VBCC October Vol2 No6 by Value-Based Cancer Care

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OCTOBER 2011 VOL 2 NO 6

www.ValueBasedCancerCare.com VBCC Perspective, page 16

ONCOLOGY BEST PRACTICES

ESMO ANNUAL MEETING

The First NCQA-Recognized Medical Home in Oncology A new model for increasing value in cancer care

The Road to Personalized Medicine Is Strewn with Obstacles Individualizing treatment: promising and complex By Audrey Andrews

Interview with John D. Sprandio, MD Consultants in Medical Oncology and Hematology, Drexel Hill, PA

Consultants in Medical Oncology & Hematology, P.C.

The patient-centered medical home (PCMH) model of care has proved successful in overcoming some of the fragmentation of primary care. Dr Sprandio and his colleagues have now demonstrated the value of applying the principles of the medical home to cancer care, with particular implications for oncologists and for payers and unique reimbursement dilemmas.

Q: Your practice is the first oncology medical home to be recognized by the National Committee for Quality Assurance? Dr Sprandio: Our hematology/oncology practice is the first, and still the only, cancer center in the country to have gained recognition from the National Continued on page 24

Therapy-Associated Complications Significantly Increase Cost of Cancer Care

Stockholm, Sweden—With recognition of common tumor mutations and a pipeline full of biologic agents that target them, personalized medicine should be all but a fait accompli. But one expert told attendees at the European Society for Medical Oncology’s 2011 European Multidisciplinary Cancer Congress, “We may be overpromising our patients.” Gordon Mills, MD, of the Zayed Institute for Personalized Cancer Therapy at the University of Texas M.D. Anderson Cancer Center, Houston, said, “We are coming closer to having a scientific underpinning for what we want to do, but integrating this remains a challenge. Can we achieve personalized therapy? Is it even doable?”

Personalized medicine—matching the right drug with the right patient— is “not the present, but it is clearly in our future,” but there are many challenges, Dr Mills said. “The biggest problem is the ‘N of 1,’” he emphasized, because each individual patient has a unique genetic tumor Continued on page 9

NCCN HEMATOLOGY CONGRESS

Novel Agents Improve Outcomes as Maintenance Therapy for Multiple Myeloma By Phoebe Starr New York, NY—Maintenance therapy is now an option for the treatment of multiple myeloma in elderly patients and in patients who have undergone autologous stem-cell transplant (ASCT). Thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib

(Velcade) have all shown benefit in the maintenance setting, said Steven Devine, MD, Professor of Medicine and Director of the Blood and Marrow Transplant Program, Ohio State University Comprehensive Cancer Center, Continued on page 18

By Caroline Helwick Stockholm, Sweden—The cost of cancer therapies is a growing concern not only for patients but also for providers and payers. Addressing the cost burden for those involved in cancer care is becoming a priority that cannot be avoided with the growing role of targeted therapies in oncology.

Cost Nearly Doubles in Metastatic Breast Cancer A study presented by Melissa Brammer, MD, Medical Director, Genentech, San Francisco, CA, shows that complications associated with treating cancer essentially double the Continued on page 14

INSIDE ...........

MEETINg HIgHLIgHTS

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VBCC PERSPECTIVE

VALUE PROPOSITIONS

Value of cost-effectiveness analyses US patients get new cancer drugs faster than in Europe FDA UPDATES

Vemurafenib approved for metastatic melanoma, with a test for BRAF V600E mutation Crizotinib approved for NSCLC, with a test for ALK mutation

ESMO annual meeting . . . . . . . . . . . . . 8 NCCN hematology congress . . . . 18 Breast cancer symposium . . . . . . . 34 ............

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Novel biomarkers ushering in new approaches to cancer therapy HEALTH POLICY

USPSTF and the future of prostate cancer screening

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NOW APPROVED FOR

BRAF V600E MUTATION-POSITIVE METASTATIC MELANOMA

Indication and Usage ZELBORAFâ&#x201E;˘ (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.

ÂŠ2011 Genentech Inc., So. San Francisco, CA BRF0000583300 08/11

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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

*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

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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

ONCOLOGY BEST PRACTICES

HEALTH POLICY

The first and only NCQA-recognized medical oncology home

USPSTF and the future of prostate cancer screening Recent ruling on genetic patents leaves many questions More….

ESMO ANNUAL MEETING New bone-targeting compound extends survival in metastatic prostate cancer New analysis boosts value of bevacizumab in ovarian cancer Everolimus-exemestane combination prolongs remission More….

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.

PARP inhibitor a promising therapy for ovarian cancer Nilotinib sustains 24-month superiority to imatinib in CML More….

NCCN HEMATOLOGY CONGRESS Novel agents for multiple myeloma maintenance Advances in chronic lymphocytic leukemia More….

Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino

IN THE LITERATURE

NOISE-CANCELING INFORMATION Submit your IT-related questions at N EW www.valuebasedcancercare.com/submit-noise

BREAST CANCER SYMPOSIUM Targeted radiation therapy reduces treatment time Novel HDAC inhibitor improves outcomes in estrogen-sensitive patients Initial order of therapy approach has no impact on outcomes More….

