willingness to speak up, and the public service of Congresswoman Debbie Wasserman Schultz and her contribution to this discourse, that could potentially have an even more dramatic impact on decisions that contribute to popularizing a personalized and precise approach to the diagnosis and treatment of cancer. stream media in an unprecedented fashion. On a nearly daily basis, there is a news report or an editorial by a major news organization related to cancer. Furthermore, celebrities have increasingly become part of this discourse and dialogue. Lance Armstrong created a franchise popularizing his bout with testicular cancer. More recently, Angelina Jolie made headlines by describing her personal story and her choice to undergo a prophylactic bilateral mastectomy after learning that she had an inherited mutation in the BRCA1 gene that increased her risk for developing breast and ovarian cancers. Although the impact that a celebrity has on any field—politics, marketing, or the media—cannot be underestimated, the impact of celebrities on the advance of cancer diagnosis and treatment, and, most important, on fundraising, has been dramatic in the past several decades. It has also helped to raise billions of dollars for organizations such as Stand Up To Cancer, LiveStrong, and Susan G. Komen. However, it is a presentation by Congresswoman Debbie Wasserman Schultz at this year’s AVBCC Annual Conference that may have a great im-

pact in oncology as molecular diagnostics and the ability to utilize our molecular understanding of cancer in treating patients increasingly play important roles in the way oncologists manage cancer. Ms Wasserman Schultz’s personal story is similar to that of Angelina Jolie, but it was not nearly as popularized in the mainstream media. And yet, although the congresswoman’s story may be similar, the implications for genetic testing and the future of genetic testing are potentially profound. At age 41, Ms Wasserman Schultz was diagnosed with breast cancer: based on her family history and other factors, it was recommended that she be tested for the BRCA1 and BRCA2 mutations. The tests did indeed show that Ms Wasserman Schultz had a BRCA mutation, and it was recommended that she undergo prophylactic bilateral mastectomies and a bilateral oophorectomy. Her immediate response was to request a second opinion, given the potential life-changing impact of these recommendations. She further appreciated just how impactful these recommendations could have been had she been significantly younger, unmarried, and without children. At her talk at the AVBCC Annual Conference, Ms Wasserman Schultz described that she had been told that the BRCA1 and BRCA2 tests were 100% reliable. Recognizing that mistakes can be made in any test, she persisted in her request for a second opinion, an opinion that could not be provided, because Myriad Genetics, Inc, held a patent on the test for mutations in the BRCA1 and BRCA2 genes, a patent that has not yet been licensed. In November 2012, the Supreme Court agreed to review an appeal filed by the American Civil Liberties Union and the Public Patent Foundation on behalf of the Association for Molecular Pathology and other organizations to determine whether patents for “products of nature” are unconstitutional by undermining the First Amendment and delimiting the free exchange of ideas related to the human body. Although Myriad’s patents on BRCA1 and BRCA2 are set to expire in several years, the ruling by the Supreme Court, which is expected in late June, will have far-reaching implications for Myriad Genetics, as well as for many other companies, researchers, patients with cancer, and the general populous, especially as we Continued on page 6

june 2013

Vol. 4 3/12/13 4:00 PM

No. 5

In This Issue VALUE PROPOSITIONS

HEALTH POLICY

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor

Genetic testing changing endometrial cancer management More….

Medicare committee rejects new genetic tests for cancer

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

Mekinist and dabrafenib for advanced melanoma with BRAF mutations More….

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

Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

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

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 © 2013 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.

Vol. 4

No. 5

ECONOMICS OF CANCER CARE

3rd CONFERENCE

Use of high-cost tests for lung cancer surveillance rising Single, older women less likely to receive guideline-based care for breast cancer More….

Genomic sequencing assay potentially a game changer Pathways creating more and more value The cost of cancer care must include value and quality of life More….

PROSTATE CANCER New guideline emphasizes sequenced therapy for CRPC

FDA UPDATE

DRUG UPDATE Kadcyla approved for treatment of HER2-positive metastatic breast cancer

ASCO ANNUAL MEETING Immunotherapy takes center stage in melanoma FDA to approve surrogate end point for neoadjuvant breast cancer trials More….

CONTINUING EDUCATION Recent Advancements in the Treatment of Multiple Myeloma

VBCC Editorial Board 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 Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care  San Francisco, CA Michael Kolodziej, MD National Medical Director, Oncology Solutions 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

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

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.

june 2013

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VALUE PROPOSITIONS Genetic Testing a Potential Game Changer in the Approach to Endometrial Cancer

Researchers have analyzed the genetic makeup of hundreds of endometrial tumors that may lead to targeted therapies for subpopulations of patients with this deadly cancer. Endometrial cancer, which affects the lining of the uterus, is the fourth most common cancer among women in the United States. Although most of the patients with type I endometrial cancer are cured, patients with type II endometrial cancer have few treatment options. This new study funded by the National Institutes of Health reveals that approximately 1 of 4 tumors classified by pathologists as high-grade endometrioid cancer have genetic changes that manifest the same characterizations as those of serous tumors. Thus, patients with these tumors may therefore benefit from similar treatments. In addition, genetic similarities were found between endometrial cancers and other types of tumors. Type II endometrial tumors share features with subtypes of breast and ovarian cancers. This information may open the door to a personalized approach for the diagnosis and treatment of patients with endometrial cancer, including new targeted therapies that are based on the genetic makeup of the tumor. “Developing therapies for each subtype independent of the other may improve outcomes,” said a coleader of the study, Elaine R. Mardis, PhD, Director of Technology Development at The Genome Institute, Washington University School of Medicine, St Louis, MO. (National Institutes of Health; June 2013)

In Search of £1 Million to Confirm Value of First Genetically Engineered Oncolytic Virus for Neuroendocrine Cancer

Neuroendocrine cancer, a rare type of cancer (that became well known after Steve Jobs was diagnosed with and died from a neuroendocrine cancer of the pancreas), may have a new lease on life, if Swedish researchers of Uppsala University in Sweden find a way of obtaining £1 million (approximately $1.5 million) to support their research. “We have developed a virus that was effective in mice, but it’s been in the freezer for the past two years because the trials in humans are too expensive for an academic center,” said Magnus Essand, MD, PhD, Professor of Neuroendocrine Cancer, Uppsala University, Sweden. Because of early publication of the results, the researchers will not be able to have a patent protection for the virus, thereby thwarting any chance of commercializing and profiting from their research. Instead, they have launched a fundraising campaign online at www.uu.se/en/support/oncolytic/. According to the website, “The treatment consists of an oncolytic virus, which has turned out to be remarkably efficient in destroying neuroendocrine tumours in mice.” Why donate? “If you donate the equivalent of one million pounds, we will name the world’s first genetically engineered neuroendocrine-specific virus in your honour….Like other virus treatments

Popularizing Cancer as a Topic... move into the age of next-generation sequencing and precision medicine. The ultimate questions are whether a gene can be patented, and if the evidence is sufficient to support a patent for the test that Myriad has developed. The current approach to our understanding, diagnosis, and treatment of

cancer will dramatically evolve in the next decade through the advent of a better understanding of gene regulation and the molecular heterogeneity of cancer cells, and a growing number of new tools that will allow us to predict one’s risk for cancer, better diagnose cancer, and better assess the prog-

Value-Based Cancer Care

june 2013

for cancer that are in development around the world, this virus is predicted to be safe and have few side-effects in humans.” If they get the funding, Professor Kjell Öberg, current Chairman of the European Neuroendocrine Tumor Society, will launch the world’s first human trials with this genetically engineered virus designed to target neuroendocrine tumors. (Uppsala University, Sweden; May 2013)

21st Century Oncology Administering First Commercial Dose of Xofigo for Advanced Prostate Cancer

Only 9 days after the US Food and Drug Administration (FDA) approved radium RA 223 dichloride (Xofigo) for the treatment of patients with meta static castration-resistant prostate cancer (CRPC) on May 15, 2013, which was 3 months ahead of the scheduled FDA review, the first worldwide commercial dose of this new therapy was administered to a patient with advanced CRPC. This event was made possible by a joint effort between 3 urology clinics in Myrtle Beach, SC, that constitute a division of 21st Century Oncology. “We are proud to begin offering Xofigo infusion on a broader scale to more patients who would otherwise have limited or potentially less effective treatments for late stage prostate cancers,” said Neal Shore, MD, FACS, a urologist associated with this group. “We are looking forward to this treatment helping our patients improve their quality of life as well as extending their survival.” Because the treatment is so new, health plans have not yet established reimbursement guidelines; however, the manufacturer has established a patient assistance program through Xofigo Access Services to help secure coverage and access to this therapy. (21st Century Oncology; May 30, 2013)

Disease Burden, Not Inefficiency in Care, Explains the Lion Share of Geographical Differences in Medicare Costs

A novel study offers a new explanation for the geographical differences seen in Medicare costs across the nation. Unlike the explanation offered mainly by the Dartmouth Atlas of Health Care and other research attributing geographical variations in care to waste and inefficiency in the delivery of healthcare, “our results suggest that the portion of the geographic variation that can be explained by patient health is much greater than previously estimated, leaving less of the geographic variation potentially attributable to inefficiency,” wrote James D. Reschovsky, PhD, a senior fellow at the Center for Studying Health System Change, and colleagues. (Center for Studying Health System Change; May 28, 2013)

Continued from page 4 nosis of patients with cancer, as well as to predict the treatments that are most appropriate and effective. This evolution will significantly impact the cost of diagnosis and treatment while simultaneously altering outcomes. It is, however, Angelina Jolie’s willingness to speak up, and the public

service of Congresswoman Debbie Wasserman Schultz and her contribution to this discourse, that could potentially have an even more dramatic impact on decisions that contribute to popularizing a personalized and precise approach to the diagnosis and treatment of cancer. n

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Patient-Centered Oncology Medical Home... Dr McAneny received a $20-million Centers for Medicare & Medicaid Services Health Care Innovation Award to create a patient-centered medical home that encompasses 7 practices across several states. Innovative On cology Business Solutions is the managing organization formed for the purpose of administering the project. The first phase of the program is already showing promising results. “We proved there are significant savings from being an oncology medical home versus a hospital-based integrated system,” she said. “So far, my patients say they are thrilled with this. They write me thank you notes and bring flowers to the office.” Project Partners Some of the grant money will go to Net.Orange, which is a health information technology company that is creat-

“We proved there are significant savings from being an oncology medical home versus a hospital-based integrated system. So far, my patients say they are thrilled with this.” —Barbara L. McAneny, MD

ing customized quality and pathway performance dashboards using claims data and integrated electronic health records. The KEWGroup will help the practice integrate genetic markers into diagnostic and treatment pathways. The University of Tennessee is providing expertise in evaluation, cost, and quality measurements, and will be using claims data for rapid-cycle feedback of cost utilization perfor-

Figure COME HOME Model: Oncology Patient 2. Electronic health records: share/track real-time patient information; monitor quality

1. Best practices care: triage, diagnostic, therapeutic pathways

3. Team-based care: medical/radiology oncologists, diagnostic radiologists, nurse practitioners, registered nurses, licensed practical nurses, pharmacists, medical technicians, care coordinators, and first responders all working as a team to keep patients in the outpatient setting and out of the emergency department and hospital 4. Active disease management: patient education, patient/ provider web portal

5. Enhanced access: 24/7 triage line with “first responders” (8-6) and on-call providers (6-8)

6. Enhanced care: on- or near-site laboratory, imaging, and pharmacy

7. Financial support: for medical home services

COME HOME indicates Community Oncology Medical Home.

Table Projected Savings to Medicare

Service

Hospital

Emergency department visits Physician

Pharmacy Other Total

Average cost per unit of service, $

Baseline total costs per patient, $a

Projected decrease in costs, %

Projected total costs per patient, $

Projected average savings per patient, $

554

1136

–52.2

543

593

8225

17,108

–21.15

13,489

3619

228

6398

+7.6

6882

–484

9480

28,573

13,355 66,569

–3.4 6.276

12,905 62,391

450 4178

Cost projections based on Medical Expenditures Panel Survey data for Medicare beneficiaries in “poor health,” inflated to reflect higher expenditures associated with cancer. a

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mance. “This is where we get a health economist to manage the data,” Dr McAneny explained. The COME HOME Model Patients with newly diagnosed or relapsed cancer from these 7 sites will be put on diagnostic and therapeutic pathways. “We will be aggressively making sure we take care of these patients,” she emphasized. Aggressive team-based patient management does not mean that all care is delivered by the oncologist, Dr McAneny said. “We will use all the members of this team to the peak of their licenses,” she said. “We don’t need nurse navigators; everyone in my practice is one. We need people interested in taking care of the patient.” At the heart of this basic Community Oncology Medical Home (COME HOME) model (Figure) is team-based care that manages the side effects of cancer and its treatments aggressively, with the goal of keeping patients out of the emergency department and hospitals. In phase 1 of the model, enhanced services include: • Patient education and medication management • 24/7 practice access: telephone triage, triage pathways, night and weekend clinic hours, and on-call physicians • On-site or near-site imaging and laboratory testing • Admitting physicians who shepherd patients through inpatient encounters, avoiding handoffs and readmissions, and ensuring seamless care. The tumor types and estimated patient enrollment, by tumor type, include breast (N = 1891), lung (N = 1830), colorectal (N = 1058), lymphoma (N = 641), melanoma (N = 523), pancreas (N = 479), thyroid (N = 175), and others (N = 2961), making a total of almost 10,000 patients treated under the COME HOME model. Diagnostic and treatment pathways are being developed for phases 2 and 3 of the model. Decision support will be provided for the proper use of genomics in the pathways.

“We will be able to manage all this, because all 7 of our practices must have medical records from which you can pull data in real time,” Dr McAneny said. Enhanced access to care is part of the plan. This means providing 24/7 triage with “first responders” and oncall providers. The practice is open until 6 pm and on weekends. “Most practices are set up for the convenience of the doctor. Ours is set up for the convenience of the patient,” she noted. “When a patient calls in and says she is sick, our answer is, ‘Come in at 2 pm.’ Everyone in the office has to be of the mindset that their job is to solve the patient’s problem. Patients know that if they get sick, we are here for them,” Dr McAneny emphasized. “My practice is the only one with extended hours so far, but others are rolling out soon. In my practice in New Mexico, for our first 3 months with extended hours, we kept 92 patients out of the emergency department,” Dr McAneny reported. In this model, the oncologists directly admit patients and do not refer to hospitalists or emergency departments. “We believe that when our patients get sick, they want their own doctor, not someone else’s.” Part of the group’s mission is to prove that their care is as good as, or better than, care received anywhere, and that the care is provided at a lower cost. To demonstrate this, the practice intends to prove that providers can follow pathways, prescribe appropriately, and produce good or equivalent outcomes that can be measured in meaningful ways. Data Management Is Key All of the practices are fully electronic, allowing for data extraction and outcomes measurements. Dr McAneny and colleagues will compare their data with Medicare claims data to determine savings. They would like to use the National Comprehensive Cancer Network member institutions as the gold standard for optimal care and for comparison of outcomes. The projected savings are already known to be substantial, she said, as shown in the Table. “We are expected to save about $4000 per patient episode, significantly more than the $7 per patient that has been shown for hospital-based groups,” she said. “We think we can go to bundled payments, but transparency is essential. We need to know what we are keeping and why.” n

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Genomic Sequencing Assay Potentially a... cancer tumors. “I looked at the first 50. No two genomic reports were identical,” he noted. “There are 50 different genomic patterns in those breast cancers, which gives you an idea of the precision that we are dealing with.”

“There are 50 different genomic patterns in those breast cancers, which gives you an idea of the precision that we are dealing with.” —Gary Palmer, MD, JD, MBA, MPH

Why the Current Testing Model Is Not Sustainable Under the new paradigm, cancer is no longer described by its tumor of origin, but by its molecular characteristics—and increasingly by its genetic mutations. Given the increasing number of mutations identified per tumor, the current method of genetic testing is not comprehensive enough, according to Dr Palmer. Most oncologists now order specific panels. The lung cancer panel, for example, tests for abnormalities in EGFR, KRAS, ALK, and ROS1. “The problem is that the number of important alterations is increasing, and

you won’t be able to send little pieces of tissue for 20 individual tests,” he explained. “Also, there is no reason to think that these 4 alterations represent all we need to know about lung cancer. We would miss all the other potential alterations if we just tested for those. The current model isn’t sustainable.” Whole-genome sequencing has identified a mean number of 15,300 genomic alterations per patient (Table), but the vast majority are passenger mutations whose clinical relevance is unknown; the current method is also likely to miss several actionable alterations in individual patients, many of which are proving to be unpredictable. For example, Foundation Medicine research has shown that HER2 amplifications and mutations occur in many solid tumors, not just breast and gastric, and that many patients with such tumors have responded to anti-HER2 agents. FoundationOne Test: A Paradigm Shift The FoundationOne pan-cancer, next-generation sequencing assay identifies actionable alterations in tumors that usually would not have been identified by the panel type of approach that is currently being used. The test, which runs on paraffin-embedded tissue, hunts for the presence of 236 genes

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known to be cancer drivers. Although the assay identifies on average 1800 alterations per tumor, approximately 10 are deemed important. The test, therefore, weeds out approximately 1790 useless genes per sample, primarily single nucleotide polymorphisms and passenger mutations. In 23% of the tumors, however, no actionable alteration is found. Of this 23%, an alteration can be identified in 14% of tumors, but a targeted treatment is currently lacking; for the other 9%, no alteration is identified. “We separate the wheat from the chaff, and we come up with driver alterations that we report to the oncologist,” Dr Palmer said. “Most impor tant, we report the data in a way that makes sense to the physician and that supports the use of a particular targeted therapy. Focused sequencing of the clinically relevant genes may be the

optimal approach for patient care,” Dr Palmer suggested (Figures 1 and 2). Page 1 of the report lists the alterations and the potential actions—that is, the use of a US Food and Drug Administration (FDA)-approved drug on label or off label, or the use of a clinical trial. Additional pages of the report provide background and content. Hundreds of physicians have been using the FoundationOne test for the common solid tumors, and for rare tumors, for which treatments are lacking. “There is no tumor type yet where I would say that we don’t stand much chance of finding anything of value,” Dr Palmer added. A summary of findings and treatment outcomes from the first 2223 patients are expected to be reported at the 2013 annual meeting of the American Society of Clinical Oncology.

Figure 1 Sample Report I

Patient and ordering physician information Summary of results and genomic alterations identified Targeted therapies and clinical trials that may be relevant based on genomic alterations identified

Focused Sequencing of the Clinically Relevant Cancer Genes May Be the Table Optimal Approach to Patient Care Mean identified genomic alterations, N Cancer type

Whole genome

Lung adenocarcinoma1

38,400

Squamous-cell lung cancer2 Colorectal cancer

Glioblastoma multiforme4

Ovarian cancer5 Breast cancer

Total

25,900 10,240

Whole exome 528 365

Foundation Medicine 3.1

7360

101

2.9

6700

2.9

15,300

212

2.9

Whole genome/exome sequencing identifies high numbers of alterations per patient, but the vast majority are passenger mutations whose clinical relevance is unknown. Uneven coverage generated by current whole/exome sequencing increases the probability of missing actionable alterations in an individual patient.

1. Imielinski M, et al. Cell. 2012;150:1107-1120. 2. Cancer Genome Atlas Research Network. Nature. 2012;489:519-525. 3. Cancer Genome Atlas Research Network. Nature. 2012;487:330-337. 4. Cancer Genome Atlas Research Network. Nature. 2011;474:609-615. 5. Cancer Genome Atlas Research Network. Nature. 2008;6:1061-1068. 6. Banerji S, et al. Nature. 2012;486:405-409.

Courtesy of Foundation Medicine.

Figure 2 Sample Report II

3.2

140

3200

Clear results presented on the first page

An interpretive statement provided for each genomic alteration, including the frequency of alteration (COSMIC), its biological implication, and what it may mean for the specific patient

The therapies section provides details on approved therapies to which the patient’s cancer may be sensitive or resistant based on their genomic profile

The clinical trials section provides detail on currently available clinical trials for which the patient may be eligible

The appendix lists all reference information for studies used in curating the report

Additional pages provide background and context Continued on page 10

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www.ValueBasedCancerCare.com

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Genomic Sequencing Assay Potentially a... Future Goals and Cost Implications The next step is to optimize the reporting of treatments that are employed and their outcomes, for which a registry has been initiated. Because randomized controlled trials will never be conducted on these very small genetic subsets, the aggregation of rare mutations can generate a database that will be very informative for oncologists whose patients fit these rare profiles. “We are heavily invested in getting this information and allowing physicians to use it,” Dr Palmer said. The availability of molecular testing on this scale leads to the question of which patients should have these tests, because there will be cost implications, he noted. In one scenario, the test is ordered after patients have exhausted their current treatment options. In the other scenario, the test

Continued from page 9

is used after a metastatic diagnosis, which could spare patients futile chemotherapy. “The economic implications would be different,” Dr Palmer pointed out. The test also raises the question of off-label drug accessibility in the absence of randomized trials. “It’s one thing to find a target, and another to get the drug off label from the insurance company,” he added.

“Focused sequencing of the clinically relevant genes may be the optimal approach for patient care.” —Gary Palmer, MD, JD, MBA, MPH

Sample Patient Using FoundationOne Test Dr Palmer described several good outcomes that have resulted from the FoundationOne test. One patient was a 43-year-old never-smoker who developed lung cancer. The Vysis ALK Break Apart FISH Probe Kit, an approved companion diagnostic for the anaplastic lymphoma kinase (ALK) mutation, was negative. Testing for the epidermal growth factor receptor

by polymerase chain reaction was also negative. The patient was started on chemotherapy, but this was ineffective. His physician contacted Foundation Medicine based on the clinical suspicion of a treatable oncogenic driver mutation. The test identified an ALK rearrangement involving intron 19. Unlike the echinoderm microtubule-associated protein-like 4-ALK rearrangement, which occurs in approximately 5% of patients with non–small-cell lung cancer, this particular mutation has not been reported in the literature. The patient was started on crizotinib, to which he continues to respond at 9 months. “This would not be found by conventional testing, which seeks only molecular information associated with cancer in a specific organ,” Dr Palmer noted. “The molecular information led to treatment with an FDAapproved agent.” n

Pathways Creating More and More Value By Caroline Helwick

Hollywood, FL—Pathways continue to be refined toward value-based care, adapting to the challenges of a rapidly shifting oncology landscape, as 2 speakers at the Third Annual Conference of the Association for Value-Based Cancer Care described. Michael A. Kolodziej, MD, National Medical Director for Oncology Strategies at Aetna, Hartford, CT, and Marcus A. Neubauer, MD, Medical Director, Oncology Services, US Oncology/McKesson Specialty Health, TX, first discussed market pressures and the need to control costs. Since 1996, the US gross domestic product has decreased by 2.4%, but healthcare costs have risen by 9.2%, and the cost of cancer medical care, as well as oncolytics, has increased by 15%. The fiscal future looks even bleaker, with cancer care costs projected to rise 39% by 2020. The consequence of this financial crisis is confusion by these market forces, Dr Neubauer suggested. “All stakeholders are struggling. Payers are struggling with rising costs and have problems getting their programs adopted by physicians. Physicians often have multiple platforms to manage. Employers are struggling with costs” (Figure 1).

Figure 1 The Consequences: Market Forces Are Creating Confusion Payers

Employers

• Limited consistency between payers • Challenges getting provider adoption • Beginning to focus on prior authorization to gain adoption

• Confusing definition of quality and coverage • Little ability to weigh cost versus quality • Need a trusted source for understanding quality

Providers

Patients/Employees

• Multiple platforms and policies to manage • Inconsistent yardsticks for quality resulting in variability in care for similar patients

• Confusing messages on quality care • “Best” option not always available • Limited ability to compare • Fear and frustration

In response, oncology management solutions are continuing to evolve, but this is creating a fragmented approach to quality. “We are not doing a great job solving this problem,” Dr Neubauer said. Dr Kolodziej said that pathways are a way to carry out Aetna’s principles: to drive the efficient use of evidence-based medicine, to avoid waste and the misuse of medical services, and to leverage and integrate the many current and future medical and pharmacy cancer care initiatives.

