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DECEMBER 2011 VOL 2 NO 7

www.ValueBasedCancerCare.com BEST PRACTICES

CTRC-AACR/SABCS MEETING

Frontier Cancer Care in Montana on the Leading Edge of Patient Care

Dual HER2 Blockade with Pertuzumab Substantially Delays Disease Progression Additional 6-month remission time reported Photo Courtesy © SABCS/Todd Buchanan 2011

The economic value of community cancer centers

By Caroline Helwick

Interview with Patrick Cobb, MD, FACP Dr Cobb is Managing Partner, Frontier Cancer Care and Blood Institute, Billings, MT, and former President of Community Oncology Alliance

San Antonio, TX—It is becoming increasingly clear that 2 agents are better than 1 in treating HER2-positive advanced breast cancer. The latest evidence comes from the results of the phase 3 clinical trial CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), which were presented at the 2011 CTRC-AACR/San Antonio Breast Cancer Symposium by Jose Baselga, MD, PhD, Professor of Medicine, Harvard Medical School and AssocContinued on page 12

ASH ANNUAL MEETING

Advances in the translation of research into medical practice have improved the lives of many patients in the United States, particularly for those with cancer. In this interview, Dr Cobb describes the state-of-the-art cancer center that he and his colleagues opened last year to further transform care for patients with cancer in Montana and set an example for Cancer Clinics of Excellence. Continued on page 9

VBCC Perspective, page 26

5-Year Analysis of VISTA Confirms Survival Advantage with Bortezomib for Patients with Myeloma Average patient lived 13 months longer with this drug added to the first-line regimen By Audrey Andrews

GPCI, or “GYPSY”: Calculated or Covert Cuts to Oncology Reimbursement

San Diego, CA—Patients with multiple myeloma receiving bortezomib (Velcade) in the pivotal VISTA trial lived more than 1 year longer than those in the control group, according to the final, 5-year analysis of the study

By Bo Gamble Director of Strategic Practice Initiatives, Community Oncology Alliance (www.communityoncology.org)

A

dear friend recently recanted to me some stories about her recent trip to Italy. One of her more memorable moments was bearing witness to a couple of young Gypsies slipping the wallets out of the

pockets of some unsuspecting tourists. Within a nanosecond, cash and credit cards were gone. Thankfully, my friend saved the day by hurriedly calling attention to the heist, and the Continued on page 16

©2011 Engage Healthcare Communications, LLC

presented at the 2011 American Society of Hematology annual meeting. The benefit was seen across multiple prespecified patient subgroups and was maintained after 5 years of followContinued on page 26

INSIDE LETTER TO THE EDITOR FDA UPDATE

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Intriguing data on medical home

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Ruxolitinib first drug approved for MF Cetuximab gains new indication MEETING HIGHLIGHTS

CTRC-AACR SABCS meeting . . .12 ESMO annual meeting . . . . . . . . . . .18 ASTRO annual meeting . . . . . . . . . .23

HEALTH POLICY

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Considerable time spent dealing with insurance companies ONCOLOGY TRENDS

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The pace of change in cancer management

DRUG DEVELOPMENT . . . . . . . . . . .50

Economic implications of oncology biosimilars


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New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

VELCADE (Vc) in combination with MP.

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.


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UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

80

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

10

MP (n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

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Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

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

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) 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.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. 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. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. 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 13%. 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 Disorders:: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, 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, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders:: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) 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, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS):: There have been reports of RPLS in patients receiving VELCADE. RPLS 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 RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events:: 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. 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, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome:: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). 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. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. 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) m 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, the drug 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 VELCADE 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 VELCADE.com.

Hepatic Events:: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment:: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing 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.

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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 © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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VALUE PROPOSITIONS Practices Are Merging to Cut Costs, Increase Quality: The Future of Cancer Care?

Targeting Tumor’s Environment a Cost-Effective Approach to Drug Development

Diablo Valley Oncology and Pacific Urology—2 of Contra Costa County, CA, largest private specialty practices—are merging forces to form the first oncology–urology multispecialty practice in their area. Responding to the impending cuts in Medicare to providers, the 2 practices have “concluded that combining our practices secures the future for both organizations and consequently the quality of care of our patients,” said Matthew Sirott, president and CEO of Diablo Valley Oncology. “In the end, it’s a win–win for us and our patients. Now we’ll be able to see more patients in more locations, reduce overhead expenses, and collaborate more closely than ever” (www.pacificurology.com/merger-announcement; November 11, 2011).

Some drug makers are shifting their focus from cancer cells to the tumor’s entire environment, including the surrounding blood vessels, proteins, and molecules as a way to inhibit tumor growth. Specifically, 3 companies in Cambridge, MA, are focusing their efforts on targeting the tumor’s environment rather than on cancer cells to kill cancer: • Infinity Pharmaceuticals is testing a drug for pancreatic cancer that disrupts the microenvironment of the tumor by depleting the protective tissue around it and allowing chemotherapy to reach the cancer cells more easily. • Pervasis Therapeutics is experimenting with embedding healthy blood vessel cells into an implant inside the tumor, which resulted in the inhibition of tumor growth in mice. • Axios Biosciences is creating diagnostic tools to enable more accurate drug testing and screening by including the tumor’s environment in the screening. This approach reflects the realization that the normal cells in the healthy environment of the tumor may have something to do with the disease itself, and therefore studying the tumor’s environment may lead to a cost-effective approach to killing tumors (New York Times, November 14, 2011).

Greater Role of NPs/PAs in Oncology Increases Practice Productivity A study published in the Journal of Oncology Practice (September 15, 2011) suggests that increasing the roles of nurse practitioners (NPs) and physician assistants (PAs) is an effective way to deal with the projected workforce shortages in oncology. The study showed that practices in which the roles of these 2 groups are expanded to work more independently with patients and with all practice physicians are 19% more productive than those in which NPs and PAs are assigned to specific physicians or do not see patients independently.

New Phenotypic Screening Platform Improves Drug Development, Reduces Cost, Time At the November 12-16, 2011, American Association for Cancer Research Molecular Targets and Cancer Therapeutics meeting, National Cancer Institute (NCI) scientists revealed a new phenotypic, cell-specific platform to evaluate the effectiveness of angiogenesis inhibitors. “This platform allows us to predict what’s going to happen in preclinical models,” said Enrique Zudaire, PhD, radiation oncology scientist at NCI. “This not only shortens the amount of time that you would need to do screenings and drug discovery, but also enhances dramatically the success you are going to have in the next phases.” Unlike past research, which focused on single molecular targets for angiogenesis inhibitors, this new platform examines the way angiogenic inhibitors simultaneously act on the entire angiogenesis process. This can reduce early-phase failure rate, by targeting not only one potential enzyme but the way the enzyme works in a complex organization that could lead to several drug options, which increases the chance for success. Using this approach has helped identify more than 100 key compounds, all of which demonstrated antitumor activity; some blocked tumor growth more effectively than currently available angiogenesis inhibitors. By improving the “initial phases of drug discovery, we can decide where to invest time and money on drugs that are a lot more likely to work,” said Dr Zudaire.

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IOM’s Report on Essential Health Benefits: Balancing Cost and Coverage On October 6, 2011, the Institute of Medicine (IOM) released its consensus statement on what constitutes essential health benefits (EHBs), as mandated by the Affordable Care Act (ACA) of 2010. This “package”of benefits constitutes the minimum set of benefits that health plans must cover under the ACA, although insurers may opt to offer additional benefits. The IOM statement notes that the committee recognized 2 competing goals: “to provide health insurance coverage for a wide range of health needs and to make it affordable” (www.iom.edu/reports/2011/essential-health-benefits-coveragebalancing-coverage-and-cost). The committee further states that “keeping the EHB affordable is necessary for consumers, employers, and taxpayers.” The committee concludes: “Unless we are able to balance the cost with the breadth of benefits covered in the EHB, we may never achieve the health care coverage envisioned in the ACA. If the benefits are not affordable, fewer individuals will buy insurance. If accessing benefits is too difficult, people will not get the care that they need. And if health care spending continues to rise so rapidly, the benefits covered under the EHB will begin to erode, eventually resulting in minimal coverage for the people who need it most.”

ACCC Launches Workbook to Assess Value of Hospital Oncolytics The Association of Community Cancer Centers (ACCC) has launched a new workbook—The Practical Cancer Pharmacy Workbook—to provide hospital cancer program pharmacy and financial teams a practical tool to assess the pharmacoeconomics of cancer drug therapies used in hospitals, “which explores the relationship between costs of healthcare interventions and the outcomes they produce” and to assess the “value associated with drugbased therapy” (ACCC press release, September 1, 2011).

www.ValueBasedCancerCare.com

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IN THIS ISSUE

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editors Brett Kaplan Lara J. Lorton Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino

CTRC-AACR SABCS ANNUAL MEETING

IN THE LITERATURE

Pertuzumab delays disease progression in HER2 breast cancer BOLERO-2: Everolimus prolongs remission SWOG: 2 antiestrogens improve survival in metastatic disease More….

Axitinib promising second-line therapy for advanced renal cancer Bortezomib–rituximab combo improves PFS in relapsed follicular lymphoma Second-generation TKIs produce optimal response much faster than imatinib More….

HEALTH POLICY Calculated or covert cuts to oncology reimbursement Medical staff members spend many hours dealing with insurance companies More….

ONCOLOGY TRENDS The pace of change in oncology management and its impact

VBCC PERSPECTIVE Clinical and economic impact of multiple myeloma

ASTRO ANNUAL MEETING Reporting gap for radiation near-misses and errors is rampant High-dose radiation does not improve survival in advanced NSCLC More….

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NOISE-CANCELING INFORMATION NE See article online or submit your questions at www.valuebasedcancercare.com/submit-noise

Business Manager Blanche Marchitto

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. BPA Worldwide membership applied for August 2010. Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881 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 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 7 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 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. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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VBCC Editorial Board Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL Immediate Past President, ACCC Past Chair, NCCN Board of Directors Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Florida Comprehensive Cancer Network, Melbourne, FL

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI Community Cancer Centers Program Towson, MD Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Ira Klein, MD, MBA Aetna Hartford, CT Crystal Kuntz, MPA Astellas Pharma US Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

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

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Lynn Nishida, RPh RegenceRX Portland, OR

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

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

Naimish Pandya, MD University of Maryland Baltimore, MD

David Hom, MBA Solucia Farmington, CT Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

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December 2011

Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY Section Editor

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

Denise K. Pierce DK Pierce & Associates Zionsville, IN

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LETTER TO THE EDITOR

Intriguing Information Provided on Oncology Medical Home To the Editor: We are so proud and happy for John D. Sprandio, MD, and his service that they have been accredited as a medical home by the National Committee for Quality Assurance (NCQA). We are certainly proud of our cancer institute being recognized by the American Society of Clinical Oncology as a Quality Oncology Practice Initiative, and we will join Dr Sprandio in seeking an NCQA accreditation. We were intrigued by the data Dr Sprandio offered in the October 2011 issue of Value-Based Cancer Care in his discussion of an oncology and hematology medical home. For many years we have viewed emergency department visits as a failure on the part of the practice, and we review all such visits the morning after they occur to determine whether they were necessary, and how they might have been prevented. We were also intrigued by Dr Sprandio’s mention that for their 9 doctors last year, his call service took 3900 calls. For the 3 providers in our own clinic service, our triage nurse takes in excess of 4000 calls annually, and additional calls go to the medical assistants and the chemotherapy nurses for problem-solving. It was gratifying for us to know that with 3 providers, we are far ahead of the standard set by the 9 providers in Dr Sprandio’s service. We further anticipate that with the implementa-

tion of an electronic medical record system in 2012, we will be able to set our own standards for the level of care provided in our oncology medical home. We appreciate the information

that the journal and Dr Sprandio have made public. It gives us some concept of where we are in terms of the level of practice and care that we provide in our own community.

Albert M. Brady, MD, FACP Cancer Institute of Washington Washington Hematology-Oncology Yakima, WA

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: Q 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Letters Readers are invited to submit letters to the editor in response to articles discussed in a previous issue of Value-Based Cancer Care or on a topic of interest relevant to the readership of this journal. Letters must be identified by the writer(s) and provide full contact information of the corresponding author, including e-mail and telephone number. Unidentified letters are not considered for publication. Length is flexible but must not exceed 400 words. All letters are edited for grammar and style. Authors are not notified if a letter is published, unless specifically requested. Submit your letter to: Jennifer@generaladminllc.com. For more information contact Jennifer at Jennifer@general adminllc.com. Tel: 732-992-1536.

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Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta ®-treated patients as compared with placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2011 Amgen. All rights reserved.

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FDA UPDATE FDA Revokes Bevacizumab’s Breast Cancer Indication The FDA has revoked its previous accelerated (and conditional) approval for bevacizumab (Avastin, Genentech) for the treatment of metastatic breast cancer (MBC), citing safety concerns that outweigh its benefits in this

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

patient population. After reviewing the postapproval clinical trial data, FDA Commissioner Margaret A. Hamburg, MD, concluded that “it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects, without proof that the use of

(n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder: Sickle cell crisis and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders: Sweet’s syndrome, are bone pain and pain in extremity. Cutaneous vasculitis Clinical Trials Experience Because clinical trials are conducted under widely varying DRUG INTERACTIONS conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice. Neulasta clinical trials safety data are based upon 932 patients these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The USE IN SPECIFIC POPULATIONS population was 21 to 88 years of age and 92% female. The Pregnancy ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy Category C 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant tumors (n = 53) and lymphoma (n = 56) received Neulasta women. Pegfilgrastim was embryotoxic and increased after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative received a single 100 mcg/kg (n = 259) or a single 6 mg doses approximately 4 times the recommended human dose (n = 546) dose per chemotherapy cycle over 4 cycles. (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta

Avastin will provide a benefit.” Bevacizumab’s associated adverse effects include severe hypertension, bleeding and hemorrhaging, heart attack or heart failure, and gastrointestinal perforations. The drug received accelerated approval in 2008 for use in combina-

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

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tion with paclitaxel for the treatment of HER2-negative MBC in patients who had not previously received chemotherapy based on demonstrated improved progression-free survival (PFS) but not improved overall survival (OS). New results from 2 postapproval studies showed that the drug had only a small effect on breast cancer tumor growth, without demonstrating improved OS or that patients had a better quality of life than those receiving chemotherapy alone. The FDA’s end point for complete (as opposed to accelerated) drug approval relies on OS data, not on PFS alone. Bevacizumab’s other indications, for the treatment for certain types of colon, lung, kidney, and brain cancers, are not affected by this decision. (November 18, 2011) ■

Asparaginase Erwinia chrysanthemi for ALL The FDA approved asparaginase Erwinia chrysanthemi (Erwinaze, Eusa Pharma) for the treatment of acute lymphoblastic leukemia (ALL) in patients with hypersensitivity to Escherichia coli–associated asparaginase and pegaspargase chemotherapy drugs used for the treatment of ALL. The approval was based on a singlearm, multicenter, open-label phase 3 trial that enrolled 58 patients with ALL who had discontinued previous pegaspargase therapy in response to hypersensitivity reactions. All patients received 25,000 IU/m2 of asparaginase E chrysanthemi in 6 doses over 2 weeks as a replacement for the pegaspargase dose remaining in their original treatment protocol. At 48 hours and 72 hours after the third dose, 100% of 48 evaluable patients had a serum trough asparaginase level ≥0.1 IU/mL, the primary end point. Adverse effects reported were anaphylaxis, pancreatitis, elevated transaminiase and bilirubin levels, blood clotting, hemorrhage, nausea, vomiting, and hyperglycemia. (November 18, 2011) ■

Ruxolitinib First Drug Indicated for Myelofibrosis Applying its priority review procedure, the FDA approved ruxolitinib (Jakafi, Incyte), an oral inhibitor of the Janus kinase (JAK) 1 and 2 gene, for the treatment of intermediate- and highrisk myelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF. Ruxolitinib is the first drug approved specifically for this indication. Ruxolitinib received accelerated approval (ahead of its regulatory date). Continued on page 11

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Frontier Cancer Care in Montana... Q: In these hard economic times, what was your motivation to build a new cancer center? Dr Cobb: Over the past 20 years, cancer treatment has evolved from a hospital-centered specialty that requires a long hospital stay to a patientcentered approach that is focused on delivering care close to home. Patients prefer treatment that is readily accessible and provides a safe, comfortable environment. Recognizing these changes, my partners and I concluded that the community was ready for a new view of cancer care. To create the ideal environment, we realized we needed to relocate away from the stresses of downtown to a calm setting, where the healing aspects of nature in Montana would have a better chance to impart a positive effect on our patients. We had several other requirements. First, the new building would have to be designed to create a caring and supportive environment for our patients. Second, it must contain the latest technology for our patients to receive stateof-the-art care. Third, it would have to be visually appealing to complement the surrounding area and reflect the best of Montana. We added new technologies to have almost everything a patient with cancer needs to be in one convenient place. We installed the latest-generation Elekta linear accelerator to provide image-guided and stereotactic radiation treatments. We have a stateof-the-art GE CT/PET scanner, Philips CT, and GE DEXA scanners. We also have the latest in brachytherapy treatments, with a new Varian iX radiation source. Our new center, which opened in August 2010, confirms our commitment to be at the forefront of cancer care. We also changed our name to Frontier Cancer Center—to reflect the frontier spirit of the people of Montana and Wyoming, as well as our dedication to stay on the leading edge of cancer care.

Q: Did economics play any part in your decision? Dr Cobb: Yes. As a result of the Medicare Modernization Act of 2003, we realized that the model of oncologists giving chemotherapy in their offices, without doing other things, would not be economically sustainable. With the marked increases in chemotherapy drugs and decreasing payments for chemotherapy administration, it was no longer economically viable to offer chemotherapy only. To stay in business, we needed to offer

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radiation oncology and imaging, as well as social services for our patients. We now have staff to help patients navigate the system, such as a patient’s assistance program to help with housing. Our previous model of only doing chemotherapy in our office did not generate enough revenue to pay for such social services.

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Q: You are also a member of the Community Oncology Alliance (COA). How active are you in COA? Dr Cobb: I was president of COA last year, and I currently lead its policy committee, so I am quite involved with COA, because I believe in the great value that the community cancer center has for patients, for payers, and for oncologists.

Q: Speaking of COA’s policy concerns, are there financial issues, such as reimbursement or the escalating cost of cancer care, that keep you awake at night?

We cannot ignore the economic realities of the oncology world. If we ignore that, we will not be in business for very long. This is an uncomfortable topic for many oncologists.

Q: Did you have to bring in new experts? Dr Cobb: We had to bring on radiation oncology, which was the biggest capital investment. And adding the imaging scanner and a CT scanner was a significant capital cost as well. To keep up with the rapidly moving pace of radiation oncology, we had to make a significant investment to acquire the best technology. And that has paid off; our patients are very happy with the conveniences that we can offer them and the level of expertise. We think that our outcomes have also improved.

Q: Can you already see financial benefits? Dr Cobb: Financially, we are certainly viable and sustainable. The biggest question is what will happen with cancer care in the future. Congress is talking about decreasing payments for chemotherapy drugs, for chemotherapy administration services, and for imaging. These types of cuts make us nervous.

Dr Cobb: One thing we found is that in the economics of oncology, much like in the clinical arena of cancer care, there are no guarantees. Opening a new cancer center like ours involves bringing on new technology and taking an entrepreneurial risk. It also means putting our capital at risk, and so we would expect a return on the investment. It is wonderful to be able to make an investment in new technology that ends up helping patients—improving outcomes, improving tolerability of radiation therapy, helping us make a correct diagnosis—but we cannot ignore the economic realities of the oncology world. If we ignore that, we will not be in the “business” of cancer care for very long. This is an uncomfortable topic for many oncologists. Ever since we were trained as physicians, we were taught, “If you just do the job of taking care of your patients, everything will work out fine.” But this is no longer true for private practice oncologists in the United States. We are seeing a huge shift away from private practice groups that were very well run and were forced out because of changes in reimbursement policy: many of these community practice oncologists ended up saying, “We’re simply not viable anymore. We have to work for a hospital.” But once you move to a hospital, you no longer run things and deliver care the way you think is best. And it ends up costing more to take care of patients with cancer in the hospital, as a result of Medicare policies. It costs Medicare at least 10% more to care for patients at a hospital-based outpatient center than at a free-standing center. As for private insurance costs, it is at least 2 or 3 times more costly to take care of the same patient: the same drugs, the same doctors, and the same outcomes, for a greater overall cost.