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI Community Cancer Centers Program Towson, MD

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Ira Klein, MD, MBA Aetna Hartford, CT

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

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

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Craig Deligdish, MD Florida Comprehensive Cancer Network, Melbourne, FL

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

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

VALUE-BASED CANCER CARE

October 2011

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

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VALUE PROPOSITIONS Value of Cost-Effectiveness Analyses for Clinical Practice Outlined by NICE The National Institute for Health and Clinical Excellence (NICE) has issued a report (Wonderling D, et al. Ann Intern Med. 2011;154:758-765) explaining the process and value of cost-effectiveness assessments and how these inform recommendations and decisions regarding clinical questions made by the UK National Clinical Guidelines Centre. The report dispels the following 3 myths regarding cost-effectiveness evaluations that further clarify the concept of value in medicine: Myth 1: The aim of health economics is to save money. This is not the case, says NICE. Rather, the purpose of health economics is to promote as much clinical value as possible for patients, based on available resources. Myth 2: Expensive interventions are not cost-effective. This is not necessarily the case. The cost of an expensive intervention may be fully or partly offset by its ability to reduce side effects and their associated costs. In addition, an expensive intervention that offers significant health gains may often justify its high cost. Myth 3: The main goal of cost-effective analyses is to support the implementation of clinical practice. Instead, says NICE, the main goal of such analyses is to determine which interventions are most cost-effective. This can mean that a clinically beneficial intervention may not be recommended if its benefit is not sufficient to justify its cost. NICE suggests that these misconceptions can explain the reluctance of providers to consider cost-effective analyses as not relevant to the clinical decision-making. Dispelling these misconceptions is therefore key to grasping the true value and implications of this type of research methodology for clinical practice.

How to Assess the Value of Clinical Interventions Another report in the same issue of the Annals of Internal Medicine focuses on the relevance of 3 concepts that can help in understanding the value of clinical interventions for those involved in clinical decisions (Owens DK, et al. Ann Intern Med. 2011;154:174-180). The authors define value as “an assessment of the benefit of an intervention relative to expenditures.” The distinction between cost and value is crucial, the authors suggest: interventions with high cost may nevertheless provide good value, because they provide a great clinical benefit. By contrast, inexpensive interventions may be tempting because of their low cost but may actually have little value, because they offer no or only little clinical benefit. Differentiating between cost and value is therefore important to clinical decision-making; supporting high-cost, high-value interventions may be justified even in a cost-conscious healthcare system. The key to slowing the rate of cost escalation is not to avoid using highcost interventions: the challenge is to promote high-value and high-quality patient care, and this may include high-cost interventions. The first step to increasing value in clinical care is to reduce or eliminate interventions that provide no benefit and may often be even harmful. Next, it is necessary to promote interventions with high value, that is, those that provide a clinical benefit that justifies the cost. Finally, when assessing the value of an intervention, it is critical to include not only the cost of the intervention itself but also any additional cost that may be added or prevented to the total cost of care for that patient as a result of the original intervention (eg, cost or prevention of side effects, disease progression).

PET Imaging an Effective Tool for Tailoring Therapy in Advanced Lung Cancer Positron emission tomography (PET) is a promising approach for differentiating which patients with inoperable lung cancer will and will not benefit from additional treatment after standard chemotherapy/radiation therapy. Lead investigator Mitch Machtay, MD, Chairman of Radiation Oncology, Seidman Cancer Center, University Hospitals Case Western

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Medical Center, presented these results at the 2011 annual meeting of the American Society for Radiation Oncology (ASTRO), based on 251 patients with stage III lung cancer at 60 cancer centers around the country. “Lung cancer remains the number 1 cancer killer in the United States. These findings have the potential to give cancer physicians a new tool to more effectively tailor treatments for patients with locally advanced lung cancer,” Dr Machtay said. “PET scans can show us which patients have the most aggressive tumors, potentially enabling us to intensify their treatment.” He noted that this was “one of the largest studies-of-its-kind to show that PET scans have great potential in predicting the prognosis for patients with inoperable lung cancer. It supports the theory that PET scans add an important new dimension to a physician’s ability to determine which patients need additional cancer therapies to best manage their disease.”

US Patients Get New Cancer Drugs Faster than in Europe The US Food and Drug Administration (FDA) is often criticized for delaying treatments for patients, especially those with terminal illnesses such as advanced cancer. However, a new drug-to-drug comparison (Roberts SH, et al. Health Aff [Millwood]. 2011;30:1375-1381) of the 35 new cancer drugs approved by the FDA and the European Medicines Agency (EMA) between 2003 and 2010 shows that: • Median time from submission to approval of a new cancer drug is 6 months in the United States, 12 months in Europe • Of the 35 oncology drugs approved either by the FDA or the EMA during that period, all the drugs approved by both agencies were available in the United States before in Europe • The FDA approved 32 of the 35 new cancer drugs, the EMA approved 23.

Ginger Root Cost-Effective for Preventing Colon Cancer In a new study funded by the National Cancer Institute and the University of Michigan Clinical Research Center, inexpensive ginger supplements reduced markers of colon inflammation, indicating that ginger root may be beneficial in preventing colon cancer (Zick SM, et al. Cancer Prev Res [Phila]. 2011 Oct 11. Epub ahead of print). Colon inflammation is a precursor of colon cancer. “Interest in this is only going to increase as people look for ways to prevent cancer that are nontoxic, and improve their quality of life in a costeffective way,” said Suzanna M. Zick, ND, MPH, a research assistant professor at the University of Michigan Medical School and lead investigator. The study included 30 patients with colon inflammation who were randomly assigned to 2 g of ginger root supplements daily or to placebo for 28 days. Most of the standard measures of colon inflammation were significantly reduced after 28 days with the ginger supplement compared with placebo; other inflammatory markers were trending toward significant reductions.

Diagnosing Melanoma Early May Soon Be Easier: MelaFind Gets Approvable Letter On September 26, 2011, the FDA issued an approvable letter to Mela Sciences, the manufacturer of MelaFind, an investigational diagnostic device for early melanoma. This letter comes almost 1 year after the FDA rejected the device, requesting more clinical data. MelaFind is a noninvasive, multispectral computerized vision system that analyzes images of skin lesions. It is designed to differentiate nonulcerated, nonbleeding cutaneous malignant melanoma and high-grade lesions <2.2 cm from all other pigmented skin lesions. MelaFind showed 98.3% sensitivity and 9.9% specificity versus 3.7% specificity of standard diagnostic methods used by dermatologists.