Value-Based Cancer Care

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As responsibility, risk, and accountability shift to the provider, pathways will become ever more important for communicating and measuring performance, Dr Kolodziej added. “They prove you are accomplishing minimal standards, but most important, they train oncologists to get in the mindset of measurements and process improvements. They are training sets for changing behavior.” Demonstrating Cost-Savings US Oncology/McKesson has re-

sponded by creating value-based pathways, believing that pathways can save money, without diminishing outcomes. Despite the size of the network—which includes more than 3000 oncologists, 2200 multispecialty practices, and 1.5 million patients with cancer annually—the pathways program is “very internal,” Dr Neubauer said. “In our physician-driven program, all our pathways are designed by oncologists, with the intent of showing that we can achieve both value and a value-based contract with payers. We have had some success in this regard,” he noted. Two recent studies provided proof of principle of this. Dr Neubauer led a study of patients with non–small-cell lung cancer that showed that on-pathway treatment saved almost $10,000— a 35% reduction—versus off-pathway treatment (Neubauer MA, et al. J Oncol Pract. 2010;6:12-18). Hoverman and colleagues (also with US Oncology) reached the same conclusions in their study of patients with colon cancer, where on-pathway treatment saved $50,000 to $60,000 per case, more than a 30% reduction versus off-pathway treatment (Hoverman JR, et al. J Oncol Pract. 2011;7(suppl):52S-59S).

Continued on page 11

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Pathways Creating More and More...

how will the “economic value proposition” be defined in a world with generic alternatives for which there is not much differentiation? How will pathways be designed for tumors that are defined more by molecular biology than by site of disease?

Combining value-based pathways with additional services, such as advanced care planning and patient support services, resulted in a 12% cost-savings within The US Oncology Network, Dr Neubauer added. Dr Kolodziej presented additional data on savings from 2 pilot studies, demonstrating that emergency department use and inpatient days steadily declined when pathways were implemented. “Both pilots are showing equal, if not better, clinical outcomes and patient satisfaction,” he said. Value-Based Pathways To further strive for value within a pathway system, US Oncology/ McKesson has partnered with the National Comprehensive Cancer Network (NCCN), capitalizing on the individual strengths of each entity (Figure 2). The Value Pathways are based on the NCCN Clinical Practice Guidelines in Oncology®—the gold standard for evidence-based oncology content—paired with quantified pharmacoeconomics, thus creating “Value Pathways that are powered by the NCCN,” Dr Kolodziej said. “With this collaborative vision, we hope to create meaningful content and a technology standard,” he commented. “We can be universally recognized for driving quality patient care; we can provide increased value transparency for providers, payers, and employers; and our content can be integrated with physician work flow to enable programs across all providers and payers.” Value Pathways will be administered via the NCCN’s new technology standard, Clear Value Plus, which is a program that integrates with patient workflow; imports patient and clinical data from frequently used electronic health records; identifies relevant

Discussion with the Experts Dr Neubauer and Dr Kolodziej responded to questions from the Association for Value-Based Cancer Care conference audience.

“With this collaborative vision, we hope to create meaningful content and a technology standard… [and] we can provide increased value transparency for providers, payers, and employers.” —Michael A. Kolodziej, MD

Value Pathways and NCCN guidelines at the point of care; and allows providers, payers, and employers to align on quality and value. “Clear Value Plus’s advanced, realtime reporting provides aggregate, actionable data for providers and payers,” Dr Kolodziej added. “Our primary customer is the physician, but we are showing this tool to payers too. We hope that physicians will be able to use this as their standard rather than having to participate in a number of different programs.” Pathways must be adapted to changes occurring across the oncology landscape, he added, but there remain unanswered questions: With the growing availability of generic drugs,

Figure 2 NCCN, the US Oncology Network, and McKesson Each Brings Complementary Strengths to Create New Solutions: Emphasis on Comprehensive Quality NCCN • Academic thought leadership • World-class content

McKesson • Community care operational excellence

• Strong payer and employer relationships

• Leading technology • Expansive provider relationships

• Recognized name brand

• Resources of a Fortune 14 company • Emphasis on value and quality

Bringing content and technology from 2 organizations closer together creates new opportunities and enhances individual strengths

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Continued from page 10

Q: Can pathways affect the need for prior authorization for new drugs?

Dr Neubauer: Obviously, pathways must be relevant, and therefore must be able to incorporate new drugs quickly. But they must be evidence based, and we must consider all factors. If we don’t think a new drug is worthy, we won’t necessarily put it onto our pathway, even if it passes muster by the US Food and Drug Administration. If the drug is expensive and produces good results, yes. Dr Kolodziej: When I joined Aetna a few months ago, one of the first things I did was review our oncology drug prior authorizations. We only require prior authorizations for 2 injectables, Xgeva and Aloxi. We don’t set that bar very high, but we do for orals, largely driven by their price tags. The beauty of pathways is that they eliminate administrative responsibilities that plans have to worry about, and they lessen the need for so many prior authorizations. Dr Neubauer: But, payers do have to step in, in some way, although prior authorization is not a long-term proposition for anyone. We must develop a way to collaborate.

Q: The elephant in the room is the cost of the drugs themselves. Is the cost structure appropriate, and how can drug costs be controlled?

Dr Kolodziej: There are proposals on the table. The government may have to step in. Bundled reimbursements may have some influence, although I am skeptical. Great Britain has started value-based reimbursements, in which companies will be reimbursed only for the first 2 cycles if their drug does not seem effective. As we set up integrated delivery systems, pharmaceutical companies may want to come to those systems with value-based propositions, perhaps based on outcomes, and negotiate a price point over the drug’s potential value. That’s a pie-in-the-sky deal, but we have been engaged in discussions

june 2013

about this as an engine to drive the correct pricing of drugs. Of course, nobody wants to take that beast on. It’s a political minefield. Dr Neubauer: I don’t understand how the government can reduce the bill for chemotherapy from average sale price (ASP) plus 6% to ASP plus 4%, but leave the ASP part—which the pharmaceutical company gets— unchanged. My opinion is that the government will start regulating prices as other countries do, or pharmaceutical companies will have to step up to the table. Pharmaceutical companies are starting to talk about value propositions, but these are early conversations and may not materialize.

“In our physician-driven program, all our pathways are designed by oncologists, with the intent of showing that we can achieve both value and a value-based contract with payers. We have had some success in this regard.” —Marcus A. Neubauer, MD

Q: How useful are patient registries in producing meaningful data?

Dr Kolodziej: I take exception to the argument that we should have provider- or community-based registries to give us information about real-world experience. That’s not to say we cannot learn something from what functionally is comparative effectiveness research. Dr Neubauer: Registries could be valuable, and there are efforts under way to develop them, such as American Society of Clinical Oncology’s CancerLinQ. But based on my efforts to try to analyze our own data, I can say it’s very difficult. n

www.ValueBasedCancerCare.com

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

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac

imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

Kyprolis™ (carfilzomib) for Injection is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma. • Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria. References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

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

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

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

Please see Brief Summary of the full Prescribing Information on adjacent pages.

FDA Update FDA Expedites Approval of Xofigo for Metastatic, Castration-Resistant Prostate Cancer

Radium Ra 223 dichloride (Xofigo; Bayer Pharmaceuticals) was approved by the US Food and Drug Adminis tration (FDA) for men with metastatic, castration-resistant prostate cancer (CRPC) that has spread to bones but

not to other organs. Ra 223 dichloride is an alpha particle-emitting radioactive therapy that is used to lower the testosterone levels for patients whose cancer has spread after medical or surgical therapy. The approval of Ra 223 dichloride was done under the FDA’s priority review program and 3 months ahead of the scheduled FDA review. “Xofigo

binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and On cology Products. “Xofigo is the second prostate cancer drug approved by the FDA in the past year that dem onstrates an ability to extend the sur-

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 2 Dosing Dosing Dosing Dosing (27 mg/m ): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• • •

• Non-Hematologic Toxicity Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • congestive heart failure; • decreased left ventricular function; • or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

Value-Based Cancer Care

june 2013

• • •

Recommended Action Withhold dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Recommended Action Withhold until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline. • Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

vival of men with metastatic prostate cancer.” The safety and efficacy of Ra 223 dichloride were demonstrated in a sin gle, randomized, placebo-controlled trial of 809 men with symptomatic CRPC that spread to bone but not to other organs. The primary end point was overall survival (OS). Interim results from a preplanned

reported (< KYPROLIS i reported (< liver abnor KYPROLIS in KYPROLIS liver abnorm Adverse Rei KYPROLIS pregnantRea w Adverse well‑control pregnant wo pregnant ra well‑controll reproductive pregnant rab If this drug reproductive shou Ifpatient this drug ADVERSE patient shou of the labelin ADVERSE R • Cardia of the labelin • Pulmon • Cardiac • Pulmon • Pulmon • Infusio • Pulmon • Tumor • Infusion • Thromb • Tumor L • Hepatic • Thromb The most c • Hepatic trials of pat The most co diarrhea, a trials of pati under wide diarrhea, an be directly under widely observed be directlyinc received observed KY in four treatm received KYP causes with four treatme attributed to causes with cardiac dis attributed to infectiondiso in cardiac intracranial infection in adverse rea intracranial pneumonia adverse rea reactions le pneumonia heart failur reactions lea each).failure Adve heart TableAdver 4: In each). Patients T Table 4: In Patients Tr

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function. • Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If not attributable to KYPROLIS, restart at the dose used prior to the event. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. a

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

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

Fatigue Anemia Fatigue Nausea Anemia Thromboc Nausea Dyspnea Thrombocy Diarrhea Dyspnea Pyrexia Diarrhea Upper resp Pyrexia Headache Upper resp Cough Headache Blood crea Cough Lymphope Blood crea Edema pe Lymphopen Vomiting Edema per Constipati Vomiting Neutropen Constipatio Back pain Neutropeni Insomnia Back pain Chills Insomnia Arthralgia Chills Muscle sp Arthralgia Hypertens Muscle spa Asthenia Hypertensio Hypokalem Asthenia Hypomagn Hypokalem Leukopeni Hypomagn Pain in ext Leukopenia Pneumoni Pain in extr Aspartate Pneumonia Dizzinessa Aspartate Hypoesthe Dizziness Anorexia Hypoesthes Pain Anorexia Hyperglyce Pain Chest wall Hyperglyce Hypercalce Chest wall Hypophosp Hypercalce Hyponatre Hypophosp a National Can Hyponatrem

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

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

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

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yocardial ation. New unction or ents (e.g., in 7% of Grade 3 or enefit/risk ass III and normalities at greater sion (PAH) han 1% of ROLIS for to restart ulmonary 3 dyspnea d manage seline [see tions were lgia, facial tightness, stration of severity of to contact mor Lysis < 1% of d to be at ee Dosage y. Interrupt KYPROLIS cycle and ma, 36% of following nuation of treatment nistration]. have been

FDA Update analysis showed that the median OS was 14 months in patients who were randomized to Ra 223 dichloride versus a median of 11.2 months for men receiving placebo plus best standard of care. The most common side effects with Ra 223 dichloride were nausea, diarrhea, vomiting, and swelling in the lower extremities. The most common

hematologic abnormalities included anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. (May 15, 2013)

Mekinist and Dabrafenib Approved for Advanced Melanoma with BRAF Mutations

On the same day, the FDA ap-

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other KYPROLIS is appropriate. Monitororliver enzymes frequentlyAfter [seeresolution, Dosage and Administration and liver abnormalities until resolved returned to baseline. consider if restarting Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause harmand when administeredand to a KYPROLIS is appropriate. Monitor liver enzymes frequently [see fetal Dosage Administration pregnant woman based on its mechanism of action and findings in animals. There are no adequate Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered toand a well‑controlled womenofusing Carfilzomib caused toxicity pregnant womanstudies based inonpregnant its mechanism actionKYPROLIS. and findings in animals. Thereembryo‑fetal are no adequate andin pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of If this drug is used during if thebecoming patient becomes while taking thisKYPROLIS. drug, the reproductive potential shouldpregnancy, be advised or to avoid pregnantpregnant while being treated with should be apprised of the potential to thebecomes fetus [seepregnant Use in Specific Populations]. Ifpatient this drug is used during pregnancy, or ifhazard the patient while taking this drug, the ADVERSE REACTIONS: following adverse are discussed greater detail in other sections patient should be apprised The of the potential hazardreactions to the fetus [see Use ininSpecific Populations]. of the labeling: ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] of the labeling: • Pulmonary Hypertension [see Warnings and Precautions] • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Complications [see Warningsand andPrecautions] Precautions] • Pulmonary Hypertension [see Warnings • Infusion Reactions [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Thrombocytopenia [see Warnings andand Precautions] • Tumor Lysis Syndrome [see Warnings Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings • Thrombocytopenia [see Warnings and Precautions] and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical diarrhea, and pyrexia. Clinical Trials Safety Experience. clinical trials are conducted trials of patients with multiple myeloma were fatigue, anemia, Because nausea, thrombocytopenia, dyspnea, under widely adverseSafety reaction rates observed in the clinical clinical trials a drug cannot diarrhea, and varying pyrexia.conditions, Clinical Trials Experience. Because trials ofare conducted be directly with ratesadverse in the clinical another in drug, and may notofreflect rates under widelycompared varying conditions, reactiontrials ratesofobserved the clinical trials a drugthe cannot observed medical practice. A total 526 patients relapsed and/or myeloma be directlyincompared with rates in theof clinical trials with of another drug, andrefractory may not multiple reflect the rates received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myelomaof four treatment cycles with a median cumulative KYPROLIS dose of Patients 993.4 mg. Deaths due to of all received KYPROLIS as monotherapy or with pre‑dose dexamethasone. received a median causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not cardiac disorder), failure 4 patients (multi‑organ hepatic failure,cardiac renal failure), attributed to diseaseend‑organ progression wereincardiac in 5 patients (acutefailure, coronary syndrome, arrest, infectiondisorder), in 4 patients (sepsis, tractfailure, bacterial infection), dyspnea and cardiac end‑organ failurepneumonia, in 4 patientsrespiratory (multi‑organ hepatic failure, renal failure), intracranial in 1 patient each, andrespiratory 1 patient tract found bacterial dead of unknown Serious infection in hemorrhage 4 patients (sepsis, pneumonia, infection),causes. dyspnea and adverse reactions were reported in 45% patients. mostfound common adversecauses. reactions were intracranial hemorrhage in 1 patient each, and 1 The patient deadserious of unknown Serious pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse adverse reactions were reported in 45% patients. The most common serious adverse reactions were reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, andand acute renal congestive failure (1% reactions leading to discontinuation of KYPROLIS occurred in 15% of patients included each).failure Adverse reactions at a rateincreased of 10% orblood greater are presented in Table 4. failure (1% heart (2%), cardiacoccurring arrest, dyspnea, creatinine, and acute renal TableAdverse 4: Incidence of occurring Adverse Reactions in ≥ 10% of Multiple Myeloma each). reactions at a rate of Occurring 10% or greater are presented in Table 4. Patients Treated with KYPROLIS Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS Patients (N = 526) [n (%)] Patients (N = 526) Grade 3 Grade 4 All [n (%)] a Events Events Event Grades Grade 3 Grade 4 All a Fatigue 292 (55.5) 38 (7.2) 2 (0.4) Events Events Event Grades Anemia 246(55.5) (46.8) 111 (21.1) Fatigue 292 38 (7.2) 27 (1.3) (0.4) Nausea 236 (44.9) 7 (1.3) 0 Anemia 246 (46.8) 111 (21.1) 7 (1.3) Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Nausea 236 (44.9) 7 (1.3) 0 Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Diarrhea 172 (32.7) (0.8) (0.2)b Dyspnea 182 (34.6) 254(4.8) 11(0.2) Pyrexia 160 (30.4) (0.4) Diarrhea 172 (32.7) 47 (1.3) (0.8) 12(0.2) Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) Headache 145 (27.6) 7 (1.3) Upper respiratory tract infection 149 (28.3) 17 (3.2) 00 Cough 137 (26.0) 1 (0.2) Headache 145 (27.6) 7 (1.3) 00 Blood creatinine increased 127 (24.1) 13 (2.5) 1 0(0.2) Cough 137 (26.0) 1 (0.2) Lymphopenia 126(24.1) (24.0) 84 (16.0) 11 (2.1) Blood creatinine increased 127 13 (2.5) 1 (0.2) Edema peripheral 126(24.0) (24.0) 3 (0.6) 0 Lymphopenia 126 84 (16.0) 11 (2.1) Vomiting 117(24.0) (22.2) 5 (1.0) Edema peripheral 126 3 (0.6) 00 Constipation 110(22.2) (20.9) (0.2) Vomiting 117 51(1.0) 00 Neutropenia 109(20.9) (20.7) 50 (9.5) 4 0(0.8) Constipation 110 1 (0.2) Back pain 106(20.7) (20.2) 15(9.5) (2.9) 0 Neutropenia 109 50 4 (0.8) Insomnia 94(20.2) (17.9) 0 Back pain 106 15 (2.9) 00 Chills 84(17.9) (16.0) 1 0(0.2) Insomnia 94 00 Arthralgia 83 (15.8) Chills 84 (16.0) 17 (1.3) (0.2) 00 Muscle spasms 76 (14.4) 2 (0.4) Arthralgia 83 (15.8) 7 (1.3) 00 Hypertension 75 (14.3) 15 (2.9) 2 0(0.4) Muscle spasms 76 (14.4) 2 (0.4) Asthenia 73 (13.9) 12 (2.3) (0.2) Hypertension 75 (14.3) 15 (2.9) 21(0.4) Hypokalemia 72 (13.7) 14 (2.7) Asthenia 73 (13.9) 12 (2.3) 13 (0.6) (0.2) Hypomagnesemia 71 (13.5) (0.4) 0 Hypokalemia 72 (13.7) 142(2.7) 3 (0.6) Leukopenia 71 (13.5) 27 (5.1) 1 0(0.2) Hypomagnesemia 71 (13.5) 2 (0.4) Pain in extremity 70 (13.3) 0 Leukopenia 71 (13.5) 277 (1.3) (5.1) 1 (0.2) Pneumonia 67 (12.7) 52 (9.9) 3 (0.6) Pain in extremity 70 (13.3) 7 (1.3) 0 b Aspartate aminotransferase increased 66(12.7) (12.5) 15(9.9) (2.9) 1 (0.2)b Pneumonia 67 52 3 (0.6) Dizzinessaminotransferase increased 66(12.5) (12.5) (1.0) (0.2) Aspartate 66 155(2.9) 11(0.2) Hypoesthesia 64(12.5) (12.2) 0 Dizziness 66 53 (0.6) (1.0) 1 (0.2) Anorexia 63 (12.0) 1 (0.2) Hypoesthesia 64 (12.2) 3 (0.6) 00 Pain 63 (12.0) 12 (2.3) Anorexia 63 (12.0) 1 (0.2) 00 Hyperglycemia 62 (11.8) 16 (3.0) 3 (0.6) Pain 63 (12.0) 12 (2.3) 0 Chest wall pain 60(11.8) (11.4) 3 (0.6) 0 Hyperglycemia 62 16 (3.0) 3 (0.6) Hypercalcemia 58(11.4) (11.0) 13 (2.5) 8 0(1.5) Chest wall pain 60 3 (0.6) Hypophosphatemia 55(11.0) (10.5) 24 (4.6) Hypercalcemia 58 13 (2.5) 83 (0.6) (1.5) Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) One event was Grade 5 severity. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. b One event was Grade 5 severity. a

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proved 2 targeted oral therapies for patients with melanoma. The 2 therapies were both developed by Glaxo SmithKline and are targeting similar, but not the same, populations of patients with melanoma and a BRAF mutation. Both drugs were approved concurrently with the FDA approval of a companion diagnostic assay THxID BRAF (manufactured by