Q: Is this an issue COA is trying to address with Congress? Dr Cobb: Indeed, that is one of the things we are doing at COA. As an example, we supported a Milliman study that was just published in October 2011, titled “Site of Service Cost Differences for Medicare Patients Receiving Chemotherapy” (http:// publications.milliman.com/publica tions/health-published/pdfs/site-ofservice-cost-differences.pdf). That study compared the data of Medicare patients being treated in a free-standing cancer center with patients treated in a hospital-based outpatient center, showing that the hospital-based treatment costs 16% more for a patient with cancer, with no added clinical benefit. The results show that a free-standing center provides the same treatment for a reduced cost, without reduction in the quality of care. Yet Medicare pays the higher cost of the hospital treatment, which makes no sense. Remember, this cost was for the same drugs, same outcomes, same medical conditions, and same providers; the one difference was that treatment in the hospital-based center cost more than the treatment at the community center. So from a cost perspective, the value of a community cancer center of a freestanding clinic is significantly greater than the value of cancer care in the hospital setting. Another example was when the University of Pittsburgh Medical Center Cancer Centers, transferred from being free-standing centers to hospital-outpatient centers, which raised the costs to their insurer, Highmark, by 2.5-fold for the same treatments and the same treating physicians. So the value of the money being spent for the same services in the community centers is considerable. It makes no sense to pay 2 or 3 times more for the same services: this is the value of the community center that we need to push forward as practicing oncologists.

Q: This would seem like an easy argument in support of the economic sense of the smaller cancer center? Dr Cobb: That message is finally being heard in Congress. I think that the problem we are facing with drug shortages is giving this cause some resonance. Those in Congress are hearing that from their constituents all the time. “Look, my doctors can’t get carboplatin,” or, “My doctor can’t get cytarabine,” because these are generic drugs. Continued on page 10

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patient to respond better to one treatment regimen than other regimens. We want to show that this approach can be applied to all types of cancer. So, personalized medicine is the decisive thing.

Q: Is Frontier Cancer Center currently involved in research?

There is no question that our patients are best served by cancer care that is delivered in one place, where they can get all their imaging, radiation, and chemotherapy needs; where everybody can collaborate in one spot.

This means we often cannot treat the patient on the appropriate day, or we have to use more expensive drugs that are not generic. It all comes down, again, to economics. There is no economic incentive to use generic drugs. Until Congress fixes that, we are going to be left with the same problem of severe drug shortages. They forget that we use these drugs to try to cure people, not just make them feel better. For example, I am currently treating a patient with testicular cancer. I need to give him cisplatin, but it is very difficult to find this drug. So, we have to use another drug that may not be as effective, or may be more toxic, or it does not have evidence supporting it. As oncologists, we get very uncomfortable with that, because we know such patients should survive if they could receive appropriate treatment. And this is a problem across the board, in hospitals and in the smaller community center. We hear this complaint from the major cancer centers, such as M.D. Anderson and the various Children’s Hospitals, which are especially hard hit.

Q: You are part of the Cancer Clinics of Excellence. What exactly is this? Dr Cobb: The Cancer Clinics of Excellence are a group of practices that came together about 6 or 7 years ago with the goal of trying to share best practices, and to explore how best to approach certain tumors. We found that the movement toward evidence-

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based treatment protocols (ETPs) for cancer made sense, and we wanted to see if we could come up with an ETP program. After spending much time reviewing the data, we came up with regimens that we think have enough data behind them. We are now moving into collaboration with a molecular diagnostics laboratory that will look at tumors and look at the genetic profile of an individual’s cancer. The goal is to come up with recommendations for best treatment based on genetic profiling. This is being pioneered in a few places, and it has not been done on this scale before. We want to take the advances that we have gained from the Human Genome Project and apply them in the community, to give our patients the best outcomes possible.

Q: Will this be done on a national level or within the context of the Cancer Clinics of Excellence? Dr Cobb: This would involve the Cancer Clinics of Excellence group, moving personalized medicine to a new level. For example, when a patient is being diagnosed with breast cancer, we will send a sample of the tumor to the molecular diagnostics laboratory to do the genetic profiling. Based on the gene expressions, we then may make recommendations for one of our treatment protocols. For most patients, there are multiple treatment protocols from which to choose. But using the patient’s genetic profiling, based on the personalized medicine paradigm, will allow the

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Dr Cobb: Yes. We have always been a participant in clinical trials that are funded and organized by the National Cancer Institute (NCI). Those trials are very important in establishing standards of care and advances in cancer therapies. Ironically, economics plays a role in this too. The payment for putting patients in an NCI trial does not come close to covering the cost of administering the trial for the patient, and the NCI funding of this has come down significantly. In the past, we did this for the good of the patient. We were just interested in making sure that we still made progress in cancer research. Today, with the declining reimbursements for oncologists in smaller centers, we have less time to commit to this type of research. As it stands right now, we actually lose money if we enroll a patient in an NCI-sponsored trial. Therefore, we have transitioned much of our research to pharmaceutical company–based research, which pays significantly more than the cooperative groups or the NCI-based trials. So we now do both clinical trials and those supported by pharmaceutical research. The pharmaceutical companies have done some very important trials. The criticism 10 years ago was that they did not fund trials of good quality, and that they were self-serving, but that’s not the case anymore. The research that we are seeing today is very good, consisting of phase 1 and phase 2 trials that are involved in emerging and novel compounds. We are glad that we are able to get those trials for our patients here in Montana, where, in the past, we were not able to do that.

Q: Has the number of patients you are able to treat in the new center grown? Dr Cobb: Billings is a city of about 100,000 people that services a very large geographic area, including eastern Montana and northern Wyoming. We have a lot more cows than people here. We get people in from a big catchment area. Other than perhaps Anchorage, Alaska, we probably have the largest physical catchment

area of any practice in the United States. This brings some challenges, but our patients enjoy coming to our place. The number of patients is stable, and may have increased a bit. There are 2 different healthcare systems in Billings, and they are competitive. That is another reason that we built the center: we wanted to give people a compelling choice, that they could come to a center that is away from the medical corridor, where they could park next to the building, and get all their cancer care in one place, as well as have access to stateof-the-art technology. We believe we have done that. Over time, we believe that when patients have a choice which cancer center to come to, they will ultimately choose ours.

Q: What are some of the lessons from your experience as a centralized cancer center? Dr Cobb: Our experience has worked out very well for our patients. There is no question that our patients are best served by cancer care that is delivered in one place, where they can get all their imaging, radiation, and chemotherapy needs; where everybody can collaborate in one spot. The bigger question that is going to come up in the near future is whether this type of free-standing cancer center is going to be economically viable. So far it has proved to be, but we are concerned about potential policy changes. The economics should be compelling enough to keep us in business, because the research shows that we are less expensive than a hospital outpatient center for Medicare, and we are markedly less expensive for our private insurers. The data clearly show that free-standing outpatient cancer centers provide more value than hospital-based cancer centers. Whether insurance companies and Medicare agree with this conclusion and move quickly to change payment models to keep private oncology practices economically viable remains to be seen. The biggest thing for an oncology practice to understand is the way in which what is happening in Washington, DC, is going to affect them. Oncologists need to take an active role in educating their senators and representatives about the effects of federal policy on practicing providers. Getting involved with COA is an excellent way for oncologists to be able to define their message, and to keep in touch with their congressional representatives. ■

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FDA UPDATE Ruxolitinib First Drug... Continued from page 8

“Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways,” said Richard Pazdur, MD, Director, FDA’s Office of Hematology and Oncology Products. The approval was based on 2 randomized, controlled clinical trials involving 528 patients with splenomegaly who were resistant or refractory to MF therapies or were ineligible for allogeneic bone marrow transplantation. The primary end point (a 35% reduction in spleen volume) was achieved by 42% of patients with ruxolitinib versus 1% with placebo after 24 weeks, and by 29% versus 0%, respectively, after 48 weeks in study 2. Furthermore, 46% of patients receiving ruxolitinib had ≥50% reduction in total symptom scores compared with only 5% of those receiving placebo (P <.001). The most common adverse effects reported were thrombocytopenia, anemia, bruising, dizziness, and headache. Grade 3 drug reactions more common with ruxolitinib than with placebo included thrombocytopenia (13% vs 1%, respectively) and anemia (45% vs 19%). (November 16, 2011) ■

FDA Updates OS Label Data for Bortezomib in Myeloma The FDA approved an update to the label of bortezomib (Velcade, Takeda) to include the newly reported 5-year OS data showing survival advantage when the drug is added to melphalan and prednisone (VMP) for patients

with previously untreated multiple myeloma. These longest available follow-up data for patients with myeloma show that patients who received the VMP regimen continued to have significantly longer OS (median 56.4 months) than those who received the

melphalan and prednisone regimen without bortezomib (median, 43.1 months). The newly released data from the trial were presented at the 2011 American Society of Hematology meeting (see article on page 1). (November 1, 2011) ■

T

Cetuximab Gains New Indication for Metastatic Head/Neck Cancer Cetuximab (Erbitux, Bristol-Myers Squibb) received a new indication for the treatment of recurrent or metastatic squamous-cell carcinoma of the head and neck, in combination with chemotherapy. The approval was based on an international phase 3 clinical trial of 442 patients with metastatic or recurrent squamous-cell cancer of the head and neck who had not received chemotherapy. Patients were randomized to chemotherapy plus cetuximab or to chemotherapy alone. Overall survival (OS) was 10.1 months with cetuximab plus chemotherapy compared with 7.4 months with chemotherapy alone. Cetuximab was associated with a higher incidence of diarrhea, respiratory and other infections, and serious infusion reactions. Cetuximab was originally approved in 2004 for epidermal growth factor receptor–positive late-stage colon cancer and in 2006 as first-line (in combination with radiation therapy) or second-line treatment for nonmetastatic head and neck cancer. (November 7, 2011) ■

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July 2011

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www.ValueBasedCancerCare.com

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CTRC-AACR SABCS ANNUAL MEETING

iate Director of the Massachusetts General Hospital Cancer Center, Boston. Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy as first-line treatment for metastatic disease extended progression-free survival (PFS) by a median of 6.1 months compared with patients who received only trastuzumab-docetaxel, Dr Baselga reported. “This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS,” Dr Baselga emphasized. Pertuzumab is designed to work in combination with trastuzumab as a dual blockade of the HER2 growth factor. Both drugs are monoclonal antibodies that bind to the HER2 receptor protein in different regions. Pertuzumab prevents the receptor from linking to HER3, which stops the formation of a “dimer” that could enhance tumor growth. “Pertuzumab is the first in a new class of drugs called ‘dimerization inhibitors,’ and its combination with trastuzumab produces dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling,” Dr Baselga said. The CLEOPATRA Study CLEOPATRA randomly assigned 808 postmenopausal women with metastatic breast cancer—without

Photo Courtesy © SABCS/Todd Buchanan 2011

Dual HER2 Blockade with Pertuzumab...

“Pertuzumab is the first in a new class of drugs called ‘dimerization inhibitors,’ and its combination with trastuzumab produces dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling.” —Jose Baselga, MD, PhD previous treatment for metastatic disease—to trastuzumab and docetaxel chemotherapy, with the addition of

Continued from cover

either pertuzumab or placebo. The PFS was 18.5 months for patients receiving pertuzumab on top of chemotherapy compared with 12.4 months for trastuzumab-docetaxel alone, a 38% reduction in the risk of progression. Adding pertuzumab to the combination also raised the objective response rate to 80.2% compared with 69.3% for the chemotherapy combination alone. Although survival outcomes are not mature, 69 deaths were reported in the 402 patients who were treated with the 3-drug regimen versus 96 among the 406 patients receiving the 2 drugs alone; this amounts to a 36% reduction in mortality. The 3-drug combination was “remarkably safe and well tolerated,” Dr Baselga noted, reporting that pertuzumab added only minimal toxicity. Enrollment is already under way in a new double-blind, randomized clinical trial, APHINITY, which will test the use of pertuzumab as adjuvant treatment for early-stage HER2positive breast cancer: “the setting in which you can really cure patients,” Dr Baselga noted. “We are looking forward to getting pertuzumab approved as soon as possible. The sooner the better,” Dr Baselga commented. Genentech recently submitted a biologic license application for per-

at a glance ➤ Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy extended PFS by a median of 6.1 months ➤ Pertuzumab is the first in a new class of drugs called “dimerization inhibitors”; its combination with trastuzumab produces dual HER2 blockade ➤ In the CLEOPATRA phase 3 trial, the 3-drug regimen reduced mortality by 36% ➤ Dual HER2 blockade demonstrated a significant advantage over a single blockade tuzumab in HER2-positive metastatic breast cancer. Lisa Carey, MD, Medical Director, the University of North Carolina Breast Cancer, Chapel Hill, who moderated a press conference, commented that the findings from the CLEOPATRA study extend the findings from neoadjuvant studies and smaller, less definitive trials “that dual HER2 blockade has a marked advantage of single blockade of HER2. The challenge will be figuring out which patients need both these drugs.” ■

Role of Adjuvant Zoledronic Acid in Endocrine ReceptorPositive Breast Cancer Being Refined New standard of care for a subset of women By Phoebe Starr San Antonio, TX—Mounting evidence from randomized controlled trials suggests that zoledronic acid added to hormonal therapy will have its optimal use as adjuvant therapy in postmenopausal women with either medically/surgically induced menopause or age-related menopause. The results of 2 trials were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. Updated results of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-12) trial showed that zoledronic acid added to adjuvant hormonal therapy improved overall survival (OS) in premenopausal women with endocrine receptor (ER)-positive early breast cancer undergoing ovarian suppression

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with goserilin plus tamoxifen or anastrozole. And a post-hoc exploratory analysis of the ZO-FAST trial suggested

that adding zoledronic acid to adjuvant letrozole improved disease-free survival, but not OS, in a subset of postmenopausal women with ER-

at a glance ➤ Adding zoledronic acid to adjuvant hormonal therapy improved OS in premenopausal women with ER-positive early breast cancer undergoing ovarian suppression

➤ In this subgroup of postmenopausal women, the addition of zoledronic acid to adjuvant endocrine therapy increased BMD and reduced the risk for disease recurrence

➤ Adding zoledronic acid to adjuvant letrozole also improves disease-free survival, but not OS, in postmenopausal women with ER-positive breast cancer

➤ However, more evidence is needed to support routine use of a bisphosphonate in postmenopausal women with ER-positive breast cancer

VALUE-BASED CANCER CARE

positive breast cancer. James N. Ingle, MD, Mayo Clinic, Rochester, MN, formal discussant of these trials, said that zoledronic acid should be considered a new standard of care for premenopausal women with ER-positive breast cancer who undergo ovarian suppression with goserilin, but at this time the data do not support routine use of a bisphosphonate in postmenopausal women with ER-positive breast cancer. He said that an exploratory analysis is not Level 1 evidence, which would be needed to establish a standard of care. ABCSG-12 These updated results confirm the initial results of the trial, according to Continued on page 13

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Adding Everolimus to Exemestane Significantly Prolongs Remission in Patients with Breast Cancer Updated results of pivotal BOLERO-2 potential paradigm change San Antonio, TX—Updated results from the phase 3 Breast Cancer Trials of Oral Everolinmus (BOLERO-2) showed that adding everolimus to the treatment regimen with the aromatase inhibitor exemestane more than doubles the time to disease progression in patients with advanced estrogen receptor (ER)-positive breast cancer whose disease has become refractory to hormonal therapy. “The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population,” said lead investigator Gabriel Hortobagyi, MD, Chair of Breast Medical Oncology, the University of Texas, M.D. Anderson Cancer Center, Houston, at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. Nearly all ER-positive patients with advanced cancer will develop resistance to hormonal therapies. Resistance to hormonal therapy in breast cancer has been associated with over-activation of the mTOR pathway. Everolimus targets the mTOR pathway, interfering with tumor cell proliferation, angiogenesis, and cell metabolism.

“Everolimus is the first treatment to significantly enhance the efficacy of hormonal therapy in this patient population, where this remains a significant unmet need,” Dr Hortobagyi noted.

at a glance ➤ Nearly all ER-positive patients with advanced cancer will develop resistance to hormonal therapies ➤ The addition of everolimus to hormonal therapy more than doubled PFS, from 3.2 months with exemestane alone to 7.4 months ➤ These new results demonstrated a 56% reduction in disease progression, nearly twice the expected rate ➤ At 1 year, disease-free survival rate is 31% in the everolimusexemestane combination arm versus 10% with exemestane alone arm

Photo Courtesy © SABCS/Todd Buchanan 2011

By Caroline Helwick

“Everolimus is the first treatment to significantly enhance the efficacy of hormonal therapy in this patient population….The study demonstrated...a 56% reduction in progression events, with a P value for which I don’t have enough fingers to count.” —Gabriel Hortobagyi, MD

Role of Adjuvant Zoledronic Acid...

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Zoledronic acid should be considered a new standard of care for premenopausal women with ER-positive breast cancer who undergo ovarian suppression with goserilin. —James N. Ingle, MD

SABCS, the primary end point of the trial (decrease in loss of BMD) was met, and also a 34% decrease in risk of recurrence was observed in patients treated with up-front zoledronic acid, according to lead investigator Richard de Boer, MD, Royal Melbourne Hospital in Victoria, Australia. ZO-FAST randomized 1050 patients who were receiving letrozole to

In the exploratory subgroup analysis, women who were menopausal at diagnosis benefited from immediate treatment with zoledronic acid, with a 29% reduced risk of recurrence and a 35% improvement in OS (not a significant difference). This represented an absolute improvement in diseasefree survival of about 3.6% during 5 years. ■

Death rates for all cancers, 1990-2006

➔ ➔ ➔

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up-front zoledronic acid every 6 months or delayed zoledronic acid, which was initiated only when patients experienced a fracture or a decline in BMD.

➔ ➔

ZO-FAST New data from an unplanned exploratory analysis of ZO-FAST showed that in the subgroup of postmenopausal women, the addition of zoledronic acid to adjuvant endocrine

therapy increased bone mineral density (BMD) and reduced the risk of disease recurrence over the longer term. In the overall analysis of the trial, which was presented last year at

Photo Courtesy © SABCS/Todd Buchanan 2011

lead investigator Michael Gnant, MD, Professor of Surgery, Medical University of Vienna, Austria, and President of ABCSG. “The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment.” The 4-arm trial randomized 1803 premenopausal women with earlystage, ER-positive breast cancer to tamoxifen or anastrozole, or each of these therapies plus 3 years of treatment with zoledronic acid. First results showed significantly improved disease-free survival in 2008. At the San Antonio meeting in 2011, 84-month data showed that zoledronic acid reduced the risk of breast cancer recurrence by 28% and the risk of death by 36%. There were no reports of osteonecrosis of the jaw or renal failure in this study.