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FDA UPDATES Vemurafenib Joins Ipilimumab for Treating Metastatic Melanoma The US Food and Drug Administration (FDA) approved the targeted therapy vemurafenib tablets (Zelboraf, Hoffmann-La Roche) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E gene mutation. The BRAF V600E mutation occurs in 40% to 60% of patients with melanoma. Vemurafenib received accelerated approval under the FDA’s priority review program, ahead of its October 28, 2011, regulatory date. “This has been an important year for patients with late-stage melanoma. Zelboraf is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA. In an international, randomized, open-label trial, 675 patients with previously untreated metastatic or unresectable melanoma with the BRAF V600E mutation received either vemurafenib 960 mg orally twice daily or dacarbazine (DTIC) 1000 mg/m2 intravenously every 3 weeks. After a median follow-up of 6.2 months in the vemurafenib arm and 4.5 months in the dacarbazine arm, the overall survival rate was significantly greater with vemurafenib than with dacarbazine (P <.001), as was the progression-free survival (PFS) rate (P <.001). The median survival of patients receiving vemurafenib had not been reached in the trial; it was 7.9 months for those receiving dacarbazine; median PFS rates were 5.3 months and 1.6 months, respectively. The most common adverse effects associated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous-cell carcinomas, including those of the skin and keratoacanthomas, were reported in 24% of patients receiving vemurafenib. Other reactions, sometimes severe, included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. The recommended dose is 960 mg, taken every 12 hours, with or without a meal. Vemurafenib is approved with a medication guide and is not indicated for patients with the wild-type BRAF (ie, no mutation) melanoma. (August 17, 2011)

molecular diagnostic for this targeted therapy—the cobas 4800 BRAF V600 Mutation Test (Roche) for the diagnosis of BRAF V600E mutation in patients with melanoma. As a realtime polymerase chain-reaction test, it is 97.3% positive in detecting the mutation. (August 17, 2011)

Brentuximab Indicated for 2 Types of Lymphomas The FDA expedited the approval of brentuximab vedotin (Adcetris, Seattle Genetics) for the treatment of Hodgkin lymphoma, as well as for systemic anaplastic large-cell lymphoma (ALCL), a rare non-Hodgkin lym-

phoma that may manifest in several parts of the body, including the lymph nodes, skin, bones, soft tissue, lungs, and liver. Brentuximab is the first CD30-directed antibody-drug conjugate approved for systemic ALCL; it is also the first treatment ever approved for this rare disease.

Companion Diagnostic for BRAF V600E Mutation Along with vemurafenib the FDA concurrently approved the companion

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FDA UPDATES Brentuximab is indicated for pa tients with Hodgkin lymphoma that has progressed after autologous stemcell transplantation (ASCT) or after 2 previous chemotherapy treatments. Brentuximab is also indicated for patients with systemic ALCL whose disease has progressed after 1 previ-

ous chemotherapy treatment. “Early clinical data suggest that patients who received Adcetris for Hodgkin lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy,” said Dr Pazdur. The approval for Hodgkin lym-

phoma was based on a single-arm trial involving 102 patients, who had an objective response rate to the drug of 73%, with 32% of patients showing complete remission and 40% showing partial remission; the median response duration was 6.7 months. The approval for systemic ALCL

What happens to the patient caught in the complications of chemotherapy-induced neutropenia? Consider your last patient with neutropenia

Figure. Overall survival by average relative dose intensity (ARDI)

Did your patient experience any consequences from severe or febrile neutropenia? According to a prospective registry study of 2,692 patients encompassing major tumor types, 29.3% overall were impacted by severe or febrile neutropenia in the first 3 cycles of chemotherapy, leaving a large opportunity for risk assessment intervention. This study also showed that the risk of severe or febrile neutropenia was greatest in the first cycle. That risk continued in subsequent cycles.*1

1.0

In a retrospective database analysis (N = 41,779), the inpatient mortality rate for febrile neutropenia–related hospitalization was 9.5%. This inpatient mortality rate was directly related to the number of major comorbidities present at the time of admission. Major comorbidities were defined as any major organ dysfunction requiring diagnostic or therapeutic intervention. Inpatient mortality ranged from 2.6% (556/21,386) for patients with no comorbidities to over 50% (181/358) for those with 4 or more.2

Optimal chemotherapy delivery was shown to improve survival in some tumor types Retrospective studies have shown that dose delays and reductions due to severe or febrile neutropenia may impact treatment plans and result in unfavorable outcomes for some diagnoses.3-7 While there are inherent risks associated with chemotherapy treatment, landmark studies in both non-Hodgkin’s lymphoma (NHL) and early-stage breast cancer have shown that closer adherence to standard doses is one factor that was associated with increased survival rates.8-11 A retrospective analysis demonstrated significantly longer median survival (7.08 years) for patients with NHL who received > 90% average relative dose intensity of CHOP-21 compared with those who received ≤ 90% (N = 210; P = 0.002) (see Figure).12 Multivariate analyses have identified several independent risk factors for reduced relative dose intensity. The risk factors for relative dose intensity < 85% among early-stage breast cancer patients included age, weight, and three-drug regimens (CAF or CMF).3

FDA Accelerates Approval of Crizotinib for NSCLC

0.8 Estimated survival

Febrile neutropenia–related hospitalization can lead to mortality

0.9

0.7 0.6

ARDI: ≤ 85%

0.5

ARDI: 86% to ≤ 90%

0.4 ARDI: > 90%

0.3 0.0 0

3 4 5 Years post-chemotherapy

Retrospective chart data of overall survival in 210 patients treated with CHOP-21 according to average relative dose intensity (ARDI). CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone. Adapted from Bosly A, et al. Ann Hematol. 2008.