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%)Renal and renal failure (9%), which were mostly Description of Selected Adverse Drug Reactions. Events: The most common renal Grade or Grade 2 in increase severity. inGrade renal adverse in 6% of were patients and adverse1 reactions were blood 3 creatinine (24%) reactions and renal occurred failure (9%), which mostly Grade 4 events occurred in 1%. Grade Discontinuations due to reactions increasedoccurred blood creatinine andpatients acute renal Grade 1 or Grade 2 in severity. 3 renal adverse in 6% of and failure were 1%occurred each. Ininone death occurred concurrent and and worsening renal Grade 4 events 1%.patient, Discontinuations due towith increased bloodsepsis creatinine acute renal function [see1% Dosage Administration]. Peripheral Peripheral neuropathy (including failure were each.and In one patient, death occurred Neuropathy: with concurrent sepsis and worsening renal all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (includingof patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious and treatment discontinuation in < 1%. Withhold or discontinue treatment as peripheral neuropathy events occurred in < 1% of patients, which resulted in doserecommended [see reduction in < 1% Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see of patients. antiviralHerpes prophylaxis patients Herpes who have a history of herpes infection. Dosage and Consider Administration]. Virusfor Infection: zoster reactivation waszoster reported in 2% INTERACTIONS: Carfilzomib is primarily metabolized peptidase and epoxide hydrolase ofDRUG patients. Consider antiviral prophylaxis for patients who have via a history of herpes zoster infection. activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase concomitant of cytochrome P450 profile inhibitors and inducers. is not expected activities, andadministration as a result, the pharmacokinetic of carfilzomib is Carfilzomib unlikely to be affected by to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected IN SPECIFIC Pregnancysection Category toUSE influence exposure ofPOPULATIONS: other drugs [seePregnancy. Clinical Pharmacology of fullDPI].[see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while can cause when administered to a pregnant woman. being treatedfetal withharm KYPROLIS. Based on its mechanism of action andCarfilzomib findings incaused animals,embryo‑fetal KYPROLIS toxicity in pregnant doses that to were lower than in patients receiving the recommended can cause fetal harmrabbits when at administered a pregnant woman. Carfilzomib caused embryo‑fetal dose. IfinKYPROLIS used at during if thethan patient becomes pregnant taking this toxicity pregnant israbbits dosespregnancy, that wereorlower in patients receiving thewhile recommended drug, IftheKYPROLIS patient should be during apprised of the potential hazard to the fetus. Carfilzomib was administered dose. is used pregnancy, or if the patient becomes pregnant while taking this intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered 2 mg/kg/daytoinpregnant rats andrats 0.2,and 0.4,rabbits and 0.8 mg/kg/day in of rabbits. Carfilzomib was not teratogenic intravenously during the period organogenesis at doses of 0.5, 1, and any dose tested. there increase inin pre‑implantation losswas at ≥not 0.4teratogenic mg/kg/day 2atmg/kg/day in rats In andrabbits, 0.2, 0.4, andwas 0.8anmg/kg/day rabbits. Carfilzomib in Inearly resorptions andan post‑implantation loss and a decrease fetalmg/kg/day weight at atand anyan increase dose tested. rabbits, there was increase in pre‑implantation loss at ≥in0.4 the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at 2 approximately respectively, of the in humans of 27inmg/m the maternally 20% toxic and dose40%, of 0.8 mg/kg/day. Therecommended doses of 0.4 dose and 0.8 mg/kg/day rabbitsbased are on body surface Mothers.ofIt the is not known whether approximately 20%area. and Nursing 40%, respectively, recommended doseKYPROLIS in humansisofexcreted 27 mg/min2 human based milk. Since manyarea. drugsNursing are excreted in human milkknown and because the potential for serious on body surface Mothers. It is not whetherofKYPROLIS is excreted in adverse human reactions nursing infants KYPROLIS, a decision be made discontinue nursing milk. Sinceinmany drugs are from excreted in human milk andshould because of thewhether potentialto for serious adverse or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing The safety the anddrug, effectiveness KYPROLIS pediatric ofpatients have not mother. been established. orUse. to discontinue taking intoofaccount the in importance the drug to the Pediatric Geriatric Use. Inand studies of KYPROLIS were no observed in safety Use. The safety effectiveness of there KYPROLIS in clinically pediatricsignificant patients differences have not been established. and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal patients with The normal renal function and and safety those with mild, moderate, and severe Impairment. pharmacokinetics of KYPROLIS were evaluated in a renal Phaseimpairment 2 trial in and patients chronic dialysis. Onand average, patients were treated for usingimpairment KYPROLIS patients with on normal renal function those with mild, moderate, and25.5 cycles severe renal 2 2 doses of 15 mg/m on Cycle 1, 20 mg/m on Cycle 2, and 27 mg/m on Cycles 3 and beyond. and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS 2 The pharmacokinetics safety of KYPROLIS by the renal doses of 15 mg/m2 onand Cycle 1, 20 mg/m2 on were Cyclenot 2, influenced and 27 mg/m on degree Cycles of3 baseline and beyond. impairment, including and the patients dialysis. were Since not dialysis clearance of KYPROLIS concentrations The pharmacokinetics safety ofon KYPROLIS influenced by the degree of baseline renal has not been studied,thethepatients drug should be administered the dialysis procedure [see Clinical impairment, including on dialysis. Since dialysisafter clearance of KYPROLIS concentrations Pharmacology section of PI].should Hepatic efficacyprocedure and pharmacokinetics has not been studied, thefull drug be Impairment. administered The aftersafety, the dialysis [see Clinical of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics offollowing laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper New York Class III and IV heart failure were eligible Impairment. limit of normal Patients (ULN) andwith bilirubin ≥ 2 Heart × ULNAssociation [see Clinical Pharmacology section of full PI].not Cardiac for the clinicalPatients trials. Safety in this population has not been Impairment. with New York Heart Association Classevaluated. III and IV heart failure were not eligible OVERDOSAGE: There is no known specific has antidote for KYPROLIS for the clinical trials. Safety in this population not been evaluated. overdosage. In the event of an overdosage, monitor and specific provide antidote appropriate OVERDOSAGE: Theretheis patient no known for supportive KYPROLIS care. overdosage. In the event of an NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. overdosage, monitor the patient and provide appropriate supportive care. Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. in vitro chromosomal test inconducted peripheralwith bloodcarfilzomib. lymphocytes. Carfilzomib not mutagenic Carcinogenicity studiesaberration have not been Carfilzomib waswas clastogenic in the the chromosomal in vitro bacterial reverse test mutation (Ames) blood test and was not clastogenic thenot in vivo mouse ininvitro aberration in peripheral lymphocytes. Carfilzomibinwas mutagenic micronucleus assay. Fertility studies have not inbeen No inbone the marrow in vitro bacterial reverse mutation (Ames) testwith and carfilzomib was not clastogenic the conducted. in vivo mouse rat and monkey toxicity effects on reproductive tissues were noted during 28‑day repeat‑dose bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity or Pharmacology. studies or in 6‑monthMonkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg 2 experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) bolus intravenous administration carfilzomib ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose experienced hypotension, increasedofheart rate, andatincreased serum levels of troponin‑T. The repeatedin monkeys using dosing schedulesof similar to those clinically resulted that were bolus intravenous administration carfilzomib at ≥used 2 mg/kg/dose in rats inandmortalities 2 mg/kg/dose in due to toxicities occurring in the similar cardiovascular failure, resulted cardiac in fibrosis, pericardial fluid monkeys using dosing schedules to those (cardiac used clinically mortalities that were accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal systems. The dose of 2 mg/kg/dose in rats dysfunction), is approximately the recommended dose in humans (glomerulonephropathy, tubular necrosis, andhalf pulmonary (hemorrhage/inflammation) 2 of 27 mg/m based body surface area.isThe dose of 2 mg/kg/dose in monkeys dose is approximately systems. The dose of 2onmg/kg/dose in rats approximately half the recommended in humans the recommended dosearea. in humans based body surfaceinarea. ofequivalent 27 mg/mto2 based on body surface The dose of on 2 mg/kg/dose monkeys is approximately PATIENT COUNSELING INFORMATION: Discuss the following with patients equivalent to the recommended dose in humans based on body surface area. prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: may cause dizziness, dropofinthe blood Advisepatients patientsthat not KYPROLIS to drive or fever, chills, fatigue, rigors, chest pain, fainting, cough, orand/or swelling feet pressure. or legs. Advise operate machinery they experience of these Advise patients they may experience may cause fatigue, ifdizziness, fainting,any and/or dropsymptoms. in blood pressure. Advisethat patients not to drive or shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within operate machinery if they experience any of these symptoms. Advise patients that they may experience a day of dosing. Advise patients to contact theirwith physicians if they shortness of breath. shortness of breath (dyspnea) during treatment KYPROLIS. Thisexperience most commonly occurs within patientsAdvise to avoid dehydration, since patients receiving KYPROLIS therapy may experience aCounsel day of dosing. patients to contact their physicians if they experience shortness of breath. vomitingpatients and/or to diarrhea. Instruct patients seek medical if they experience symptoms Counsel avoid dehydration, since topatients receivingadvice KYPROLIS therapy may experience of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms contraceptive measures to prevent pregnancy treatment with KYPROLIS. Advise the ofeffective dizziness, lightheadedness, or fainting spells. Counselduring females of reproductive potential to use patient that if she becomes pregnant duringpregnancy treatment,during to contact her physician immediately. Advise effective contraceptive measures to prevent treatment with KYPROLIS. Advise the patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise breastfeeding afterKYPROLIS treatment,treatment advise herwhile to discuss theorappropriate timing her wishes physician. Advise patients not to take pregnant breastfeeding. If awith patient to restart patients to discuss with theiradvise physician medication they are timing currently prior to starting breastfeeding after treatment, her toany discuss the appropriate withtaking her physician. Advise treatment KYPROLIS, or prior to starting new medication(s) during treatment with toKYPROLIS. patients to with discuss with their physician any any medication they are currently taking prior starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 South San Francisco, CA 94080 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

june 2013

bioMérieux) for the detection of BRAF V600E and BRAF V600K mutations. Trametinib (Mekinist tablet) was approved for the treatment of patients with metastatic or unresectable melanoma and the BRAF V600E and BRAF V600K mutation who have not been previously treated with a BRAF inhibitor therapy. The recommended dosage for trametinib is 2 mg orally until disease progression or unacceptable toxicity, to be taken ≥1 hour before or 2 hours after a meal. The FDA’s approval of trametinib was based on a demonstrated improvement in progression-free survival (PFS) in a multicenter, international, open-label, active-controlled trial with 322 patients with stage IIIc or stage IV melanoma with either BRAF V600E and BRAF V600K mutation. Patients with >1 previous chemotherapy regimen or those who received BRAF or MEK inhibitors were excluded from the trial. The patients were randomized in a 2:1 ratio to oral trametinib 2 mg daily or to intravenous chemotherapy with dacarbazine or paclitaxel every 3 weeks. Overall, 51 (47%) patients in the chemotherapy arm received trametinib at the time of disease progression. The median PFS was 4.8 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.34-0.65; P <.001). Objective response rates were 22% with trametinib and 8% with chemotherapy. Data for OS were not mature. In a single-arm trial of 40 patients with unresectable or metastatic melanoma and BRAF V600E or BRAF V600K mutation who had received previous BRAF inhibition therapy, the administration of trametinib showed no evidence of antitumor activity (ie, no response) in these patients. The most common (≥20) adverse events (AEs) reported with trametinib were rash, diarrhea, and lymphedema. Serious AEs included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin reactions. Dabrafenib (Tafinlar capsule) was approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. Dabrafenib is not approved for patients with the wild-type melanoma (ie, without BRAF mutation); in those patients it could potentially lead to tumor promotion. The recommended dosage is 150 mg twice daily until disease progression or until unacceptable toxicity. Continued on page 24

www.ValueBasedCancerCare.com

3rd Conference

The Cost of Cancer Care: We Must Incorporate Value and Quality of Life into the Mix An expert’s perspective on the conundrum of curing cancer By Caroline Helwick Hollywood, FL—The cost of cancer care or cancer cure means different things to different stakeholders. Finding a consistent definition may be impossible, but in today’s environment “it is probably unfair to focus on costs without incorporating value,” said John E. Hennessy, MBA, CMPE, Vice President, Operations Midwest Division Oncology, Sarah Cannon Cancer Center, Nashville, TN, who spoke at the Third Annual Conference of the Association for Value-Based Cancer Care. The types of costs in cancer care include: • Direct (“per-click”) costs • Indirect costs that are part of “the package” • Opportunity costs (the beyond-thebill impact) • Hard currency costs for patients mean out-of-pocket costs • Quality-of-life or productivity costs for drugs, diagnostics, and radiation. The Cost of Drugs Drug costs are almost always direct costs, and they are almost always “reimbursed on a line-item basis.” The direct cost of drugs is highly variable in a system in which there are many effective generics; “teaching old dogs new tricks”; and highly focused, targeted, expensive agents—$6000, $8000, $12,000, or even $20,000 monthly. These new agents are very effective in

at a glance ➤ Drug costs are often driven by patent expirations and research rather than value ➤ Indirect costs of drugs can be substantial, including unwanted side effects ➤ Diagnostics costs can add unnecessary spending, but diagnostics can be cost-saving ➤ Radiotherapy direct costs are rising, but are variable ➤ Quality-of-life costs are often not addressed, or are addressed via pathways ➤ It is difficult to speak with patients with cancer about cost, but discussions are needed and must include value and qualityof-life issues

“In a market where people aren’t able to choose freely among drugs, or to have perfect information, you get an imperfect market, and you get prices that are out of control.” —John E. Hennessy, MBA, CMPE

a small subset of patients, but are therefore very expensive. Costs are often driven by drug patent expirations and research rather than value, Mr Hennessy said. “In a market where people aren’t able to choose freely among drugs, or to have perfect information, you get an imperfect market, and you get prices that are out of control,” he said. The indirect costs of drugs can also be substantial, incorporating the unwanted consequences of treatment, such as toxicities, and the need for staff support to keep patients on protocol. Opportunity costs are part of drug delivery as well. When one treatment option is chosen, another may be eliminated or delayed. When a new treatment is introduced, an old option is often being ignored, as less effective. For example, failing to initiate neoadjuvant chemotherapy may lead to a loss of opportunity for a pathologic complete response before surgery, and clinical trial opportunities may be limited by previous treatments. “Premium costs are impacted by drug costs,” Mr Hennessy said, noting that Missouri has an oral chemotherapy parity law, but the business com-

Value-Based Cancer Care

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munity there fought against it, to keep insurance costs down by maintaining high copayments. Reinsurance issues may become part of this drug cost component, as the Affordable Care Act caps maximum out-of-pocket costs and reinsurance companies are brought in to off-source the commercial payers’ losses. “Out-of-pocket costs are obviously substantial,” Mr Hennessy said. Although patients are shielded from the 100% of the cost of the drug, they are not shielded from the 20% of the cost. “Oral chemotherapy parity…is also beginning to shield patients in certain states from these costs,” and industry-supported patient assistance programs are also shielding patients from the cost of the drug. But copayment can be very substantial, and many patients with cancer cannot afford it: “20% of forever for a Medi care patient is really a big deal,” he emphasized. Finally, quality-of-life costs related to drugs—primarily side effects—are addressed rarely, and if addressed, it is done so “indirectly, with pathways.” According to Mr Hennessy, “common” side effects “are not so common to patients,” who suffer losses in productivity and capabilities. Incorporat ing quality-of-life costs into the economic analysis is a challenge, not only to society at large but also to providers, who must spend time dealing with these issues, and are largely uncompensated for this. Diagnostics Cost For diagnostics, “we have a lot of new tools, and we are challenged with establishing their clinical value,” Mr Hennessy said. “The challenge is that we are an ‘action society’: I see something, I want it.” But some have asked, “are we treating the findings rather than the disease?” Are we getting real value from our very sophisticated diagnostic tools? Do we know what to do with the findings? Questions to be answered include what is the right tool, the right time, and the right frequency of use? What is the tool’s relative value in screening, diagnostics, and surveillance? These settings require different approaches to utility and cost, he said, adding that “with broad swaths can come unexpected consequences.” The indirect costs of diagnostics

largely pertain to determining the tests’ clinical values. Diagnostics that lack clinical meaningfulness contribute to unnecessary spending; however, diagnostic testing also saves money when it enhances timely diagnosis, determines disease stage, and guides treatment. Newer diagnostics may be bundled with their related procedures. Out-of-pocket costs related to diagnostics continue to be problematic for patients, who may be unable to afford the recommended surveillance and monitoring. Quality-of-life costs remain ill-defined for diagnostics; however, “when we find something, we do something,” and therefore, side effects will accompany these interventions, Mr Hennessy emphasized. Radiation Costs The direct costs of radiotherapy are rising, whereas the number of fractions delivered is dropping, and with a variety of modalities in use, costs are variable. Bundling and case rates could be on the horizon. Modalities that deliver radiation more precisely have limited the indirect costs of radiotherapy, although the risk of secondary cancers resulting from earlier radiation exposure remains a concern. Indirect costs, or lack of incremental revenue, may stifle innovation or may limit treatment options, he suggested. Newer targeted technologies may be creating new opportunity costs, because their value is largely unclear. “The challenge is that, once a physician has a particular machine, there’s a slot available for the next patient,” Mr Hennessy remarked. Premium and out-of-pocket costs are not much of an issue with radiotherapy; however, third parties continue to try to manage this area. Qualityof-life costs, by contrast, are significant. “You’ll be alive, but lose the ability to taste and smell,” he commented. Value In closing, Mr Hennessey maintained that “value” must be part of the conversation regarding costs, although the translation of cost into value and utility remains challenging. “Although it may be hard to engage patients in a cost discussion,” he said, “it may be appropriate to have a value discussion. Somewhere down the line, the rubber will meet the road.” n

Vol. 4

No. 5

3rd Conference

Oncology Practices Need to Transform the Way They Deliver Cancer Care By Caroline Helwick

Hollywood, FL—Oncology practices need to transform the way they deliver cancer care, said John D. Sprandio, MD, FACP, Chief of Oncology at Delaware County Memorial Hospital in Drexel Hill, PA, and Medical Director of ION Solutions. “According to Darwin, it’s not the strongest of a species that survives; the species that survives is the one that is adaptable to change,” Dr Sprandio said. “Practices and programs need to plan their response.” Dr Sprandio, who is also an oncology management consultant, shared his viewpoints at the Third Annual Conference of the Association for Value-Based Cancer Care. “The fundamental question not being adequately addressed,” he pointed out, “is, ‘How is care best delivered? What are the best settings, best processes, and plan of care? The challenge is how to consistently deliver care.” Dr Sprandio pointed to 6 oncologypractice–related categories in which money is wasted: delivery, coordination, overutilization, pricing, administrative burden, and fraud. Half of these are areas in which physicians can have an impact. The magnitude of the cost issue has created a “market demand for better value,” with legislative pressures now being felt as well, he noted. The Doctor–Patient Relationship Is Central Dr Sprandio’s practice “got on the path” 10 years ago, he said, based on a 2007 white paper advocating physician engagement as an essential means of driving quality. That paper highlighted the centrality of the doctor– patient relationship by emphasizing: • Clinical interaction that defines healthcare (eg, explanation, prediction, plan of care) • Physicians have broadest scope of professional jurisdiction (ie, drive the provision of goods and services) • Patient experience is based on oneon-one relationships • Physicians are the portal to the rest of the system (ie, referrals, education, interpretation of insurance benefits) • Physicians face barriers on their way to becoming accountable for quality and the consistency of the care that they deliver. Physicians face numerous barriers to quality that are essentially “time stealers,” he said. But these can be tackled

Vol. 4

No. 5

when the work environment is designed in a way that is standardized, simplified, clinically relevant, and engaging for patients, and that fixes accountability at the locus of control. “We followed the paper’s advice and started streamlining processes of care, making everything our physicians touched clinically relevant. We tackled this with full implementation of the oncology-specific electronic medical record that contained a software overlay that gave us real-time information,” Dr Sprandio said.

Table 1 Patient- and Payer-Centered Outcomes Measures Patient experience

•Agency for Healthcare Research and Quality: Consumer Assessment of Healthcare Providers and Systems Outcomes

• Staging compliance • Chemotherapy guideline adherence • Emergency department evaluations • Hospital admissions/length of stay • Outpatient visit reduction • End-of-life care parameters • Diagnostics: imaging and laboratory

Table 2 Self-Instructional Guide for Practices and Cancer Programs Instructions and materials helping oncology practices meet the challenge of quality and value Self-guided website

• Written material, audio support, supporting documents and resources Tools to ease implementation

• To-do list –Track completed and open tasks –Assign tasks to a user in your practice

• Resource library –Move documents to your resource library –Save for later, print, or fill out online

“Improving delivery and reducing utilization are different sides of the same coin. Physicians need help in these.” —John D. Sprandio, MD, FACP Oncology in the Era of Healthcare Reform “The era of healthcare reform followed this, and now it’s all about quality and cost,” Dr Sprandio said. “But where does cancer care fit into healthcare reform?” The foundation of the patient-centered medical home (PCMH) and accountable care organizations (ACOs) is primary care. There is virtually no mention of cancer care in ACO discussions, he pointed out. “Complex care outside the scope of primary care requires delegation to specialists. How does the primary PCMH or ACO manage the rising cost of cancer care if management is transferred to oncology? They need to rely on those delivering the care.” Provider Accountability “The government can write legislation to encourage behavior, but it can-

• Interactive assistance –Implementation experts available

Workshop-based coaching; optional consulting not mandate it,” he said. “The people delivering the care must step up and change it.” Failure to control cancer costs (by reducing waste) will result in further funding cuts and will have unintended clinical consequences for the most vulnerable: reduced access, increased copays, and reduced compliance, Dr Sprandio predicted. “Improving delivery and reducing utilization are different sides of the same coin,” he said. “Physicians need help in these.” To this end, chemotherapy guidelines and pathways are partially helpful; anything that standardizes care is good, Dr Sprandio said. But the oncology PCMH pertains to delivery beyond chemotherapy drug selection, and requires practice transformation. “We delivered an oncology PCMH model focusing on the delivery of care beyond chemotherapy,” Dr Sprandio remarked. “We made a business case for quality by focus on controlling cost and improving value.” The “intertwined” components of his oncology PCMH include pretreatment services, active treatment, survi-

june 2013

vorship, palliative care, and end-of-life care. His group is prepared for future payment models and for the need to interact with other systems that adopt new organizational structures, such as ACOs, and hospital system and payer hybrids. The PCMH embraces processes that drive patient- and payer-centered outcome measures (Table 1), which are measured in real time and are presented to the physicians in his practice. “Our internal data show that we reduced emergency room use by 68% since 2007, and reduced hospital admission rates from 1.1 per year to 0.5 per chemotherapy patient,” he reported. Dr Sprandio’s practice has taken a “scalable approach” and has created a self-instructional guide for practices and cancer programs (Table 2). The PCMH’s components pertain to building payer value, building practice value, and to enhancing patient value. Users can select only the modules they need. It provides “consulting expertise at a fraction of the cost” and is “the most efficient way to build practice quality and value,” Dr Sprandio maintained. n

www.ValueBasedCancerCare.com

3rd Conference

The Changing Landscape of Oncology

Value-based perspectives from a community oncologist and the head of the NCCN By Caroline Helwick Hollywood, FL—At the Third Annual Conference of the Association for Value-Based Cancer Care, 2 oncologists representing opposite corners of the oncology care landscape discussed the current trends in the delivery of patient care, and the challenges that are facing oncologists. Robert W. Carlson, MD, the new Chief Executive Officer of the National Comprehensive Cancer Network (NCCN), called the new delivery models and processes in oncology “the tip of the iceberg.” “Oncology care is changing,” Dr Carlson said. The healthcare system has been struggling to institute Medicaid expansion, accountable care organizations (ACOs), medical homes, and bundled/episode-of-care payments, but things are about to get really interesting, he predicted. “Health exchanges, or ‘marketplaces,’ will go live October 1. We are shifting the conversation, because in the next 8 months millions of individuals will be newly insured,” Dr Carlson noted. He predicted that the private sector will drive the model “that ultimately works,” and the government will “hop in after the brain damage is suffered.” How Will Health Exchanges Change the Picture? Health exchanges (or marketplaces) must be established in each state by January 2014. Currently, there are 17 state-based (plus Washington, DC) exchanges, with 26 states defaulting to the federal exchange program, and

Dr McAneny said that, in her area, support services are embedded within the physician’s offices, and as such there is the opportunity for “teachable moments.” “It will take a significant amount of patient education,” she said. “We are going to use our medical home project to work with federally qualified health services to manage patients.”

“A lot of these cancer patients have been receiving care but have not been able to select where they got that care. There is a big population who previously had to pick state-based institutions, and they can now…walk into my office to find the best value.” —Barbara L. McAneny, MD 7 states planning for a partnership exchange. “The exchanges are pretty much rolling along. A lot of rules are in place regarding central health benefits, which drugs are required to be provided, and network adequacy within the plans, with bronze, silver, platinum, and gold levels of risk. But one of the challenging issues,” Dr Carlson added, “will be explaining these to naïve insurance purchasers.” From the community oncology practice perspective, Barbara L. McAneny, MD, Chief Executive Officer and Managing Partner of the New Mexico Cancer Center, Albuquerque, suggested that business will be brisk at first, because the newly insured are a population with “a pent-up demand”; how-

Table Potential Cost-Savings from Medical Homes Study

Group Health Cooperative of Puget Sound, 12 mo

Community Care of North Carolina HealthPartners Medical Group BestCare PCMH, 5 yrs

Genesee Health Plan HealthWorks PCMH, 4 yrs

Johns Hopkins Guided Care, 12 mo

Geisinger Health System ProvenHealth Navigator

Intermountain Healthcare Medical Group PCMH

Emergency Inpatient Patient types department visits admissions All patients

–29%

–11%

Asthma

–16%

–40%

All patients

–39%

–24%

All patients

–50%

–15%

Chronic disease

–15%

–24%

—

–14%

All patients

—

–10%

Chronic disease

PCMH indicates patient-centered medical home.

Value-Based Cancer Care

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ever, “data show that after this point, things will stabilize.” “A lot of these cancer patients have been receiving care but have not been able to select where they got that care,” Dr McAneny pointed out. “There is a big population who previously had to pick state-based institutions, and they can now shop with their feet and walk into my office to find the best value.” Addressing how NCCN member institutions are dealing with the coming health exchanges, Dr Carlson noted that these cancer centers will have to adhere to the processes put in place within their own states, although this could get more complicated when organizations cross state lines. “The Affordable Care Act has the risk of actually increasing, not decreasing, the variability of care in the United States,” Dr Carlson proposed. Dr McAneny agreed, and noted that her practice has been approached by local payers “using this as a way to lock in market share by signing up physicians at low-cost Medicare levels.” States that do not accept Medicaid expansion will have tremendous gaps in access to care, they both noted. How Will Changes Be Communicated? NCCN members are developing systems to handle the “huge bolus of patients arriving at their doors,” Dr Carlson said. One problem with communication could be access to patients. “Traditionally, the uninsured or marginally insured populations are difficult to get in contact with, and the typical systems we have as a society don’t work well with these groups.”

Accountable Care Organizations Along with health exchanges, the oncology landscape should see the ramping up of cancer-specific ACOs, which have formed in many states. But there are no specialty ACOs within Medicare (which services 60% of the country’s patients with cancer), so this will be driven by the options offered within health exchanges, Dr Carlson pointed out.

“It’s not going to be possible to have increased personalization of medicine at the expense of increased cost, so the big question is when and how the transformation in drug pricing will happen. The way we pay for drugs in oncology must change.” —Robert W. Carlson, MD

He maintained that academic centers may be most suitable to the ACO model. “They are already organized in an ACO-like structure,” Dr Carlson pointed out, “but this is counterbalanced by challenges that are different from community practices.” These challenges include the comContinued on page 22

Vol. 4

No. 5

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. 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 • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide

were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044a

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The Changing Landscape of Oncology... peting priorities of patient care, service, teaching, training, and research. “This fragments to some extent how each individual provider within these centers cares for patients,” and potentially compromises the continuum of care, Dr Carlson said. “At the end of

the day, however, they will have to participate. The days of fee for service and buy and bill are almost over.” By contrast, Dr McAneny has experience partnering with an ACO as a community oncology medical home (see article on the cover). She noted

Continued from page 18

that the cost-savings with this model have already emerged. Although the Centers for Medicare & Medicaid Services have attempted a variety of projects, she said, most have been based within large integrated health systems of hospitals and have

not shown cost-savings—“until now, with the medical home projects” (Table, page 18). Transformation Is Happening With regard to payment and quality in oncology care, Dr Carlson said, “We

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This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily. 500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

Value-Based Cancer Care

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. Cosmos Communications

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.