Continued from page 12

BOLERO Details The new findings represent an additional 5 months of follow-up from the data first presented at the European Multidisciplinary Cancer Congress in September 2011, which garnered much attention. The updated analysis presented in San Antonio showed that treatment with everolimus plus hormonal therapy more than doubled progressionfree survival (PFS), from 3.2 months with exemestane alone to 7.4 months, representing a highly significant 56% reduction (P <1 × 10-16)in the risk of progression. “While this analysis was done with local tumor assessment, another assessment by central independent review found even greater benefit, with PFS of 11.0 months versus 4.1 months, a 64% risk reduction (P <1 × 10-16),” Dr Hortobagyi reported. In remarking on the robustness of the findings at a media briefing, Dr Hortobagyi noted that the prolongation of progression far exceeded the investigators’ expectations. “The study demonstrated not the 26% reduction in progression, as we had expected, but a 56% reduction in progression events, with a P value for which I don’t have enough fingers to count.” Disease-free survival rates at 1 year were 31% in the combination arm versus 10% in the exemestane-alone arm. Side effects were consistent with those previously reported with everolimus. The most common grade 3 or grade 4 adverse events were stomatitis, anemia, hyperglycemia, dyspnea, fatigue, and pneumonitis, all occurring in <10% of patients receiving the combination. The addition of everolimus did not impact the quality of life, according to the patients’ Global Health Scores. As of December 2011, deaths had occurred in 29.3% of the placebo arm and 23.1% of the everolimus arm. The manufacturer is planning a regulatory submission for everolimus based on the BOLERO-2 results. ■

Women:

Men:

12.4%

21%

2011 estimates Incidence: 1,596,670 Deaths: 571,950

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New Prognostic Tool to Guide Treatment of Ductal Carcinoma In Situ The validated DCIS score should help to individualize therapy By Caroline Helwick San Antonio, TX—The treatment of ductal carcinoma in situ (DCIS)— breast cancer confined to the ducts—is a clinical challenge, as patients carry varying risks of recurrence and may easily be undertreated or overtreated. But Genomic Health, which markets Oncotype DX for assessing risk of recurrence in invasive cancers, has developed a similar test for DCIS that may prove useful for individualizing treatment in this subset of breast cancer. The test is expected to become

at a glance ➤ Breast cancer confined to the ducts presents a clinical challenge, because of varying risks of recurrence, and is often undertreated or overtreated ➤ A new prognostic tool, the DCIS score based on tumor gene expression information, has been developed to predict the risk of recurrence and the need for surgery ➤ A 10-year study showed the DCIS score a significant indicator of local recurrence beyond the traditional measures of tumor size, tumor grade, and margin status

available for physicians for use on December 28, 2011. “DCIS is a very common presentation, and due to screening mammography, its incidence is rising. Most patients can undergo breast-conservation surgery, but the question is whether patients with a diagnosis of DCIS require invasive therapy, especially radiation,” said Lawrence J. Solin, MD, Chair of Radiation Oncology, Albert Einstein Medical Center, Philadelphia. “We have developed a prognostic tool for these patients.” Using a subset of genes from the Oncotype DX Recurrence Score, Dr Solin and colleagues calculated a prespecified “DCIS score” (0-100) for these patients to predict recurrence, based on these risk categories: low risk (<39), intermediate risk (39-54), or high risk (≥55). They also prospectively validated the quantitative multigene reverse transcriptase polymer chain reaction assay and found the DCIS score reliable. The tumor gene expression information complements traditional clinical and pathologic factors, guiding oncologists in selecting patients with DCIS who should be treated with surgery alone or surgery plus radiation. The validation study of the DCIS score was a collaboration among the

Eastern Cooperative Oncology Group (ECOG), North Central Cancer Treatment Group, and Genomic Health, using samples from the ECOG E5194 study of patients with low-, intermediate-, or high-grade DCIS who had been treated surgically but had not received radiation. Tumors from these patients were tested to determine the risk of recurrence, and researchers applied the Oncotype DX assay and the new DCIS score algorithm to study the tumor samples. DCIS Score Accurately Predicted Risk The 10-year results of E5194, showing that 46 patients developed local recurrence of DCIS or an invasive cancer in the same breast, found the DCIS score to be significantly associated with these breast events and provided value beyond the traditional measures of tumor size, tumor grade, and margin status. Patients with a high DCIS score had a 10-year risk for an ipsilateral breast event of 27.3%; intermediate-risk patients had a 24.5% risk, and low-risk patients had a 12.0% risk (P = .02), Dr Solin reported. “DCIS score was a significantly strong predictor of local recurrence or invasive local recurrence. Fortunately, three quarters of patients were

in the low-risk group,” he said. “We think the DCIS score provides a new clinical tool to guide treatment selection for patients with newly diagnosed DCIS.”

“Most patients can undergo breast-conservation surgery, but the question is whether patients…require invasive therapy, especially radiation…. If we can spare adjuvant therapies in some patients, it [the new test] becomes very cost-effective.” —Lawrence J. Solin, MD

Jennifer Ligibel, MD, of DanaFarber Cancer Center, Boston, who moderated a press briefing where the results were highlighted, commented, “This is very important work as we try to better tailor therapy for our patients.” Dr Solin said he did not know what the test would cost, “but in a broader sense, you have to consider the total cost of care. If we can spare adjuvant therapies in some patients, it becomes very cost-effective.” ■

San Antonio, TX—Two antiestrogen agents may be better than one in the treatment of metastatic hormone receptor-positive breast cancer patients, according to a study conducted by the Southwest Oncology Group (SWOG) clinical trials network and presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. In SWOG 0226, which involved 72 centers, 707 postmenopausal women with metastatic hormone receptor– positive breast cancer were randomized to standard treatment with 1 mg daily of anastrozole (Arimidex) alone or to the combination of anastrozole plus a 250-mg monthly injection of fulvestrant (Faslodex), after an initial 500-mg injection on day 1 and a 250-

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mg injection on day 14. The combination extended median overall survival time by more than 6 months compared with anastrozole alone (47.7 months vs 41.3 months, respectively), representing a 29% risk reduction (P = .049), and increased disease-free survival by about 6 weeks (15 months vs 13.5 months, respectively), reported study investigator Rita S. Mehta, MD, clinical oncologist, at the University of California, Irvine Medical Center. “These patients have not had a new treatment that gave them an overall survival benefit in more than a decade,” Dr Mehta said. Anastrozole reduces the production of tumor-promoting estrogen, and fulvestrant interferes with the

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Photo Courtesy © SABCS/Todd Buchanan 2011

SWOG: Two Hormonal Agents Extend Survival over Anastrozole Alone in Metastatic Breast Cancer “These patients have not had a new treatment that gave them an overall survival benefit in more than a decade.” —Rita S. Mehta, MD receptors that allow estrogen to signal cells to grow and reproduce. The complementary modes of action of these 2 agents—“taking away estrogen and the estrogen receptor as

well”—appears to enhance the efficacy of endocrine therapy in this subset of patients, which comprises more than 50% of all cases of breast cancer. The benefit of the combination therapy was most pronounced among women who had not received tamoxifen (Nolvadex), whose median survival with the combination was 47.7 months, versus 39.7 months with anastrozole alone—a 26% risk reduction (P = .036); patients who had previously received tamoxifen had only a nonsignificant 9% reduction in risk. Although this finding may suggest that the real benefit is only for patients who are tamoxifen-naïve, it “could also be a false lead from an unplanned analysis,” Dr Mehta said. —CH ■

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The Hedgehog Pathway:

PTCH

A critical factor in cancer development SMO

1 Following mutation in SMO or PTCH, SMO is translocated to the cell surface

2 Once at the cell surface, SMO activates the GLI family of transcription factors

GLI

3 Nucleus

GLIs travel to the nucleus to trigger tumor cell growth and proliferation

Nucleus

Mutations in the Hedgehog pathway are implicated in over 90% of basal cell carcinomas (BCCs)1 The Hedgehog pathway plays an important role in regulating cell growth and differentiation during normal human embryonic development but remains inactive in most adult tissues. Mutations in the Hedgehog pathway can occur and may lead to different types of cancer.2 Most notably, Hedgehog pathway mutations are known to occur in BCC, medulloblastoma, and BCC in Gorlin syndrome.3,4

Genentech is actively researching the potential of Hedgehog pathway inhibition and how it may fit into the therapeutic paradigms of various malignancies.

Key components of the Hedgehog pathway include Smoothened (SMO), which enables the signaling cascade, and Patched (PTCH), which normally suppresses the activity of SMO. In preclinical models, mutations in SMO or PTCH render the pathway constitutively active, triggering the activation of GLI transcription factors. GLI, in turn, mediates the expression of genes involved in tumor cell growth, differentiation, and proliferation.1,5-7

For more information about the Hedgehog pathway and its components, please visit:

www.ResearchHedgehog.com

References: 1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743-754. 2. Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30:303-312. 3. Unden AB, Holmberg E, Lundh-Rozell B, et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res. 1996;56:4562-4565. 4. Pietsch T, Waha A, Koch A, et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997;57:2085-2088. 5. Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384:129-134. 6. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates Hedgehog signaling at the primary cilium. Science. 2007;317:372-376. 7. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100:423-434.

Demonstrating the Value of Innovation Š2011 Genentech, Inc., So. San Francisco, CA HED0000596500 09/11

A Member of the Roche Group


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HEALTH POLICY

GPCI, or “GYPSY”: Calculated or Covert Cuts to Oncology... Continued from cover Italian polizia were quickly in pursuit. This episode got me to thinking about the stark similarities between this incident and the impending changes and cuts to Medicare fees— more specifically, the Geographic Practice Cost Indices (GPCIs)—which will inevitably impact physicians in all specialties and locations in 2012. The thought process behind GPCI, or “GYPSY,” starts with language and culture. One of the core beliefs among the nomadic Gypsy people is Jainism, which, in their Romani language means “understanding” (www.romanoliloro.com/understanding-gypsyculture.htm). Our GPCI is spoken in Relative Value Units (RVUs), which translates to “not understood.” GPCI functions as the weighting factor for 90 geographic locations throughout the United States and Puerto Rico and is meant to be the cost-of-living adjustment for each of these locations. The weights apply to the work, practice, and malpractice components of each RVU for each Current Procedural Terminology (CPT), or service billing, code. An example of this cloaked reduction using CPT code 99215, Established Patient Level 5, adjusted for South Carolina with 2012 GPCI values, looks like this: • Without GPCI applied: (RVU work + RVU practice expense + RVU malpractice) × 2011 conversion factor, or (2.11 + 1.86 + 0.14) × $33.9764 = $139.64 • With GPCI applied: [(RVU work × GPCI work) + (RVU practice expense × GPCI practice expense) + (RVU malpractice × GPCI malpractice)] × 2011 conversion factor, or [(2.11 × 0.967) + (1.86 × 0.904) + (0.14 × 0.322)] × $33.9764 = $129.89 So, as you can see, the computation is not easily understood, and while you were not looking, the Gypsy lifted a 7% reduction from your pocket! Some say that Gypsies came into existence in the mid-ninth century. By the mid-1400s, they had populated most of Europe and, deservedly or not, they developed a reputation as “tricksters” (www.squidoo.com/gypsymagic-customs). Our GPCIs were created from the Omnibus Budget Reconciliation Act of 1989 to measure resource cost differences. Snooping into the details, we learn a few things that may have gone unnoticed. The Patient Protection and Affordable Care Act of 2009 set a floor of 1.00 for the work component of the GPCI, to preserve neutrality. This floor was set to expire in 2010 but

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In West Virginia, Oklahoma, and Mississippi, GPCIs have been reduced by 6.38%, 5.97%, and 5.52%, respectively. Locales with GPCI decreases outnumber locales with gains by a 2:1 ratio. The average decrease in reductions is 2.53%. —Bo Gamble was extended through 2011. The good news is that this offered some protection from reductions to the work component for 3 years. The bad news is that this was merely a loan and not a gift—it only delayed the inevitable. (Sound familiar?) The SGR (sustainable growth rate) dialect is related to the RVU dialect. Luckily, the Budget Reconciliation Act also requires that “catch-up” adjustments cannot be accomplished all in 1 year but rather gradually, over a 2-year period. Other possible “tricks” of the GPCI include:

that 3- to 4-year-old wage data are used to manage physician wages, that the Centers for Medicare & Medicaid Services (CMS) physician cuts in those years will again be felt 3 to 4 years later, and that depressed wages from other industries will impact the medical profession? •The practice expense GPCI is gathered from the same Bureau of Labor Statistics and 2-bedroom residential apartment rent data from the Department of Housing and Urban Development. So then, are physician staff wages subject to the same 3year lag time and influences of other industries? If housing starts are up (good economy) and apartment rentals are down (lower apartment costs), can we then expect that practice expense reimbursement will also be down? We fail to see the correlation here. The 2012 final Physician Fee Schedule document has indicated that efforts are under way to assign more logical and applicable background statistics to practice expense adjustments. Until that happens, we are subject to the self-prophesying results that were typical of the Gypsy practice of fortune telling. Finally, and not to make light of the historical persecution of the Gypsies, there does appear to be an oppression of sorts from our own 2012 GPCIs. The average adjustment from all 90 GPCI locales is –1.7% (based on impact analysis of the 2012 final Medicare Physician Fee Schedule prepared by Community Oncology Alliance, using provider data from 38 GPCI locations). This reduction is being referred to as the “stealth” cut by many provider advocate organizations. With all of the

The 2012 final Physician Fee Schedule document has indicated that efforts are under way to assign more logical and applicable background statistics to practice expense adjustments. Until that happens, we are subject to the self-prophesying results that were typical of the Gypsy practice of fortune telling.

• The work component of the GPCI is calculated from the Occupational Employment Statistics from years 2006-2008 by the Bureau of Labor Statistics. So then, does this mean

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recent discussions over the SGR, the Super Committee outcomes, and a possible drug reimbursement change to the average sales price plus 3%, these GPCI reductions have gone vir-

tually unnoticed, but they will have a devastating impact. Consider our colleagues in the states of West Virginia, Oklahoma, and Mississippi, where GPCIs have reduced by 6.38%, 5.97%, and 5.52%, respectively, between 2011 and 2012. Locales with GPCI decreases outnumber locales with gains by a 2:1 ratio. The decreases are also much deeper than any gains. The average decrease in the 67 locales with GPCI reductions is 2.53%. The 20 locales with gains are realizing an average increase of only 0.86%. On the surface, these numbers are not very alarming; however, the devil (or Gypsy) is in the details. Although this may be difficult to prove, when the variations in the different GPCI regions are examined, the disparity by total population seems to be even higher: • The medical economic index reflects an annual increase of approximately 2%—not a 1.7% decrease—from 2004 through 2010; it seems there is no other healthcare expense that goes down every year, other than the reimbursement to the individuals who are taking care of our sick • If a new physician in one of the Southern states decides to physically hang his shingle on one side of the street, he will realize a 3.4% reimbursement reduction from the 2011 rate, but if he chooses the opposite side of the street, his reimbursement will be 0.4% higher. Go figure. This world of GPCI adjustments is complicated, not very transparent, and often hidden by other fee schedule cuts and changes. If only we could share the language and culture of the Gypsy nation so that we may be better able to understand this aspect of our world and actually read our future more effectively. Until that happens, we need more stewards like my dear friend to halt these stealthy thefts. We hope that state medical societies and other physician support organizations will lobby against these 2012 changes and pressure CMS to review the numerous and more logical and rational approaches to GPCI adjustments. As it stands now, we have literally just had our pockets picked, and most of us do not even realize it. Acknowledgment I wish to thank Mary Kruczynsk, Director of Policy Analysis, Community Oncology Alliance, for her contributions to the Gypsy aspect of this article, which has been imparted to her via her Romanian heritage. ■

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Medical Staff Members Spend Many Hours Dealing with Insurance Companies Study finds Canadian medical practices have it easier By Caroline Helwick

M

edical practices in the United States spend much more money and time dealing with third-party payers than do Canadian practices, according to a recent report (Morra D, et al. Health Aff. 2011;30:1443-1450). The study showed that medical staff in the United States spend nearly 21 hours weekly dealing with insurance issues—addressing drug coverage, prior approvals, and other reimbursement issues—while their Canadian counterparts spend less than 3 hours weekly. Among physicians, there is a little more parity: US doctors spend 3.4 hours weekly on these tasks compared with 2.5 hours for Canadian physicians. The study was a collaboration between US and Canadian researchers, led by Dante Morra, MD, University of Toronto, and Sean Nicholson, PhD, a policy professor at Cornell University, Ithaca, NY. The

researchers sent surveys to officebased physicians and practice managers in Ontario and compared their

A key difference was the time they spent obtaining prior authorizations before treatment. US physicians spend about 1 hour weekly on this task, and US office staff spend 13 hours. findings with those of a similar study of US physicians. The survey, which was completed by 216 Canadians, pointed to substantially different amounts of time that physicians and their staff spend dealing with insurers. A key difference was the time they spent obtaining prior authorizations before treatment. US physicians spend about 1 hour weekly

on this task, and US office staff spend 13 hours. Canadians spend very little time on this task, because their singlepayer health system offers 1 service; procedures for approvals, payments, and so forth are much more streamlined, the study suggested. “Having multiple payers clearly generates more administrative costs than a single-payer system,” the authors observed.

Huge Difference in Administrative Costs The big difference in time spent on these tasks translates into big money spent as well. Researchers estimated that it costs $23 billion to $31 billion for US physicians to interact with private insurance plans annually. This was based on $82,975 per physician compared with $22,205 per Canadian physician to negotiate within the single-payer system. If US practices had administrative costs similar to those of the Canadians, the estimated savings would be $28 billion annually, the investigators determined.

Pointing to the benefits of a multiple-payer system—such as enhancement of innovation through competition and more choices for individuals —the author suggests that medical practices could deal with the payers more efficiently. Survey respondents agreed that standardizing transactions and encouraging electronic transactions may help. Under a proposed rule by the Department of Health and Human Services, insurers would be required to provide uniform information and use uniform formats when communicating claims and coverage information. Part of the Affordable Care Act, the proposed rule could save $12 billion for healthcare providers and insurance companies. Accountable care organizations, which move physicians away from fee-for-service, are also expected to reduce administrative costs. The authors conclude that “everyone—health plans, physicians and their staffs, and patients—will be better off if inefficiencies in transactions between physicians and health plans can be reduced.” ■

The Bush-Obama Rx Shortages Critical cancer drugs are in short supply thanks to price controls

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his week [on October 31, 2011] President Obama finally confronted a major US healthcare disgrace—the growing shortages of lifesaving drugs, especially anticancer therapies. For some reason the White House lumped its executive order with its “we can’t wait” campaign against House Republicans, but the pity is that we will have to wait, because the only genuine fix is a liberal anathema: market prices. Shortages have more than tripled since 2005, according to the University of Utah’s Drug Information Service, and by the end of the year more than 300 products are likely to be backordered, in short supply or totally unavailable. Some are anesthetics and pain therapies, others emergency room “crash cart” drugs. But most—about 70% in 2010—belong to the class of drugs known as “sterile injectables” that are mainstays of the chemotherapy arsenal, such as paclitaxel or cytarabine. The result is that more and more patients are receiving substandard Reprinted with permission from the Wall Street Journal; November 2, 2011. All rights reserved.

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care—relying on less effective or more expensive substitutes or else forced to postpone treatment. In oncology, delays of weeks or even days can be fatal. Most sterile injectables have been off-patent for decades, but unlike other cheap generic drugs with low profit margins, production is complex and requires special facilities. Nonetheless, George W. Bush and the Republican majority decided that Medicare was “overpaying” for these cancer drugs and included a 6% cap on price increases every six months in the 2003 prescription drug bill. These new price controls (which apply to the providers that purchase the drugs) took effect in 2005, when the shortages began. In a rational market, sterile injectable prices would now be rising to encourage more supply, since the demand for cancer drugs is inelastic. The old reimbursement system, called “buy and bill,” was imperfect, but at least it allowed prices to float and wasn’t producing the scarcity that central planning always does. The sterile injectables that are in short supply currently sell for $37.88 a dose, on average, and modest price increases could make the market economic.

The problem is compounded because the US Food and Drug Administration (FDA) rules cause pointless delays. It takes as long as two

Mr Obama’s executive order will do little if any good since it doesn’t address or even mention this underlying distortion that Medicare has created. Instead, it merely expands the FDA reporting requirements about production interruptions or terminations.

and a half years to receive FDA manufacturing approval for a generic, so other drug makers can’t ramp up production if a company cancels a product line due to these disincentives or even if the fragile supply chain for sterile injectables is contaminated and manufacture is delayed. Mr Obama’s executive order will do

little if any good since it doesn’t address or even mention this underlying distortion that Medicare has created. Instead, it merely expands the FDA reporting requirements about production interruptions or terminations. This is supposed to be an early warning system, but the scandal is that the availability of basic medicines could be allowed to become an emergency. The order also tells the Justice Department to crack down on the “grey markets” that have sprung up to deliver supplies to doctors and hospitals, albeit with the inevitable markups. So rather than allow price signals to govern supply and demand, Mr Obama wants to suppress them further. The larger danger apart from the risks to the patients forced to receive compromised treatment is to the future of cancer progress. The common chemotherapy drugs are critical in clinical trials as the standard regimen or in combination with new options, and the Coalition of Cancer Cooperative Groups reports that as many as half of all ongoing trials require the drugs that are vanishing. This is a delay that really is killing people. ■

www.ValueBasedCancerCare.com

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ESMO ANNUAL MEETING

Predictive Biomarker for Bevacizumab May Be Emerging By Audrey Andrews

See also page 20

Stockholm, Sweden—Investigators appear to be closer to identifying a biomarker that may predict response to bevacizumab (Avastin). At the European Society for Medical Oncology’s 2011 European Multidisciplinary Cancer Congress, several presentations focused on baseline levels of a short isoform of the vascular endothelial growth factor (VEGF), plasma (p) VEGF-A. Thanks to a novel, highly sensitive enzyme-linked immunosorbent assay, this can now be measured. Investigators analyzed blood samples from 6 randomized trials in various tumor types and correlated pVEGF-A with clinical outcomes. Median baseline levels of several candidate biomarkers were prespecified

as a cut point to categorize patients as being low or high in pVEGF-A. “Of several putative predictive biomarkers for bevacizumab, pVEGF-A is a lead candidate,” said Gordon C. Jayson, PhD, of the University of Manchester, United Kingdom.