For patients with NHL, age > 60 years, advanced disease stage and poor performance status were associated with relative dose intensity < 85%.4

You can intervene for your next patient A comprehensive risk assessment protocol is critical to helping you identify patients at risk for clinically significant febrile neutropenia.

Consider the risk of the chemotherapy regimen ie, chemotherapeutics administered, alone or in combination

Assess patient risk factors eg, age ≥ 65 years, poor performance status

Risk increases with more comorbidities eg, COPD, cardiovascular disease, diabetes mellitus

Evaluate each patient prior to every cycle To request a febrile neutropenia Risk Assessment Checklist, email: FNchecklist@amgen.com.

Assess the risk.

*Crawford J, et al. J Natl Compr Canc Netw. 2008. Nationwide, prospective registry study conducted in 115 community-based, randomly selected, IRB-approved sites, evaluating the incidence and timing of neutropenia and neutropenic events in the first cycle and in cycles 2–3 across major tumor types. References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Kuderer N, et al. Cancer. 2006;106:2258-2266. 3. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 4. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 5. Lyman G, et al. J Natl Compr Canc Netw. 2009;7:99-108. 6. Link B, et al. Cancer. 2001;92:1354-1367. 7. Picozzi V, et al. Oncology. 2001;15:1295-1306. 8. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 9. Bonadonna G, et al. BMJ. 2005;330:217-222. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Kwak L, et al. J Clin Oncol. 1990;8:963-977. 12. Bosly A, et al. Ann Hematol. 2008;87:277-283.

was based on a single-arm clinical trial in 58 patients; treatment with brentuximab showed 86% objective response: 57% complete remission and 29% partial remission. The median objective response duration was 12.6 months. The recommended dosage is a 1.8mg/kg intravenous infusion administered over 30 minutes every 3 weeks. Treatment may continue up to 16 cycles or until disease progression or unacceptable toxicity occurs. The most common adverse effects associated with this drug include neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, fever, cough, vomiting, and thrombocytopenia. (August 19, 2011)

Using a priority review, the FDA approved oral crizotinib (Xalkori, Pfizer) for the treatment of locally advanced or metastatic non–small-cell lung cancer (NSCLC) in patients with the anaplastic lymphoma kinase (ALK) genetic mutation, as detected by the companion test concurrently approved by the FDA. Approximately 3% to 5% of patients with NSCLC are ALK-positive. Crizotinib “represents a paradigm shift in NSCLC treatment, where we’re moving away from a one-size-fits-all approach to biomarker-based treatment decisions,” said Paul A. Bunn, Jr, MD, the James Dudley Chair in Cancer Research, University of Colorado, Denver. Crizotinib was approved about 1 month ahead of its scheduled regulatory date. The approval was based on 2 multicenter, single-arm trials involving 255 ALK-positive patients with locally advanced or metastatic NSCLC. In the first study, the objective response was 50%, with a median response duration of 42 weeks; in the second study, the objective response rate was 61%, with a median response of 48 weeks. Complete responses were observed in 1% of the patients. The most common adverse reactions (≥25%) were vision disorders, nausea, diarrhea, vomiting, edema, and constipation. Grade 3 or 4 adverse reactions (in ≥4% of patients) included increased alanine transaminase levels and neutropenia. Life-threatening or fatal treatment-related pneumonitis occurred in 1.6% of patients within 2 months after the initiation of crizotinib therapy. The recommended dosage is 250 mg orally twice daily. (August 26, 2011)

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New Bone-Targeting Compound Improves Survival in Metastatic Prostate Cancer Potentially practice-changing drug By Caroline Helwick Stockholm, Sweden—An investigational alpha-pharmaceutical not only prevented skeletal-related events (SREs) in patients with prostate cancer with bone metastases in a phase 3 study presented at the 2011 European Multidisciplinary Cancer Congress, but it also improved overall survival. “This is the first drug targeted to bone metastases in prostate cancer to improve survival,” said lead investigator Chris Parker, MD, Royal Marsden Hospital, London. “There are other bone drugs used in prostate cancer, but they help to minimize symptoms; they don’t improve survival. In my opinion, radium-223 is likely to become a new standard of treatment for advanced prostate cancer,” Dr Parker told journalists at a press briefing. Jean-Charles Soria, MD, Institut Gustave Roussy, Villejuif, France, who cochaired the meeting’s scientific program, agreed. “This is really practice changing, and after regulatory approval, I think this is going to be a major player

in advanced prostate cancer.” A US coinvestigator of the trial, Oliver Sartor, MD, Tulane University, New Orleans, LA, said the radiophar-

“This is really practice changing, and after regulatory approval, I think this is going to be a major player in advanced prostate cancer.” —Jean-Charles Soria, MD maceutical is far superior to prior compounds of the sort, and the study results were highly impressive. Radium-223 chloride (Alpharadin)

was recently granted a fast-track designation by the US Food and Drug Administration. The company plans to file a new drug application in mid-2012. The Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial was a phase 3, randomized, doubleblind, placebo-controlled international study that compared radium-223 chloride plus current standard of care with placebo plus current standard of care in 922 men with symptomatic castration-resistant prostate cancer that had spread to the bone. Patients had multiple skeletal metastases on bone scan