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are in a time of transition, and the timeline is short. Transformation is more likely than transition. We will see consolidation, because it’s hard for a single physician to impact quality. This means multiple physicians and multiple components in your office

practice working in harmony.” Dr Carlson predicted that bundled payments “are our future,” and considers this a positive change. “Bundled payments have the opportunity to realign the incentives for the patient, the provider, and the payer, but if, and

only if, they are bundled with quality metrics to assure that the cost-savings are not achieved by sacrificing quality of care.” Transformation in terms of drug pricing, however, is less predictable, he added. “It’s not going to be possible

to have increased personalization of medicine at the expense of increased cost,” Dr Carlson commented, “so the big question is when and how the transformation in drug pricing will happen. The way we pay for drugs in oncology must change.” n

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(continued)

Vol. 4

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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FDA Update Mekinist and Dabrafenib... Continued from page 15

Dabrafenib should be taken ≥1 hour before or 2 hours after a meal. The presence of BRAF V600E mutation must be confirmed before prescribing dabrafenib, which could potentially promote tumor growth in patients with wild-type melanoma. The approval was based on a multi-

center, international, open-label, randomized, active-controlled trial of 250 patients with treatment-naïve unresectable stage III or stage IV melanoma. A total of 28 patients in the dacarbazine arm received dabrafenib when their disease progressed. The median PFS was 5.1 months with dabrafenib versus 2.7 months in the dacarbazine arm (HR, 0.33; 95%

CI, 0.20-0.54; P <.001). The objective response rates were 52% with da brafenib, which included 3% complete response, versus 17% with dacarbazine (P <.001). The median response duration was approximately 5 months in both arms. OS was not significantly different. The most common (≥20%) AEs with dabrafenib included hyperkeratosis, T:7”

Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Serious AEs involved new primary skin cancer, including cutaneous squamous-cell carcinoma, new primary melanoma, and keratoacanthomas; febrile drug reactions requiring hospitalization; hyperglycemia; and uveitis/ iritis. Dabrafenib was approved with a

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea General disorders and administration site conditions

Cardiac Disorders

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n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications K

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Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

FDA Update medication guide informing patients of these serious risks. (May 29, 2013)

SGX942 Receives Fast Track Designation for Oral Mucositis

The FDA has granted a fast track designation for the development of SGX942 (Soligenix) for the treatment of oral mucositis associated with radi-

ation and/or chemotherapy used in patients with head and neck cancer. SGX942 is a fully synthetic, 5-amino acid peptide with high aqueous solubility and stability. Extensive in vivo preclinical studies have demonstrated a significant reduction in tissue damage associated with chemotherapy, radiation, trauma, and inflammation. (June 2, 2013)

Lenalidomide Receives New Indication for MantleCell Lymphoma

The FDA approved lenalidomide capsules (Revlimid; Celgene Cor poration) for the treatment of patients with mantle-cell lymphoma whose disease has relapsed or progressed after 2 previous therapies, one of which included bortezomib (Velcade).

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

Lenalidomide is already approved for multiple myeloma (as is bortezomib). The FDA approved the new indication for lenalidomide based a single-arm, multicenter clinical trial of 134 patients (median age, 67 years) with mantle-cell lymphoma. All of the patients previously received treatment with bortezomib, and 60% of the 134 patients had disease that was refractory to bortezomib therapy. Overall, the patients received a median of 4 previous therapies for mantle-cell lymphoma; 61% of the patients had mantle-cell lymphoma for at least 3 years. The efficacy end points were overall response rate (ORR) and duration of response. The ORR was defined as the proportion of patients whose best response was complete response (CR), CR unconfirmed, or partial response (PR). The ORR was 26% (95% confidence interval [CI], 18.4-33.9) among the 133 evaluable patients, CR or CR unconfirmed was achieved by 9 (7%) patients, and 25 (19%) patients achieved a PR. The median duration of response of the patients who achieved any response was 16.6 months (95% CI, 7.7-26.7). The median duration of therapy was 95 days, and 58% of the patients received ≥3 cycles of therapy. Overall, 19% of the patients discontinued treatment because of adverse events. The most common (≥5%) grade 3 to 4 adverse reactions were neutropenia, thrombocytopenia, anemia, pneumonia, leukopenia, fatigue, febrile neutropenia, dyspnea, and diarrhea. The recommended oral dose and schedule for lenalidomide is 25 mg once daily on day 1 through day 21 of a 28-day cycle. Lenalidomide should be taken at approximately the same time daily, with no regard to food. In addition, as part of this new supplemental indication, the FDA also approved a new 20-mg capsule strength of lenalidomide. (June 5, 2013)

FDA Requests More Data for Tivozanib

The FDA denied the approval of a New Drug Application for tivozanib, which was submitted by its manu facturer (Aveo Pharmaceuticals/ Astellas), for the treatment of renal-cell carcinoma. In its Complete Response letter to the company, the FDA noted that the survival results from the TIVO-1 clinical trial were inconsistent, which made the results “uninterpretable and inconclusive.” The FDA requested that the company provide new survival data from new clinical trials. Tivozanib is currently in phase 2 clinical trials for the treatment of colo rectal cancer. (June 10, 2013) n

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ASCO Annual Meeting

Variations in Cancer Treatment Raise Average Cost... reviews treatment plans for commercial payers. For this study, treatment plans for all cancer types were reviewed from March 2009 to March 2012 for adherence to national guideline recommendations. The cost difference between the proposed treatment and the expected treatment (when the treatment was nonadherent or not a medically justified deviation) was calculated. For prospective reviews, “we had discussions with oncologists to see if there was some patient-specific factor

to justify a deviation. If that wasn’t the case, if in our conversation with the doctor the treatment was changed to a recommended drug, we calculated the exact cost related to what the doctor initially wanted to do versus what they changed the treatment to,” Dr Forastiere observed. In retrospective situations in which no justification for a treatment could be identified, the lowest-cost evidence-based treatment that yielded a comparable outcome was used as the comparator. Average wholesale pricing was used for chemotherapy and for supportive drugs. Medicare pricing was used for radiation therapy. Some of the major deviations in drug use were growth factor overutilization (in particular, the overuse of white blood cell growth factor), the use of combination therapies that have not been shown to be beneficial or indicated, more cycles of chemotherapy than are recommended in an adjuvant setting, and the use of drugs that are not approved for a particular indication, according to Dr Forastiere. For radiation, the overutilization of technologies, such as image-guided radiation or intensity-modulated radiation, could qualify as deviations. Of the 2544 patients included in

at a glance ➤ In this study, more than 25% of patients had treatment plans that did not conform to evidence-based cancer care ➤ Inappropriate deviations from the standards of care for cancer costs >$25,000 per patient ➤ Overspending can bear >$13 million in cost of chemotherapy or radiation therapy for cancer ➤ Decision support tools that are used at the point of care can help avoid overspending

“If you consider that 1 in 4 [patients] is likely getting some treatment that is inappropriate, multiply that by $25,000, and you’re talking about billions of dollars. That $25,000 is a very conservative number, because it’s just first-order savings.” —Arlene A. Forastiere, MD

this analysis, 730 (28.7%) had “unjustified” non–evidence-based treatment plans. The mean per-patient excess cost for unjustified deviations was $25,579. With an expected annual incidence of 2500 new cancer cases per 1 million commercially insured lives, 1875 patients would receive chemotherapy or radiation therapy as part of their treatment. With a 28.7% rate of inappropriate deviations from evidence-based standards of care, 538 patients would receive treatment outside of these standards, and the overspending in this group would be >$13 million, based on a $25,000 cost per patient, according to Dr Forastiere. She concluded, “Another way of looking at it, which is even more striking, is that we know that there are 1.6 million new cases of cancer diagnosed per year in the [United States] currently. If you consider that 1 in 4 [patients] is likely getting some treatment that is inappropriate, multiply that by $25,000, and you’re talking about billions of dollars. That $25,000 is a very conservative number, because it’s just first-order savings. It doesn’t include hospitalizations as a result of overtreatment or complications.” n

Pazopanib: First Positive Maintenance Trial in Ovarian...

to angiogenesis inhibitors: hypertension, elevated liver enzymes, neutropenia, and diarrhea.

were randomized in a 1:1 ratio to receive 800 mg of pazopanib orally once daily or placebo for up to 2 years after

“Pazopanib maintenance therapy prolongs the time the patient has control over the disease versus the time the disease controls the patient’s life. Pazopanib might be a valuable option for treatment of stages II to IV ovarian cancer.”

Photo by © ASCO/Scott Morgan 2013

control over the disease versus the time the disease controls the patient’s life. Pazopanib might be a valuable option for treatment of stages II to IV ovarian cancer,” stated lead investigator Andreas Du Bois, MD, Director, Department of Gynecology and Gy necologic Oncology, at Kliniken Essen Mitte, Germany. Although patients with ovarian cancer typically respond to initial therapy with surgery and chemotherapy, the relapse rate is approximately 75%. The rationale for maintenance therapy is to keep patients in remission, but results of studies to date have been disappointing. Given the cost and the added toxicity of maintenance therapy, demonstrating improved survival with an agent is important. Pazopanib is an oral multikinase inhibitor that is approved by the US Food and Drug Administration for the treatment of renal-cell carcinoma and soft-tissue sarcoma. Medication side effects reported in the current trial were class-specific

—Andreas Du Bois, MD

Most Patients Had Advanced Disease This phase 3 multicenter trial included 940 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers. Trial eligibility criteria included stage II to IV disease, but most patients had stage III or IV ovarian cancer. Participants

Value-Based Cancer Care

JUNE 2013

standard surgery and chemotherapy. The median time to disease progression was 17.9 months for the paz opanib group compared with 12.3 months for the placebo group, representing a 5.6-month advantage for patients receiving the targeted therapy, for a 24% reduction in the risk of recurrence or of death.

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At 24 months, however, no significant difference in overall survival was observed. Longer follow-up is needed to see if there is an overall survival benefit. “There is currently no standard of care for maintenance therapy. Evidence continues to mount that targeting angiogenesis is important in ovarian cancer. The bottom line from several studies is that targeting angiogenesis is effective in ovarian cancer. These results show that pazopanib extends PFS as maintenance therapy, similar to the results of previous trials of bevacizumab,” said Carol Aghajanian, MD, Chief, Gynecologic Medical Oncology Service, Memorial SloanKettering Cancer Center, New York. “This large trial shows us that targeting multiple molecular cancer drivers can have a substantial impact on this cancer’s ability to grow,” Dr Aghajanian said. “This study offers a real-world example of how the precision medicine era of cancer research is paying off in areas where no alternate approved drugs exist.” n

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ASCO Annual Meeting

FDA Expected to Approve Surrogate End Point for Neoadjuvant Breast Cancer Trials at a glance New guidance for manufacturers should accelerate drug approvals Chicago, IL—For years, the cancer research community has pushed for the use of surrogate end points in clinical trials as a means of hastening the drug approval process. These efforts will soon bear fruit, with the anticipated release by the US Food and Drug Administration (FDA) of its final guidance to drug manufacturers for accelerated drug approval for neoadjuvant breast cancer therapies. At the 2013 American Society of Clinical Oncology (ASCO) annual meeting, the speakers discussed the potential implications for researchers, providers, and patients. Under the new guidance for the pharmaceutical industry, accelerated approval could be granted based on a surrogate end point that predicts for clinical benefit; such an approval would require subsequent confirmation in a clinical trial. For neoadjuvant breast cancer, this end point would likely be pathologic complete response (pCR) rate. Although achieving a pCR has been associated with superior outcomes in multiple studies, the correlation needs further validation, said Tatiana M. Prowell, MD, Breast Cancer Scientific Lead, Breast Oncology Group, FDA, and Assistant Professor of Oncology, Johns Hopkins, Baltimore, MD. It is expected that pCR will be the surrogate end point in this setting, but other outcomes have been studied in patients with breast cancer, including tumor response on imaging, measurement of the tumor proliferation marker Ki-67, preoperative endocrine prognostic index, and residual cancer burden after treatment.

Photo by © ASCO/Rodney White 2013

By Caroline Helwick

Moving clinical trials from adjuvant to the neoadjuvant setting can yield important information about drugs that are under evaluation and should identify active agents faster, which serves patients. —Angela DeMichele, MD, MSCE Faster Drug Approval to Most Benefit High-Risk Patients The traditional drug approval process averages 10 to 15 years. The goal of accelerated approval is to provide early access to effective drugs and to provide incentives for developing drugs for particular breast cancer subtypes with unmet needs. Under the new approval process, a single trial or a short-duration trial would be appropriate for accelerated approval, and a simultaneous longer trial would be conducted to support “regular” approval, according to speakers at a session at the ASCO meeting entitled “Pushing the Limits of Upfront Care and Drug Devel opment: Neoadjuvant Opportuni ties in Breast Cancer.” The use of pCR to support accelerated approval is appropriate “for highly promising drugs and high-risk patient

populations,” Dr Prowell maintained. Session Chair Angela DeMichele, MD, MSCE, Co-Program Leader, Breast Cancer Program, Abramson Cancer Center, University of Penn sylvania, Philadelphia, noted that there is a “fertile environment” for new drug development in the neoadjuvant breast cancer treatment setting, because the many benefits of neoadjuvant therapy are now established. Moving clinical trials from adjuvant to the neoadjuvant setting can yield important information about drugs that are under evaluation, such as the ability of pharmacodynamic markers to provide in vivo evidence of biologic effects. But most important, this should identify active agents faster, which serves patients, Dr DeMichele said. She emphasized that surrogate markers must be robust (ie, reproducible and standardized), and their correlation

➤ Under the new FDA guidance, accelerated drug approval in the neoadjuvant breast cancer setting could be granted based on a surrogate end point that predicts clinical benefit ➤ Accelerated approval would require subsequent confirmation in a clinical trial ➤ Early approval provides access to effective drugs and incentives for developing drugs for breast cancer subtypes with unmet needs ➤ For patients with neoadjuvant breast cancer, the end point is likely pathologic complete response rate, which is appropriate for very promising drugs and high-risk patients with the true end point, such as overall survival, must be more than a simple “correlation.” In this case, pCR must be strictly defined as the elimination of all invasive and noninvasive disease in the breast and lymph nodes, rather than a “looser” definition. Its relationship with the final end point can only be assured through long-term follow-up of patients, Dr DeMichele added. She also proposed that pCR may not be a valid surrogate end point for every breast cancer. Although it may be appropriate for HER2-positive, triple-negative, and highly proliferative estrogen receptor (ER)-positive disease, it may not be a good surrogate for low-proliferation ER-positive tumors. At present, Dr DeMichele believes that Ki-67 is the best surrogate for the latter, although it is not perfect. Better surrogates are needed for this subset, she noted. n

Bevacizumab an Effective New Treatment Option for Relapsed Cervical Cancer First targeted therapy to prolong survival in this setting By Wayne Kuznar Chicago, IL—Adding bevacizumab (Avastin) to standard chemotherapy improves overall survival (OS) in women with metastatic or relapsed cervical cancer, representing the first instance in which a targeted therapy has significantly prolonged OS in this

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patient population. This phase 3 randomized clinical trial showed a near 4-month improvement in survival by adding bevacizumab to either paclitaxel (Taxol) plus cisplatin (Platinol) or to paclitaxel plus topotecan (Hycamtin), said Krishnansu S. Tewari,

MD, Professor of Obstetrics and Gynecology, University of Cali fornia, Irvine, at the 2013 American Society of Clinical Oncology annual meeting. Few options currently exist for women with relapsed cervical cancer. Cisplatin plus paclitaxel is the standard of care, but it extends survival by ≤12 months. Acquired drug resistance

JUNE 2013

to cisplatin plus paclitaxel or to platinum-based chemoradiation renders these treatments less effective for recurrence, leading to poor outcomes, said Dr Tewari. Because angiogenesis appears to play an active role in cervical carcinogenesis and its progression, an antian-

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Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment benefits in clinical trials.2,3 Use of a PRO instrument can evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. Incorporating PROs into a clinical trial program provides a means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make betterinformed decisions.4

Myelofibrosis (MF) is a life-threatening, progressive disease characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, double-blind placebo-controlled study, COMFORT-I, for Jakafi. Spleen reduction, as measured by imaging (MRI or CT), was the primary and biologic endpoint, and a reduction in total symptom score (TSS), the PRO measure, was a key secondary endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

0 -20 -40

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IMPROVEMENT

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Change From Baseline (%)

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Upper 50th Percentile

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PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials. 3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901. 6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

In the Literature has been shown to improve outcomes in patients with recurrent disease. The benefit of rituximab (Rituxan) mainThe majority of patients with follicu- tenance has been shown in patients lar lymphoma will relapse after initial with relapsed follicular lymphoma 1INC007response JK0 BS 12P_Layout 1 11/16/11 9:16 AMchePage 1 in the first-line and salvage settings to therapy. A high-dose motherapy and autologous stem-cell but not in the setting of second-line transplantation (HDC-ASCT) strategy maintenance after HDC-ASCT. The

Rituximab Maintenance Prolongs PFS in Patients with Relapsed Lymphoma

first randomized study has now investigated the role of rituximab as a purging agent before collecting the stem-cell product and as post-ASCT maintenance therapy (Pettengell R, et al. J Clin Oncol. 2013;31:1624-1630). Between October 1999 and April 2006, 280 patients with relapsed fol-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). a Reactions Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

licular lymphoma who achieved complete remission (CR) or very good partial remission (VGPR) were enrolled in the European Group for Blood and Marrow Transplantation Lymphoma 1 trial. (The trial was stopped early because of slow recruitment.) Patients were randomized in a 2 × 2 factorial design to rituximab purging versus no rituximab purging, and to rituximab maintenance versus no rituximab maintenance. The randomization was stratified by CR versus VGPR and by number of remissions. The primary end point was progression-free survival (PFS). After reinduction chemotherapy, 30% of the patients had a CR and 70% had a VGPR. In vivo purging with rituximab had no effect on PFS at 10 years. By contrast, rituximab maintenance had a significant impact on PFS: at 10 years, the PFS rate for rituximab maintenance was 54% versus only 37% without rituximab maintenance. No impact on overall survival (OS) was seen in any of the groups. This study shows for the first time the benefit and safety of rituximab maintenance for up to 8 months after HDC-ASCT in prolonging patients’ PFS.

Crizotinib Superior to Standard Chemotherapy in Patients with ALK-Positive Lung Cancer

Crizotinib (Xalkori), an inhibitor of the anaplastic lymphoma kinase (ALK) gene, has shown significant response rates in patients with advanced non– small-cell lung cancer (NSCLC) and the ALK rearrangement. One study in patients with ALK-positive advanced NSCLC showed a 60% objective response rate and a median PFS of 8.1 months with crizotinib; in a second study, the PFS was 9.7 months with crizotinib. A new study compared the response rates of crizotinib versus standard chemotherapy in patients with ALK-positive advanced NSCLC (Shaw AT, et al. N Engl J Med. 2013 Jun 1 [Epub ahead of print]). This phase 3, open-label clinical trial included 374 patients with locally advanced or metastatic ALK-positive NSCLC who had previously received 1 platinum-based regimen. The patients were randomized in a 1:1 ratio to oral crizotinib 250 mg twice daily or to intravenous chemotherapy with pemetrexed (Alimta) 500 mg/m2 of body surface area or with docetaxel (Taxotere) 75 mg/m2 every 3 weeks. Patients receiving chemotherapy whose disease progressed were allowed to cross over to receive crizotinib as a separate study. The primary end point was PFS. Patients were Continued on page 34

Value-Based Cancer Care

june 2013

Vol. 4

No. 5

ASCO Annual Meeting

Sorafenib Effective in Metastatic Differentiated Thyroid Cancer By Audrey Andrews

DTC is the most common subtype of thyroid cancer, and its incidence is rising. DTC is rarely fatal, although up to 15% of patients become resistant to the current standard of care, radioactive iodine, and can die from the malignancy. For this group, there has never been an effective treatment, said Marcia S. Brose, MD, PhD, Assistant Professor of Otorhinolaryngology, Head and Neck Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “We have had no effective drugs for these patients for many years, so it is very exciting to have an oral drug that halts cancer growth for several months,” Dr Brose said at a press briefing. “This is the first time we have had a systemic treatment that can help them.”

at a glance ➤ Sorafenib is effective for the treatment of differentiated thyroid cancer that has become resistant to radioactive iodine ➤ Patients receiving sorafenib had a median PFS of 10.8 months versus 5.8 months with placebo, for a 42% reduction in mortality ➤ The response rate was 12.2% in the sorafenib arm and 0.5% in the placebo arm ➤ Stable disease was achieved by 42% of the patients receiving sorafenib ➤ The use of sorafenib should be based on the presence of symptoms and the location and growth rate of the disease

Remission Prolonged by 5 Months The 89-center Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial enrolled 417 patients who had become resistant to radioactive iodine. Patients were randomly assigned to sorafenib 400 mg twice daily or to placebo. On disease progression, the placebo recipients could cross over to receive sorafenib. The median progression-free survival was 10.8 months in the sorafenib

70% of patients have crossed over to receive active treatment, Dr Brose said. Responses were observed in 12.2% of patients in the sorafenib arm versus in 0.5% of patients in the placebo arm. Stable disease was achieved by 42% of the patients receiving sorafenib, reflecting a disease control rate of 54% with the drug compared with 34% with placebo.

Photo by © ASCO/Rodney White 2013

Chicago, IL—Sorafenib (Nexavar) has become the first drug in years to prove effective in the treatment of differentiated thyroid cancer (DTC) that has become resistant to radioactive iodine, according to phase 3 study results that were reported at the 2013 American Society of Clinical Oncology annual meeting.

“We have had no effective drugs for these patients for many years, so it is very exciting to have an oral drug that halts cancer growth for several months. This is the first time we have had a systemic treatment that can help them.” —Marcia S. Brose, MD, PhD arm versus 5.8 months in the placebo arm, for a 42% reduction in mortality that was highly significant (P <.001). The median overall survival has not been reached in either arm, but a difference is unlikely to emerge, because

Bevacizumab an Effective New Treatment...

Vol. 4

No. 5

therapy alone (48% vs 36%, respectively; P = .0078). Most notable, median OS was 17.0 months in the arms that received bevacizumab versus 13.3 months for those that received chemotherapy without

Photo by © ASCO/Rodney White 2013

giogenesis therapy, such as bevaciz umab, was a logical option to study in patients with relapsed or advanced disease, he said. The National Cancer Institute–funded study included 452 women with recurrent or metastatic cervical cancer who were randomized to 1 of 4 arms— treatment with paclitaxel plus cisplatin, paclitaxel plus cisplatin plus bevacizumab, paclitaxel plus topotecan, or paclitaxel plus topotecan plus beva cizumab. Patients could not have received previous chemotherapy for a recurrence. There was no significant difference in OS between the 2 chemotherapy arms. Progression-free survival was improved from a mean 5.9 months with chemotherapy alone to 8.2 months with the addition of bevaciz umab. The response rate was significantly higher with bevacizumab plus chemotherapy compared with chemo-

Continued from page 27

well,” said Dr Tewari. There were 4 fatal adverse events each with bevacizumab and with chemotherapy alone. “No new side effects were identified with bevacizumab,” he emphasized. Gastrointestinal fistula

“I’m hoping that the data are strong enough to allow this drug to be approved for this indication, and I do believe ultimately that it will change practice.” —Krishnansu S. Tewari, MD

bevacizumab—a 29% reduction in the risk of death (P = .0035). The 3.7-month OS improvement “is clinically meaningful in a population of patients that doesn’t respond to chemotherapy very

occurred in 7 (3%) bevacizumab-treated patients and in none of the patients receiving chemotherapy alone. “This is a recognized complication of this drug,” Dr Tewari added.

june 2013

New Standard of Care? Commenting on this study at the plenary session, Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, IL, commented, “These patients finally have options.” Dr Cohen was enthusiastic about the data, but he reminded oncologists that “not all iodine-refractory patients need treatment.” He noted that 25% of placebo recipients did not progress during the trial, and in reality, most patients with radioactive iodine–refractory disease are asymptomatic. Dr Cohen said that the choice to use sorafenib should be based on the presence of symptoms, as well as the location and growth rate of the disease. He also noted that DTC that becomes refractory to vascular endothelial growth factor receptor inhibitors, such as sorafenib, “is an emerging entity that needs to be addressed.” n

Grade ≥2 hypertension was a complication in 54 (25%) of the patients in the bevacizumab group and in 4 (2%) of the group that received chemotherapy alone, but no patients withdrew from the study because of hypertension. Health-related quality of life, as measured by the Functional As sessment of Cancer Therapy for cervical cancer index, was marginally worse, a maximum of 2.95 points, in the bevacizumab group versus the group that received only chemotherapy. (The score on this index ranges from 0 to 116 points, with a clinically meaningful change being 4 to 5 points.) “I’m hoping that the data are strong enough to allow this drug to be approved for this indication, and I do believe ultimately that it will change practice,” said Dr Tewari. The finding may open the door to testing other antiangiogenesis drugs in the setting of advanced cervical cancer, he suggested. n

www.ValueBasedCancerCare.com

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. 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 At 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 $1,506 per 3.5-mg vial as of July 2012 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 Crizotinib Superior to... Continued from page 30

screened from February 2010 through February 2012 for study eligibility. The prespecified number of progression events or death was reached in March 2012, and the data cutoff date was March 30, 2012.