“Of several putative predictive biomarkers for bevacizumab, pVEGF-A is a lead candidate.” —Gordon C. Jayson, PhD The analysis showed that baseline pVEGF-A is potentially predictive (for

response to therapy) and prognostic (for outcome, regardless of treatment) in metastatic breast, gastric, and pancreatic cancers, based on findings from the pivotal AVADO, AVAGAST, and AVITA trials, respectively. In AVADO, progression-free survival was greatest for metastatic breast cancer patients with high pVEGF-A receiving bevacizumab (hazard ratio [HR], 0.49; P = .08); the marker was prognostic for overall survival (OS) in AVADO. In AVAGAST, the OS was greatest for patients with metastatic gastric cancer and high pVEGF-A receiving bevacizumab (HR, 0.72; P = .07). Similarly, in AVAIL, high baseline pVEGF-A correlated with worse OS in the placebo arm, but treatment with

bevacizumab improved outcomes enough to put patients on par with those who had low baseline pVEGF-A (P = .03). But pVEGF-A is prognostic only (not predictive) in metastatic colorectal cancer, non–small-cell lung cancer, and renal-cell carcinoma based on the AVF2107g, AVAIL, and AVOREN trials, respectively. It is unclear why the biomarker is robust in some tumor types but not in others. The difference in its predictive potential may be a reflection of variations in sample handling among these trials, Dr Jayson suggested, “although we cannot exclude a true negative in colorectal, non–small-cell lung cancer, and renal cancer.” ■

Thromboembolism after Chemotherapy Raises Healthcare Costs about 30% By Caroline Helwick Stockholm, Sweden—The development of venous thromboembolism (VTE) in patients with cancer has a significant impact in terms of morbidity and mortality and healthcare costs, according to a “real-world analysis” reported at the 2011 European Multidisciplinary Cancer Congress. Gary H. Lyman, MD, MPH, an oncologist and Director of Comparative Effectiveness and Outcomes Research, Duke University School of Medicine, Durham, NC, was principal investiga-

Figure

Healthcare Costs of Patients with and without VTE 120,000

100,000

Healthcare costs, $

tor. “VTE development was associated with a significant economic burden in terms of healthcare expenditure,” Dr Lyman said. Dr Lyman and colleagues assessed the economic impact of VTE events using the US-based InVision Data Mart Multiplan/Integrated Health Care Information Solutions database. They retrospectively identified 30,552 patients with cancer who initiated chemotherapy in the 4-year period ending in 2008. Healthcare costs such

—Gary H. Lyman, MD, MPH

$110,362

VTE No VTE

$77,984

80,000

60,000

40,000

$37,542 $35,342

20,000

0

1 year preindex

1 year postindex

VTE-related outcomes VTE indicates venous thromboembolism.

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“The decision for the use of thromboprophylaxis in cancer patients undergoing chemotherapy should be based on the balance between the potential benefits and harms, including any bleeding risk.”

VALUE-BASED CANCER CARE

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as inpatient, pharmacy, emergency department, and outpatient expenses were assessed at 1-year pre- and postindex treatment (first day of chemotherapy after cancer diagnosis). The incidence of VTE 3.5 months after the initiation of chemotherapy ranged from 4.8% to 11.9%, depending on the tumor site. The highest risk was observed in patients with pancreatic, stomach, and lung cancer. The incidence continued to increase over time postindex treatment, peaking at 9.9% to 21.5% at 12 months, Dr Lyman reported.

High Healthcare Costs Patients who developed VTE within 3.5 months postindex treatment had healthcare costs at baseline that were comparable with persons not developing VTE. During first-year postindex treatment, the costs for patients with VTE were significantly higher than those for patients without VTE; the increase was driven primarily by higher inpatient and outpatient costs (Figure). The overall healthcare costs 1 year before receiving chemotherapy were $37,542 for patients developing VTE and $35,342 for those without VTE. By 1-year postindex treatment, costs had risen to $110,362 and $77,984, respectively, Dr Lyman reported. Costs were higher for patients with VTE in each category of expenditure: inpatient, outpatient, emergency department, and pharmacy. “Similar results were seen for patients who developed VTE within 12 months postindex,” he said. “The decision for the use of thromboprophylaxis in cancer patients undergoing chemotherapy should be based on the balance between the potential benefits and harms, including any bleeding risk associated with a therapy,” Dr Lyman pointed out, emphasizing the need to assess costeffectiveness and cost-utility of prevention in this setting. ■

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Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

goal One goal: discovering and delivering breakthrough medicines to combat cancer. Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

To learn more, visit us at millennium.com. ©2011 Millennium Pharmaceuticals, Inc. All rights reserved.


VBCC_Dec_11_4_Follow ASCO Tabloid 12/23/11 9:11 AM Page 20

ESMO ANNUAL MEETING

Delivering Affordable, Evidence-Based Cancer Care in High-Income Countries Global panel calls for radical changes that factor in economics By Caroline Helwick Stockholm, Sweden—A consortium of world cancer specialists, economists, and policymakers is tackling the issue of equitable cancer care in the face of rising cost of care in high-income countries. Their report (Sullivan R, et al. Lancet Oncol. 2011;12:933-980) coincided with a key presentation at the 2011 European Multidisciplinary Cancer Congress. The report focused on the delivery of equitable and affordable care in the United States, Europe, Canada, Australia, and New Zealand. Richard Sullivan, MD, PhD, from Kings Health Partners at King’s College Integrated Cancer Centre, Guy’s Campus Hospital, London, who spoke at the Presidential Session, said the problem is urgent. “Affordable cancer care needs to be at the heart of policy discussions now,” he emphasized, adding, “There is internal panic regarding what we should do.” A $300-Billion Problem The Economist Intelligence Unit estimates the costs associated with new cancer cases alone (worldwide) in 2009 to be at least $286 billion ($107 billion in the United States). Medical costs make up more than 50% of the economic burden, and productivity losses account for nearly 25% of the burden. By 2030, there will be an esti-

mated 22 million new patients with cancer annually worldwide, which will greatly exacerbate the problem. “The global challenge to countries is how to deliver reasonably priced cancer care to all citizens in a way that respects what patients want,” Dr Sullivan said. The massive increase in expenditure on cancer care in high-income countries over the past 2 decades results from many factors: overutilization (eg, tests that are useful in one setting but not another), high-cost innovations, disincentives driven by reimbursement rules and defensive medical practice (more tests and treatment to counter a litigation-driven culture), consumer-driven overdemand, and futile overtreatment at the end of life, the panel concluded. “Radical Action Is Needed” The panel identified a range of immediate and medium-term measures that could be introduced to reduce the current cost base and to manage the future cost curves of particularly expensive interventions. For one thing, radical action is needed, they said, to simplify and integrate patient treatment pathways and new models of care with lower cost bases. A new approach to costly interventions must be driven through health-

“It is of the utmost importance that oncology professionals promote evidence-based discussion of the economics of cancer care.” —Michael Baumann, MD care systems. These would range from mandatory cost-effectiveness analysis to the prohibition of off-label use and new economic models for reimbursement and incentivization. “The cancer profession and industry should also take responsibility and not accept an ethos of very small benefit at whatever cost. Rather we need delivery of fair prices and real value from new technologies,” Dr Sullivan said. Introducing Value into Patient Care It is also important to bring these issues to the public. “Making individual patients more sensitive to the costs of care is necessary for an informed public debate around the critical issues,” Dr Sullivan pointed out. “We need to educate the public that valuebased cancer care is not poor care.” “Getting technology to the patient

See also page 18 faster” is an existing concept that must be rethought. In the current healthcare culture, patients want immediate rewards, particularly novel therapies,” he said, but this is a cost-driver. Individuals should also take more responsibility for their own health, and make lifestyle changes in keeping with cancer prevention, the panel suggested. Billions of dollars could be saved in the treatment of lung cancer alone, by smoking prevention. “The question is how to incentivize both professionals and patients to engage in cost-effectiveness treatments and behaviors that will prevent cancer,” according to Dr Sullivan. The panel observed that too many non–evidence-based approaches are being taken and “ad hoc decisions” are being made at the local level. “This must stop,” he commented. “We believe that value and affordable cancer care can be introduced into the cancer policy lexicon, without detracting from quality, and that the management tools, evidence, and methods are available to affect this transformation across all developed countries,” Dr Sullivan concluded. President of the European Cancer Organization, Michael Baumann, MD, commented, “It is of the utmost importance that oncology professionals promote evidence-based discussion of the economics of cancer care. This can only be safeguarded by transparent and evidence-based analysis and policy development. This initiative is a very important step in this direction.” ■

ASCO BREAST CANCER SYMPOSIUM

Young Patients Are Served Equally Well by Lumpectomy or Mastectomy San Francisco, CA—Breast cancer in women under age 40 years is often considered a more aggressive disease than in older women, and this often leads clinicians to recommend mastectomy over breast-conserving therapy (BCT), that is, lumpectomy or radiation. However, 2 studies presented at the 2011 Breast Cancer Symposium suggest that younger age in itself is not a reason for mastectomy. Andrew D. Seidman, MD, of Memorial Sloan-Kettering Cancer Center, who moderated a press briefing, commented, “This is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy.” To determine the risk of recurrence “in the modern era of multimodal treat-

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ment,” Juliette M. Buckley, MD, Massachusetts General Hospital, Boston, spearheaded a retrospective review of 628 young women (≤40 years) diagnosed with stage I-III breast cancer. The analysis showed that BCT did not result in a higher rate of locoregional or distant recurrence than mastectomy. On multivariate analysis, only tumor size >2 cm and positive lymph nodes were independent predictors of recurrence. Therefore, “lumpectomy is indeed a safe option for young women,” Dr Buckley concluded. Other researchers at M.D. Anderson Cancer Center, Houston, analyzed the Surveillance, Epidemiology, and End Results database of 14,764 young women (≤40 years) with early breast cancer. After adjusting for potential

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“This is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy.” —Andrew D. Seidman, MD

confounders, women who received BCT had no worse overall survival or breast cancer–specific survival than women who had mastectomy. Dr Seidman advised that the type of

surgery should no longer be considered a key issue. “We are starting to look beyond the usual prognostic factors, such as tumor size, grade and lymph node, estrogen-receptor, and HER2 status, and are moving into biological subtyping to obtain additional information regarding the risk of relapse,” he said. Of note, in spite of equivalent survival for lumpectomy, several studies have shown that mastectomy rates are increasing across all age-groups, noted Rakesh Patel, MD, Western Radiation Oncology, El Camino, CA, who discussed the M.D. Anderson Cancer Center research. He attributed this to improved reconstruction options, use of preoperative magnetic resonance imaging, and identification of patients with genetic predispositions. “And all the factors have a greater influence in younger patients,” Dr Patel noted. ■

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NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

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 • It has been observed that patients with platelet counts <200 X 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 X 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 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 Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a trademark of Incyte Corporation. © 2011, Incyte Corporation. All rights reserved.

RUX-1004C

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IN THE LITERATURE Axitinib Promising SecondLine Treatment for Advanced Renal Carcinoma This is the first phase 3 clinical trial to compare the effectiveness of 2 second-generation antiangiogenic agents          —axitinib and sorafenib—for metastatic renal-cell cancer, showing great promise for the investigational drug

axitinib (Rini BI, et al. Lancet. 2011;378: 1931-1939). This randomized trial included 723 patients (from 175 sites in 22 countries) with renal-cell carcinoma that had progressed despite the use of first-line therapy with sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were randomized

to axitinib 5 mg initially and titrated up to 10 mg twice daily (N = 361) or to sorafenib 400 mg twice daily (N = 362). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate, response duration, and time to deterioration. The median PFS was significantly

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 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 Reactions Grades 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

(42%) longer with axitinib (6.7 months) than with sorafenib (4.7 months). In those who had previously received cytokines, the median PFS was 12.1 months with axitinib compared with 6.5 months sorafenib; in those who had previously received sunitinib it was 4.8 months versus 3.4 months, respectively. The objective response rate was 19% with axitinib versus 9% with sorafenib. A total of 14 (4%) of the 359 patients who received axitinib and 29 (8%) of the 355 patients who received sorafenib discontinued treatment because of adverse effects. The most common adverse events reported were diarrhea, hypertension, and fatigue in the axitinib group and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib group. ■

Bortezomib–Rituximab Combo Improves PFS in Relapsed Follicular Lymphoma A phase 3 study comparing the efficacy and safety of rituximab alone and in combination with bortezomib in patients with relapsed grade 1 or 2 follicular lymphoma who were rituximab-naive or rituximab-sensitive showed extended PFS with the drug combination compared with rituximab alone (Coiffier B, et al. Lancet Oncol. 2011;12:773-784). This open-label trial included 676 patients from 164 centers across Europe, the Americas, and Asia. Patients were randomized to five 35day cycles of rituximab either alone (N = 340) or in combination with bortezomib (N = 336). The primary end point was PFS. Secondary end points were time to progression, time to next treatment, and OS. After a median follow-up of 34 months, the median PFS was 11.0 months with rituximab alone and 12.8 months with bortezomib plus rituximab. The estimated 2-year PFS rates were 23.5% and 31.2%, respectively. In a subgroup analysis, bortezomib plus rituximab combination therapy was associated with a significantly longer PFS than rituximab alone in patients with high risk factors and in younger patients (≤65 years), but not in older patients. In patients who received previous lines of therapy, the differences between the 2 treatment arms were not significant. In patients who had received any previous rituximab therapy, the median PFS was 9.2 months with rituximab alone versus 11.4 months with the bortezomib–rituximab combination. The most common grade 3 or higher adverse events reported were neutropenia, infection, diarrhea, herpes Continued on page 32

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VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 3:25 PM Page 23

ASTRO ANNUAL MEETING

Reporting Gap for Near-Misses and Errors in Radiation Oncology Is Rampant See also page 25

By Phoebe Starr Miami, FL—Most radiation personnel believe that errors and near-misses of radiation treatment should be reported, but this does not always happen, according to a study of survey results from 4 academic radiation oncology practices that was presented at the 2011 American Society for Radiation Oncology meeting. “Although 97% of radiation oncology team members believe they have a responsibility to report near-misses and errors, up to one third reported having been involved with, or aware of, a minor event but not reporting it to voluntary in-house systems designed to capture them. This reporting gap… was seen among all members of the clinic,” said lead investigator and radiation oncology resident Kendra M. Harris, MD, Radiation Oncology, Johns Hopkins Medical Center, Baltimore. The study comes in the aftermath of a January 23, 2010, front-page article in the New York Times on serious radiology errors, causing many radiology departments to take stock of their performance.

The study was based on an anonymous survey sent to radiation staff (including attending physicians, resi-

“Even in departments with sophisticated reporting systems, all radiation oncology team members admit there is a ‘reporting gap.’” —Kendra M. Harris, MD

dents, radiation therapists, nurses, dosimetrists, and physicists) at Johns Hopkins Medical Center; North Shore– Long Island Jewish Health System; Washington University School of Medicine; and the University of Miami. The response rate was 81% (N = 274). The most prominent barrier to reporting events was a concern about professional sanctions. Other reasons given were cited by:

• Embarrassment, 49% attending; 58% resident physicians • “Getting my colleagues in trouble,” 41% attending physicians, 54% resident physicians, 40% nurses, and 47% radiation therapists • “Admitting liability,” 33%: 41% attending physicians and 42% residents cited that as a barrier to reporting errors. Communication failures were a common source of errors, including setup errors and those associated with complex stereotactic treatments and computer-related events. Improving communication could help to address the problem, Dr Harris said. Dr Harris said that there are strict rules that govern the appropriate reporting of serious radiation events, but there are no mandates regarding the reporting of lesser events or nearevents and no recommendations regarding the monitoring of these events for system-based improvements. “Even in departments with sophisticated reporting systems, all radiation

at a glance ➤ Up to 33% of errors and nearmisses during radiotherapy are never reported ➤ The most-cited reasons include embarrassment, admitting liability, and getting colleagues in trouble ➤ Although serious events must be reported, the reporting of lesser events is not required ➤ This was a survey of 4 academic practices, in which 97% of the radiation oncology team members said they believed they had a responsibility to report these

oncology team members admit there is a ‘reporting gap,’” Dr Harris said. Survey respondents indicated that reporting is their responsibility, they are not too busy, and they know what to report. ■

High-Dose Radiation Does Not Improve Survival in Stage III NSCLC Miami, FL—A regimen of high-dose radiation had no survival advantage over standard radiation with concurrent chemotherapy in patients with advanced unresectable non–smallcell lung cancer (NSCLC) that had spread to the lymph nodes, according to an interim analysis of a late-breaking study presented at the 2011 American Society for Radiation Oncology meeting. The phase 3 RTOG 0617 trial showed that overall survival was 74% in the high-dose group versus 81% in the standard-dose arm, and median survival was 22 months versus 20 months, respectively. “The first study in 30 years to see if a higher dose of radiation would have a survival benefit found no benefit for 74 Gy over 60 Gy. The 74-dose arms were closed in June 2011, and we believe that the 60-Gy dose should remain the accepted standard,” said lead investigator Jeffrey D. Bradley, MD, Washington University, St. Louis, MO. The study plans to enroll 500

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patients with stage III NSCLC in this ongoing trial. This interim analysis was based on 423 patients randomized to 1 of 4 arms: • Standard-dose radiation (60 Gy) plus chemotherapy (paclitaxel/

at a glance ➤ The first study in 30 years to investigate the benefit of highdose radiation plus cetuximab in NSCLC showed no survival benefit over standard radiation, with or without cetuximab ➤ High-dose radiation, nonsquamous histology, and smaller tumor volume were significantly associated with reduced survival ➤ The major challenge for patients with advanced lung cancer is distant metastases, and radiation is targeted at achieving local, not distant control

carboplatin) and cetuximab • Standard-dose radiation with chemotherapy and no cetuximab • High-dose radiation (74 Gy) chemotherapy plus cetuximab • High-dose radiation with chemotherapy and no cetuximab. This study will also address the question whether cetuximab is of incremental benefit to radiation and chemotherapy in stage III NSCLC. This aspect of the trial is ongoing. Both groups had similar baseline characteristics. The average follow-up time for the 423 patients has been 9 months. Until now, deaths have resulted primarily from the disease’s progression. No significant difference in treatment-related toxicity was reported between the radiotherapy arms. Adverse events were similar in both groups. Grade 5 treatment-related adverse events occurred in 8 patients in the high-dose arm and in 5 patients in the standard-dose arm. Two deaths from radiation pneumonitis were reported for each arm.

A multivariate analysis showed that high-dose radiation, nonsquamous histology, and smaller tumor volume were significantly associated with a lower survival rate.