Pemetrexed Plus Bevacizumab Maintenance Keeps NSCLC at Bay Longer Stockholm, Sweden—Two expensive drugs may be better than 1 for maintenance treatment of advanced non– small-cell lung cancer (NSCLC), according to a study at the 2011 European Multidisciplinary Cancer Congress. Adding pemetrexed (Alimta) to bevacizumab (Avastin) maintenance therapy reduced the risk of disease progression in the phase 3 AVAPERL trial. Pemetrexed is approved by the US Food and Drug Administration for the maintenance treatment of nonsquamous, locally advanced or metastatic NSCLC that has not progressed after 4 cycles of platinum-based chemotherapy. AVAPERL was the first phase 3 trial to investigate the combination of pemetrexed plus bevacizumab as maintenance therapy. Patients receiving the combination had a median progression-free survival (PFS) of 10.2 months from the start of first-line induction therapy versus 6.6 months with single-agent bevacizumab maintenance, amounting to a 30% reduction in risk (P <.001), reported Fabrice Barlesi, MD, Assistance Publique Hôpitaux de Marseille, France.

Similarly, from study randomization to maintenance therapy, median PFS was doubled with the combination: 7.4 months versus 3.7 months—a 52% reduction in risk (P <.001). Overall survival from induction was 15.7 months with single-agent bevacizumab and

“First-line cisplatin, pemetrexed, and bevacizumab followed by continuation maintenance with bevacizumab and pemetrexed achieved a patient PFS benefit of unprecedented magnitude.” —Fabrice Barlesi, MD has not been reached with the combination used for maintenance. “First-line cisplatin [Platinol], pemetrexed, and bevacizumab followed by continuation maintenance with bevacizumab and pemetrexed achieved a patient PFS benefit of unprecedented magnitude,” Dr Barlesi maintained. All the 376 patients enrolled in AVAPERL received four 3-week

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October 2011

cycles of first-line induction with bevacizumab, pemetrexed, and cisplatin. After this treatment, patients with a response or stable disease were randomized to continuation maintenance with bevacizumab (N = 125) or bevacizumab plus pemetrexed (N = 128). PFS was assessed from the beginning of induction therapy to progression or death. Notably, grade 3-5 hematologic adverse events were greater with the bevacizumab plus pemetrexed arm, 10% versus 0% in the control arm. Grade 3-5 nonhematologic events were noted for 31% and 22%, respectively. —CH ■ New Warnings for Bevacizumab On September 30, 2011, the US Food and Drug Administration issued label changes for bevacizumab (Avastin), adding these 3 warnings: an increased risk for ovarian failure in premenopausal women who use the drug in combination with the mFOLFOX regimen; a risk for venous thromboembolism (VTE) and bleeding in patients using anticoagulation therapy after a first VTE event while receiving bevacizumab; and a risk for osteonecrosis of the jaw.

and were taking regular analgesics for bone pain. At a planned interim analysis, the patients who received radium-223 had the following positive outcomes: • Median overall survival: 14 months compared with 11.2 months for the placebo group, a 30% reduction in mortality (P = .00185) • Time to first SREs: 13.6 months versus 8.4 months, a 64% improvement (P = .00046) • Total alkaline phosphatase (bone marker) normalization: 33% versus 1% (P <.001) • Time to prostate-specific antigen progression: 49% improvement (P = .00015).

at a glance ➤ The investigational drug radium-223 chloride is the first agent targeted to bone metastases in prostate cancer that has shown improved survival ➤ It also prevented skeletalrelated events in this patient population ➤ Based on these results, the phase 3 study was stopped early and those receiving placebo were offered radium-223 ➤ The company plans to file a new drug application in mid-2012 ➤ Experts suggest this new therapy may be a “game changer”

Nonhematologic adverse events were not significantly worse with radium-223 versus placebo; the most common grade 3-4 adverse events were bone pain (18% vs 23%, respectively). Other serious toxicities were uncommon. Based on the interim analysis, the data monitoring committee recommended the study be stopped and patients in the placebo arm be offered radium-223. ■

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profile that requires a finely tuned drug regimen. “Some subgroups will be so small, it will be impossible to implement clinical trials [to evaluate such regimens] with sufficient power,” he said. Intratumor Heterogeneity Emerging data further suggest that tumors within one patient may be heterogeneous. Discordance between the primary (initial, nonmetastatic) tumor and the recurrent or metastatic lesion has been recently established. Although this has been evaluated for estrogen receptor and HER2 status, genetic mutations can also vary. Some discordance between primary and advanced disease has been observed in as many as 40% of patients in some studies, and this presents a big clinical problem. “We found one patient with 2 metastases, with 2 different mutations in PI3K, and the primary tumor was called a wild type [ie, lacking the mutation]. If you treated according to the primary tumor, you would not give this patient a PI3K inhibitor. But it turns out there was heterogeneity in the primary tumor,” Dr Mills said. “The mutations were there. If this is the case, will we have to grind up the whole tumor and look deeply? Yes, or we will run the risk of treating the wrong disease. This is the future: biopsy, biopsy, biopsy.” Better categorization will also be required of the mutations that are discovered, in particular, distinguishing mutations that are “drivers” and “druggable” from those that are “passengers” and thus exert no harm. Tumors will need to be sequenced in depth to capture important subclones, he said. “We are finding hundreds, if not thousands, of mutations, and not all are created equal. How will we integrate this information to find drivers that can be targeted for each patient? And for the actionable aberrations we have a limited number of drugs,” Dr Mills pointed out. Even when the tumor is well described, and a drug has been marketed to target the patient’s various receptors and mutations, resistance ultimately develops in metastatic disease, and responses—which can be dramatic with some targeted agents— are not durable. “We have to figure out how to make durable, combinatorial therapy to improve outcomes,” he said. Pilot Study Results Dr Mills and his colleagues at the Zayed Institute for Personalized Cancer

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The Road to Personalized Medicine...