The median PFS was 7.7 months with crizotinib versus 3.0 months with chemotherapy, with a hazard ratio for progression or death with crizotinib of 0.49 (P <.001). Overall response rates were 65% with crizotinib versus 20% with chemotherapy, a significant difference (P <.001). At the time of the

Brief Summary 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. 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.

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data cutoff, the median follow-up for OS was similar between the 2 groups: 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group. Also at that time, 49% of patients in the crizotinib group and 16% of patients in the chemotherapy group were still receiving therapy. Overall,

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 © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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58 patients receiving crizotinib continued therapy beyond the predefined period of progression compared with 17 patients receiving chemotherapy, and the median therapy duration was 15.9 weeks with crizotinib versus 6.9 weeks with chemotherapy. In general, patients reported greater reductions in symptoms of lung cancer, including chest pain, cough, and fatigue, and greater improvement in global quality of life with crizotinib than with chemotherapy.

Prostate Cancer Risk Doubles in Men with Lynch Syndrome

Lynch syndrome (LS) is an inherited syndrome of predisposition to cancer with an increased risk for colorectal cancer ranging from 30% to 80%. Prostate cancer has been described as a component tumor of LS, but the lifetime risk of prostate cancer in patients with LS has not been quantified because of inherent difficulties. In a new analysis, researchers have used genetic data to define the risk of prostate cancer in men with LS (Raymond VM, et al. J Clin Oncol. 2013;31:1713-1718). Mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are the leading causes of LS. The investigators identified 198 families with pathogenic mutations in the MMR genes MLH1, MSH2, MSH6, and PMS2 who have registered with 2 cancer genetics clinics. Each family was comprised of all first-degree through fourth-degree relatives of the first person in the family to undergo MMR-related gene testing. Mutation status was known for 597 men; of these patients, 412 had at least 1 of the MMR-based mutations, and 185 men had no mutations. Medical records were used to analyze prostate cancer data. Of the 4127 men included in the prostate cancer analysis, 97 (2.4%) had a personal history of prostate cancer; the median age at prostate cancer diagnosis was 65 years. The cumulative lifetime risk (to age 80) for prostate cancer was 30% in patients with 1 of the MMR-based mutations compared with 17.84% for the general population (P = .07). The US Preventive Services Task Force recently recommended against prostate-specific antigen (PSA) screen ing in asymptomatic men aged <75 years. However, based on the findings in this study, early screening for prostate cancer, including PSA testing, may be of benefit in men who are at an increased risk for prostate cancer, including men with a family history of prostate cancer or a genetic predisposition to prostate cancer, such as LS. n

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ASCO Annual Meeting See also FDA Update, page 15

Immunotherapies Take Center Stage in Melanoma Major advances in drug development will push value questions to the forefront By Audrey Andrews

Growth Factors Boost Ipilimumab’s Activity Investigators presented new data showing a way to boost the alreadypotent response to ipilimumab (Yervoy) by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF) in a phase 2 study that showed improved overall survival (OS) with the combination versus with ipilimumab alone. “Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” said F. Stephen Hodi, Jr, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute, Boston, at a press briefing. GM-CSF works within the immune system by enhancing granulocytes and macrophages, while the antibody ipilimumab “takes the brakes off” immune blockade, allowing the body to fight the tumor itself, Dr Hodi said. ECOG 1608 randomly assigned 245 patients with previously treated metastatic melanoma to receive ipi limumab and maintenance treatment, or the same plus the growth factor sargramostim (Leukine). The addition of GM-CSF to ipilimumab significantly improved OS from a median of 12.7 months with ipilimumab alone to 17.5 months, a 36% reduction in mortality. Tolerability was better with the combination than with the single agent. “With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Dr Hodi suggested. Lynn Mara Schuchter, MD, Program Leader of the Melanoma Program at Abramson Cancer Center, University of Pennsylvania, Philadelphia, commented that because both of these drugs are approved, physicians could start using this combination immediately, although she questioned wheth-

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er third-party payers would reimburse for the growth factors. New Class of Anti–PD-1 Blockade Agents May Be a Blockbuster A new class of immunotherapeutic agents blocks the programmed death1 (PD-1) and PD-1 ligand and helps keep T-cells primed and ready to attack tumor cells. This class of agents is poised to again change the standard of care of patients with melanoma, according to melanoma experts. Interest in these agents is so great that an entire clinical science symposium was devoted to the drug class at ASCO.

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade.” —F. Stephen Hodi, Jr, MD

Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients with melanoma showed median OS approaching 17 months, with a very favorable toxicity profile, reported Mario Sznol, MD, Professor of Medical Oncology, Melanoma Pro gram, Yale Cancer Center, New Haven, CT. In this study of 107 patients who received nivolumab, response rates reached 41% among patients receiving optimal doses, and median OS was 20 months; responses were prompt and averaged 24 months. “We are in an era of remarkable advances for melanoma,” he said. “Median survival with vemurafenib is 16 months. For ipilimumab it is similar. But here, with nivolumab, it’s 16.8 months, and the median duration of response of 2 years is one of the highest numbers I have seen.” Antoni Ribas, MD, of the University of California, Los Angeles, presented data for lambrolizumab, the anti–PD-1 agent that recently received “break-

through therapy” status by the US Food and Drug Administration. He discussed preliminary results of an ongoing phase 1b expansion trial at the Clinical Science Symposium on anti–PD-1. Lambrolizumab was administered every 2 or 3 weeks until disease progression or unacceptable toxicity. Of the 294 enrolled patients with melanoma, 179 did not receive ipilimumab and 115 patients were pretreated with ipilimumab. As of December 2012, the median response duration has not been reached. “We found that efficacy and safety were similar in ipilimu mab-naïve patients and those who had received prior treatment with ipilimumab,” Dr Ribas noted. Dual Blockade with PD-1 Packs Bigger Punch Combining the CTLA-4–blocking antibody ipilimumab and the PD-1 blocker nivolumab achieved deep, rapid, and durable tumor responses in a phase 1 study that was presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, NY, and was published online simultaneously (Wolchok JD, et al. N Engl J Med. 2013 Jun 2. Epub ahead of print). Of the 86 patients, 53 received concurrent therapy with the 2 agents, and 33 received sequential therapy (ie, they previously received ipilimumab and were now receiving nivolumab every 2 weeks for up to 48 doses). The results were impressive. Among the 53 patients receiving concurrent treatment, 53% had an objective response, with all patients showing tumor reduction of ≥80%, including 18% who achieved a complete response. After a median follow-up of 13 months, 90% of responders were still stable. The estimated 1-year survival rate with this regimen was 82%. “The proportion of patients with a rapidly declining tumor burden is reminiscent of responses to targeted pathway inhibitors, yet the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Dr Wolchok said at the Clinical Science Symposium on anti–PD-1. Walter J. Urba, MD, PhD, Director of Cancer Research at the Providence Cancer Center in Oregon, predicted that PD-1 blockade is “certainly going to change the state of the care of patients with melanoma once again.”

june 2013

Harnessing an Oncolytic Virus The cancer-killing virus talimogene laherparepvec (T-VEC) is the first oncolytic virus to produce benefits in patients with melanoma. T-VEC directly kills tumor cells and elicits a host response that targets distant metastases as well, said Howard L. Kaufman, MD, Director of the Rush University Cancer Center, Chicago. Photo by ©ASCO/Scott Morgan 2013

Chicago, IL—Data continue to build for the application of immunotherapy for patients with metastatic melanoma. At the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO), several sessions were devoted to recent advances in melanoma, focusing on new ways to boost the activity of current therapies, introducing a new class of immunotherapy in development, and a new form of immunotherapy—an oncolytic vaccine.

“We are in an era of remarkable advances for melanoma. With nivolumab…the median duration of response of 2 years is one of the highest numbers I have seen.” —Mario Sznol, MD

The phase 3 OPTiM trial randomized 436 patients with advanced melanoma to intratumoral injections of T-VEC or to subcutaneous GM-CSF injections. T-VEC significantly improves responses ≥6 months compared with GM-CSF (16.3% vs 2.1%; P <.001), meeting the study’s end point. Median time to treatment failure with T-VEC was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P <.001). In the interim analysis, the median OS was 23.3 months with T-VEC and 19.0 months with GM-CSF. The treatment was also very well tolerated, he said. Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, commented that because GM-CSF is not a standard treatment for metastatic melanoma, it may not be a good comparator for the novel therapy. She suggested that the best use of T-VEC may be in combination with another immune mediator, such as ipilimumab. Arlene H. Sharpe, MD, PhD, Co director of the Harvard Institute of Translational Immunology at Harvard Medical School, commented that “Tar geting immunoinhibitory pathways is providing a new strategy for immunotherapy….There are synergies among inhibitory pathways. Co-blockade enables better rescue of exhausted T-cells and therapeutic efficacy than blockade of a single inhibitory pathway.” n

www.ValueBasedCancerCare.com

Health Policy

Medicare Committee Gives Thumbs Down to New Genetic Tests for Cancer By Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH

Mr Margulies is an Associate, Foley Hoag, LLP, and Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

n May 1, 2013, the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC), Medicare’s clinical advisory committee, held a public advisory board meeting on “Selected Genetic Tests for Cancer Diagnosis and Treatment Selection.” MEDCAC typically holds several meetings annually to evaluate new and emerging technologies that have the potential to greatly impact the health of Medicare beneficiaries (the last meeting, which was held in January 2013, featured an evaluation of positron emission tomography imaging in the management of dementia). Any MEDCAC recommendation to the Centers for Medicare & Medicaid Services (CMS) on whether to support coverage for a technology, although not binding, can have a tremendous impact on CMS’s decision to issue a National Coverage Determination (NCD) on an existing technology. Based on a number of concerns voiced by panelists about the 2 genetic tests that were considered, it seems unlikely that CMS will open up an NCD on either test.

Ross D. Margulies

Jayson Slotnik

The 2 Oncology Tests On the agenda for the meeting were 2 very different tests. The first, a genetic test to predict a cancer diagnosis in patients presenting with a cancer of unknown primary (CUP) site, has been developed by several independent laboratory companies and is focused on the small percentage of cancers in which a patient is not easily classified to a primary tumor type by location. The second test, fluorescent in situ hybridization (FISH) tests for high-risk human papillomavirus (HPV) genotypes, is designed for women who have abnormal Pap smear results. Although MEDCAC considers a number of various resources in reviewing a technology—including input

The technology assessment reports on both technologies were moderately negative and focused on the lack of outcomes data for patients who used or did not use the test under a clinical trial design. from scientific experts and industry, medical literature, and the general public—to aid in its decision-making, MEDCAC often solicits a technology assessment report from the Agency for Healthcare Research and Quality. At this most recent meeting, the panelists reviewed technology assessment reports on both technologies, and both reports were moderately negative and focused on the lack of outcomes data for patients who used or did not use the test under a clinical trial design. In particular, the CUP technology assessment focused on the lack of any gold standard in identifying a tumor of an “unknown” origin, and the panelists questioned whether treating patients with chemotherapy tar-

geted to the CUP’s biological tissue might have greater harm than benefit. Furthermore, the panelists were generally concerned that the FISH tests for HPV lacked robust evidence, pointing to major research gaps in the harm versus benefit to the patient. Neither technology was able to meet even the first voting roadblock, which asks the panelists to vote on whether there is enough evidence to confirm any impact on patient care. The panelists voted down both technologies, emphasizing the need for randomized controlled trials to generate appropriate evidence. For the larger cancer community, this recent MEDCAC meeting provides a glimpse of what is often seen as an overly bureaucratic Medicare coverage process. The discussion (see full transcript at www.cms.gov) also adds color to the burden faced by the biopharmaceutical industry in developing new molecular diagnostic tests, and the significant barriers to approval when facing medical evidence committees. Perhaps most important, it gives oncologists an insight into what is (and, in this case, what is not) coming down the diagnostic pipeline. n

Economics of Cancer Care

Use of High-Cost Tests for Lung Cancer Surveillance Rising By Wayne Kuznar

Chicago, IL—The use of costly diagnostic imaging of uncertain value is increasing rapidly for patients with localized non–small-cell lung cancer (NSCLC), according to data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Frequent surveillance imaging was found for white patients and for those with higher socioeconomic status, despite lack of evidence for its value and its high cost, said Jason D. Wright, MD, Assistant Clinical Professor of Gyne cologic Oncology, Columbia Uni ver sity, New York, at the 2013 American Society of Clinical Oncology meeting. Computed tomography (CT) screening of high-risk individuals has led to an increase in diagnosis and treatment of early-stage tumors,

which is then followed by surveillance. “Despite the increasing number of cancer survivors, there are little evidence-based data to guide surveillance strategies,” said Dr Wright. Guidelines from the National Comprehensive Cancer Network suggest continued surveillance after tumor diagnosis, including a CT scan every 6 to 12 months, and then annu ally. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are not routinely indicated. Lacking evidence, most of these recommendations are based on expert opinion, he noted. For patients in remission, the goals of surveillance are to detect recurrent disease and second primary tumors, and to facilitate access to care for other chronic diseases. “The goal of the analysis was

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to capture testing for patients without recurrent disease,” Dr Wright said. This study evaluated records from the SEER-Medicare database of patients with stage I or stage II NSCLC who underwent curative surgical resection from 2000 to 2007. Three periods after cancer-directed surgery (6-18 months, 18-30 months, and 30-42 months) were examined. A separate analysis was performed to examine high-intensity surveillance, defined as at least 1 advanced imaging test (ie, CT, MRI, or PET) during each surveillance period. The 6 to 18 months postsurgery use of high-cost chest CT climbed from 48% in 2000 to 78% in 2007 and PET use increased from 2% to 23%, whereas the use of chest radiography and bone scanning decreased over time.

Similar trends were noted for the other 2 surveillance periods. MRI was used infrequently throughout the study. “The average cost of surveillance testing during period 1 increased from $397 in 2000 to a peak of $1080 in 2005, and then decreased slightly to $878 in 2007,” said Dr Wright. “Similar trends were noted for subsequent surveillance periods.” Among 5269 patients who were included in the analysis of high-intensity surveillance, 21.0% diagnosed in 2000 had at least 1 high-cost surveillance test annually; this increased to 47.7% in patients who were diagnosed in 2006. In addition, patients with high socioeconomic status were more likely to undergo annual surveillance imaging; Hispanics and older patients were less likely to undergo testing. n

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Economics of Cancer Care

Single, Older Women Less Likely to Receive GuidelineRecommended Treatment for Breast Cancer in Rural Georgia By Neil Canavan

New Orleans, LA—Researchers looking at whether guideline-directed adjuvant treatments for breast cancer were actually being administered in rural areas of the United States found that only 41% of the patients in this study received all of the suggested treatment modalities for breast cancer. Being single and advancing in age were negative predictors for receiving guideline-based care. “Identifying and addressing modifiable factors that lead to nonguideline concordant treatment may reduce disparities in treatment and improve cancer outcomes,” stated Gery P. Guy Jr, PhD, MPH, and colleagues, Emory University, Rollins School of Public Health, GA. Dr Guy presented the results of this study at the 2013 International Society for Pharma co economics and Outcomes Research annual conference. Dr Guy and his team reviewed the medical records of 845 women with breast cancer who were treated at cancer centers in southwest Georgia, a relatively unstudied population. The guideline-recommended treatment modalities reviewed included: • Adjuvant chemotherapy • Adjuvant radiation therapy

• Adjuvant hormonal therapy • All 3 adjuvant treatments jointly. The study population was largely (70%) white, roughly 50% of the women were married, 70% had private insurance, 50% were below the

“Identifying and addressing modifiable factors that lead to nonguideline concordant treatment may reduce disparities in treatment and improve cancer outcomes.” —Gery P. Guy Jr, PhD, MPH

poverty level, and most of them lived in a rural area. The vast majority of the patients were diagnosed with early-stage (I-II) breast cancer, 66% had undergone a mastectomy, and 76% were hormone receptor–positive.

Disparities in Care Results showed that although only 41% of the patients were managed with all 3 treatment modalities in accordance with current guidelines, the use of a specific treatment varied considerably: • Chemotherapy was used as recommended 63% of the time • Adjuvant radiation was used as recommended 81% of the time • Hormonal therapy was used 78% of the time. Patients with higher socioeconomic status were 3 times more likely to receive all guideline-concordant adjuvant treatments for breast cancer, and patients with Medicaid insurance were 4 times as likely to receive the appropriate adjuvant chemotherapy compared with uninsured patients. The likelihood of being guideline concordant for adjuvant chemotherapy and adjuvant radiation therapy decreased by 50% for women who were unmarried; increasing age was also a negative predictor of appropriate care. The investigators noted that they were unable to control for patient or physician attitudes and preferences that may have impacted care; some patients do not want to be aggressive-

at a glance ➤ Only 41% of patients in a rural area in Georgia received all 3 of the suggested treatment modalities for breast cancer ➤ Chemotherapy was used as recommended 63% of the time; adjuvant radiation, 81%; and hormonal therapy, 78% ➤ Predictors of care included socioeconomic status, type of insurance, marital status, and age ly treated, and some oncologists are wary of guidelines. They also did not look at the level of education for this patient cohort. A number of recent studies have shown that not adhering to consensus guidelines is associated with increased rates of cancer recurrence (and subsequent mortality). Identifying modifiable reasons why guideline-recommended adjuvant treatments are unused and embracing the drivers for enhanced compliance with treatment guidelines may reduce treatment disparities and improve outcomes, the investigators suggest. n

Urologists’ Prescribing of Gonadotropin-Releasing Hormones Agonists for Prostate Cancer Vary by Practice Affiliation New Orleans, LA—An analysis comparing the prescribing habits of urology practices shows that, despite treatment guideline recommendations to the contrary, gonadotropin-releasing hormone (GnRH) agonists, which are only indicated for the palliative treatment of advanced prostate cancer, are routinely prescribed for patients with localized, low- or intermediate-grade prostate cancer, particularly by urologists who have no practice affiliation with a medical school. “Such treatment patterns are not consistent with patient-centered clinical guidelines and [are] unlikely to have significant survival benefit,” noted lead investigator, Ruben G. Quek, MPhil, with the American Can cer Society and Emory University, Atlanta, GA, and colleagues. They presented their findings at the 2013 International Society for Pharmaco economics and Outcomes Research

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annual conference. Conducting a retrospective study by using the American Medical Associ ation and Medicare databases, the team looked at the prescribing habits of academic-affiliated and non–academic-affiliated urology practices of GnRH for prostate cancer just before and just after the 2003 Medicare Modernization Act (MMA). The measures introduced by the MMA were intended to curtail reimbursement rates for GnRH agonists, which promoted this investigation of the effect of the new reimbursement rates on urologists’ prescribing practices for patients with cancer. The analysis included the medical rec ords of 10,301 patients, who were treated by 1577 urologists. All patients (aged ≥66 years) were diagnosed between 2003 and 2005 with localized, low- to intermediate-grade prostate cancer. The team looked at GnRH agonists

The overall odds of patients with prostate cancer receiving unnecessary GnRH agonists decreased after the MMA was introduced, but urologists who are not linked to medical schools are still significantly more likely to prescribe these agents for low-grade tumors. that were prescribed for patients within 6 months of diagnosis—a regimen that is at variance with clinical guidelines—and then asked if a treatment bias according to a urologist’s practice affiliations could be demonstrated. The results showed that compared

june 2013

with their medical school–affiliated colleagues, the patients managed by urologists who are not affiliated with a medical school were significantly more likely to receive GnRH agonists as part of their treatment regimen, which is against current recommendations. After the MMA went into effect, the nonaffiliated prescribers tapered off in their activities somewhat, but they were still significantly more likely to administer GnRH agonists than the affiliated urology practices. This unwarranted treatment, although further diminished, still persisted through 2005. “Even though the overall odds of patients receiving unnecessary GnRH agonists decreased after the MMA reimbursement reduction, urologists without practice affiliations with medical schools were still significantly more likely to prescribe GnRH agonists,” concluded Mr Quek and his colleagues.—NC n

www.ValueBasedCancerCare.com

Personalized Medicine

Companion Diagnostics Information Not Easily Obtained By Charles Bankhead

San Diego, CA—Getting technical information about companion diagnostic tests required to make formulary decisions about oncology drugs may not be easy, according to a small telephone survey conducted by Aashish Surti, PharmD can didate, and Iris Tam, PharmD, Director, Managed Care Med ical Communications, Genentech. They reported their survey results in a poster presented at the 2013 Academy of Man aged Care Pharmacy (AMCP) meeting. Only 1 of 20 phone calls to test and drug manufacturers resulted in the direct provision of the package insert for a diagnostic test. The remaining calls resulted in referrals to different departments, websites, or companies. When information was provided, it usually came in the form of generic product information or “uninformative” medical letters about the tests. “This study suggests that gaps exist in obtaining diagnostic test information—including information about a

test’s analytical validity, clinical validity, and clinical utility—from diagnostic test and drug manufacturers,” the investigators concluded.

A survey of manufacturers of companion diagnostics for several oncology biomarkers, including ALK, V600E, EGFR, HER2, and KRAS gene mutations, shows that obtaining technical information about these tests is not easily accessible. Obtaining information about companion diagnostics may be important to evaluate cancer drugs that are used in conjunction with companion diagnostic tests associated with specific

biomarkers to make appropriate formulary decisions. The US Food and Drug Admini s tration (FDA) has released a draft guidance related to drug and device manufacturers’ responses to unsolicited requests about medical information for new products. In response to the FDA’s action, most drug manufacturers have developed standard policies and procedures for responding to unsolicited requests for information. Less is known about how manufacturers of diagnostic tests respond to requests for information about companion tests required for drugs undergoing formulary review, they said. Companion Diagnostics for Targeted Oncology Therapies The role of companion diagnostic tests has expanded with the growing number of targeted therapies, particularly in oncology. Effective and cost-effective use of agents requires selection of patients most likely to benefit from the drugs.