“The first study in 30 years to see if a higher dose of radiation would have a survival benefit found no benefit for 74 Gy over 60 Gy. We believe that the 60-Gy dose should remain the accepted standard.” —Jeffrey D. Bradley, MD

When asked why high-dose radiation did not improve survival, Dr Bradley indicated that the major challenge for patients with advanced lung cancer is distant metastases, and radiation is targeted at achieving local, not distant control. —PS ■

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ONCOLOGY TRENDS

The Pace of Change in Oncology Management Greater than the Sum of Its Parts Cost and access remain major concerns By Lee Goldberg, Senior Manager, and Tracey Ryan, Senior Analyst, The Zitter Group

I

nnovative medications target the molecular structure of cancer cells with increasing precision, resulting in reduced adverse effects. Novel therapies enlist the patients’ own immune systems to defeat cancer. At the same time, as personalized medicine comes of age, improved diagnostic tests match the right patients to these new treatments. The accelerating pace of these developments is improving expectations of patient survivability and the total number of survivors. This excitement, however, needs to be tempered by the recognition that these advances come at a steep price. According to Medco Health Solutions, the net cost in the category of oncology drugs for 2010 has increased by 21.2%, fueled by a 13.7% rise in unit cost daily. This is more than the growth in rheumatoid arthritis and multiple sclerosis drugs (Medco 2011 Drug Trend Report). Not only do payers struggle to balance costs with access, physicians, patients, government agencies, and manufacturers also face difficult cost-of-care decisions. The Zitter Group’s recently released, “Managed Care Oncology Index: Summer 2011” (www.zitter.com)—a seminal survey of 100 oncologists, 100 payers, and 100 oncology practice managers—identified 3 evolving issues that stand to have a significant impact on the cost–access dynamics within the oncology therapy land-

scape over the next 6 to 12 months: • Practice consolidation • Routes of administration • Competing treatment options. Individually, each of these factors is changing at a measured pace. But their confluence portends an accelerating pace of change in the access environment for patients. What Is the Scope of Practice Consolidation? Oncologists expect the financial viability of their practices to decrease over the next 2 years. Efforts of government agencies and payers to control costs cast a pall over oncologists’ financial outlook. Practices of all sizes face reduced drug reimbursement combined with prospective steep cuts in Medicare reimbursement. Increasing administrative requirements of payers command a dedicated staff to process the paperwork (Figure 1). It is not surprising that roughly 80% of both oncologists and practice managers believe that tighter oncology management by payers will force smaller practices to consolidate into larger ones. The question that remains is, not if, but when? Despite marginally increasing commercial buy-and-bill reimbursement rates (likely because of the influence of generic contracts), 57% of oncologists, a 36% increase in the past 6 months, report a decline in revenue as a direct

result of the average sales price (ASP) reimbursement. A majority of oncologists’ revenue declined in the range of 10% to 20%. A majority of practice managers also report a decline in revenue as a direct result of the ASP reimbursement over the past 6 to 12 months. In fact, roughly one third of oncologists and practice managers have encountered commercial payer reimbursements lower than their acquisition costs for oncology products when utilizing buy-and-bill distribution. Nonetheless, because they express greater comfort with their current financial situation than 6 months ago, the majority of oncologists, and 41% of practice managers, have not been approached, or approached another party themselves, regarding consolidation. Neither are accountable care organizations (ACOs) spurring action. Only 4% of oncologists have joined an ACO by the time of this survey, while the majority remains undecided. Finally, from the payers’ perspective, actual consolidation in the market is also far too limited. All parties see the process as being driven by the hospitals or healthcare systems themselves.

intravenous (IV) therapies, given comparable safety and efficacy profiles. A majority of oncologists and practice managers report that patient preference runs in the same direction, preferring oral medications for therapeutic and supportive treatments. Both groups cite ease of route of administration as the main reason for patients’ preferences. Data show that payers’ preference is driven by ease of management. Fewer than half of payers believe strict management of pharmacy benefit medications encourages patients to use medications covered under the medical benefit. Given what oncologists and practice managers report of patients’ preference for oral agents (pharmacy benefit drugs), payers may indeed be right. However, oral medications face greater numbers of prior authorizations. For the patient, oral agents also come with higher price tags. Patients now face an average $30 copayment for second-tier drugs (up from $25 last year) and 26% of payers use a fourth tier in their most representative costsharing design, likely adjudicating at a 20% coinsurance rate. Contrast this to payer policies that use medical benefit agents. Only 50% of plans require patient cost-sharing at all; patients covered by the other 50% of payers pay nothing directly for their infused

Routes of Administration Since the summer of 2010, twothirds of payers have consistently expressed a strong preference that patients use oral agents rather than

Continued on page 25

Figure 2 Patient Cost-Sharing: Medical Benefit Therapies Figure 1 Impact of Payer Management on Practice Consolidation Q: Does your most representative commercial benefit design require patient cost-sharing for prescription therapies managed under the medical benefit?

Q: Do you believe that tighter oncology management by payers will force smaller oncology practices to consolidate into larger ones? Neutral (3), responses not shown

Strongly disagree (1) or disagree (2)

Yes

Winter 2011 (N = 103)

4.07

Summer 2010 (N = 100)

4.15

Summer 2011 (N = 100)

3.97

Winter 2011 (N = 101)

3.95

Summer 2010 (N = 100)

4.02

Q: Does your most representative commercial benefit design distinguish between preferred and nonpreferred prescription therapies managed under the medical benefit? Asked of payers that require patient cost-sharing for prescription therapies managed under the medical benefit

No significant difference between date of survey completed or stakeholders. The Zitter Group © 2011. All Rights Reserved.

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27%

Yes

71%

No

Unsure

Percentage of respondents

49% Percentage of payers

Payers (N = 101)

Percentage of payers (N = 49)

Practice managers

Oncologists

Mean 4.19

Unsure

49%

Believe it (4) or strongly believe it (5)

Summer 2011 (N = 100)

No

Mean

Median

Preferred prescription Nonpreferred prescription

$20.00

$17.50

$48.75

$37.50

All therapies

$27.89

$20.00

2%

The Zitter Group © 2011. All Rights Reserved.

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ONCOLOGY TRENDS

The Pace of Change in Oncology...

How Might Comparable Products Influence Utilization Management? When considering future management over the next 18 months, a majority of payers intend to expand the scope of their current management interventions, particularly quantity limits, even among payers that do not currently use them. More than 50% of payers intend to introduce clinical pathways. Oncologists believe that payers are most likely to expand linking diagnostic tests to drug approval, whereas practice managers expect payers to expand their use of prior authorizations. Recent drug approvals for chronic myeloid leukemia, colorectal, non–

small-cell lung, and prostate cancer add a new wrinkle to oncology utilization management—agents with similar mechanisms of action for use for the same type of cancer. Currently, a majority of oncologists expressed a treatment preference of one agent over another in these categories, whereas a majority of payers hold no preference. However, grouping subtypes by their management priority data shows that decreasing

payer perceptions of unmet need correlates to incrementally higher priority (Figure 3). If the physicianprescribing behavior evolves into codified best practice via compendia listings, payer history indicates that their management policies will follow suit: as we can see, they are already paying attention. Implications Taken together, ACOs, healthcare

Figure 3 Relating Management Priorities to Unmet Need: Payer Perspective High management priority

Moderate management priority Oncology chaperoning

5 Enjoy it while it lasts 14

Unmet Therapeutic Need

medication (Figure 2). The cost advantage to patients of using an IV agent is only partially offset by the cost of the visit to the site for the infusion that is still required by only 67% of plans. The evolution in route of administration is tied to physician reimbursement and practice viability. Oral agents eliminate the buy-and-bill dynamic from physicians’ balance sheets. For infusible drugs, payers expect officeadministered, infusible-therapy volume to shift away from buy-and-bill in favor of specialty pharmacies over the next 12 months, with 52% of payers preferring the latter channel. Practice managers do not expect such a large shift, but the continual reduction in infusion revenue makes oral agents twice as attractive to payers.

Continued from page 24

13 12 15 19

3

6 Chronic lymphocytic

7

9

8 6

leukemia

2

5

10

16 17 18

1 Breast 2 Colon and rectal 3 Lung 4 Prostate 5 Multiple myeloma

3

High unmet need

Low management priority

1 4

7 Melanoma 8 Chronic myeloid

leukemia

11

9 Non-Hodgkin

lymphoma 10 Kidney (renal cell) 11 Hodgkin disease

Low unmet need

12 Liver 13 Ovarian 14 Pancreatic 15 Head and neck

Commodity

1 No curfew 1 Low management priority Payers (N = 101)

3 High management priority 5

Payer management priority

16 Endometrial 17 Gastrointestinal

stromal tumor 18 Thyroid 19 Bladder

The Zitter Group © 2011. All Rights Reserved.

at a glance ➤ Rapid developments in targeted therapies and diagnoses are accelerating the survival rates for patients with cancer; however, the costs of care are increasing just as dramatically ➤ Three evolving issues are impacting the cost-to-access dynamic: practice consolidation, routes of administration, and competing treatment options ➤ The trend toward consolidation in healthcare is affecting all parties involved, forcing small practices into larger ones, leaving fewer players to control more treatment decisions, and patients with fewer choices ➤ The majority of oncologists resist consolidation; only 4% have joined an ACO systems, payer expansion, and physician aggregation, point toward fewer players controlling more treatment decisions. With the government encouraging creative reorganization, and payer reimbursement impacting practice viability, payers, healthcare systems, and oncologists may find themselves in closer partnerships than ever before—and leaving patients with fewer choices. ■

ASTRO ANNUAL MEETING

Hypofractionated Radiotherapy in Prostate Cancer More Convenient for Patients See also page 23 Less costly, but has more adverse effects than conventional radiation By Phoebe Starr Miami, FL—Delivering higher doses of external-beam radiation over a shorter period (hypofractionated radiation) was as effective as conventional radiation in preventing treatment failure in men with intermediate- to high-risk prostate cancer. The hypofractionated regimen shortened treatment time by 2.5 weeks compared with conventional radiation. However, the frequency of grade 2 or higher genitourinary (GU) adverse events, particularly urinary incontinence, was much higher with the hypofractionated regimen in a phase 3 trial presented at the meeting. The study hypothesis was that hypofractionation would be superior to conventional radiotherapy in avoid-

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ing biochemical failure and would not cause greater toxicity, but the results failed to show this. Lead investigator Alan Pollack, MD, Chair of Radiation Oncology, University of Miami, FL, said that hypofractionated radiation was an option for men with intermediate- to high-risk prostate cancer, but there may be a trade-off between shorter treatment time and an increase in GU adverse events with this regimen. “Hypofractionation is more convenient for patients and less costly,” Dr Pollack said. The study population included 303 men with intermediate (66%)- or highrisk (33%) prostate cancer. Two thirds had intermediate-risk cancer and one

third had high-risk cancer. Baseline characteristics were similar for both groups. Treatment failure was defined as a prostate-specific antigen rise of ≥2 ng/mL from the lowest value. The 5year cumulative incidence of treatment failure was 13.9% in the hypofractionation group versus 14.4% in the conventional radiotherapy group. Overall, biochemical failure was reported for 61 patients, with no significant difference in failure rate between the 2 arms. The 5-year rates of local regional failure or distant metastasis were similar for both arms: 1.3% for the hypofractionation group and 1% for the conventional radiotherapy group.

Hypofractionation was associated with a higher rate of grade 2 and higher GU toxicity: 18.3% for hypofractionation versus 8.3% for conventional radiotherapy. Urinary incontinence was the most frequent GU adverse event, and the rate of late urinary problems was more favorable in both treatment arms compared with previous studies. The long-term rates of gastrointestinal adverse events and erectile dysfunction were identical for the 2 arms. In a post hoc analysis, the American Urological Society (AUA) symptom score for pretreatment urinary function was the strongest predictor of GU adverse events in the hypofractionation group. Overall, the median AUA score was 5. ■

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ASH ANNUAL MEETING

5-Year Analysis of VISTA Confirms Survival Advantage... up, despite substantial use of novel agents as salvage therapies. Patients who received bortezomib as first-line treatment had longer overall survival (OS) than those who received bortezomib or other therapies in subsequent treatment lines during the 5-year follow-up. “The OS subanalyses in patients receiving subsequent therapy demonstrate the importance of providing optimal first-line treatment that incorporates bortezomib, rather than reserving bortezomib for salvage therapy and using conventional first-line treatment,” said Jesús F. San Miguel, MD, PhD, of the Hospital Clinico Universitario in Salamanca, Spain, who presented the findings. VISTA Details The VISTA trial included 655 previously untreated patients with multiple myeloma who were randomized to nine 6-week cycles of bortezomib-melphalan-prednisone (VMP) or to the melphalan-prednisone (MP) regimen (ie, control group). Patients were followed at least every 12 weeks for survival and subsequent therapy use, with a median follow-up of 60.1 months. Dr San Miguel’s presentation was based on the final OS analysis of the study, representing 95% of the initial cohort (ie, only 5% in each arm were lost to follow-up).

“The OS subanalyses in patients receiving subsequent therapy demonstrate the importance of providing optimal firstline treatment that incorporates bortezomib, rather than reserving bortezomib for salvage therapy and using conventional first-line treatment.” —Jesús F. San Miguel, MD, PhD

Mortality Risk Reduced by 31% At 5 years, mortality risk was reduced by 31% with VMP, based on a

median OS of 56.4 months with the bortezomib-containing regimen and 43.1 months with MP (P = .004), Dr San Miguel reported. The median time to next treatment was 27 months with VMP versus 19.2 with MP (P <.001), and the treatmentfree interval was 16.6 months versus 8.3 months (P <.001). The benefit of adding bortezomib was seen across virtually all subsets of patients, including a 29% reduction in mortality among patients aged 75 years and older; a 23% risk reduction among those with International Staging System stage III disease; and a 30% risk reduction among patients with creatinine clearance <60 mL/min. However, the small subgroup of patients with documented high-risk cytogenetics did not gain additional benefit from bortezomib therapy. For this group of 46 patients, median OS was 44.1 months with VMP compared with 50.6 months with MP, which was not a significant difference. There was no reported increase in second malignancies. Dr San Miguel also reported that bortezomib was not associated with an increased incidence of secondary primary malignancies—a topic of recent concern in myeloma treatment. Hematologic malignancies were observed in only 1% in each arm, whereas solid tumors

Continued from cover

at a glance ➤ New, 5-year results in patients with multiple myeloma show a significant OS benefit with bortezomib therapy ➤ Patients receiving VMP in the pivotal VISTA trial lived >1 year longer than those in the control group receiving the MP regimen ➤ After 5 years, the mortality risk had decreased by 31% for those receiving the VMP regimen versus those receiving MP ➤ Bortezomib therapy did not increase the incidence of secondary primary malignancies ➤ However, the small subgroup of 46 patients with high-risk cytogenetics did not gain additional benefit from bortezomib therapy

were seen in 5% of the VMP arm and 3% of the MP arm. “The overall incidence rate in both arms was consistent with the background rate of all cancers in the general US population aged 65 to 74 years,” Dr San Miguel said, adding that based on this large final analysis he believes that bortezomib “is completely safe.” ■

VBCC PERSPECTIVE

Clinical and Economic Impact of Multiple Myeloma Exciting results in a condition with no cure By Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services, SelectHealth, Murray, UT

T

he clinical and economic impact of multiple myeloma is tremendous. With the onset of novel therapies used in multiple myeloma, as well as the release of new data demonstrating progression-free survival and overall survival, therapy used in multiple myeloma is now on the radar for payers, despite the relatively low incidence of the disease. In addition, contributing to the awareness of payers is the reality that maintenance therapy and multitherapy or combination regimens are becoming very common in the approach to treatment of patients with multiple myeloma. As a result of using newer agents, the 5-year survival rate has increased to 40% for patients diagnosed with this disease between 2001 and 2007.1,2

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The data from the VISTA trial reported at the recent American Society of Hematology annual meeting and discussed in the article above are interesting and encouraging in their long-term perspective. The VISTA trial evaluated the safety and efficacy of melphalan and prednisone (MP) therapy versus bortezomib in combination with MP as initial therapy for nontransplant patients with multiple myeloma.3 In this trial, both the response rates and a marker for osteoblast activation (ie, alkaline phosphatase) were superior in the group of patients receiving bortezomib-based therapy compared with those receiving the MP regimen alone. So far, the role of bortezomib in bone disease has not been demonstrated in patients in the transplant or relapsed

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December 2011

The ability to see long-term survival, with a follow-up period of 5 years, is particularly exciting in a condition that is without a cure. At 5 years mortality was reduced substantially, by more than 30%, in this patient population compared with the conventional first-line therapy with MP.

setting. However, the ability to see long-term survival, with a follow-up period of 5 years, is particularly exciting in a condition that is without a cure. At 5 years mortality was reduced substantially, by more than 30%, in this patient population compared with the conventional first-line therapy with MP. These data will help to continually shape appropriate guideline/protocol development. ■ References 1. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-6073. 2. Ludwig H, Beksac M, Bladé J, et al. Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. Oncologist. 2011;16:388-403. 3. Delforge M, Terpos E, Richardson PG, et al. Fewer bone disease events, improvements in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs melphalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 2011;86:372-384.

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WHAT DOES THE DISCOVERY OF A

Distinct gene MEAN FOR PATIENTS WITH LOCALLY ADVANCED OR METASTATIC ALK-POSITIVE NSCLC?


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XALKORI (crizotinib) is now approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

XALKORI is the first ALK-directed therapy offering targeted antitumor activity in patients with locally advanced or metastatic ALK-positive NSCLC 1

In early-phase trials of 255 patients taking XALKORI...* EFFICACY PARAMETER

STUDY A (N=136)

STUDY B (N=119)

ORR (CR+PR)a [% (95% CI)]

50% (42%, 59%) 68 41.9 (6.1+, 42.1+)

61% (52%, 70%) 71 48.1 (4.1+, 76.6+)

Number of responders Duration of responseb [median (range) weeks]

SELECTED SAFETY INFORMATION XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients with treatment-related pneumonitis. Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and 4% of patients in Study B. Three patients from Study A (2%) and 1 patient from Study B (<1%) required permanent

discontinuation from treatment. Concurrent elevation in ALT and total bilirubin have occurred. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for grade 2-4 transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 3:38 PM Page 29

The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation ➤ Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia

XALKORI adverse reactions were usually manageable through dose modification ➤ Dosing interruptions occurred in 36% and 45% of patients, and lasted greater than 2 weeks in 13% and 19% of all patients in Studies A and B, respectively ➤ 44% of patients in Study A and 29% of patients in Study B reduced their dose due to adverse events (AEs) ➤ 6% of patients in Study A and 3% of patients in Study B permanently discontinued therapy due to treatment-related AEs

*XALKORI for the treatment of locally advanced or metastatic NSCLC was investigated in 2 multicenter, single-arm studies. Study A was a phase 2 trial in 136 patients; ALK-positive NSCLC was identified using the Vysis ALK Break Apart FISH Probe Kit. Study B was a phase 1 trial in 119 patients; ALK-positive NSCLC was identified using a number of local clinical trial assays. Patients enrolled in these studies had received prior systemic therapy, with the exception of 15 patients in Study B who had no prior systemic therapy for locally advanced or metastatic disease. The primary efficacy end point in both studies measured objective response rate based on RECIST criteria; duration of response was also evaluated. a One patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B. b Preliminary estimate using Kaplan-Meier method. +Censored values.

to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

Take a picture of this icon with your smart phone to learn more about XALKORI


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 3:40 PM Page 30

Now thereâ&#x20AC;&#x2122;s a reason to check Pretreatment testing can help guide therapeutic decisions2 Approval of XALKORI is a compelling reason to start testing advanced NSCLC patients for ALK An FDA-approved test should be used to determine which patients have ALK-positive NSCLC

Please see accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com. XALKORI is a registered trademark of Pfizer Inc. References: 1. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773-1780. 2. Perez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(Suppl 1):S38-S45.