Continued from cover

“The cost of looking for mutations should be far less than the cost of treating patients with expensive therapies that will not work in them.” —José Baselga, MD, PhD

Therapy “are finding actionable mutations and doing ‘N of 1’ clinical trials in an efficient manner to determine which populations could benefit from a particular drug,” he said. They are observing very high re sponses in many patients for whom they are able to identify the “driver” mutations and match these to an effective agent. But they have also found that in their first 1000 patients, only about 40% have genetic aberrations in the tumor, and only 25% have “actionable” mutations. This means that the pool of patients who will truly be candidates for personalized medicine may be narrower than originally believed. “There are still many patients who

Dr Mills also discussed the potential cost implications of genomic medicine. “The cost of implementing personalized cancer therapy has added a massive burden to healthcare costs at a very minor improvement in outcomes for a small population,” said Dr Mills. He noted that although there has been modest success so far, there have been “spectacular failures” as well. “We are far from understanding the challenges and overcoming the pitfalls to the implementation of personalized cancer therapy,” he said, and one of these is the cost of technology and treatment in this new era. “The cost of assessing molecular markers such as genetic sequencing and the cost of targeted therapies

“We are finding hundreds, if not thousands, of mutations, and not all are created equal. How will we integrate this information to find drivers that can be targeted for each patient? And for the actionable aberrations we have a limited number of drugs.” —Gordon Mills, MD will benefit, but in terms of delivering ‘personalized medicine’ to all patients, we are way below the desired numbers,” Dr Mills said. Cost Considerations in Personalized Cancer Therapy The new era of personalized medicine in oncology raises economic concerns of the cost-benefit ratio. The use of molecular testing, some argue, is adding a significant burden to the total cost of therapy. But others have shown, for example in relation to KRAS, that although the cost of testing is considerable, a true economic analysis shows that genetic testing actually reduces the total costs, by decreasing the number of patients who receive a high-cost therapy that does not benefit them.

that benefit only a few patients constitute incredible burdens on already strained healthcare resources. Nextgeneration sequencing [NGS] approaches are held as the next great step forward in implementing personalized cancer therapy. Indeed, it is possible to sequence a human genome for under $10,000, and the costs continue to drop rapidly. However, NGS is currently fraught with major problems,” Dr Mills maintained. “The cost of $10,000 for a human genome is presupposed on a depth of sequencing of 30- to 60-fold. Unfortunately, at this depth of sequencing, achieving a true-positive rate of 60% results in a false-positive rate approaching 60%. Both of these are unacceptable for patient manage-

ment. Further, the $10,000 does not include the costs of bioinformatics analysis of data storage and handling. Indeed, it has been estimated that even the eventual $1000 genome will cost $100,000 to manage and interpret,” he said. Accurate treatment calls for targeting the specific tumor characteristics, and for patients with metastatic disease this means rebiopsying, perhaps repeatedly, to reveal important subclones within each tumor. “This would massively increase the cost, as well as be associated with the morbidity of repeat biopsies. The goal of replacing biopsies with molecular imaging or characterization of circulating tumor cells or DNA remains an important dream, but a dream nevertheless,” he said. Resistance to targeted therapies is another challenge in recurrent disease; therefore, combination regimens will be necessary to address compensatory signaling pathways and to help overcome resistance. “This is fraught with its own challenges of increased costs, increased toxicity, and difficulty in getting multiple companies to cooperate in clinical trials,” Dr Mills said. However, José Baselga, MD, PhD, Codirector of the Massachusetts General Hospital Cancer Center, who is a clinician and a translational scientist, was more optimistic about the economics of this approach. He commented that, “The cost of looking for mutations should be far less than the cost of treating patients with expensive therapies that will not work in them.” With a goal of advancing personalized medicine over the next 10 years, Dr Baselga called for dedicated facilities to study the treatment of patients with novel agents, expansion of tumor genotyping and next-generation sequencing, creation of tumor biomarker facilities, sharing of data, incorporation of novel technologic platforms, innovative clinical trial design, and recruitment of “the best pool of physician scientists into a culture of team work.” ■

Death rates for esophageal cancer, 1990-2006

Women:

Men:

0.2%

9.7%

▼

2011 estimates Incidence: 16,980 Deaths: 14,710

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in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s v ra le ly u an ll M nt tag y e re e lo at m ed a

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If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT IMPOR TANT 3-YEAR UPDATEUPDA ATETE- SUST SUSTAINED TAINED AINE BENEFIT AINED UPDATED VIST UPDATED VISTA* TA* A* OVERALL OVERALLL SURVIV SURVIVAL VAL AL (OS) ANALYSIS: ANALLY YSIS: VcM VcMP P† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Pa Patients tients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier estimate.

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

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

VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/17/11 3:37 PM Page 12

Brief Summary INDICATIONS: 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. ®

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. 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. 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%.

Patients with 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. ADVERSE EVENT DATA:

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. 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:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. 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.