The growing number of biomarkers identified in association with certain tumor types has fueled development of tests to identify subpopulations of patients with targeted genetic mutations. This study focused on several FDAapproved, commercially available companion diagnostic tests for oncol ogy biomarkers, including tests for ALK, V600E, EGFR, HER2, and KRAS gene mutations. The investigators made telephone calls to request information about diagnostic tests from manufacturers of the diagnostic tests and from the associated drug companies. Of the calls that were made to the test manufacturers, only 1 response led directly to the requested information. The AMCP recently released the Format for Formulary Submissions, Version 3.1, which includes an addendum specific to companion diagnostic tests. Whether that development will influence manufacturers’ responses to requests for information about diagnostic tests remains to be seen. n

Economics of Cancer Care

Patient-Reported Outcomes More Common in EU Labeling than FDA Labeling of Drug Approved for Lung Cancer By Neil Canavan

New Orleans, LA—A study comparing patient-reported outcomes (PROs) labeling claims in Europe and in the United States showed that the European Medicines Agency (EMA) is more proactive in considering patientgenerated feedback in their drug labeling decisions—this despite the US Food and Drug Administration (FDA)’s 2009 guidance that emphasized the importance of gathering and disseminating such data. “Our analysis suggests a higher receptivity of the EMA to quality of life as a global concept,” stated Martine Caron, PhD, Development Director at Mapi Research Trust, Lyon, France, and colleagues, who presented their data at the 2013 International Society for Pharmacoeconomics and Outcomes Research annual conference. A PRO is any report that comes directly from patients about how they function or feel in relation to a health condition and its treatment; this patient feedback is not subject to the healthcare provider’s interpretation,

but it is a true self-assessment. PROs are considered a vital adjunct in developing the paradigm of personalized medicine, especially in relation to side effects associated with the disease and its treatment. Properly utilized, PROs can be used to help direct patient care. The investigators looked at the labels of 15 drugs approved by the FDA for the treatment of non–small-cell lung cancer, of which 6 were also approved by the EMA. Of the 6 EMA-approved drugs, 4 had PROs claims in their labels— docetaxel (Taxotere), erlotinib (Tarce va), gefitinib (Iressa), and paclitaxel (Paxene). Of the FDA-approved drugs, only 2 had PROs included in their labels—paclitaxel (Taxol) and gemcitabine (Gemzar). For all the drugs with PROs labeling, claims were related to quality-oflife issues and symptoms. However, the FDA label for paclitaxel lacks a quality-of-life claim. Except for gefitinib, both agencies granted or denied PROs claims based

Value-Based Cancer Care

JUNE 2013

The European Medicines Agency is more proactive in considering patientgenerated feedback in their drug labeling decisions— this despite the US Food and Drug Administration’s 2009 guidance that emphasized the importance of gathering and disseminating such data.

on data from the same clinical trials; to explain the different decisions made by the FDA and the EMA, the study investigators looked at the agencies’ communications. For the most part, the FDA expressed concerns about quality-of-life study designs and any related analyses.

Will the Trend Continue? A presumed reluctance on the part of the FDA to grant PROs labeling actually may not be the case. A review published in 2012 found no PROscontaining labels for the 15 oncology agents approved by the FDA between 2006 and 2010 (Gnanasakthy A, et al. Value Health. 2012;15:437-442); however, 3 reasons were suggested to explain the drug manufacturer's role: 1. The FDA often issues warning letters when PROs are “overemphasized” 2. Drug manufacturers do not want to spend the extra money in early drug development to collect data on nonprimary (ie, PROs) end points 3. Increasing use of multinational trials poses too many hurdles for the manufacturer to collect PROs data. However, 24% of recently approved drugs have PROs labeling— just not in oncology. In oncology, PROs are frequently used to assess treatment benefits and toxicity to evaluate the impact of treatment on quality of life. n

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No. 5

Drug Update

Kadcyla (Ado-Trastuzumab Emtansine): First Antibody-Drug Conjugate Approved for the Treatment of HER2-Positive Metastatic Breast Cancer By Lisa A. Raedler, PhD, RPh

pproximately 25% of women who are diagnosed with breast cancer have HER2-positive tumors. The HER2 gene, which resides on chromosome 17, directs tumor cells to manufacture HER2 protein. This protein is a cell-surface receptor that compels the tumor cell to grow and to divide more frequently than normal, making HER2-positive breast cancer an aggressive phenotype. Before the advent of HER2-directed therapies, patients diagnosed with HER2-positive disease had significantly shorter disease-free survival compared with patients with other breast cancer subtypes.1

Unmet Need in TrastuzumabResistant Breast Cancer The American Cancer Society estimates that approximately 232,340 women will be diagnosed with invasive breast cancer, and approximately 39,620 deaths will occur from the disease in 2013.2 Since 1989, death rates

from breast cancer have declined, with relatively larger decreases in women aged <50 years, in part as a result of earlier detection and increasingly improved treatments.2 Much of the increased survival for patients with HER2-positive breast cancer is attributed to the development of HER2-targeted therapies, including trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb).3 The first phase 3 clinical trial that compared trastuzumab plus chemotherapy versus chemotherapy alone in patients with HER2-positive metastatic breast cancer demonstrated robust improvements in response rate (50% vs 32%, respectively), median time to progression (7.4 months vs 4.6 months, respectively), and median overall survival ([OS] 25.1 months vs 20.3 months, respectively) with the addition of trastuzumab.4 In addition, 2 meta-analyses have confirmed the OS benefit of adding HER2-targeted therapy to standard treatment in pa-

EMILIA: Efficacy End Points of Ado-Trastuzumab Emtansine versus Table 1 Lapatinib plus Capecitabine Outcome parameter

PFS (independent review) Patients, N (%) Median PFS, mo

Ado-trastuzumab emtansine (N = 495)

Lapatinib plus capecitabine (N = 496)

265 (53.5) 9.6

304 (61.3) 6.4

149 (30.1) 30.9

182 (36.7) 25.1

Hazard ratio, stratifieda (95% CI) P value (log-rank test, stratifieda)

Overall survivalb Patients, N (%) Median survival, mo

Hazard ratio, stratifieda (95% CI) P value (log-rank testa)

OR rate (independent review) Patients with measurable disease, N Patients with OR, N (%)

Difference (95% CI)

Duration of OR, mo Patients with OR, N Median duration, mo (95% CI)

0.650 (0.549-0.771) <.001

0.682 (0.548-0.849) .006

397 173 (43.6)

389 120 (30.8)

173 12.6 (8.4-20.8)

120 6.5 (5.5-7.2)

12.7 (6.0-19.4)

Stratified by world region (ie, United States, Western Europe, or other), number of previous chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs >1), and visceral versus nonvisceral disease. b The second interim analysis for OS was conducted when 331 events were observed. The results are presented in this table. CI indicates confidence interval; OR, objective response; PFS, progressionfree survival. Source: Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information]. South San Francisco, CA: Genentech, Inc; February 2013. a

Value-Based Cancer Care

JUNE 2013

“Use of the immunoconjugate— trastuzumab linked to a microtubule inhibitor—was shown in trials to be better in every way: response, progression-free survival, overall survival, and tolerability.” —Hope S. Rugo, MD

tients with early-stage or metastatic HER2-positive breast cancer.5,6 However, primary and secondary resistance to trastuzumab occurs in the advanced breast cancer setting: none of these patients is cured. In 2013, approximately 13,000 patients with HER2-positive metastatic breast cancer will have disease recurrence after trastuzumab treatment.7 Concerted efforts are under way to identify the mechanisms of trastuzumab resistance, as well as novel “druggable” targets for this patient population.8 Currently, treatment strategies for patients with trastuzumab-resistant HER2-positive breast cancer are selected on the basis of patient-specific factors (ie, age, comorbidities), diseaserelated factors, and cost.9 Therapy alternatives include the combination of pertuzumab, trastuzumab, and a taxane; lapatinib plus trastuzumab; lapatinib plus capecitabine; and the continued use of trastuzumab plus chemotherapy.10 FDA Approval of Ado-Trastuzumab Emtansine Fills an Unmet Need In February 2013, the US Food and Drug Administration (FDA) granted accelerated approval for ado-trastuzumab emtansine (Kadcyla; Genentech, Inc), also known as TDM-1, for the treatment of patients with HER2positive metastatic breast cancer who were previously treated with trastuzumab and with taxanes.11 The approval was based on the result of a single, open-label trial of patients with HER2positive metastatic breast cancer: TDM-1 demonstrated a significant 5.8month improvement in median OS and a 3.2-month improvement in median progression-free survival (PFS)

compared with the combination of lapatinib plus capecitabine.12 In an interview regarding TDM-1, Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco, stated, “Use of the immunoconjugate—trastuzumab linked to a microtubule inhibitor [DM-1]—was shown in trials to be better in every way: response, progression-free survival, overall survival, and tolerability.”9 According to the drug manufacturer, 1 cycle (once in 21 days) of TDM-1 costs $9800. For comparison, the combination of lapatinib and capecitabine costs approximately $10,460 monthly.13 Dosing and Administration TDM-1 is administered intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. No loading dose or premedications are required. Treatment with TDM-1 should be continued until disease progression or until unacceptable toxicity. For the first infusion, TDM-1 should be administered over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes after the initial dose for fever, chills, or other infusion-related reactions. For subsequent infusions, TDM-1 can be administered over 30 minutes if previous infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after. TDM-1 should not be administered at doses greater than 3.6 mg/kg. TDM-1 should not be substituted for or coadministered with trastuzumab.12

Dose Modifications Based on Toxicity

The dose of TDM-1 may be modified if hematologic or nonhematologic toxicities occur, including grade 3 or 4 cytopenias; cardiac, hepatic, or renal toxicities; pulmonary complications; neurotoxicity; or other toxicities. In general, TDM-1 is withheld until resolution, followed by restarting therapy at the same dose or at a reduced dose, depending on the type of toxicity and whether it was attributable to TDM-1.12 Mechanism of Action TDM-1 is a HER2-targeted antibody drug conjugate. The antibody is the humanized anti-HER2 immunoglobuContinued on page 42

Vol. 4

No. 5

SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

DESIGNATION OF CREDIT STATEMENTS SPONSORS

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

GBCKsize20813

PMPMERSONALIZED EDICINE IN ONCOLOGY O

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

Drug Update

Kadcyla (Ado-Trastuzumab Emtansine)... lin G1, ado-trastuzumab. The smallmolecule drug DM-1 is a microtubule inhibitor. On binding to subdomain IV of the HER2 receptor, TDM-1 undergoes receptor-mediated internalization and lysosomal degradation, resulting in intracellular release of DM-1–containing cytotoxic catabolites. Binding of DM-1 to tubulin disrupts microtubule networks in the cell, resulting in cell-cycle arrest and cell death. In vitro studies have shown that similar to trastuzumab, TDM-1 inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress the HER2 gene.12 The availability of an antibody drug conjugate for selected patients with breast cancer offers an exciting and novel approach, particularly for women who wish to avoid the side

effects of chemotherapy. According to Julie R. Gralow, MD, Director, Breast

TDM-1 “is a true magic bullet. For the 20% to 25% of breast cancer patients that have HER2-positive breast cancer (HER2-expressing breast cancer), this is an antibody that can take chemotherapy directly to the tumor cell and deliver it inside the cell.” —Julie R. Gralow, MD

Medical Oncology, Seattle Cancer Care Alliance, WA, TDM-1 “is a true magic

Continued from page 40

bullet. For the 20% to 25% of breast cancer patients that have HER2positive breast cancer (HER2expressing breast cancer), this is an antibody that can take chemotherapy directly to the tumor cell and deliver it inside the cell. Then the bulk of the body does not get exposed to the chemotherapy.”14 EMILIA: A Phase 3 Clinical Trial TDM-1 was approved by the FDA based on the results of the EMILIA trial, a randomized, multicenter, open-label trial of 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer.15 Previous taxane- and trastuzumabbased therapies were required before trial enrollment. Patients who had only received previous adjuvant therapy were required to have disease recurrence during or within 6 months of completing adjuvant therapy. Tumor

Table 2 Ado-Trastuzumab Emtansine: Warnings and Precautions Warnings and precautions Infusion reactions

Extravasation

Thrombocytopenia Peripheral neuropathy Hepatic toxicity and hepatic failure

Left-ventricular dysfunction

Pulmonary toxicity Embryo-fetal toxicity

Description

• Occurred in 1.4% of patients receiving the drug; 1 case of a serious, allergic/ anaphylactic-like reaction was reported • Characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, tachycardia • Monitor patients closely for infusion reactions, particularly during first infusion • Occurs within 24 hours of infusion • Characterized by mild erythema, tenderness, skin irritation, pain, swelling at the infusion site • Monitor the infusion site closely for possible subcutaneous infiltration during administration

• Occurred in 31.2% of patients; 14.5% were grade 3/4 • Higher incidence and severity of thrombocytopenia were noted in Asian patients • Monitor platelet counts frequently • Occurred in 21.2% of patients; 2.2% were grade 3/4 • Monitor frequently for signs and symptoms of neurotoxicity

• Mainly asymptomatic transient increases in serum transaminase concentrations • Because TDM-1 can cause elevated serum transaminases and bilirubin, liver enzymes should be monitored frequently • Serious hepatobiliary disorders, including ≥2 deaths resulting from severe drug-induced liver injury and associated hepatic encephalopathy, were reported • Of 884 patients in TDM-1 clinical trials, 3 had NRH of the liver identified from liver biopsies; consider NRH in patients with clinical symptoms of portal hypertension, normal transaminases, and no manifestations of cirrhosis

• A decrease of LVEF to <40% has been observed in patients treated with TDM-1 • Left-ventricular dysfunction occurred in 1.8% of patients receiving TDM-1 and in 3.3% of patients treated with lapatinib plus capecitabine in the randomized trial • Assess LVEF before initiation of TDM-1 and at regular intervals (eg, every 3 months) during treatment to ensure LVEF is within the institution’s normal limits • Cases of interstitial lung disease (eg, pneumonitis), including some leading to acute respiratory distress syndrome or death, have been reported • Pneumonitis incidence was 0.8% in clinical trials, including 1 case of grade 3

• Exposure to TDM-1 can result in embryo-fetal death or birth defects • Patients should be advised of this risk and the need for effective contraception

LVEF indicates left-ventricular ejection fraction; NRH, nodular regenerative hyperplasia; TDM-1, ado-trastuzumab emtansine. Source: Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information]. South San Francisco, CA: Genentech, Inc; February 2013.

Value-Based Cancer Care

JUNE 2013

samples were required to show evidence of HER2 overexpression, defined as 3+ immunohistochemistry by Dako’s HercepTest, or evidence of HER2 overexpression defined as a fluorescence in situ hybridization (FISH) amplification ratio of ≥2.0 by Dako’s HER2 FISH pharmDx test kit.12,15

Trial Design and Patient Popu lation. Patients in the EMILIA trial

were randomized to TDM-1 or to lapatinib plus capecitabine.12 Ran domization was stratified by world region (ie, United States, Western Europe, or other), the number of previous chemotherapy regimens used for unresectable locally advanced or metastatic disease, and by visceral versus nonvisceral disease as determined by the investigators. TDM-1 was given intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. Lapatinib was administered orally at 1250 mg once daily in a 21-day cycle. Capecitabine was administered orally at 1000 mg/m2 twice daily on days 1 through 14 of a 21-day cycle. Patients were treated with TDM-1 or with lapatinib plus capecitabine until disease progression, consent withdrawal, or until reaching an unacceptable toxicity level.12 The patient demographics and baseline tumor characteristics were balanced between treatment arms in the EMILIA trial.12 All patients had metastatic disease at study entry. The median age was approximately 53 years (range, 24-84 years); 74% of patients were white, 18% were Asian, and 5% were black. All but 5 patients were women. Tumor prognostic characteristics, including hormone receptor status (positive, 55%; negative, 43%), presence of visceral disease (68%) and nonvisceral disease only (33%), and the number of metastatic sites (<3, 61%; ≥3, 37%), were similar in the study arms.12 Efficacy. Of the 991 patients who were enrolled in the EMILIA trial, 978 received treatment.16 The median dose intensity was 99.9% for patients receiving TDM-1, 77.2% for patients receiving capecitabine, and 93.4% for patients treated with lapatinib. The key study findings are summarized in Table 1 (page 40). Dose reduction was necessary for 16.3% of patients in the TDM-1 arm; capecitabine doses and lapatinib doses were reduced for 53.4% and 27.3% of the patients, respectively.16 At the time of the primary efficacy analysis, median time with therapy was 5.7 months for TDM-1, 4.9 months Continued on page 44

Vol. 4

No. 5

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

Drug Update

Kadcyla (Ado-Trastuzumab Emtansine)... for lapatinib, and 4.8 months for capecitabine.12 The coprimary efficacy end points were PFS based on tumor response assessments by an independent review committee and on OS. PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause (whichever occurred earlier). OS was defined as the time from the date of randomization to the date of death from any cause. Secondary end points included PFS based on investigator tumor response assessments, objective response rate, duration of response, and time to symptom progression.12 Subgroup analyses using baseline patient characteristics indicated that the use of single-agent TDM-1 was superior to lapatinib plus capecitabine for all patient subsets except those aged ≥65 years.15 A subsequent biomarker analysis demonstrated that patients in EMILIA whose tumors expressed high HER2 messenger RNA levels derived more benefit from TDM-1 than patients with lower levels of expression. In high HER2 express ors, the median PFS was 34.1 months with TDM-1 versus 24.8 months with lapatinib plus capecitabine.17 Safety Profile Single-agent TDM-1 has been evaluated in 884 patients with HER2positive metastatic breast cancer.12 These patients received a median of 7.6 months of TDM-1 treatment. The most common (frequency, ≥25%) drug-related adverse events (AEs)

seen in patients receiving TDM-1 were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation. Grades 3 and 4 AEs were reported in 43.1% of patients receiving TDM-1 and in 59.2% of patients receiving lapatinib plus capecitabine. Overall, 32 (6.5%) patients discontinued TDM-1 as a result of an AE. The most common AEs leading to TDM-1 withdrawal were thrombocytopenia and increased transaminases. Eighty (16.3%) patients receiving TDM-1 experienced AEs leading to dose reductions. These AEs included thrombocytopenia, increased transaminases, and peripheral neuropathy. AEs that led to dose delays occurred in 23.7% of patients receiving TDM-1 and included neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases, and pyrexia.12 Hepatotoxicity. Serious hepatotoxicity has been reported, including liver failure and death, in patients receiving TDM-1. Serum transaminases and bilirubin should be monitored before the initiation of TDM-1 treatment and before each TDM-1 dose. The dose of TDM-1 should be reduced or discontinued as appropriate in cases of increased serum transaminases or increased total bilirubin.12 Cardiac Toxicity. TDM-1 administration may lead to reductions in left-ventricular ejection fraction. Leftventricular function should be evaluated in all patients before and during treatment with TDM-1. Treatment should be withheld if a clinically sig-

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nificant decrease in left-ventricular function is detected.12 Warnings and Precautions A number of adverse reactions associated with TDM-1 are discussed in the “Warnings and Precautions” section of the prescribing information and are summarized in Table 2 (page 42).12 The FDA has issued a warning to prescribers advising that they should add “ado-” to the nonproprietary name “trastuzumab” when discussing TDM-1 to avoid confusion between Herceptin and Kadcyla, which was reported in clinical trials.18 Conclusion TDM-1, which several experts have called a “magic bullet,” combines ado-trastuzumab and chemotherapy without causing traditional chemotherapy side effects, such as alopecia, neutropenia, or vomiting. For first-, second-, and third-line patients with HER2-positive metastatic breast cancer who are resistant to trastuzumab and to taxanes, single-agent TDM-1 offers clinically and statistically significant OS and PFS benefits, with a favorable tolerability profile on a convenient, once-every-3-week dosing schedule. n References

1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182. 2. American Cancer Society. Breast cancer: what are the key statistics about breast cancer? February 26, 2013. www.cancer.org/cancer/breastcancer/detailedguide/ breast-cancer-key-statistics. Accessed May 13, 2013. 3. Swain SM, Kim S-B, Cortes J, et al. Confirmatory overall survival (OS) analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled phase 3 study

with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive first-line (1L) metastatic breast cancer (MBC). Cancer Res. 2012;72(24 suppl 3):Abstract P5-18-26. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792. 5. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of HER2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153. 6. Harris CA, Ward RL, Dobbins TA, et al. The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol. 2011;22:1308-1317. 7. Genentech. Kadcyla (ado-trastuzumab emtansine) is the first FDA-approved antibody-drug conjugate (ADC) for HER2-positive metastatic breast cancer. Kadcyla fact sheet. February 2013. www.genentech-forum.com/files/ documents/kadcyla-fact-sheet.pdf. Accessed May 21, 2013. 8. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer. 2012;106:6-13. 9. Patient Power. ASCO update: the latest news in advanced breast cancer. YouTube. June 15, 2012. www.youtube.com/ watch?v=ET8upnD1ujw. Accessed May 21, 2013. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®: Breast Cancer. Version 3.2013. May 3, 2013. www.nccn. org/professionals/physician_gls/pdf/breast.pdf. Accessed May 21, 2013. 11. US Center for Drug Evaluation and Research. Kadcyla approval letter. February 22, 2013. www.accessdata.fda. gov/drugsatfda_docs/nda/2013/125427Orig1s000Approv.pdf. Accessed May 21, 2013. 12. Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information]. South San Francisco, CA: Genentech, Inc; February 2013. 13. Herper M. A triumph in breast cancer—and another expensive drug. Forbes.com. February 22, 2013. www.forbes.com/sites/matthewherper/2013/ 02/22/a-triumph-in-breast-cancer-and-anotherexpensive-drug/. Accessed May 21, 2013. 14. Patient Power. What does new HER-2 positive drug approval mean for advanced breast cancer? YouTube. March 13, 2013. www.youtube.com/watch?v=WkNLKKfWHB8. Accessed May 21, 2013. 15. Verma S, Miles D, Gianni L, et al, for the EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367:1783-1791. 16. EMILIA: T-DM1 demonstrates greater safety, efficacy for advanced HER2-positive breast cancer. ASCO Daily News. June 2012. http://chicago2012.asco.org/ ASCODailyNews/LBA1.aspx. Accessed May 21, 2013. 17. Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2positive metastatic breast cancer (MBC). Abstract presented at the 2013 AACR Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-63. 18. US Food and Drug Administration. FDA warns about potential medication errors resulting from confusion regarding nonproprietary name for breast cancer drug Kadcyla (ado-trastuzumab emtansine). Podcast; updated May 7, 2013. www.fda.gov/Drugs/DrugSafety/ DrugSafetyPodcasts/ucm351075.htm. Accessed May 23, 2013.

Prostate Cancer

New Guideline Emphasizes Sequenced Therapy for Castration-Resistant Prostate Cancer By Charles Bankhead

San Diego, CA—Evidence-based drug sequencing should form the basis of treatment for castration-resistant prostate cancer (CRPC), according to a new guideline from the American Urolo gical Association (AUA) released at the 2013 AUA annual meeting. Organized into strategies for 6 types of patients with CRPC (“index patients”), the guideline emphasizes therapies that have demonstrated efficacy in the specific index patient. Over the past 3 years, 4 new therapies for CRPC have received US Food and Drug Administration approval.

Other drugs in development have shown promise and could eventually lead to even more options for a disease that once had virtually no effective treatment options. In part, the AUA guideline is a response to the rapid development of treatments for CRPC, according to Michael S. Cookson, MD, Professor of Urologic Surgery, Vanderbilt University, Nashville, TN, who chaired the guideline panel. “We wanted to offer physicians guidance in navigating the maze of treatment options that have become available in fairly rapid succession,”

Value-Based Cancer Care

JUNE 2013

said Dr Cookson. “The guideline is based on the strongest and most current information available; yet, we think physicians will find it easy to understand and use.” The 6 Index Patients, by Disease Status The 6 types of index patients that form the basis of the guideline represent the key conditions that define different stages of CRPC. Those situations include: • Presence or absence of metastases • Presence or absence of symptoms

and severity of symptoms • Performance status • History of exposure to docetaxel (Taxotere). Index Patient 1 has no symptoms or metastases. Observation is an option, and antiandrogens or androgen-synthesis inhibitors may be offered to men who refuse observation. Chemothera py or immunotherapy should not be used, except in a clinical trial setting. Index Patient 2 has metastatic CRPC, but no symptoms or only mild symptoms, and has not been treated

Continued on page 46

Vol. 4

No. 5

Cancer Center Profile

Meridian Cancer Care’s Multidisciplinary Approach to Patient Care By Mark J. Krasna, MD Corporate Medical Director of Oncology, Meridian Cancer Care, NJ

rom the beginning, decisions about cancer treatment can be overwhelming. To help patients get back to the life and the people they love, Meridian Cancer Care offers every medical advantage. Medical collaboration is critical in the treatment of cancer. At Meridian Health, surgeons, medical oncologists, radiation oncologists, and other specialists work together to provide the best treatment plan for patients with cancer. Meridian Health, a leading not-forprofit healthcare organization in New Jersey—comprising Jersey Shore University Medical Center and K.

it is an integrated, 6-hospital system, with outstanding interhospital communication. By utilizing systemwide resources and building on the strengths already existing at each site, our goal is to provide excellence in cancer evaluation and treatment, with the caring and personal attention that is so important to patients and their families. Disease-Specific Multidisciplinary Program Meridian Health recently launched a new systemwide disease-site–specific multidisciplinary program that is

By utilizing systemwide resources and building on the strengths already existing at each site, our goal is to provide excellence in cancer evaluation and treatment. Hovnanian Children’s Hospital, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, Bayshore Community Hos pital, and Meridian Partner Com panies—is the first and only “system partner” of the Cancer Institute of New Jersey (CINJ). Meridian Health is unique, because

focused on elevating the level and the quality of care for patients. The renewed focus on a multidisciplinary, patient-centered approach provides opportunities for state-of-the-art care and research trials. Over the past 1.5 years, Meridian Health has instituted 9 disease-site– specific multidisciplinary conferences,

New Guideline Emphasizes... with docetaxel. Abiraterone (Zytiga) plus prednisone, docetaxel, or sipuleucel-T (Provenge) are options for patients with good performance status. First-generation antiandrogens, ketoconazole-plus-steroid combinations, and observation are other options for such patients, particularly patients who cannot use or who do not want to use standard therapies. Index Patient 3 has symptomatic metastatic CRPC, good performance status, and no previous exposure to chemotherapy. Patients with good performance status should be offered docetaxel, according to the guideline. Physicians may offer the combination of abiraterone and prednisone. For se-

JUNE 2013

which allow physicians to prospectively discuss cases and to reach a consensus regarding what is ultimately the best treatment plan for each patient. Focus on the Patient For patients, the result is more comprehensive, coordinated care. Once the treatment plan is established, nurse navigators work side by side with the patient, providing support and guidance and coordinating their care through every step of the cancer journey. The nurse navigators are the “glue” that holds the team together and the “go-to” people for patients and their families at any time in their care. Meridian Cancer Care has also recruited some of the top physician leaders in the country; the Thyroid Cancer Program, led by Alexander L. Shifrin, MD, will soon launch the first-ever multidisciplinary thyroid cancer clinic in the state of New Jersey. Over the past year, physicians at Meridian Cancer Care have published many articles and have shared their clinical knowledge in professional venues through meeting presentations, courses, and grand rounds.