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 3:42 PM Page 31

XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

IMPORTANT SAFETY INFORMATION Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Other causes of pneumonitis should be excluded. XALKORI should be permanently discontinued in patients with treatment-related pneumonitis. Hepatic Laboratory Abnormalities: Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and 4% of patients in Study B. Three patients from Study A (2%) and 1 patient from Study B (<1%) required permanent discontinuation from treatment. Concurrent elevation in ALT and total bilirubin have occurred. Liver function tests including ALT and total bilirubin should be monitored once a month and as clinically indicated, with more frequent repeat testing for grade 2-4 transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. QT Interval Prolongation: QTc prolongation has been observed. XALKORI should be avoided in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval, periodic monitoring with electrocardiograms and electrolytes should be considered. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to â&#x2030;¤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions are available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (â&#x2030;Ľ25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in â&#x2030;Ľ4% of patients in both studies included ALT increased and neutropenia. Ť Ä&#x2013;ŤŤ(2(.-Ť"(2.1"#12Ť(-!+4"(-%Ť5(24+Ť(,/(1,#-3Ä?Ť/'.3./2(Ä?Ť5(2(.-Ť +411#"Ä?Ť5(31#.42ŤǏ.3#12Ä?Ť/'.3./'. (Ä?Ť-"Ť"(/+./(Ť6#1#Ť1#/.13#"Ť in 159 (62%) patients in clinical trials. Ophthalmological evaluation should be considered, particularly if patients experience /'.3./2(Ť.1Ť#7/#1(#-!#Ť-#6Ť.1Ť(-!1#2#"Ť5(31#.42ŤǏ.3#12Ä&#x17D;Ť#5#1#Ť.1Ť6.12#-(-%Ť5(31#.42ŤǏ.3#12Ť-"Ä°.1Ť/'.3./2(Ť!.4+"Ť+2.Ť #Ť signs of a retinal hole or pending retinal detachment. Caution should be exercised when driving or operating machinery by patients who experience vision disorder. Ť Ä&#x2013;ŤŤ#41./3'8Ť331( 43#"Ť3.Ť234"8Ť"14%Ť62Ť1#/.13#"Ť(-ŤÄ&#x2026;Ä&#x2021;ŤijÄ&#x192;Ä&#x2026;Ĺ&#x201C;ĴŤ/3(#-32Ä&#x17D;Ť1"#ŤÄ&#x201E;Ť,.3.1Ť-#41./3'8Ť-"Ť%1"#ŤÄ&#x2026;Ť/#1(/'#1+Ť neuropathy were reported in 1 patient each. Ť Ä&#x2013;Ť1"8!1"(Ť'2Ť ##-Ť1#/.13#"Ť(-ŤÄ&#x192;Ä&#x201E;ŤijÄ&#x2030;Ĺ&#x201C;ĴŤ/3(#-32Ť31#3#"Ť6(3'Ť  Ä&#x17D;Ť++Ť.$Ť3'#2#Ť!2#2Ť6#1#Ť%1"#ŤÄ&#x192;Ť.1ŤÄ&#x201E;Ť(-Ť2#5#1(38Ä&#x17D; Ť Ä&#x2013;ŤŤ.,/+#7Ť1#-+Ť!8232Ť'5#Ť ##-Ť1#/.13#"Ť(-ŤÄ&#x201E;ŤijÄ&#x192;Ĺ&#x201C;ĴŤ/3(#-32Ť31#3#"Ť6(3'Ť  Ä&#x17D;Ť'#1#Ť6#1#Ť-.Ť1#/.132Ť.$Ť -.1,+Ť41(-+82#2Ť or renal impairment in these cases. Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were seen in 5.2%, 0.4%, and 11.4% of patients, respectively. Drug Interactions: Caution should be exercised with concomitant use of moderate CYP3A inhibitors. Grapefruit or grapefruit juice may increase plasma concentrations of crizotinib and should be avoided. The concurrent use of strong CYP3A inducers and inhibitors should be avoided. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Treatment with XALKORI should be used with caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Caution should be used in patients with severe renal impairment or patients with end-stage renal disease.

CRI00127A/282258

Š 2011 Pfizer Inc.

All rights reserved.

Printed in USA/ October 2011


VBCC_Dec_11_4_Follow ASCO Tabloid 12/23/11 9:16 AM Page 32

IN THE LITERATURE Bortezomib–Rituximab Combo... Continued from page 22 zoster, nausea or vomiting, and thrombocytopenia. Drug-related adverse events leading to death occurred in 3 (1%) patients who received bortezomib plus rituximab and in none of those who received rituximab alone. ■

Letrozole More Effective than Tamoxifen in Postmenopausal Breast Cancer The Breast International Group (BIG) 1-98 is a randomized, phase 3, double-blind clinical trial that includes 8010 postmenopausal women with early-stage hormone receptor–positive

breast cancer. The current study reports the median 8.1-year follow-up outcomes of the BIG 1-98, reflecting the long-term risk for recurrence and death in this patient population (Regan MM, et al. Lancet Oncol. 2011; 12:1101-1108). A total of 2459 patients were randomized to monotherapy with letro-

zole or tamoxifen for 5 years. In the 4arm option, 6182 patients were randomized to 1 of 4 sequential therapy groups, beginning either one drug (tamoxifen or letrozole) for 3 years followed by the other drug (tamoxifen or letrozole) for 2 years; or 2 years with the first drug followed by 3 years with the other drug. In 2005, after a significant disease-free survival (DFS) benefit was reported with letrozole, the study protocol was amended to allow patients to cross over from tamoxifen therapy to letrozole therapy. The final treatment phase ended in 2008. The primary study end point was DFS. Secondary end points were OS, distant recurrence-free interval, and invasive breast cancer–free interval. After a median follow-up period of 8.1 years, 2074 patients showed DFS compared with 1569 patients showing DFS by the protocol-specified update in 2009. The additional 505 events (a 32% increase) occurred between 2003 and 2011, in the latter phases of the study. In addition, 5936 (74%) of the patients were reported to be alive and without a DFS event at their most recent follow-up. At a median followup of 8.7 years, letrozole monotherapy continued to show significantly better DFS compared with tamoxifen monotherapy. Sequential treatment with one drug then the other did not improve DFS compared with letrozole monotherapy in patients with breast cancer–free interval or distant recurrence–free interval. With more than 8 years of followup, this study confirms that letrozole is more effective than tamoxifen in the long-term management of early-stage postmenopausal breast cancer. ■

Second-Generation TKIs Produce Faster Optimal Response than Imatinib in CML The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib produce optimal cytogenetic response after 3 months of treatment in the majority of patients with chronic myeloid leukemia (CML) in the chronic phase, a much faster rate than the 12 to 18 months for the peaked response reported with imatinib (Jabbour E, et al. J Clin Oncol. 2011;29:4260-4266). In 2 simultaneous phase 2 trials, 167 patients with newly diagnosed chronic-phase CML were randomized to nilotinib (N = 81) or to dasatinib (N = 86). At 3 months, all 160 evaluable patients demonstrated optimal response (ie, complete hematologic response) with either of the secondgeneration TKIs. By 18 months, 99 of 118 evaluable patients achieved an Continued on page 44

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Y A OD T R 100 E T $ S I G AVE E R S Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery

The One Conference You Canâ&#x20AC;&#x2122;t AFFORD to Miss!

March 29-31, 2012 â&#x20AC;˘ JW Marriott â&#x20AC;˘ Houston, Texas

TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

EDUCATIONAL OBJECTIVES â&#x20AC;˘ Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery â&#x20AC;˘ Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered â&#x20AC;˘ Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively â&#x20AC;˘ Examine the current trends in personalized care and companion diagnostics â&#x20AC;˘ Analyze the patient issues around cost, quality, and access to care

CONFERENCE REGISTRATION

SAVE $100 off full conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

CONTACT/SUPPORT If you have any questions please contact: Association for Value-Based Cancer Careâ&#x201E;˘ 241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831 Phone: 732-992-1040 association@avbcconline.org

DESIGNATION OF CREDIT STATEMENTS Physician Accreditation

CONFERENCE CO-CHAIRS

The Medical Learning Institute designates this live activity for a maximum of 13.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Medical Learning Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Gary Owens, MD

Registered Nurse Designation

President Gary Owens Associates

Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

This activity is jointly sponsored by Medical Learning Institute, Inc., and Association for Value-Based Cancer Care 

Burt Zweigenhaft, BS President, CEO OncoMed


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 3:48 PM Page 34

AMERICAN PATHOLOGISTS MEETING

Is Sentinel Lymph Node Biopsy Truly the Standard of Care in Melanoma? Experts debate current practice By Rosemary Frei, MSc Grapevine, TX—Two expert oncologists presented the clinical data in support for and against the use of sentinel lymph node biopsy (SLNB) in melanoma as the standard of care during the 2011 College of American Pathologists annual meeting. Vernon Sondak, MD, Chair, Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, supported the use of SLNB as the standard of care in melanoma. J. Meirion Thomas, MD, attending oncologist, Royal Marsden Hospital and Imperial College, London, said that routine SLNB in melanoma is unwarranted. Boris Bastian, MD, PhD, Professor of Dermatology and Pathology, University of California San Francisco, moderated the debate. He told ValueBased Cancer Care (VBCC) that “standard of care” should be reserved for procedures supported by conclusive evidence that the benefits outweigh the risks. “While SLNB is unquestionably commonly practiced, this is not sufficient to qualify it as the standard of care. There is compelling evidence that patients with a positive sentinel lymph node have a worse prognosis, but the knowledge of this information currently does not translate into a significant survival benefit, and instead may lead to inappropriately aggressive treatment in patients.” The Pivotal Trial: MSLT-1 The debate largely centered on the results of the ongoing, randomized Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1). An interim analysis was published in 2006, and more than 15 years of follow-up data were presented at the 2010 Society of Surgical Oncology annual meeting. A total of 1269 patients with intermediate-thickness primary melanoma were randomized to wide excision plus SLNB, or to wide excision alone (observation). Lymphadenectomy was performed immediately in patients in the SLNB arm who had a positive biopsy. In the observation arm, lymphadenectomy was delayed after a regional lymph node metastasis became clinically apparent. The interim analysis results did not show a survival difference between the 2 approaches, but the 5-year diseasefree survival (DFS) rate was higher in those undergoing SLNB (78.3% vs 73.1%, respectively). In addition, the 5-

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year overall survival (OS) rate was 20% higher in the SLNB arm. Skewed Results? Dr Thomas noted that the 5-year DFS was based on a post-hoc analysis of subgroups who had different characteristics. In the MSLT-1 trial, more patients in the observation arm had first recurrence in the nodes than in the biopsy arm, which was used to suggest that SLNB followed by lymphadenectomy extends DFS. However, he contends that using nodal disease to assess DFS is problematic, because the nodal basin was preemptively removed in one group but not in the other. To determine whether SLNB and complete lymphadenectomy improve DFS, nodal recurrence should have been excluded and only distant metastases included. Jeffrey Abrams, MD, Chief of the Clinical Investigations Branch of the Cancer Therapy Evaluation Program, National Cancer Institute, supports this view. In a 2007 letter to Dr Thomas, Dr Abrams wrote, “we agree that in a trial where one arm has nodal disease removed at the outset and the other arm does not, calculation of either distant disease-free survival or excluding nodal recurrence from the calculation is appropriate.”

“Patients come to me after having been advised by a surgeon to have SNB….But I tell them there is another option….Ultrasound is less invasive, and also ultimately is cheaper.” —J. Meirion Thomas, MD The 5-year OS analysis is also being challenged because the study also compared potentially heterogeneous subgroups: SLNB-positive patients with microscopic disease and patients in the observation arm who developed clinically detectable or macroscopic nodal disease. Dr Thomas pointed out that the proportion of patients in the immediatelymphadenectomy arm with positive sentinel lymph nodes was more than 20% higher than the proportion of patients in the observation arm who developed regional metastases.

VALUE-BASED CANCER CARE

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December 2011

“A proportion of the nodes deemed positive in patients who were then given immediate lymphadenectomy must therefore have been false-positives,” Dr Thomas said, noting that “a large part of these false-positives are micrometastases that are not destined to progress to palpable nodal disease.”

“This procedure is useful to our patients, and informed patients continue to choose sentinel node biopsy.” —Vernon Sondak, MD

He therefore said that the results of the trial were inappropriately skewed in favor of biopsy and immediate lymphadenectomy in patients with positive SLNB. Hence, clinicians and patients who take this approach are not making a fully informed choice, at least for intermediate-thickness melanoma. “Patients come to me after having been advised by a surgeon to have SNB, and of course they are inclined to do what the surgeon tells them. But I tell them there is another option, to have ultrasound screening and surveillance instead,” Dr Thomas said. “Ultrasound is less invasive, and also ultimately is cheaper….The problem is that this term ‘standard of care’ with respect to SNB is being pushed very hard by a group of people in the US who are the heads of important surgical/academic institutions and of the surgical journals.” Dr Thomas discusses his position regarding MSLT-1 in a letter to the editor of the Annals of Surgical Oncology (Epub July 20, 2011). Defending the Use of SLNB Dr Sondak noted that Dr Thomas has not published or presented any new data to support his position. “None of the recommendations for use of SLNB are based on its impact on disease-free survival. It’s obvious that SLNB reduces lymph-node reoccurrence, and that’s important to patients. They’d rather have us do a biopsy while we’ve got them in the [operating room] to excise their primary tumor than having them back in a couple of years, when they feel a lump in their groin and want it investigated. But frankly none of us who do SLNB do it because of the [DFS] advantage. We do it because of all the other advantages of SLNB, and they outweigh any disadvantages. Plus, patients really want

to know whether their lymph nodes are positive or not.” Dr Sondak stood by the MSLT-1 results, stating that the available data indicate all disease detected by SLNB, including micrometastases, is clinically significant. Most, if not all, micrometastases will eventually progress to tumors that will require resection, whether they are in the lymph nodes or in distant sites, he believes. In response to the claim that SLNB alone can cause lymphedema in 6% of patients, based on a study of 250 patients with melanoma by Estourgie and colleagues, Dr Sondak stood by the conclusions from MSLT-1, stating that “the long-term risk of lymphedema from SLNB is less than 1%, and, in fact, most of this may actually be due to lymphedema from the wide excision itself.” He pointed to a response to Dr Thomas’s letter written by Donald Morton, MD, lead investigator of MSLT-1, and colleagues (Faries MB, et al. Ann Surg Oncol. Epub Aug 12, 2011). Citing their previous study, these authors state that “[Dr Thomas] ignores our published data that show no significant difference in lymphedema rates between patients treated by wide excision alone or wide excision with SLN biopsy.” Routine Use of SLNB for Melanoma? Dr Sondak supports these views. He said that clinicians can deviate from the standard of care whenever they feel it is in the patient’s best interest, but “deviating from standard medical treatment ethically and legally requires informed consent and a discussion of the reasons why and the potential consequences.” Dr Bastian told VBCC, “by no means does it appear justified for proponents of SLNB to warn of legal consequences if the procedure is not performed. This is a development that is really surprising, unsettling to some degree, because the evidence is very thin that there is a true outcome benefit delivered to the patient by this procedure….There’s a variety of incentives behind this, but clearly the argument for SLNB is being overplayed on several levels.” Dr Sondak says that surgeons are not simply performing SLNB for the sake of doing surgery. Rather, SLNB “is uniformly incorporated into national and international management guidelines as the standard of care. This procedure is useful to our patients, and informed patients continue to choose sentinel node biopsy.” ■

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NOW APPROVED FOR

BRAF V600E MUTATION-POSITIVE METASTATIC MELANOMA

Indication and Usage ZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma, serious hypersensitivity reactions including anaphylaxis, serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, QT prolongation, liver laboratory abnormalities, photosensitivity, ophthalmologic reactions, and new primary malignant melanoma have all been observed or associated with ZELBORAF treatment. ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients appropriate for ZELBORAF therapy. The most common adverse reactions of any grade (•30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. Please see brief summary of full Prescribing Information on the following page for additional important safety information or visit ZELBORAF.com for full Prescribing Information.

©2011 Genentech Inc., So. San Francisco, CA BRF0000583300 08/11

10:52 AM


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ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced  >  1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc  >  500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both  >  500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

-

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritis 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were  ≥ 65 years. Elderly disorders patients (≥  65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

8

-

-

7

-

-

12

-

-

10

-

-

-

-

-

14

-

-

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422000 Initial U.S. Approval: August 2011 © 2011 Genentech, Inc

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THE CANCER PATIENT

AMA Calls for More Transparency in Patient Navigation Programs

at a glance

By Caroline Helwick New Orleans, LA—The House of Delegates of the American Medical Association (AMA) laid out guidelines for patient navigator programs during their November 2011 Interim Meeting. The aim is to ensure that patient navigators “enhance, rather than undermine, the delivery of high-quality patient care,” the resolution states. Patient navigators have become part of the oncology team in many centers, and although that development is generally viewed as positive, oncologists have concerns. One concern is that patient navigators may be overstepping clinical boundaries and functioning without sufficient direction. Another is that patients are unfairly referred to certain providers or cancer centers. The resolution adopted by the AMA addressed these and other concerns, recommending that patient navigators should: • Foster patient empowerment and provide information to enhance the patients’ ability to make appropriate choices • Refrain from clinical activities • Fully disclose relevant training, experience, and credentials to help patients understand the scope of

services they are qualified to provide • Fully disclose potential conflicts of interest, including employment arrangements.

“People outside of our offices are taking these roles, and we have legitimate concerns about whether healthcare dollars are going to pay people who are not under our supervision.” —Barbara Arnold, MD The guidelines also suggest that navigator programs establish procedures to ensure direct communication between the navigator and the patient’s medical team. Barbara Arnold, MD, Chair of the AMA Medical Service and Practice Advocacy Committee, which brought the recommendation, addressed another issue: patient navigators are usurping roles and being paid for duties already assumed by other staffers. “We are giving language to something that has been done within

our personal offices for years,” she said. “I call my billing clerk and receptionist my ‘patient care coordinators.’ What’s happening is that people outside of our offices are taking these roles, and we have legitimate concerns about whether healthcare dollars are going to pay people who are not under our supervision,” said Dr Arnold. Although Dr Arnold practices ophthalmology in Sacramento, CA, she said that the AMA leadership is going to bat for all physicians, particularly oncologists. Johannes Nunnink, MD, an oncologist at Vermont Cancer Center in Colchester, noted that the original purpose of patient navigators was to enhance access to care for underserved populations and suggested this aim is being diverted. “In my experience, some hospitals use these navigators to direct patients into a specific system. I set up a breast care center in my hospital and found that some of my patients were, under navigators, being directed to certain caregivers, even though [those patients were] actively being taken care of by me. It is a critical principle that the navigator system be fair and transparent,” he said.

➤ Oncologists are concerned that patient navigators may be overstepping clinical boundaries and functioning, without sufficient direction ➤ They are also worried that patients are unfairly referred to certain providers or to specific cancer centers ➤ The AMA has issued a new guideline to foster patient empowerment and provide information to enhance the patients’ ability to make appropriate choices ➤ Calling on patient navigations to refrain from clinical activities and disclose all their activities

In general, the oncologists viewed patient navigators as useful members of the team, but they recognized the need for guidelines. Charles Wilson, MD, of the AMA’s Council for Medical Services, said, “We believe this resolution gets into what the care team of the future will be. Many individuals will be on that [team] who are not employed by physicians…but physicians should be the leaders and we should never give up that position.” ■

AMERICAN PATHOLOGISTS MEETING

Pathologists Can Play Key Role in the Era of Personalized Oncology By Rosemary Frei, MSc Grapevine, TX—The role of pathologists in gathering and interpreting oncologic information has never been as complex as it is today, but neither has it been as clinically impactful, suggested presenters at the 2011 College of American Pathologists meeting. “The genetic and molecular information we’re collecting does have real clinical impact,” Neal Lindeman, MD, Assistant Professor of Pathology, Harvard Medical School, Boston, told Value-Based Cancer Care. “It’s part of modern personalized treatment, it is getting bigger, and it needs to be included as part of the standard treatment or diagnostic approach.” Dr Lindeman discussed acute myeloid leukemia (AML) at the meeting. “Pathologists are no longer just looking down a microscope for morphological information,” he said. They are also integrating the patient’s history with genetic and molecular diag-

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nostic information to determine each tumor’s specific diagnostic and prognostic categories and which treatment, including molecular targets, the clinicians should focus on. Megan Lim, MD, PhD, Director of Hematopathology, University of Michigan Medical School, Ann Arbor, agreed it is important for pathologists to embrace the rapidly growing array of molecular and genetic tests. “Oncologists send material to the pathologist, they send material to the molecular lab, and they want someone to put that information together for them and let them know what’s pertinent and what the ways are to proceed with the best management of the patient,” Dr Lim said. “Right now the oncologists are doing it, but they do appreciate when pathologists integrate the information for them.” Dr Lindeman and his team discussed the 4 categories of the World

“The genetic and molecular information we’re collecting does have real clinical impact. It’s part of modern personalized treatment, it is getting bigger, and it needs to be included as part of the standard treatment approach.” —Neal Lindeman, MD

Health Organization classification system for AML, including: • AML with characteristic genetic abnormalities, which now comprises just under 50% of AML cases • AML with multilineage dysplasia • AML and myelodysplastic syndromes, therapy-related • AML not otherwise categorized,

which used to comprise just under 50% of cases but now comprises about 25% of them. Using a case-based approach, they noted that the category of each tumor is determined and can be used to deduce information for a correct diagnosis, prognosis, targeted treatment, and disease monitoring. This is particularly important for postremission treatment options, because molecular and cytogenetic characteristics have as much or more importance at this stage than in initial treatment. “New genetic tools are leading to new genetic discoveries in hematopoietic tumors as well as solid neoplasms, and it’s changing every month,” said Dr Lim. “So the molecular-pathology laboratory workload has been one of the fastest-growing areas in pathology, and that will continue for the foreseeable future. Both pathologists and the oncologists they work with can benefit from harnessing these developments to provide as clinically relevant information as possible.” ■

www.ValueBasedCancerCare.com

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CANCER DRUGS

Ruxolitinib a New Oral Option for the Treatment of Patients with Intermediate- or High-Risk Myelofibrosis Disorders By Rhonda Williams

M

yeloproliferative neoplasms (MPNs) are a group of closely related hematologic malignancies that arise from abnormal development and function of the body’s bone marrow cells. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) comprise the Philadelphia chromosome (Ph)-negative MPNs.1 Myelofibrosis (MF) can arise on its own, which is called PMF, or it can result from the progression of other MPNs, such as postpolycythemia vera MF (PPV-MF) and postessential thrombocythemia MF (PET-MF).1 The Burden of Disease and Its Impact MF is characterized by cytopenias, splenomegaly, poor quality of life, and shortened survival.1 Because chronic MPNs previously were not classified as hematologic malignancies, limited epidemiologic studies are available to estimate the incidence of MF. Multiple regional studies suggest that an estimated 6328 new cases of chronic myeloproliferative disorders (CMPDs as they were previously known) occurred in the US population in 2004.2 Of these patients, 45% had PV, 24% had ET, and 10% had PMF.2 The average annual age-adjusted

incidence in the United States between 2001 and 2003 was 2.1 per 100,000 persons, with rates ranging among states from a low of 0.8 per 100,000 persons in Delaware to as high as 4.1 per 100,000 persons in Idaho.2 The incidence was significantly higher in males (2.6 per 100,000) than in females (1.8 per 100,000; P <.05).2 In addition, the incidence increased significantly with age, reaching 13.3 per 100,000 persons among individuals aged ≥80 years.2 Although appropriate treatment of patients with ET and PV is associated with prolonged survival, patients with symptomatic forms of PMF have a median survival of <5 years.1 The prognosis of MF is quite variable; however, those who develop anemia generally have a poorer prognosis. Patients with a good prognosis can live for many years without experiencing major symptoms, whereas those with a poor prognosis may have a significantly shorter survival. A small percentage of patients with MF can transform to acute myeloid leukemia, which is often difficult to treat and can be fatal. Few treatment options exist for patients with MF. Until recently, the choice of treatment was often dictated by a patient’s symptoms and specific circumstances. Some patients with MF

Table 1 Baseline Characteristics of Patients in Study 1 and Study 2

Baseline characteristic

Study 1 (N = 309)

Study 2 (N = 219)

Median age, yrs (range)

68 (40-91)

66 (35-85)

Patients aged >65 yrs, %

61

52

Male patients, %

54

57

Primary myelofibrosis, %

50

53

Postpolycythemia vera myelofibrosis, %

31

31

Postessential thrombocythemia myelofibrosis, %

18

16

Median hemoglobin, g/dL

10.5

10.4

Median platelet count, × 109/L

251

236

16

15

Disease state

Hematologic value

Median palpable spleen length below the costal margin, cm Median spleen volume, cm3 (range)

2595 (478-8881) 2381 (451-7765)

Source: Reference 10.