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. 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.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved. Printed in USA V1215 12/09

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ESMO ANNUAL MEETING

Value of Bevacizumab in Ovarian Cancer Got a Boost in a New Analysis “Bevacizumab should be continued until disease progression” By Caroline Helwick Stockholm, Sweden—The indefinite use of bevacizumab (Avastin) in patients with relapsed ovarian cancer got another boost at the 2011 European Multidisciplinary Cancer Congress, with a subanalysis of the phase 3 OCEANS trial showing consistent benefit across subgroups. The main finding of OCEANS, which was reported earlier at the 2011 American Society of Clinical Oncology annual meeting, was that the addition of bevacizumab to carboplatin (Paraplatin)/gemcitabine (Gemzar) in patients with advanced ovarian cancer reduced the risk of disease progression by 52%. OCEANS enrolled 484 women with a first recurrence of ovarian cancer and no prior treatment with bevacizumab. In the experimental arm, bevacizumab 15 mg/kg was given concurrently with chemotherapy followed by bevacizumab maintenance until disease progression or unacceptable toxicity occurred. Patients in the control arm received chemotherapy plus placebo

and placebo maintenance. In Stockholm, OCEANS investigators reported a consistent effect across the majority of clinically relevant subgroups, including not only platinumsensitive patients and those with less bulky disease but also those with partially platinum-sensitive disease and bulky disease, who tend to fare poorly.

“It seems that patients with a relatively poor outlook have the most to gain. A key message is that in recurrent disease, bevacizumab should be given with chemotherapy and continued until disease progression.” —Stanley Kaye, MD For patients with a platinum-free interval (PFI) of <24 months (indicating platinum sensitivity), median progression-free survival (PFS) was 16.6

months with bevacizumab and 11.6 months with placebo, for a 38% reduction in risk. For patients with a PFI of 12 to 24 months (indicating partial platinum sensitivity), median PFS was 12.3 and 8.6 months, respectively, for a 48% risk reduction. Patients with PFI <12 months, indicating less platinumsensitive disease, had a median PFS of 12.5 months and 7.4 months, respectively, for a 64% risk reduction, Dr Aghajanian reported. Overall survival data are not yet mature. “Bevacizumab plus chemotherapy followed by bevacizumab until disease progression should be considered an option for recurrent ovarian cancer,” said Carol Aghajanian, MD, of Memorial Sloan-Kettering Cancer Center, New York. Putting the results of OCEAN together with those of 2 other key trials— ICON7 and Gynecologic Oncology Group (GOG)-218—the study’s formal discussant, Stanley Kaye, MD, Royal Marsden Hospital and Institute for Cancer Research, London, commented

on the status of vascular endothelial growth factor inhibition in ovarian cancer. “This is its finest hour,” he said. “It seems that patients with a relatively poor outlook have the most to gain. A key message is that in recurrent disease, bevacizumab should be given with chemotherapy and continued until disease progression.” Quality of Life Not Worsened with Frontline Bevacizumab Additional studies analyzed quality-of-life data in the ICON7 and GOG trials, showing that incorporating bevacizumab into frontline therapy of patients with ovarian cancer did not worsen, or improve, quality of life. Although the studies had somewhat different designs and end points and used different doses of bevacizumab, together they provide “an unprecedented database on quality of life in ovarian cancer that will be valuable for future studies,” said Ate G. J. van der Zee, MD, of University Medical Center in Groningen, the Netherlands. ■

Positive Data Continue to Accrue for Crizotinib in ALK-Positive NSCLC Visual effects reported as transient, don’t affect dosing Stockholm, Sweden—In patients with advanced non–small-cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) gene rearrangements, treatment with crizotinib (Xalkori) provided clinically meaningful antitumor activity, producing responses in 51% of patients, in the multicenter phase 2 PROFILE 1005 study reported at the 2011 European Multidisciplinary Cancer Congress. Rearrangements in ALK (ie, activating ALK mutations or translocations) are seen in up to 5% of patients, and crizotinib—a first-in-class, oral, potent, and selective small molecular entity— competitively inhibits ALK. The report was based on an ongoing open-label phase 2 study of the first 133 evaluable patients, who received crizotinib 250 mg twice daily on a continuous basis until progression. Ob jective responses were observed in 50.4% of patients, with 1 being a complete response. Stable disease was observed in another 33.8%, reported

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Dong-Wan Kim, MD, Clinical Researcher, Seoul National University Hospital, South Korea.

“The majority of patients reported that each visual effects event was transient, lasting either 30 seconds or less or between 30 and 60 seconds.”

About half the patients completed patient-reported outcomes for key symptoms and global quality of life. Clinically meaningful improvements (change, ≥10 points) were reported for pain, dyspnea, and cough from as early as cycle 2 and for fatigue from cycle 5; these positive changes were maintained through all subsequent cycles. Global quality of life was also maintained during treatment, with clinically meaningful improvement seen by cycle 7, Dr Kim reported.

—Ben Solomon, MD

Of all responders, 79.4% demonstrated a response within the first 8 weeks of treatment and maintained it for an average of 42 weeks. A total of 32% of patients discontinued the study, but only 4.4% as a result of adverse events. Treatment-related grade 3-4 adverse events were reported in 26% of patients, mainly elevated liver enzymes and neutropenia.

Visual Effects Evaluated One of the most frequently reported side effects of crizotinib treatment is visual events. These are described as image carryover, flashing/trailing lights and floaters, and/or blurry vision, often occurring during light adaptation. A patient-reported questionnaire (Visual Symptom Assessment Questionnaire [VSAQ]) was developed to further characterize these symptoms and their effect on

activities of daily living. Ben Solomon, MD, of the Peter MacCallum Cancer Centre, located in Melbourne, Australia, reported a preliminary analysis of VSAQ findings in 57 patients, showing that the visual effects associated with crizotinib had no or only minimal impact on patients’ daily activities. “The majority of patients reported that each visual effects event was transient, lasting either 30 seconds or less or between 30 and 60 seconds,” Dr Solomon noted. Approximately 56% of patients at cycle 2 and 50% at cycle 3 and cycle 4 reported visual effects, but these did not require dose alterations, he said. The frequency of visual effects varied during cycles 2 to 4. Most patients said they were not bothered by the visual effects events or found them “only a little bothersome,” Dr Solomon said. No clinically meaningful changes were noted on ophthalmic examinations. —CH ■