Clinical Trials Portfolio A dedicated cancer research team is responsible for the ongoing expansion of an oncology clinical trials portfolio. These include cooperative group trials, Radiation Therapy Oncology Group trials, Gynecologic Oncology Group trials, and trials in conjunction with CINJ (CINJ Oncology Group). In addition, industry trials and new investigator-initiated trials for clinical and translational research have recently begun. With the support and the efforts of Meridian’s oncologists, the goals for cancer research in 2012 were surpassed at all Meridian facilities. Range of Services Meridian Cancer Care offers a complete range of services, including screenings; diagnostic tests; medical, surgical, and radiation oncology treatment options; onsite cancer registry; and pre- and posttreatment support groups. Meridian Cancer Care’s hospitals have each received accreditation from the American College of Surgeons Commission on Cancer and commendation for their cancer programs. n

Continued from page 44

lected patients who do not want or who cannot use standard therapy, physicians may offer ketoconazole plus a steroid, mitoxantrone (Novantrone), or radionuclide therapy. Patients in this category should not be offered estramustine (Emcyt) or sipuleucel-T. Index Patient 4 is defined by the presence of symptoms, metastases, and poor performance status, and no previous exposure to docetaxel therapy. These patients may be offered abir aterone plus prednisone, or alternatively, ketoconazole plus a steroid or radionuclide therapy when they are unable or are unwilling to use abir aterone. If a patient’s performance status is directly related to the disease,

Value-Based Cancer Care

Meridian's Nurse Navigators

physicians may offer docetaxel or mitoxantrone. This type of patient should not be offered sipuleucel-T. Index Patient 5 is symptomatic, has good performance status, and has been treated previously with docetaxel. These patients should be offered abir aterone plus prednisone, cabazitaxel (Jevtana), or enzalutamide (Xtandi). If those drugs are unavailable, physicians may offer ketoconazole plus a steroid. Retreatment with docetaxel also may be offered to patients who were benefiting from treatment but who discontinued because of reversible side effects. Index Patient 6 is symptomatic, has poor performance status, and has been

treated with docetaxel. Palliative care should be offered to patients in this category. Selected patients may be offered abiraterone plus prednisone, enzalutamide, ketoconazole plus a steroid, or radionuclide therapy. The patients should not be offered systemic chemotherapy or immunotherapy. Bone Health The guideline also addresses bone health in patients with metastatic CRPC. Physicians should offer treatment aimed at preventing fractures and skeletal-related events. Either den osumab (Xgeva) or zoledronic acid (Zometa) is an option for preserving bone health in this population. n

Vol. 4

No. 5

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

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 CareTM, is to provide our 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 explore a specific topic to be considered when developing value-based strategies. IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation. Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies. Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW 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 provide our 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-ef topic to be considered when developing value-based newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5 By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6 By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

www.valuebasedcancer.com/myeloma AVBCC100Ksize21213

CONTINUING EDUCATION

Faculty Perspectives

JUNE 2013 • VOLUME 4 • NUMBER 1

™

RECENT ADVANCEMENTS IN THE TREATMENT OF MULTIPLE MYELOMA PUBLISHING STAFF

LETTER

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

FROM THE

EDITOR

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

Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski

Sincerely,

Chief Operating Officer Pam Rattananont Ferris

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

Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

FACULTY

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

Meletios A. Dimopoulos, MD Chairman, Department of Medical Therapeutics University of Athens School of Medicine Athens, Greece

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean

Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, New York

Jesús F. San Miguel, MD Professor of Hematology University of Salamanca Head of the Department of Hematology University Hospital of Salamanca Spain

Digital Programmer Michael Amundsen

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

Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski

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

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

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june 2013

Vol. 4

No. 5

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

• Outline contemporary prognostic and predictive biomarkers and patient characteristics for multiple myeloma and apply the results to create an individualized approach to managing each patient

Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

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.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. 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 application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-013-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with multiple myeloma, and integrate key findings into clinical practice

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss either non-FDA-approved or investigational use for the following products/devices: lenalidomide, bortezomib, thalidomide, elotuzumab, MLN9708, carfilzomib, dexamethasone, cyclophosphamide, prednisone, melphalan, daratumumab, and pomalidomide. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose. Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose. Faculty Disclosures Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Johnson & Johnson, Millennium: the Takeda Oncology Company, and Novartis. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Meletios A. Dimopoulos, MD, is on the Advisory Board for Celgene Corporation and Ortho Biotech. He does intend to discuss either non-FDA-approved or investigational use for the following products/devices: lenalidomide and carfilzomib in the frontline treatment of MM.

Sergio A. Giralt, MD, is on the Advisory Board for and is a Consultant to Bioline, Celgene Corporation, Janssen Pharmaceuticals, Inc, Onyx Pharmaceuticals, sanofi-aventis, Seattle Genetics, Skyline Diagnostics, and Spectrum Pharmaceuticals, Inc. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Jesús F. San Miguel, MD, is on the Advisory Board for Celgene Corporation, Janssen Biotech, Millennium: the Takeda Oncology Company, Novartis, and Onyx Pharmaceuticals. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005A. 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: 1.0 hour Date of initial release: June 12, 2013 Valid for CME/CPE/CE credit through: June 12, 2014

Proceedings From a Post-IMW Roundtable Introduction The 14th International Myeloma Workshop (IMW 2013) held April 3-7, 2013, in Kyoto, Japan, was attended by renowned researchers and thought leaders from around the world. The numerous abstracts and presentations at this workshop demonstrated the outstanding progress that has been made in multiple myeloma (MM) management in the past 10 to 15 years and provided important insights for future clinical practice.

SMOLDERING MYELOMA Should Smoldering Multiple Myeloma Be Treated?

Smoldering multiple myeloma (SMM) is a precursor to symptomatic myeloma, and is characterized by an excess of monoclonal protein in the blood and urine, in which the patient experiences none of the symptoms (ie, elevated calcium levels, kidney failure, anemia, or bone lesions) typically associated with active disease.1 Overall, the risk for SMM progressing to MM is approximately 10% per year in the first 5 years.1 Although patients with SMM are at a higher risk for developing active myeloma than the general public, the current standard of care is the so-called “watch and wait” approach, in which they are regularly monitored and treatment only begins once the disease progresses to symptomatic MM. However, certain factors have been shown to be associated with an increased risk of progression in patients with SMM. These include a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10% in the bone marrow; an elevated level of phenotypically abnormal plasma cells in the bone marrow; an abnormal free light chain ratio; the presence of chromosomal abnormalities in plasma cells; and lower than normal levels of one or more types of immunoglobulin.1 At IMW 2013, María-Victoria Mateos, MD, and Jesús F. San Miguel, MD, discussed the question, “Should we treat smoldering MM?”2 They began by review-

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ing the history of studies that investigated the use of melphalan plus prednisone (MP), thalidomide, and/or bisphosphonates in patients with SMM. In the 1980s, a study by Hjorth and colleagues randomized 25 patients to receive MP therapy, started at the time of diagnosis, and another 25 patients to receive deferred therapy, in which MP was started at the time of disease progression. Results showed that no differences in response rate, duration of response (DOR), or survival were observed between treatment groups.3 Due to these findings, and the potential leukemic risk of long-term melphalan, the hematology community decided to dismiss the idea of early treatment and proposed instead that patients with SMM not be treated until they developed symptomatic disease.4 Later, when bisphosphonates were added to the MM armamentarium, investigators again decided to explore therapy for SMM. They observed that, although the number of skeletal-related events was lower and bone disease was delayed with these agents, no obvious antitumor effect was observed.5 With the advent of novel agents, the idea of early treatment was examined further.6 Witzig and colleagues conducted a small trial in which thalidomide plus zoledronic acid was compared with zoledronic acid alone for asymptomatic MM.7 Although the thalidomide arm was associated with a delay in time to biologic progression, no effect was seen regarding overall survival (OS) or time to progression (TTP) and the toxicity profile proved challenging. Therefore, the notion of treating SMM with thalidomide was not pursued.

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CONTINUING EDUCATION

Figure 1. Best response rates following a median of 5.5 cycles of CRd in high-risk SMM.10

100

100%

Patients Achieving Response (%)

87.5% 80

75%

12.5%

Perspective ORR

≥VGPR

nCR/CR/sCR

VGPR

CR indicates complete response; CRd; carﬁlzomib, lenalidomide, and dexamethasone; nCR, near-complete response; ORR, overall response rate; sCR, stringent complete response; SMM, smoldering multiple myeloma; VGPR, very good partial response.

Mateos and colleagues from the Spanish Myeloma Group hypothesized that patients with standard-risk SMM may not benefit from treatment, whereas highrisk patients may desire greater benefit. Therefore, they conducted a study in 125 high-risk patients in which 1 arm received 9 cycles of treatment with lenalidomide plus dexamethasone (Rd), followed by lenalidomide maintenance therapy, whereas the control arm received no treatment until disease progression to active MM.8 The results of this study showed that high-risk patients who received early treatment had significantly better outcomes than patients who did not receive treatment until disease progression. The response rate for the experimental arm was 82%, with 26% complete response (CR). Time to disease progression was longer for the actively treated patients (not yet reached at a median follow-up of 40 months in the experimental arm vs 21 months in the control arm), as was OS at 5 years after diagnosis (94% vs 80%, respectively). Perspective “The question, ‘Should we treat SMM?’, has been raised repeatedly over the years, and previous studies indicated that there was no difference in survival between early and deferred treatment. However, none of these previous studies focused on what I think should be the target for treatment in the SMM setting: the high-risk population. When the Spanish Myeloma Group investigated the use of early treatment with Rd in high-risk SMM patients, we found a very similar response rate to what we would expect in symptomatic patients and much higher than the response rates previously reported with thalidomide. In addition, the median TTP has not been reached in the experimental arm, whereas it was 21 months in the control arm. It is also important to emphasize that tolerability of this orally administered combination therapy was very good. However, probably the most relevant finding of the study is that we have observed a significant benefit in OS with a hazard ratio (HR) of 3.4 with a 3-year OS of 94% in the experimental arm versus 80% in the control arm. I think this is showing for the first time that early treatment could be of clear benefit for patients with high-risk smoldering disease. Additional trials focusing on this SMM population are needed to confirm these results.” ~Jesús F. San Miguel, MD

Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk SMM

On July 20, 2012, the US Food and Drug Administration granted accelerated approval for carfilzomib, a next-generation proteasome inhibitor, for the

treatment of patients with MM who had received ≥2 prior therapies including bortezomib and an immunomodulatory drug, and demonstrated disease progression on or within 60 days of completion of last therapy.9 At IMW 2013, Landgren and colleagues presented preliminary outcomes for 9 evaluable patients with high-risk SMM who were treated with a combination of carfilzomib, lenalidomide, and dexamethasone (CRd) in an ongoing phase 2, single-arm, pilot study.10 Patients received eight 28-day cycles of treatment consisting of carfilzomib (20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16); lenalidomide (25 mg/day on days 1-21); and dexamethasone (20/10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Those who achieved stable disease or better received 12 cycles of lenalidomide maintenance therapy (10 mg/day on days 1-21). Results showed that all patients responded to CRd therapy. Responses were rapid: the median time to CR/stringent CR, which was achieved in 4 patients, was 107 days. The best response rates (after a median of 5.5 cycles) are shown in Figure 1. Grade 3/4 nonhematologic toxicities included rash/pruritus, heart failure, and liver function abnormalities. Grade 3/4 hematologic toxicities included lymphopenia, anemia, neutropenia, and thrombocytopenia.

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“In this study, there was an impressive rate of very high-quality responses to CRd, with approximately 80% of patients achieving very good partial response or better (≥VGPR). The toxicities observed included hematologic toxicities such as lymphopenia and neutropenia, as well as one case of severe heart failure that required discontinuation of therapy and another case of significant liver dysfunction. To date, none of the evaluable patients have progressed to symptomatic MM. The overall response rate (ORR) is very encouraging and warrants further study.” ~Paul Richardson, MD

NEWLY DIAGNOSED MM Cyclophosphamide, Prednisone, and Lenalidomide vs Melphalan, Prednisone, and Lenalidomide vs Lenalidomide Plus Dexamethasone

Larocca and colleagues presented the results of a multicenter phase 3 study of cyclophosphamide, prednisone, and lenalidomide (CPR) versus melphalan, prednisone, and lenalidomide (MPR) versus Rd to evaluate the best combination in 663 patients with MM who were not eligible to receive autologous stem cell transplantation (ASCT).11 Results showed that CPR, MPR, and Rd produced response rates in elderly patients (>75 years) that were similar to those seen in the overall population (Figure 2). Grade 3/4 hematologic toxicities were experienced by 62% of patients in the MPR group, 29% of those in the CPR group, and 28% of those in the Rd group. Grade 3/4 nonhematologic adverse events (AEs) were similar in the 3 groups. Perspective “I think this is an important trial because it addresses patients who are not eligible for high-dose treatment. The preliminary data indicate that Rd produces good response rates and is much better tolerated than MPR. We are eager to see the impact of this regimen on progression-free survival (PFS) and OS. In addition, it will be important to see what second malignancies are reported. I suspect that fewer secondary malignancies will develop in the group of patients receiving Rd.” ~Meletios A. Dimopoulos, MD

Carfilzomib, Cyclophosphamide, and Dexamethasone

Palumbo and colleagues presented results from a phase 2 study of carfilzomib, cyclophosphamide, and dexamethasone (CCd) in 54 patients with newly diagnosed MM.12 Patients received carfilzomib (20 mg/m2 on days 1 and 2, and 36 mg/m2 on days 8, 9, 15, and 16 in cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 2-9); cyclophosphamide (300 mg/m2 on days 1, 8, and 15); and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for 9 cycles, followed by maintenance with carfilzomib (36 mg/m2 on days 1, 2, 15, and 16) every 28 days until progression.

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FACULTY PERSPECTIVES

Perspective “This is an important preliminary study of the frontline use of CCd. The response rate is remarkable. Essentially all patients achieved at least a PR, including approximately 1 in 4 patients who achieved an sCR. In addition, the responses were rapid. The PFS and OS data are excellent, as well. Furthermore, this treatment was well tolerated and the discontinuation rate was low; about 10% of patients discontinued treatment due to toxicities. I believe this is a very interesting combination that requires further evaluation in phase 3 trials.” ~Meletios A. Dimopoulos, MD

Cyclophosphamide, Bortezomib, and Dexamethasone

Areethamsirikul and colleagues presented results from a phase 2 study of induction therapy with the combination of cyclophosphamide (300 mg/m2 weekly); bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11); and dexamethasone (40 mg on days 1-4, 9-12, and 17-20) (CyBorD), given for four 28-day cycles, in newly diagnosed MM patients preparing for ASCT.13 Results showed an ORR of 88%, including 61% who achieved ≥VGPR. In an expanded cohort using weekly bortezomib (1.5 mg/m2) and dexamethasone (40 mg once weekly for cycles 3 and 4), similar response rates were attained (ORR 93%; ≥VGPR 60%). To compare the effectiveness of this regimen in the real-world setting, the authors reviewed their institutional experience (N=83) with CyBorD. The median age of these patients was 59 years (range, 37-71 years). MM subtypes included IgG 55%, IgA 20%, light chains only 22%, and other 3%. After a median of 4 cycles, responses were high (ORR 93%; ≥VGPR 70%). Grade 3/4 neutropenia (3.6%) and thrombocytopenia (<1%) were uncommon, and there were no cases of grade 3/4 peripheral neuropathy (PN). Dose delays/ reductions of any agents were required in 18% of patients. Stem cell mobilization was not compromised. Eighty of 83 patients proceeded to ASCT. The ORR at day +100 post-ASCT was 97% (≥VGPR 79%). The authors concluded that weekly CyBorD induction is highly effective in clinical practice, with response and toxicity profiles comparable to phase 2 trial data. Perspective “CyBorD is a highly active induction regimen for newly diagnosed patients. The therapy in this study was of particular interest because CyBorD was given weekly. I think it is very encouraging that 70% of patients had manageable toxicities with this approach and that no grade 3/4 neuropathy was reported. In fact, dose reductions were only necessary in 18% of patients and there was no compromise in stem cell collection with this regimen.” ~Paul Richardson, MD

Continuous Lenalidomide Therapy

Palumbo and colleagues reported the results of a phase 3 randomized study (MM-015), in which MPR induction followed by lenalidomide maintenance (MPR-R) was compared with MPR or MP followed by placebo in 459 transplant-ineligible patients with newly diagnosed MM who were ≥65 years of age.14 Results previously reported showed that median PFS in the overall population was significantly higher with MPR-R (31 months) than with MPR (14 months; P<.001) or MP (13 months; P<.001). The benefit was observed mainly in patients aged 65 to 75 years. At IMW 2013, the authors provided updated efficacy and safety data from this 65- to 75-year-old patient population. The proportion of patients in this

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Figure 2. Responses with CPR, MPR, and Rd: overall ITT population vs ITT population >75 years.11 100

Patients Achieving Response (%)

The median duration of treatment was 5 cycles. Responses improved with the duration of treatment reaching after 9 cycles: 100% partial response (PR), 77% VGPR, and 53% CR/near-complete response (nCR). Responses were rapid, with the median time to PR of 1 month and the median time to CR of 2 months. After a median follow-up of 7.5 months, the 1-year PFS was 87% and the 1-year OS was 88%. Grade 4 hematologic toxicities included neutropenia (5%). Grade 3/4 nonhematologic toxicities were infection (10%), cardiac events (5%), and gastrointestinal complications (2.5%). Five patients (12%) discontinued treatment and 7 patients (17%) required carfilzomib dose reductions due to AEs.

80 49%

45%

VGPR

ITT Population >75 Years of Age

Overall ITT Population 39%

54%

42%

37%

40 28% 27%

18%

13%

20%

11% 12%

CPR (n=222)

MPR (n=217)

Rd (n=220)

CPR (n=80)

14% 4%

MPR (n=86)

Rd (n=83)

CR indicates complete response; CPR, cyclophosphamide, prednisone, and lenalidomide; ITT, intent-to-treat; MPR, melphalan, prednisone, and lenalidomide; nCR, near-complete response; ORR, overall response rate; PR, partial response; Rd, lenalidomide plus prednisone; sCR, stringent complete response; VGPR, very good partial response.

age group was similar across treatment groups (76% MPR-R, 76% MPR, 75% MP). With a median follow-up of 30 months at final adjudication prior to unblinding, MPR-R significantly prolonged median PFS compared with MPR and MP (31 months vs 15 months vs 13 months, respectively; P<.001). With an updated median follow-up of 53 months, OS was 56 months with MPR-R, 54 months with MPR, and 52 months with MP. During induction, grade 3/4 neutropenia occurred in 68% (MPR-R), 63% (MPR), and 31% (MP) of patients; thrombocytopenia was reported in 36% (MPR-R), 41% (MPR), and 12% (MP); and febrile neutropenia in 4% (MPRR), 3% (MPR), and 0% (MP). During lenalidomide maintenance, the most common grade 3/4 newly occurring or worsening AEs (≥5% of patients) were thrombocytopenia (8%), anemia (7%), neutropenia (5%), diarrhea (5%), and bone pain (5%). The authors concluded that continuous treatment with lenalidomide is highly effective in transplant-ineligible patients aged 65 to 75 years, and could be considered a standard of care in this population. Perspective “This is an update of the MM-015 trial in which the subset of patients 65 to 75 years of age was analyzed. In this elderly population, no difference was seen between the 3 treatment groups in terms of OS; however, a significant improvement in PFS favoring the administration of lenalidomide maintenance was observed. This is the first trial in transplant-ineligible patients that showed an improvement in PFS with lenalidomide maintenance, and I think this information is very important. The ongoing phase 3 MM-020 study (also known as the FIRST study) is investigating Rd versus melphalan, prednisone, and thalidomide in patients with previously untreated myeloma. We expect results from that study to be presented later this year.” ~Meletios A. Dimopoulos, MD

Bortezomib Incorporated Into ASCT

At IMW 2013, Cavo and colleagues presented updated results of the outcomes of 1610 newly diagnosed MM patients, all of whom had available data on the presence or absence of del(13q), t(4;14), and/or del(17p), from the analysis of four phase 3 studies comparing up-front bortezomib (B)-based versus nonbortezomib (NB)-based single or double ASCTs.15 Results showed that, in comparison with NB-ASCTs, B-ASCTs significantly improved PFS in the overall population (HR=0.76), a benefit retained across both low-risk (HR=0.79) and high-risk (HR=0.58) subgroups, with improved OS (HR=0.85)

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CONTINUING EDUCATION seen with B-ASCTs. In a stratified multivariate analysis, independent variables associated with extended PFS and OS in the overall population included B-ASCTs (HR=0.74 and 0.79), achievement of CR (HR=0.46 and 0.44), and double ASCT (HR=0.44 and 0.31). These variables were also independent predictors for prolonged PFS and OS in patients with t(4;14) and/or del(17p). Patients who carried both of these cytogenetic abnormalities had the poorest prognosis and, in a multivariate analysis, were likely to benefit only from double ASCT (HR=0.13 for PFS and HR=0.28 for OS). The authors concluded that B-ASCTs significantly improved PFS in comparison with NB-ASCTs, but did not completely overcome the adverse prognosis related to the presence of t(4;14) and/or del(17p) and more mature data are needed before definite conclusions regarding the impact of B-ASCTs on OS can be made. Perspectives “This analysis was designed to compare outcomes for bortezomib-based induction regimens versus nonbortezomib-based induction regimens in a high-risk population that was defined by the presence of t(4;14) and/or del(17p). The results indicate that independent predictors of longer PFS and OS were bortezomib-based induction regimens, achievement of a CR, and double ASCT. The study showed a significant increase in PFS for bortezomib-treated patients in the overall population, and particularly in the population with high-risk cytogenetics. There was also a trend in favor of OS with bortezomib-based regimens. Overall, the analysis indicates that the use of bortezomib-based induction regimens improved the outcomes of patients with MM, although it did not completely overcome the detrimental effect of high-risk cytogenetics. Importantly, I think an intriguing result from this analysis was the benefit of double ASCT, particularly in patients with both abnormalities [ t(4;14) and del(17p)].” ~Jesús F. San Miguel, MD “I thought this was a very interesting presentation on many fronts. First of all, it established that the use of a proteasome inhibitor as part of induction therapy with transplant should be considered a new standard of care given the clinical benefit seen in this comprehensive analysis. In addition, this analysis provided new information about the use of double transplant in patients with high-risk cytogenetics. Prior to the era of novel therapies, the use of transplant in this high-risk group wasn't just ineffective, it was actually deleterious, presumably enhancing resistance, particularly in the del(17p) patients. Therefore, these results potentially provide a biological clue that the rebooting of the immunological profile of the patient with ASCT in conjunction with novel therapies may create a new therapeutic paradigm.” ~Paul Richardson, MD

Bortezomib, Reduced-Intensity ASCT, Followed by Lenalidomide

Magarotto and colleagues reported the results of a multicenter phase 2 study that evaluated a sequential approach including ASCT in 102 elderly patients with newly diagnosed MM.16 Patients received 4 cycles of bortezomib, pegylated doxorubicin, and dexamethasone, followed by tandem melphalan (100 mg/ m2) and ASCT (MEL100-ASCT), 4 cycles of lenalidomide plus prednisone (LP) consolidation, and lenalidomide maintenance until progression. In an intent-to-treat analysis, the CR rate was 33% after MEL100-ASCT, 49% after LP, and 54% after lenalidomide maintenance. At a median follow-up of 66 months, median TTP was 55 months, median PFS was 48 months, median OS was not reached, and OS at 5 years was 63%. The achievement of CR correlated with longer TTP (median, 70 months), PFS (median, 63 months), and OS (83% at 5 years). Median survival from relapse was 28 months. Overall, the main grade 3/4 toxicities included thrombocytopenia, neutropenia, infections, PN, gastrointestinal AEs, dermatologic toxicity, and thromboembolism. The incidence of second malignancies (skin cancer excluded) was 0.5% per year of follow-up. Deaths related to AEs occurred in 8 of 102 patients (only during induction or transplantation) and were higher in patients >70 years than in younger patients (19% vs 5%; P=.024).