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may remain symptom-free for many years, without undergoing treatment; however, monitoring for any signs or symptoms that may suggest worsening of the disease is required. For patients who require symptomatic treatment, chemotherapeutic agents, immunomodulatory drugs, and biological response modifiers (eg, hydroxyurea, androgen therapies, corticosteroids, thalidomide, lenalidomide, and interferon) are often used.

In November 2011, the FDA approved ruxolitinib for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF. It is important to note that these therapies are not always directed to the biological processes that underlie the origin of disease or lead to progression of PMF. Therefore, these strategies are often primarily palliative in nature, and their effect on survival is uncertain. Finally, surgery or radiation therapy may also be used in those who fail to respond to other treatments. For many patients with MF, however, available treatments may be ineffective and allogeneic stem-cell transplantation may be the only potential known cure. A decisive advance in our understanding of the underlying molecular mechanisms of MPNs has been the discovery of a somatic gain-of-function point mutation in the Janus kinase (JAK) 2 gene, which is a common clinical feature in patients with ET, PV, and PMF.3,4 We now know that approximately 50% of patients with MF have a gain-of-function mutation in the JAK2 gene.5,6 Discoveries in the molecular pathogenesis of PV, ET, and PMF enabled the genetic classification and molecular diagnosis of these neoplasms. The World Health Organization diagnostic criteria, which were based largely on clinical and pathologic descriptions, were subsequently revised for PV, ET, and PMF to include the incorporation of testing for JAK2 and other genetic mutations.7 In addition to modifying the criteria for diagnosing, monitoring, and

assessing patients with ET, PV, and PMF, the discovery of JAK2 involvement in patients with MF also led to the development of small-molecule inhibitors that specifically target JAK2. Although JAK2 mutations are responsible for the majority of dysregulated signaling in Ph-negative MPNs, JAK1 and JAK2 may interact, resulting in their transactivation.8,9 Armed with this information and a greater understanding of the cellular and molecular events that lead to the development of PMF, the possibility of more targeted and effective therapies for this disorder has become a reality. In November 2011, the US Food and Drug Administration (FDA) granted marketing approval of oral Jakafi (ruxolitinib) tablets for the treatment of patients with intermediate- or highrisk MF, including PMF, PPV-MF, and PET-MF.10 Clinical Pharmacology Mechanism of Action Jakafi, a kinase inhibitor, inhibits the Janus-associated kinases JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.10 MF is known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617Fpositive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutated cells in the spleen, and decreased circulating inflammatory cytokines (eg, tumor necrosis factor– alpha and interleukin-6).10 Pharmacodynamics. In healthy persons and in patients with MF, ruxolitinib inhibited cytokine-induced STAT3 phosphorylation in whole blood. The maximal inhibition of STAT3 phosphorylation occurred 2 hours after dosing, returning to nearbaseline levels by 10 hours in both groups of people. Pharmacokinetics. Maximal plasma concentration (Cmax) of ruxolitinib occurred 1 to 2 hours after oral administration. Pharmacokinetic studies Continued on page 39

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demonstrated no evident food effect on the absorption of ruxolitinib; when administered with a high-fat meal, the mean Cmax decreased moderately (24%) and the area under the curve remained nearly unchanged (ie, 4% increase). In early clinical trials, the volume of distribution at steady state was between 53 L and 65 L in patients with MF.10 Phase 3 Clinical Trials Jakafi was approved by the FDA based on the results of 2 randomized, phase 3 trials (Study 1 and Study 2) conducted in patients with MF.10 These trials are described in detail in the product prescribing information, with key data highlighted in this article. Trial Designs Study 1 was a randomized, doubleblind trial that compared ruxolitinib with placebo in patients with MF who were refractory to or were not candidates for available therapy. The primary end point was the proportion of patients achieving a reduction in spleen volume of >35% from baseline at week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT). Secondary end points included the duration of >35% reduction in spleen volume from baseline and the proportion of patients with a >50% reduction in Total Symptom Score from baseline to week 24. The latter was measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.10 Study 2 was a randomized, openlabel trial that compared ruxolitinib with the best available therapy in patients with MF. The study investigators selected the best available therapy on a patient-by-patient basis, with the most frequently used agents, including hydroxyurea (N = 47%) and glucocorticoids (N = 16%). The primary end point of this trial was similar to that in Study 1—the proportion of patients achieving a reduction in spleen volume of >35% from baseline, but at week 48 (as measured by MRI or CT). The secondary end point of Study 2 was the proportion of patients achieving a >35% reduction in spleen volume from baseline to week 24.10 In both trials, patients were required to have palpable splenomegaly >5 cm below the costal margin, as well as an MF risk category of intermediate-2risk (2 prognostic factors) or high-risk (>3 prognostic factors).10 Dosing in these trials was based on platelet counts. The starting dose of ruxolitinib was 15 mg administered orally twice daily in patients with base-

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line platelet counts of 100 to 200 x 109/L and 20 mg administered orally twice daily in patients with baseline platelet counts >200 x 109/L. The doses of ruxolitinib were then adjusted during the course of therapy based on efficacy and tolerability. Maximum doses based on platelet counts were as follows10: • Platelet count 100 to ≤125 x 109/L: 20 mg twice daily • Platelet count 75 to ≤100 x 109/L: 10 mg twice daily • Platelet count 50 to ≤75 x 109/L: 5 mg twice daily. Patient Populations Baseline characteristics of patients enrolled in Study 1 and Study 2 are shown in Table 1. The 2 patient populations were very similar in terms of demographics and the extent of disease before study treatment.10 Efficacy The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2 (Table 2). A significantly greater percentage of ruxolitinib-treated patients achieved this magnitude of reduction in baseline spleen volume compared with either placebo (41.9% vs 0.7%, respectively; P <.001) or best available therapy (28.5% vs 0%, respectively; P <.001).10 In Study 1, a secondary end point was improvement in symptoms, as measured by the MFSAF v2.0. This scale captures MF-related symptoms, including abdominal discomfort, pain under the left ribs, night sweats, itching, bone or muscle pain, and early satiety. A higher proportion of ruxolitinib-treated patients experienced a ≥50% reduction in Total Symptom Score compared with placebo (45.9% vs 5.3%, respectively; P <.001). The median time to symptom response was <4 weeks.10 Safety Profile Because clinical trials are conducted under widely varying conditions, rates of adverse reactions observed in the clinical trials of a particular drug cannot be compared directly with rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ruxolitinib was assessed in 617 patients in 6 clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in 2 phase 3 studies. In these 2 studies, patients had a median duration of exposure to ruxolitinib of 9.5

Table 2 Percentage of Patients with ≥35% Reduction in Baseline Spleen Volume Study 1 (24 wks) Ruxolitinib (N = 155)

Placebo (N = 154)

41.9%

0.7%

Study 2 (48 wks) Ruxolitinib P value (N = 146) <.001

Best available treatment (N = 73) P value

28.5%

0%

<.001

Source: Reference 10.

Adverse Reactions and Laboratory Abnormalities Reported in Study 1: Table 3 Ruxolitinib versus Placebo Ruxolitinib (N = 155) Reported outcomes

Placebo (N = 151)

All Grade 3, Grade 4, All Grade 3, Grade 4, grades, % % % grades, % % %

Adverse reaction Bruisinga

23.2

0.6

0

14.6

0

0

b

Dizziness

18.1

0.6

0

7.3

0

0

Headache

14.8

0

0

5.3

0

0

Urinary tract infectionc

9.0

0

0

5.3

0.7

0.7

Weight gaind

7.1

0.6

0

1.3

0.7

0

Flatulence

5.2

0

0

0.7

0

0

1.9

0

0

0.7

0

0

e

Herpes zoster

Laboratory abnormalityf Thrombocytopenia

69.7

9.0

3.9

30.5

1.3

0

Anemia

96.1

34.2

11.0

86.8

15.9

3.3

Neutropenia

18.7

5.2

1.9

4.0

0.7

1.3

Elevated ALT

25.2

1.3

0

7.3

0

0

Elevated AST

17.4

0

0

6.0

0

0

a

Includes contusion, ecchymosis, hematoma, injection-site hematoma, periorbital hematoma, vessel puncture-site hematoma, increased tendency to bruise, petechiae, and purpura. b Includes dizziness, postural dizziness, vertigo, balance disorder, Ménière disease, and labyrinthitis. c Includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, and nitrite urine present. d Includes weight increased and abnormal weight gain. e Includes herpes zoster and postherpetic neuralgia. f Worst grade values are presented, regardless of baseline. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. Source: Reference 10.

months (range, 0.5-17 months), with 88.7% of patients treated for >6 months and 24.6% treated for >12 months. A total of 111 patients started treatment at 15 mg orally twice daily and 190 patients started at 20 mg orally twice daily.10 The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.9 A total of 11.0% of patients receiving ruxolitinib and 10.6% of patients receiving placebo discontinued therapy because of adverse events.9 The rates of adverse reactions and laboratory abnormalities reported in

Study 1 are summarized in Table 3. The median time to onset of grade 2 or higher anemia was approximately 6 weeks. Mean decreases in hemoglobin of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy were reported in ruxolitinib-treated patients, recovering gradually to reach a new steady state of approximately 1.0 g/dL below baseline.10 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks. Patients with baseline platelet counts of 100 to 200 x 109/L experienced a higher incidence of grade 3 or 4 thrombocytopenia than did those with baseline platelet counts >200 x 109/L.10 Continued on page 40

www.ValueBasedCancerCare.com

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CANCER DRUGS

Ruxolitinib a New Oral Option for the Treatment of... Dosing Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose. When discontinuing ruxolitinib therapy for reasons other than thrombocytopenia, gradual tapering of the dose may be considered—for example, by 5 mg twice daily each week.10 In patients who are unable to ingest tablets, ruxolitinib can be administered through a nasogastric tube (8 French or greater) by suspending 1 tablet in approximately 40 mL of water and stirring for approximately 10 minutes. Within 6 hours after the tablet has dispersed, the suspension can be administered via a nasogastric tube using an appropriate syringe. After use, the tube should be rinsed with approximately 75 mL of water. The effect of

tube-feeding preparations on ruxolitinib exposure during administration through a nasogastric tube has not been evaluated.10 The recommended starting dose of ruxolitinib is based on platelet count (Table 4). A complete blood count (CBC) and platelet count must be performed prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.10 Treatment with ruxolitinib should be interrupted in patients with platelet counts <50 x 109/L. Once the platelet count recovers to >50 x 109/L, dosing may be restarted or increased following recovery of platelet counts to acceptable levels. Table 5 shows the maximum allowable dose that may be used when restarting ruxolitinib therapy following a previous interruption.10

Table 4 Proposed Ruxolitinib Starting Doses Platelet count, × 109/L

Starting oral dose

>200

20 mg twice daily

100 to 200

15 mg twice daily

Source: Reference 10.

Table 5 Maximum Restarting Doses for Ruxolitinib after Safety Interruption Current platelet count, × 109/L

Maximum restarting dosea

≥125

20 mg twice daily

100 to <125

15 mg twice daily

75 to <100

10 mg twice daily for at least 2 wks; if patient is stable, may increase to 15 mg twice daily

50 to <75

5 mg twice daily for at least 2 wks; if patient is stable, may increase to 10 mg twice daily

<50

Continue hold

a

When restarting therapy, begin with a dose at least 5 mg twice daily below the dose at interruption.

Source: Reference 10.

Table 6 Dosing Recommendations for Thrombocytopenia Dose at time of platelet decline 25 mg twice 20 mg twice 15 mg twice 10 mg twice 5 mg twice daily daily daily daily daily

Platelet count, × 109/L

New dose

100 to <125 20 mg twice 15 mg twice No change No change No change daily daily 75 to <100

10 mg twice 10 mg twice 10 mg twice No change No change daily daily daily

50 to <75

5 mg twice 5 mg twice 5 mg twice 5 mg twice No change daily daily daily daily

<50

Hold

Hold

Hold

Hold

Source: Reference 10.

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December 2011

Hold

Patients who develop anemia may require blood transfusions. Dose modifications of ruxolitinib in patients who develop anemia may also be considered.10 Neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) was generally reversible and was managed by temporarily withholding ruxolitinib. CBCs should be monitored as clinically indicated, with dosing adjusted as required.10 Dose Modification Based on Response If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5mg twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more often than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement is observed since initiation of ruxolitinib therapy.10 Based on limited clinical data, longterm maintenance with a 5-mg twicedaily dose has not demonstrated responses, and continued use of this dose should be limited to patients in whom the benefits outweigh the potential risks.10 Dose increases may be considered in patients who meet all of the following criteria10: • Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume, as measured by CT or MRI • Platelet count >125 x 109/L at 4 weeks and platelet count never <100 x 109/L • ANC >0.75 x 109/L. Dose Adjustment, Concomitant Strong CYP3A4 Inhibitors On the basis of pharmacokinetic studies in healthy volunteers, when administering ruxolitinib along with strong cytochrome (CY)P3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose is 10 mg twice daily for patients with platelet counts ≥100 x 109/L. Additional dose modifications should be made with careful monitoring of safety and efficacy. Concurrent administration of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts <100 x 109/L.10

Continued from page 39

Contraindications, General Warnings, and Precautions There are no black box warnings or contraindications associated with the use of ruxolitinib. Warnings and precautions associated with use of the agent include such hematologic adverse reactions as thrombocytopenia, anemia, and neutropenia. As indicated earlier, a CBC and platelet count must be performed prior to initiating therapy with ruxolitinib. In clinical trials, patients with platelet counts <200 x 109/L at the start of therapy were more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible, however, and was usually managed by modifying or interrupting the dose of ruxolitinib in clinical trials. Patients may also require a platelet transfusion, if clinically indicated. Dose reductions should be considered if platelet counts decrease, with the goal being to avoid dose interruptions for thrombocytopenia (Table 6).10 Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Active serious infections should have resolved prior to initiating ruxolitinib therapy. Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection, and should initiate appropriate treatment promptly. Physicians should inform patients about early signs and symptoms of herpes zoster, and should advise patients to seek treatment as early as possible. ■ References 1. Verstovsek S, Kantarjian H, Mesa R, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-1127. 2. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52. 3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397. 4. Kralovics R, Passamonti F, Buser AS, et al. A gain-offunction mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. 5. Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136. 6. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061. 7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009; 113:2895-2901. 8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131:612.e1. 9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1:979-993. 10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2011.

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April 20-22, 2012 â&#x20AC;˘ Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: â&#x20AC;˘ Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma â&#x20AC;˘ Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics â&#x20AC;˘ Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATION Teresa Petrella, BSc, MD, MSc, FRCPC

SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-089-L01-P.

          Early registration of $425 ends January 13, 2012!

   

         


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 4:05 PM Page 42

New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

VELCADE (Vc) in combination with MP.

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.


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 4:07 PM Page 43

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

80

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

10

MP (n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

9:27 AM


VBCC_Dec_11_4_Follow ASCO Tabloid 12/22/11 4:09 PM Page 44

IN THE LITERATURE Second-Generation TKIs... Continued from page 32

optimal response. Overall, 155 patients achieved a complete cytogenetic response (CCyR) after a median followup of 33 months, including 146 who achieved a major molecular response (MMR) and 46 who achieved complete

molecular response (CMR). At months 6, 12, and 18, the rates of suboptimal response (ie, less than MMR) were 2%, 1%, and 12%, respectively. The failure response was only demonstrated on month 18, by 5 patients. At each time point, DFS did not differ significantly between

patients who achieved CCyR without an MMR or CMR and those who achieved CCyR with an MMR or CMR. These results confirm that secondgeneration TKIs used in the front-line setting are highly efficacious, with the majority of responses (99%) occurring within the first 3 months of therapy.

In contrast, the results obtained with imatinib therapy showed that CCyR rates peak around 12 to 18 months. This study shows that the secondgeneration TKIs produce CCyRs at a much faster response rate than with imatinib. ■

Azacitidine Treatment Failure Outcomes in Patients with MDS or AML

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

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

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) 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.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. 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. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. 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 13%. 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 Disorders:: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, 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, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders:: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) 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, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS):: There have been reports of RPLS in patients receiving VELCADE. RPLS 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 RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events:: 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. 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, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome:: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). 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. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. 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) m 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, the drug 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 VELCADE 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 VELCADE.com.

Hepatic Events:: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment:: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing 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.