Perspective “I would like to highlight several points in this interesting trial conducted in

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early myeloma patients. First, the CR rate is very high; it started at 33% and at the end of the study was 54%. In the maintenance phase, there was a prolonged PFS of 48 months and an OS at 5 years of 63%. I think this speaks in favor of aggressive treatment in this cohort of patients. Nevertheless, I believe that the major issue was the treatment-related mortality in patients older than 70 years. Therefore, from my point of view, this intensive approach may be a valid alternative for fit patients without comorbidities who are younger than 70 years.” ~Jesús F. San Miguel, MD

Early vs Delayed Transplantation

At IMW 2013, Philippe Moreau, MD, and Paul Richardson, MD, discussed the question, Should ASCT be used early in all eligible patients, or kept in reserve as a salvage treatment at the time of progression for selected patients achieving a high-quality response?17 In 2009, Stewart and colleagues published an article in which they wrote, “A reasonable goal of MM treatment in younger ‘transplant eligible’ patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control. To achieve this goal we recommend induction therapy with multiagent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteroids) which when employed together elicit frequent, rapid, and deep responses. We recommend consolidation with high-dose melphalan and ASCT in the majority of patients willing and able to undergo this procedure and subsequent maintenance therapy in those failing to achieve a CR or at high risk for early relapse based on prognostic, genetically defined risk factors. Defining genetic risk for early relapse is therefore an important aspect of early diagnostic testing, and attention to minimizing expected toxicities once therapy begins is critical in ensuring the efficacy of modern combination therapy approaches.”18 In 2010, Cavo and colleagues conducted a randomized phase 3 study of bortezomib, thalidomide, and dexamethasone (VTD) compared with thalidomide plus dexamethasone (TD) as induction therapy before, and consolidation therapy after, double ASCT in 480 newly diagnosed MM patients.19 After induction therapy, CR or nCR was achieved in 31% of patients who received VTD, and 11% of patients who received TD (P<.0001). The authors concluded that VTD induction therapy before double ASCT significantly improves rate of CR or nCR, and represents a new standard of care for patients with MM who are eligible for transplant. Richardson and colleagues at the Dana-Farber Cancer Institute conducted a phase 1/2 study of lenalidomide, bortezomib, and dexamethasone (RVD) combination therapy in 66 patients with newly diagnosed MM.20 One hundred percent of patients achieved ≥PR, with 74% in the phase 2 study and 67% of patients overall achieving ≥VGPR. Twenty-eight patients (42%) proceeded to transplantation. With a median follow-up of 21 months, estimated 18-month PFS and OS for RVD with and without transplantation were 75% and 97%, respectively. In 2011, Moreau and colleagues from the Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib plus dexamethasone (VD) as induction before high-dose therapy and ASCT versus a combination of reduced doses of VTD in 199 newly diagnosed MM patients.21 After 4 cycles, the CR rate was the same in both groups (13% in the VTD arm, 12% in the VD arm; P=.74). However, the CR plus VGPR rate was significantly higher in the VTD arm (49% vs 36%; P=.05). After ASCT, the CR plus VGPR rate was 74% in the VTD arm versus 58% in the VD arm (P=.02). McCarthy and colleagues conducted a study to determine whether lenalidomide maintenance therapy prolongs TTP after ASCT in 460 patients who were younger than 71 years and who had SD or a minimal response (MR), PR, or CR 100 days after undergoing ASCT.22 The study-drug assignments were unblinded when a planned interim analysis showed a significantly longer TTP in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease (PD) or had died (P<.001). Of the remaining 128 patients who received placebo and who did not have PD, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients (37%) who received lenalidomide and 132 of 229 patients (58%) who received placebo had disease progression or had died. The median TTP was 46 months in the lenalidomide group and

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FACULTY PERSPECTIVES 27 months in the placebo group (P<.001). More grade 3/4 hematologic and grade 3 nonhematologic AEs occurred in patients who received lenalidomide (P<.001 for both comparisons). Second primary malignancies (SPMs) occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). The authors concluded that lenalidomide maintenance therapy, initiated at day 100 after ASCT, was associated with greater toxicity and secondary cancers but a significantly longer TTP and significantly improved OS. Attal and colleagues also conducted a phase 3, placebo-controlled trial investigating the efficacy of lenalidomide maintenance therapy in 614 patients <65 years of age who had nonprogressive disease after first-line ASCT.23 Results showed that the median PFS was 41 months with lenalidomide maintenance therapy versus 23 months with placebo (P<.001). The incidence of SPMs was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patientyears in the placebo group (P=.002). Median event-free survival (EFS) (with events that included SPMs) was significantly improved with lenalidomide (40 months vs 23 months with placebo; P<.001). The authors concluded that lenalidomide maintenance after transplantation significantly prolonged PFS and EFS. Four years after randomization, OS was similar in the 2 study groups but more mature follow-up on these outcomes is eagerly awaited. Perspectives “In the comparison of early versus delayed transplant, the data that are available so far are in favor partially of early transplant based on the Siegel study derived from the ECOG trial in which lenalidomide plus high-dose or low-dose dexamethasone were analyzed. One subset of patients continued on primary therapy while another subset received early transplant. The 3-year OS was in favor of the patients who received early transplant.24 We also have data from a randomized trial in which, after 4 cycles of Rd, the patients were randomized to receive either 6 cycles of MPR or MEL-200 and then maintenance or no maintenance.25 So far, the study indicates that high-dose melphalan and autologous transplant is associated with a significant benefit in 2-year PFS, but no difference in OS. My personal position regarding early versus delayed ASCT is in favor of early transplant until we see results from the ongoing randomized IFM/ DFCI2009 trial,26 which is comparing conventional dose treatment using RVD versus high-dose treatment with peripheral ASCT in the initial management of myeloma in patients 65 years or younger. Until this data is available, I prefer early transplant because the patient is more fit upfront to tolerate intensive and repetitive therapies and is also more prepared psychologically for intensive therapies. In addition, I favor early transplant because it is associated with long-term treatment-free intervals during which patients experience an excellent quality of life, and also because, in countries such as Spain, transplant is a less costly approach than those that use novel agents. My final argument for offering my patients early transplant (until the randomized data from the aforementioned trial becomes available) is that, at the time of relapse after MEL-200, patients are very sensitive to novel agents. I don't know yet what the efficacy of MEL-200 is after long-term exposure to novel agents. This is because most of the data that we have so far with late transplant has been with chemotherapy, not novel agents. Therefore, for these reasons I prefer to be conservative and continue to offer early autologous transplant until data from randomized trials become available.” ~Jesús F. San Miguel, MD “The current data that we have in support of early transplant are based on regimens that do not include a proteasome inhibitor. Because of this, it is still premature to say that early transplant is the standard. I think we recognize that, for a proportion of patients, early transplant may be beneficial. The key question is: Is it beneficial for all patients? In the United States, patients remain quite reluctant to undergo early transplant—particularly with the excellent results now achieved with novel therapy combinations. I think Dr San Miguel’s point about resistance is well taken but, certainly from a pharmacological standpoint, one might expect the opposite, where resistance after prior conventional chemotherapy with melphalan would be the worry but would not be so with novel therapies. In fact, we didn't see this in our current studies, suggesting that we wouldn't expect primary resistance. However, I do agree that the timing of myeloablation and immunological

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reconstitution is a critical question, and I think this is what we'll learn from the ongoing randomized trials. The notion that patients are better able to tolerate a transplant early does certainly apply to a subgroup of patients, but not to all patients. Regarding psychological readiness for transplant, some patients actually find undergoing transplant later in their disease course somewhat easier to come to terms with than they would have soon after diagnosis. In addition, we must be concerned about genotoxic injury in a small subset of patients who are vulnerable to secondary myelodysplasia and leukemia. Therefore, it is very important to identify these patients and potentially spare them from the real risk of such complications both acutely and long term.” ~Paul Richardson, MD

RELAPSED/REFRACTORY MM Lenalidomide Plus Low-Dose Dexamethasone

At IMW 2013, Gomes presented results of a retrospective study in 7 first-relapse MM patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) who were treated with Rd.27 Results showed an ORR of 71% (5/7 patients). The 2 patients who did not respond had prior exposure to thalidomide. The median DOR was 21 months, and in 4 of 7 patients (57%) the response was longer than 2 years. Forty-three percent of patients experienced renal improvement, and 2 patients continued on dialysis. No serious infections or SPMs were observed.

Perspective “As we are all aware, the first relapse after initial primary therapy is extremely difficult to treat and we have very little randomized phase 3 data on this population. In addition, while it is difficult to treat patients in this population who have normal renal function, it is even more difficult to treat those patients with impaired renal function. This is especially true because there is a false perception that lenalidomide should not be used in patients with impaired renal function even though adequate guidelines have been published on how to safely use this drug in patients with low CrCl. The study by Gomes demonstrated that good, durable remissions with an acceptable safety profile could be achieved when Rd was administered to a group of first-relapse patients with severe renal impairment. Although the number of patients was relatively small, these preliminary results suggest that this combination may be helpful for such patients who cannot take bortezomib or for whom carfilzomib is not available.” ~Sergio A. Giralt, MD

Pomalidomide Plus High- vs Low-Dose Dexamethasone

Dimopoulos and colleagues reported updated survival results of a phase 3, multicenter, randomized, open-label study (MM-003) of pomalidomide plus either low-dose dexamethasone (POM+LoDEX) or high-dose dexamethasone (POM+HiDEX) in 455 patients with relapsed/refractory MM.28 Patients must have been refractory to their last prior therapy (ie, they must have developed PD during or within 60 days) and failed lenalidomide and bortezomib (alone or in combination) after receiving ≥2 consecutive cycles of each. The study design was described previously at ASH 2012.29 Patients had received a median of 5 prior therapies and 72% were refractory to lenalidomide and bortezomib. Median follow-up was 4 months. PFS and OS were significantly longer in the group that received POM+LoDEX than the group that received POM+HiDEX in the overall population, as well as in patients refractory to lenalidomide and bortezomib, in those with lenalidomide or bortezomib as their last prior therapy, and in both those with normal (CrCl ≥60 mL/min) or moderately impaired (CrCl <60 mL/min) renal function. After data evaluation, the Data Monitoring Committee recommended crossover from POM+HiDEX to POM+LoDEX. With updated data, ORRs were 21% for POM+LoDEX and 3% for POM+HiDEX (P<.001). The most frequent grade 3/4 AEs for the lowdose versus high-dose dexamethasone groups were neutropenia (42% vs 15%), anemia (27% vs 29%), and infections (24% vs 23%). The rates of discontinuations due to AEs were low: 7% in the POM+LoDEX group and 6% in the POM+HiDEX group.

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Figure 3. Responses to POM+LoDEX vs pomalidomide alone.30

Table. Determining the MTD in a Phase 1 Study of PVD31

Patients Achieving Response (%)

ORR

Low-Dose Dexamethasone Dose (Days 1-2, 4-5, 8-9, and 11-12b)

Cohort

1 mg/day

1 mg/m2

20 mgc

2 mg/day

1 mg/m

20 mgc

3 mg/day

1 mg/m2

20 mgc

4 mg/day

1 mg/m

20 mgc

4 mg/day

1.3 mg/m2

20 mgc

31%

Cohort 6 (Expansion Cohort; n=6) at MTD/MPD

For cycles 1-8, then Days 1 and 8 for cycle 9 and beyond. b For cycles 1-8, then Days 1-2 and 8-9, for cycles 9 and beyond. c 10 mg for patients older than 75 years. a

15%

14%

MTD indicates maximum planned dose; MTD, maximum tolerated dose; PVD, pomalidomide, bortezomib, and low-dose dexamethasone.

Pomalidomide + Low-Dose Dexamethasone (n=113)

Pomalidomide Alone (n=108)

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

Perspective “I think this randomized, controlled phase 3 trial is very important because it evaluates the role of a novel combination, pomalidomide plus low-dose dexamethasone, in patients with very advanced, refractory myeloma. The control arm received high-dose dexamethasone because patients for whom lenalidomide and bortezomib are not options, and who have no access to clinical trials with novel investigational agents, steroids (such as high-dose dexamethasone) are frequently administered to palliate their disease. The main finding of the study is that the administration of pomalidomide with low-dose dexamethasone improves PFS. In fact, the PFS is doubled with this regimen. In addition, an OS advantage clearly favoring this combination was seen. This regimen was relatively well tolerated, considering the advanced nature of the disease in this population of patients, who have frequent infectious episodes and borderline blood counts. The main toxicity observed was myelosuppression. The main nonhematologic toxicities were infections, which were equally distributed between the 2 groups. It is important to note that no significant deep-vein thrombosis or PN were reported with this regimen.” ~Meletios A. Dimopoulos, MD

Pomalidomide Plus Low-Dose Dexamethasone

Jagannath and colleagues presented the results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide alone versus POM+LoDEX in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.30 The encouraging responses for the overall population are shown in Figure 3. The median DOR (for patients who achieved ≥PR) was 45 months in the POM+LoDEX group and 31 months in the pomalidomide alone group. Results of a subanalysis based on age (≥65 years vs <65 years) showed that age had no impact on the duration or depth of response. The median PFS for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received pomalidomide alone. The most common grade 3/4 AEs were neutropenia (41%), anemia (22%), thrombocytopenia (19%), and pneumonia (22%). Tolerability was similar across the different age groups. The authors concluded that, in patients with relapsed and refractory MM who have received multiple prior treatments including lenalidomide and bortezomib, pomalidomide (with or without low-dose dexamethasone) was clinically effective and generally well tolerated. Response rates were encouraging and consistent, as well as durable regardless of age.

Bortezomib Dose (Days 1, 4, 8, 11a)

34%

Number of Patients

Pomalidomide Dose (Days 1-14)

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Perspective “In our intent-to-treat analysis, we found that efficacy outcomes for the overall population of the subgroups were very promising in such a heavily treated population. In the patients who were younger than 65 years, the ≥PR rate for POM+LoDEX was 31%, and the ≥MR rate was 47%. These rates were similar in the older patients (37% and 43%, respectively). The median DOR rates were also similar between groups. The results of this analysis show that patients with relapsed and refractory MM respond well to POM+LoDEX, irrespective of age.” ~Paul Richardson, MD

Pomalidomide, Bortezomib, and Low-Dose Dexamethasone

Richardson and colleagues presented results of a phase 1 multicenter, dose-escalation study (MM-005) of pomalidomide, bortezomib, and low-dose dexamethasone in 15 patients with relapsed and/or refractory MM.31 Patients were divided into 5 cohorts in a 3 + 3 design for 21-day cycles, as shown in the Table, followed by an expansion cohort. They were evaluated every 21 days and followed for 5 years. Patients with 1 to 4 prior antimyeloma therapies, PD during a lenalidomide-containing treatment or within 60 days of last dose, and proteasome inhibitor exposure (but not bortezomib-refractory) were eligible to participate. All 15 patients had prior lenalidomide and bortezomib exposure; 73% of patients had progressed on lenalidomide as their last prior regimen. As of October 15, 2012, no dose-limiting toxicities (DLTs) were observed. Confirmation of the maximum tolerated dose is ongoing. Grade 3/4 AEs included thrombocytopenia (27%) and neutropenia (27%). Grade1/2 PN (none painful) occurred in 4 patients. No thromboembolism occurred. Three patients discontinued therapy, but none due to AEs. At the data cutoff, 73% of patients had achieved ≥PR, including 27% VGPRs (Figure 4). Responses were also observed in patients with adverse cytogenetic profiles. Perspective “In this trial, patients had to have received 1 to 4 prior anti-myeloma therapies; it was required that they were refractory to lenalidomide but had to be responsive to bortezomib. The ORR was 73% at data cutoff, with a rapid median time to response and very favorable tolerability. This regimen will now provide a platform for an ongoing phase 3 trial of pomalidomide 4 mg, bortezomib 1.3 mg/m2, and dexamethasone 20 mg (according to the schedule described) versus bortezomib, dexamethasone, and placebo administered on the classic schedule (D 1, 4, 8, 11 every 21 days).” ~Paul Richardson, MD

MLN9708

At IMW 2013, Kumar and colleagues reported the safety and pharmacokinetic results of early studies of MLN9708, administered alone in relapsed/ refractory MM patients or in combination with lenalidomide and dexameth-

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Figure 4. Duration of responses with PVD.31

Unconﬁrmed PR as of data cut. PD indicates progressive disease; PR, partial response; PVD, pomalidomide, bortezomib, and lowdose dexamethasone; SD, stable disease; VGPR, very good partial response.

asone in newly diagnosed MM patients.32-34 In the ongoing phase 1 single-agent study in relapsed/refractory MM patients, DLTs included grade 3 rash and gastrointestinal AEs. Common drug-related AEs included thrombocytopenia (45%), diarrhea (37%), and nausea (35%); grade ≥3 AEs included thrombocytopenia (33%), diarrhea (17%), and neutropenia (17%). Grade 1/2 PN was observed in 10% of patients, with no grade ≥3 PN observed. Pharmacokinetic data showed rapid absorption, a terminal half-life of 4 to 12 days, and a proportional increase in plasma area under the curve with dose (0.8-3.95 mg/m2). Thus, single-agent MLN9708 appeared generally well tolerated; the long terminal half-life supports weekly dosing.33 In an ongoing phase 1/2 study of MLN9708 plus lenalidomide and dexamethasone in newly diagnosed patients, common AEs included rash (68%), fatigue (48%), nausea (42%), and PN (32%; 3% grade 3). MLN9708 pharmacokinetic data showed no apparent differences between single-agent and combination dosing, suggesting no pharmacokinetic interaction with lenalidomide or dexamethasone.34 Data from these studies provide the rationale for weekly dosing of MLN9708 at 4.0 mg combined with lenalidomide and dexamethasone in an ongoing phase 3 trial in relapsed/refractory MM. MLN9708 in combination with lenalidomide and dexamethasone is also being evaluated in another phase 3 study in patients with newly diagnosed MM who are not candidates for transplant. Perspective “MLN9708 has been referred to as ‘the oral bortezomib.’ We were all impressed regarding the response rates in patients with relapsed/refractory myeloma as well as in the upfront setting. I think we are going to see a new generation of anti-myeloma agents that have new mechanisms of action (eg, monoclonal antibodies) and oral agents that will make treatment much easier to administer.” ~Sergio A. Giralt, MD

References

1. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347–1349. 2. Mateos MV, San Miguel J. Should we treat smoldering multiple myeloma? Haematologica. 2013;13(suppl 1):S20-S21. Abstract S11-3. 3. Hjorth M, Hellquist L, Holmberg E, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993;50:95-102. 4. San Miguel JF, Bladé Creixenti J, García-Sanz R. Treatment of multiple myeloma. Haematologica. 1999;84:36-58. 5. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer. 2008;113: 1588-1595. 6. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008;112:3122-3125.

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7. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013;27:220-225. 8. Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance therapy with Len alone vs no treatment. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 991. 9. Krypolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 10. Landgren CO, Manasanch E, Kwok M, et al. Phase II study: carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) in high risk SMM (early myeloma). Haematologica. 2013;13(suppl 1):S39-S40. Abstract O-6. 11. Larocca A, Magarotto V, Offidani M, et al. Lenalidomide-dexamethasone vs melphalan-prednisone-lenalidomide vs cyclophosphamide-prednisone-lenalidomide in NDMM. Haematologica. 2013;13(suppl 1):S113-S114. Poster P-146. 12. Palumbo A, Bringhen S, Petrucci MT, et al. A phase II trial of carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma patients. Haematologica. 2013;13(suppl 1):S112-S113. Abstract P-145. 13. Areethamsirikul N, Masih-Khan E, Chu CM, et al. CyBorD induction therapy for multiple myeloma in clinical practice. Haematologica. 2013;13(suppl 1):S140. Abstract P-202. 14. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide therapy in patients with newly diagnosed MM aged 65-75 years: MM-015 update. Haematologica. 2013;13(suppl 1):S152. Abstract P-227. 15. Cavo M, Sonneveld P, Moreau P, et al. Impact of bortezomib incorporated into auto transplantation on outcomes of myeloma patients with high-risk cytogenetics. Haematologica. 2013;13(suppl 1):S158-S-159. Abstract P-241. 16. Magarotto V, Gay F, Rossi G, et al. Bortezomib, reduced-intensity transplantation followed by lenalidomide for newly diagnosed elderly MM patients. Haematologica. 2013;13(suppl 1): S119-S120. Abstract P-158. 17. Moreau P, Richardson P. Debate: early or delayed transplantation for multiple myeloma in the era of novel therapies: does one size fit all? Haematologica. 2013;13(suppl 1):S17. Abstract S9-4. 18. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114:5436-5443. 19. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 20. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116:679-686. 21. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduceddose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118: 5752-5758; 5982. 22. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. 23. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 24. Siegel DS, Jacobus S, Rajkumar SV, et al; on behalf of the Eastern Cooperative Oncology Group. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 38. 25. Palumbo A, Cavallo F, Hardan I, et al. A phase III study to compare melphalan, prednisone, lenalidomide (MPR) versus melphalan 200 mg/m2 and autologous transplantation (MEL200) in newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 3573. 26. ClinicalTrials.gov. Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years (IFM/DFCI2009). http://clinicaltrials.gov/ct2/show/NCT01191060. 27. Gomes FR. Lenalidomide in the treatment of first relapsed multiple myeloma patients with severe renal impairment. Haematologica. 2013;13(suppl 1):S95. Abstract P-108. 28. Dimopoulos MA, Weisel KC, Moreau P, et al. Progression-free survival (PFS) and overall survival (OS) advantages with pomalidomide + low-dose dexamethasone: MM-003. Haematologica. 2013;13(suppl 1):S134. Abstract P-189. 29. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract LBA-6. 30. Jagannath S, Richardson PG, Hofmeister C, et al. Pomalidomide with or without low-dose dexamethasone in relapsed and refractory multiple myeloma: updated analysis. Haematologica. 2013;13(suppl 1):S143-S144. Poster P-210. 31. Richardson PG, Hofmeister CC, Siegel DS, et al. Ph 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma. Haematologica. 2013;13(suppl 1):S128-S129. Poster P-178. 32. Kumar S, Niesvizky R, Berdeja JG, et al. Safety and pharmacokinetics of weekly MLN9708, an investigational oral proteasome inhibitor, alone and in combination. Haematologica. 2013;13(suppl 1):S154. Abstract P-230. 33. Kumar S, Bensinger WI, Craig B, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: results from a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 816. 34. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 332.

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