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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 © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

December 2011

V-11-0264

12/11

Azacitidine is the current standard of care for high-risk myelodysplastic syndrome (MDS), but many patients experience treatment failure. No study has previously analyzed patient outcomes of those who fail azacitidine therapy. This new analysis combined data from 4 international clinical trials to describe patient outcomes after failing azacitidine treatment (Prébet T, et al. J Clin Oncol. 2011;29:3322-3327). The study combined data of 435 patients with high-risk MDS or with acute myeloid leukemia (AML) who demonstrated treatment failure after receiving azacitidine therapy between 2000 and 2009. Of these patients, 302 had received therapy for MDS, and 133 had received therapy for AML. The median follow-up after failing azacitidine therapy was 15 months. The median OS in the combined 4 trials was 5.6 months, and the 1-year and 2-year survival probability was 28.9% and 15.3%, respectively. This study shows that there is no standard second-line chemotherapy treatment for patients with high-risk MDS or acute AML after azacitidine failure. Best supportive care or cytotoxic chemotherapy (ie, hydroxyurea, mercaptopurine, low-dose cytarabine, low-dose melphalan, or intense AMLlike chemotherapy) were not of any substantial benefit. Postfailure treatment data available for 270 patients showed worst prognosis for those who received unknown salvage therapy (OS, 3.6 months) or best supportive care (OS, 4.1 months) and was best for those who received investigational agents— DNA methyltransferase enzyme inhibitor alone or in combination with histone deacetylase inhibitor, thalidomide-derivative (ie, lenalidomide or thalidomide), treatments for patients in clinical trials evaluating nonregistered drugs (including immunotherapy, bryostatin, triapine, farnesyl transferase inhibitors, and mammalian target of rapamycin inhibitors)—(OS, 13.2 months) or allogeneic stem-cell transplantation (OS, 19.5 months). Poor outcomes were also observed in patients who received low-dose chemotherapy (OS, 7.3 months) or intensive AML-like chemotherapy (OS, 8.9 months). ■

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COMMUNITY CANCER CENTERS

A New Paradigm of Value-Based Cancer Care: The NCCCP As implemented by Catholic Health Initiatives’ St. Joseph Cancer Institute at Towson, MD oncology literature makes team leaders more reasonable “shepherds” for the team. Supporting a team approach will ultimately lead to patient-centered, compassionate care.5,7

Mark J. Krasna, MD Corporate Medical Director, Meridian Health Care, Neptune, NJ

T

he goals set by the National Cancer Institute (NCI) to establish the NCI Community Cancer Centers Program (NCCCP) are intended to1: • Enhance access to cancer diagnosis and care with a focus on healthcare disparities • Improve quality across the care continuum using evidence-based medicine and a multidisciplinary team • Use electronic health records to enhance communication between all providers (initially with implementation of the cancer Biomedical Informatics Grid) • Expand research by increasing the number of clinical trials offered, including early-phase studies; enhance survivorship programs • Introduce biospecimen collection best practices in the community • Establish connections with national research efforts. This collaboration affords the NCI the opportunity to access large community hospitals with disparate populations; learn how to coordinate care in communities; provide optimal screening, follow-up, and support systems; and ensure comprehensive, evidencebased cancer care.

Defining Optimal Cancer Care Many clinical trials today can be offered in community settings. The NCCCP community cancer centers would evaluate how best to provide the NCI with research opportunities in a community setting and to investigate the value of public/private partnerships between the NCI, hospitals, and physician groups involved in this care. In addition, this effort is essential in furthering research, dissemination, and advances in our pillar areas. One of the quality-of-care pillar goals is to increase multidisciplinary, site-specific cancer care conferences and clinics—multidisciplinary centers (MDCs); increased use of evidencebased guidelines is encouraged. Sites are expected to participate in NCCCP quality improvement projects and expand genetic and molecular-testing programs. Another novel approach is to establish and adopt cancer center– specific physician conditions of participation, which would impact all other pillars. These conditions would help define the relationship and accountabilities between the physicians and the cancer center.2-4 The nurse coordinator/navigator is

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pivotal to the success of any MDC program.5 The navigator triages new patients to appropriate team members and is responsible for the organization, prioritization, and scheduling/coordination of care. They manage patient flow in the clinic and act as an interface between the team and the patient. In addition to providing follow-up, triage, communications, education, support, and continuity of care, they can facilitate clinical trial eligibility. They are, as many patients call them, the “go-to” people. Uncoordinated versus Coordinated Care MDC team members include physicians, midlevel providers, nurses, dietitians, social workers, genetic counselors, financial counselors, spiritual care providers, smoking-cessation counselors, research and registry staff, and administrative coordinators. How can we integrate physicians into multidisciplinary cancer care? There is obvious value to patients and physicians, but, as always, physicians have time constraints. The navigator/ coordinator can help to facilitate cancer care for which the physicians may not have time. Although it requires more time and coordination of scheduling, multidisciplinary care clinics are especially helpful for today’s patient with cancer who receives multimodality therapy. Introducing this concept into the physician practice must be done gently and respectfully, which is achieved by creating a culture of partnership. One way of ensuring this relationship is to offer fair market value for time spent in cancer care, especially in clinics. The use of the work relative value unit or equivalent to measure productivity can help measure the success of physicians in the program and even allow for incentives. Ultimately, the goal of effective patient flow is to make the right information available to the doctor and the patient at the right time. This allows for seamless care, minimal patient waiting time, minimal physician waiting time, and enhanced patient and staff satisfaction. The Benefits of Multidisciplinary Care Although it is inherently apparent that MDC care provides better cancer care, there is a need for more data. We need to demonstrate improved patient

The NCCCP integrates activities by eliminating disparities, improving quality of care and information technology across the cancer continuum, linking with many other NCI programs.

satisfaction, use multidisciplinary care clinics in addition to conferences, develop and distribute treatment summaries, and show improved processes. Over time, we should demonstrate increased referrals to physicians who participate; identify data for outcomes measurement, such as shorter time to diagnosis and treatment, length of hospital stay, and better survival rates: overall improved patient care. Several obvious, and less obvious, benefits to the system or to the cancer center are associated with instituting MDC care. Improving quality and packaging MDC care may result in lower costs; oncology reputation spins off other business for institutions. Improvements could also increase physician alignment and engagement, facilitate clinical trials accrual to generate revenue, and improve efficiency.6 Cancer center administrators must prove the return on investment of comprehensive services for their senior leadership to “buy in” to MDCs. How can we ensure the success of MDCs? The physician program leaders and members must realize that they do not have all the answers to all the questions or resources. Recognizing the value in involving other team members in the care of these patients and remaining open-minded to others’ ideas are necessary. These leaders must also be willing to accept criticism and embrace other specialties. Learning the medical, radiologic, pathologic, surgical, and radiation

NCCCP Sites’ Deliverables Metrics Each of the 30 NCCCP sites has deliverables with metrics for each core component, which are established by the NCI and monitored through SAICFrederick subcontracts. Progress is tracked through detailed annual assessment surveys reported quarterly to SAIC-Frederick. The NCCCP is a unique program that integrates activities by eliminating disparities, improving quality of care and information technology across the cancer continuum, linking with many other NCI programs, incorporating how knowledge gained from NCI programs can be translated into a community setting, developing a strong hospital-based community cancer center network to support NCI goals, and supporting the research infrastructure. The NCCCP: A Look into the Future Thus far, the NCCCP has demonstrated that community cancer centers and systems can deliver MDC care, participate in clinical trials, and begin to bridge disparities in cancer care. It has shown that the public–private partnership works with a strategic vision to the future of cancer care. The challenges for year 5 are to complete outcomes studies, codify what works, continue dissemination of best practices and results, collaborate with NCIdesignated cancer centers on a large number of these issues, and consider what additional studies might further our initial efforts. ■ Acknowledgment This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.

References 1. NCI Community Cancer Centers Program. Community access to the latest science. http://ncccp.cancer.gov. Accessed November 17, 2011. 2. Krasna M, Petrelli N, Salner A. Multidisciplinary cancer care: a new model for community cancer centers. Part I. J Multidiscipl Cancer Care. 2009;1:1,12-13. 3. Krasna M, Petrelli N, Salner A. Roundtable on multidisciplinary care: the NCCCP. Part II. J Multidiscipl Cancer Care. 2009;2:23,29. 4. Zaren HA. Conditions of participation: developing effective partnerships. Oncol Issues. January/February 2011:29-32. 5. Swanson PL, Strusowski P, Asfeldt T, et al. Expanding multidisciplinary care in community cancer centers. Oncol Issues. January/February 2011:33-37. 6. Krasna MJ. Multidisciplinary cancer clinics: a vision for optimal cancer care. Oncol Business Rev. January 2009:12-13. 7. Petrelli NJ. A community cancer center program: getting to the next level. J Am Coll Surg. 2010;210:261-270.

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Effective January 1, 2012

J9179 Injection, eribulin mesylate, 0.1 mg Product coding does not guarantee payor coverage or payment.* For more details visit www.halavenreimbursement.com

Indication Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia • Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had

not recovered within a median follow-up duration of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation • In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment

• For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 3050 mL/min) renal impairment, a reduction in starting dose is recommended Please see accompanying brief summary of Halaven full Prescribing Information. plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, Oncology™: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed October † phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative 18, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Lancet. 2011;377(9769):914-923. Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel *Eisai cannot guarantee payment of any claim. Coding, coverage, and reimbursement may vary significantly by payor, plan, patient, and setting of care. Actual coverage and reimbursement decisions are made by individual payors following the receipt of claims. For additional information, customers should consult with their payors for all relevant coding, reimbursement, and coverage requirements. It is the sole responsibility of the provider to select the proper code and ensure the accuracy of all claims used in seeking reimbursement. All services must be medically appropriate and properly supported in the patient medical record. †Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed October 18, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

HALAVEN ® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA/December 2011 ERI 81AR2



Scan this code to visit www.halaven.com


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A preferred single agent in the NCCN Guidelines™1

DISCOVER

OVERALL SURVIVAL Halaven®: The FIRST and ONLY third-line, single-agent therapy proven to significantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10 The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events (deaths) had been observed, median OS with Halaven vs Control Arm (Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2,11

UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2 1.0

Halaven

0.9

PROPORTION OF PATIENTS ALIVE

0.8

(n=508)

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

0.7 0.6

Halaven

0.5

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Control Arm

0.4 0.3 0.2 0.1 0.0

0

6

12

18

24

30

36

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC Arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.2,11

CI=confidence interval; HR=hazard ratio. *EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2

Halaven: Safety profile • Studied in the Phase III EMBRACE trial2

Most Common Adverse Reactions • Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) • The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation






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NCCN ANNUAL CONGRESS

“Pediatric-Inspired” Regimens Improve Outcomes in Adults with ALL By Phoebe Starr New York, NY—Adults with acute lymphoblastic leukemia (ALL) have a poor prognosis compared with children, but recent studies suggest that using “pediatric-inspired” regimens can improve outcomes for patients with Philadelphia chromosome(Ph)-

negative ALL. Children with ALL have higher cure rates than adults. The 5-year survival is between 60% to 80% up to the age of 15. Evidence suggests that the distribution of cytogenetic abnormalities in children is different from that in adults

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information. 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm3 – Grade 3 or 4 non-hematological toxicities • The Day 8 dose may be delayed for a maximum of 1 week. – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later. Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. • Do not re-escalate HALAVEN dose after it has been reduced. Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3. 5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less. 5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. 5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day  1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/ fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%). The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group. Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 HALAVEN (n=503) Control Group (n=247) MedDRA ver 10.0 All Grades ≥ Grade 3 All Grades ≥ Grade 3 a Blood and Lymphatic System Disorders Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders Peripheral neuropathyb 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1%

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with ALL, said Daniel DeAngelo, MD, Dana-Farber Cancer Institute, Boston, at the recent National Comprehensive Cancer Network Hematologic Congress. Dr DeAngelo discussed strategies for treating adult ALL. The treatment recommendations differ according to whether the disease is Ph-negative or

Table 2 (cont’d) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders Alopecia 45% NAc 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia). Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colonystimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy. Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption. 8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established. 8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination. • Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

December 2011

Ph+. Regimens used for Ph-negative disease include the CALGB regimen (which is complicated and based on a 5-drug induction with dexamethasone, high-dose cytarabine, and methotrexate), or hyper-CVAD, a somewhat less complex regimen (ara-C plus methotrexate with cyclophosphamide, vincristine, doxorubicin, and dexamethasone). Both regimens achieve similar rates of disease-free survival in adults, but neither has improved overall survival (OS). One option for adults with Ph-negative ALL is a matched-sibling allogeneic stem-cell transplant (SCT). In the 2008 International ALL trial, the 5-year survival was 53% for patients with a donor and 45% for those without a donor. The benefit of matched-sibling allogeneic SCT was confined mainly to patients with standard risk. Older patients who were at high risk had increased mortality from transplantation. More recently, pediatric-inspired regimens have been studied in young adults, with encouraging results. A pediatric protocol (standard 5-drug/5week induction chemotherapy followed by consolidation and maintenance therapy for those in complete remission) demonstrated improved event-free survival and OS in patients aged 19 to 30 years, which was similar to the rates in adolescents (aged 15-18 years). Other studies have also shown a benefit for pediatric-inspired approaches in event-free survival and OS in young adults. In a study conducted at the Dana-Farber Cancer Institute, adults with Ph+ ALL achieved a disease-free survival rate of 66.2% at 45 months using a regimen derived from a Pediatric Consortium trial. In Ph+ ALL, until the advent of imatinib, this disease was difficult to treat. Outcomes have been improved with imatinib in patients of transplant age. Allogeneic SCT is standard treatment for patients with Ph+ ALL in complete remission, and imatinib has improved outcomes in patients who underwent the procedure. Dasatinib, a second-generation tyrosine kinase inhibitor, also shows good results in Ph+ ALL. Therapy with dasatinib may help avoid the necessity for transplant in newly diagnosed Ph+ ALL. A recent study of patients with newly diagnosed Ph+ ALL showed that dasatinib therapy administered in alternation with hyper-CVAD and high-dose cytarabine plus methotrexate was associated with a complete remission rate of 94%. Patients in complete remission were given maintenance therapy with daily dasatinib and monthly vincristine and prednisone for 2 years followed by dasatinib. ■

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     "   

   #  !  #  

PROGRAM OVERVIEW

CO-CHAIRS

This is the first 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.

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice. â&#x20AC;˘ Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

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.

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.0 contact hours.

RĂźdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

       

REGISTERED PHARMACY DESIGNATION Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.0 contact hours (0.12 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-11-088-L01-P.

Early registration of $425 ends January 13, 2012!

COMMERCIAL SUPPORT ACKNOWLEDGMENT This activity is supported by educational grants from Genentech, Inc. and Millennium Pharmaceuticals, Inc.

       !


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DRUG DEVELOPMENT

Economic Implications of Biosimilars in Oncology Ready for prime time? By Caroline Helwick

A

lternative versions of biologic agents—biosimilars—will be coming soon to a formulary near you. In the meantime, many details must be worked out before patients can be safely and effectively treated with these new products. Gary H. Lyman, MD, MPH, an oncologist and the Director of Comparative Effectiveness and Outcomes Research, Duke University School of Medicine, Durham, NC, and his colleague Bradford Hirsch, MD, recently published an article on biosimilars titled “Are Biosimilars Ready for Primetime in the United States?” (Hirsch BR, Lyman GH. J Natl Compr Canc Netw. 2011;9:934-942). Dr Lyman discussed this issue with Value-Based Cancer Care.

Biosimilars Coming Soon to Cancer Care Biosimilars will enter the marketplace as patents for many cancer agents near expiration. First among these are the hematopoietic growth factors and erythropoietin, but active treatment agents will follow. The process has already started in Europe, where the first monoclonal antibody is expected to be rituximab (Rituxan). Teva Pharmaceuticals announced it has an agent set to begin clinical trials in anticipation of rituximab’s patent expiration in 2013. The European Union in 2004 intro-

at a glance ➤ Alternative versions of patented biologics known as biosimilars will soon be available in the United States ➤ Biosimilars are expected to drive down the cost of all biologics, including the brandname originator drugs ➤ The Congressional Budget Office estimates savings of $25 billion per decade with biosimilars ➤ Discounts ranging from 20% to 30% are expected in the US market ➤ Like generics, biosimilars may be perceived as subpar products ➤ The NCCN has recently begun working on a white paper to guide the use of biosimilars

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duced a new regulatory path for biosimilars; approval will be a stepwise process that is similar to the approval of traditional biologics. In the United States, however, the US Food and Drug Administration (FDA) has not yet finalized a biosimilar path, for which many believe that better analytic tools (such as new laboratory techniques) are needed to characterize critical aspects of biosimilars. “We are still waiting for final FDA rules on what will be required for approval,” Dr Lyman said. Companies are moving ahead in Europe and are submitting applications in the United States based on anticipated requirements, “but these will not be acted upon until FDA regulations are approved and implemented.” The FDA is expected to finalize its regulations regarding biosimilars by the end of this year, which means that some biosimilars could emerge on the market by early next year, unless new clinical trials are mandated. And the requirement for new clinical trials would mean an “enormous investment, especially if the goal is to bring down the cost of drugs,” Dr Lyman said. Huge Economic Implications The economic implications are huge: nearly $67 billion was spent on the top 20 biologics in 2009, of which 6 are routinely used in oncology—rituximab, trastuzumab (Herceptin), bevacizumab (Avastin), epoetin alfa (Epogen, Procrit), pegfilgrastim (Neulasta), and darbepoetin alfa (Aranesp). “These are a big part of what insurance companies are paying out,” Dr Lyman noted. Because of the complexity of their production, biosimilars are unlikely to achieve the price discounts of generics, according to Dr Lyman. It is estimated that bringing a biosimilar to market will cost between $10 million and $40 million and take 6 to 9 years compared with the $1-million to $2-million cost and 3-year process for generics. It is expected, therefore, that biosimilars will be marketed at 20% to 30% the cost of the original products— whereas generics are sold at about a 75% discount. “However, even a 20% discount on the $66 billion spent in 2009 on the top 20 biologics is substantial,” he noted. The US Congressional Budget Office estimates that biosimilars could save consumers an aggregate of $25 billion per decade.

VALUE-BASED CANCER CARE

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December 2011

“Biosimilars will be routinely used only when clinicians are convinced of their safety and efficacy. This will be a difficult but essential balance to achieve moving forward.” —Gary H. Lyman, MD, MPH

“These drugs are not ready at the moment, but there is going to be big pressure among payers to find ways to encourage their use,” he predicted. “The hope is that the presence of biosimilars in the marketplace will drive down the cost of the entire class of drugs, that is, that the cost of the originator drugs will also drop.” The originator product will probably always have the market share and will command more dollars, backed by more extensive research and clinical experience, he acknowledged. “But if the cost is 2 to 4 times that of the biosimilar, and there is no evidence that they are significantly different clinically, then the originator product will lose market share,” he predicted. “I think biosimilars will gravitate into use and prices will come down, but not as substantially as for the generics. There is too much up-front cost in development.” Biosimilars versus Generics Generics must prove their bioequivalence by showing that the active substance and characteristics of an agent are similar to its predecessor (the pharmacokinetic range must be 80% to 125% of the original, according to Drs Hirsch and Lyman). Since generics can be produced with some consistency, large clinical trials are often unnecessary, the article states. The case of biosimilars is more complicated. It is uncertain that a given biosimilar is the “same functional entity” as the originator compound. Pharmacokinetic equivalence does not ensure “comparability,” and inherently, there are variations in the development of biosimilars, which may not

result in clinically meaningful differences but may affect the immunogenicity or other important attributes of the newer product. The development of these products is more difficult, and the approval process will be more stringent, probably requiring more extensive clinical testing. “Whether they will be required to show comparability or true interchangeability remains to be seen,” Dr Lyman added. Interchangeability is a more stringent requirement, mandating that the new agent provide the same clinical result in any given patient. “Clearly, this is a high bar.” Payers’ and Physicians’ Dilemmas Payers will be “torn in 2 directions,” Dr Lyman predicts. They will want, and need, to bring down the cost of treating cancer. But they will resist any notion of promoting a “subpar product.” “Also, how quickly and to what extent providers and hospitals will embrace biosimilars is unclear,” Dr Lyman added. Pharmacy and therapeutics committees will have significant financial incentives to integrate biosimilars into their formularies as long as adequate safety and comparability data are available. Community oncologists may embrace biosimilars as long as the financial incentives are aligned appropriately; however, comfort and experience with the older agent may influence decisions in clinical practice, he suggested. “Companies may meet regulations and conduct trials, but that doesn’t mean that clinicians will use these agents with comfort, or that patients will accept them,” he pointed out. “This is not irrational, because we have seen a lack of FDA oversight in the manufacturing of generics. The comfort level may be even less clear for biosimilars, so their use is not a foregone conclusion.” “Biosimilars will be routinely used only when clinicians are convinced of their safety and efficacy,” Dr Lyman concluded. “This will be a difficult but essential balance to achieve moving forward.” More guidance on incorporating biosimilars into cancer care will soon come from the National Comprehensive Cancer Network, which has convened a panel of stakeholders— scientists, oncologists, industry, regulators, payers, and patients—to generate a white paper. ■

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Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you. Thatâ&#x20AC;&#x2122;s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: É?&RYHUDJHDQGUHLPEXUVHPHQWRIRQFRO\WLFV É?2QFRORJ\PDQDJHPHQWVWUDWHJLHV É?&OLQLFDOSDWKZD\V The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Managerâ&#x20AC;&#x201C;Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services. Visit www.lillyoncology.com.

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DECEMBER 2011, VOL 2, NO 7