www.ValueBasedCancerCare.com

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ESMO ANNUAL MEETING

Everolimus-Exemestane Combination Prolongs Remission by 4 Months in Metastatic Breast Cancer “The most important advance in breast cancer since trastuzumab”

at a glance

Stockholm, Sweden—The use of everolimus (Afinitor) together with the aromatase inhibitor exemestane (Aromasin) more than halved the risk for disease progression in patients with advanced breast cancer, adding an average of 4 disease-free months, investigators reported at the 2011 European Society for Medical Oncology European Multidisciplinary Cancer Congress. Lead investigator José Baselga, MD, of Massachusetts General Hospital, Boston, predicted that this combination “could represent a new therapeutic option” for postmenopausal women who have received previous hormonal therapy. The hypothesis is that the mTOR inhibitor could reverse the resistance to endocrine therapy that inevitably develops in hormone receptor–positive patients, a concept based on strong preclinical evidence. Fabrice André, MD, PhD, of the Institut Gustav Roussy, Villejuif, France, commented on the results, saying, “I would consider the efficacy of everolimus in the range of the most important advances in medical oncology.” BOLERO-2 The phase 3 trial BOLERO-2 was halted early after an interim analysis showed a 57% reduced risk for progression in postmenopausal patients

Photo Courtesy © ASCO/Todd Buchanan 2007

By Caroline Helwick

“I would consider the efficacy of everolimus in the range of the most important advances in medical oncology. Our results could represent a paradigm shift in the management of patients with hormone receptor– positive breast cancer.” —José Baselga, MD with estrogen receptor–positive, HER2negative disease. In earlier phase 2 trials, the mTOR inhibitor everolimus—approved for the treatment of renal-cell carcinoma—

was effective as monotherapy and in combination with hormonal therapy. A double-blind, placebo-controlled phase 3 trial then evaluated the combination in women who had previously received letrozole (Femara) or anastrozole (Arimidex) whose disease continued to progress. The 724 patients were randomized to either everolimus 10 mg/day or placebo; all patients also received exemestane daily. At an interim analysis, investigators observed significantly better progression-free survival (PFS) for the combined treatment group versus placebo: median 6.9 months versus 2.8 months, respectively (P <.001), according to local investigator assessment. By central review, the benefit was even greater, with median PFS, 10.6 months versus 4.1 months, respectively, a 64% risk reduction (P <.001). Overall survival data are immature, but Dr Baselga said there had been 83 deaths overall, including 13% in the placebo arm and 10% in the combination therapy arm. Future analyses will determine the effects on bone metabolism, because everolimus is expected to counteract the bone problems that have been associated with aromatase inhibitors. Numerically, there were more grade 34 side effects with the combination, but these were very uncommon in both arms and did not worsen quality of life

Therapy-Associated Complications... cost of treating metastatic breast cancer. The treatment of metastatic breast cancer varies from $3000 to $8000 per patient per month, but treating the complications that are associated with the cancer treatment adds another $3000 to $4000 to the total cost of therapy, according to Dr Brammer. She re ported the results of her study at the 2011 European Multidisciplinary Cancer Congress. “Incremental costs of treating ad verse events should be considered in evaluating new therapies. There is a need for treatments that are effective, but do not incur significant toxicities,” Dr Brammer suggested. She and her coinvestigators used the PharMetrics Integrated Database (2004-2009) to select patients with metastatic breast cancer who were

treated with chemotherapy and/or agents targeting HER2. They identified episodes of treatment with single-agent or combination therapies for a course of at least 30 days. They determined the complica-

VALUE-BASED CANCER CARE

October 2011

for patients taking the 2 drugs, he said. “Our results could represent a paradigm shift in the management of patients with hormone receptor– positive breast cancer,” Dr Baselga concluded. Dr André said the study was well designed, used an appropriate control arm, and appeared to be molecularly enriched for mTOR activation on the basis of the subjects’ resistance to endocrine therapy. “Everolimus not only improves outcomes but opens perspectives in the field of kinase inhibitors in general. I think this is the most important advance in breast cancer since trastuzumab [Herceptin].” ■

Continued from cover

tion, leukopenia, and neutropenia. A total of 1551 patients with 3157 eligible episodes of treatment met the inclusion criteria. The most common treatment-associated complications were anemia, bilirubin elevations, and

“Incremental costs of treating adverse events should be considered in evaluating new therapies. There is a need for treatments that are effective but do not incur significant toxicities.” —Melissa Brammer, MD

tions associated with treatment, using medical claims with a diagnosis for one of the following events of interest: anemia, alopecia, arthralgia, bilirubin elevation, dehydration, dyspnea, infec-

➤ Everolimus plus exemestane more than halved the risk for disease progression in patients with advanced breast cancer ➤ The combination of everolimus plus the aromatase inhibitor added an average of 4 months of progression-free survival ➤ This combination could represent a new therapeutic option for postmenopausal women who have received previous hormonal therapy ➤ The efficacy of everolimus can be considered one of the most important advances in oncology

leukopenia, with substantial variation across type of regimen, Dr Brammer reported. Anemia was the most common event with trastuzumab (Herceptin)/

vinorelbine (Navelbine) (70%), singleagent gemcitabine (Gemzar) (70%), and vinorelbine (65%); it was least likely with capecitabine (Xeloda). Bilirubin elevations were most common with trastuzumab/vinorelbine (35%), trastuzumab/docetaxel (Taxotere) (31%), and single-agent paclitaxel (Taxol) (31%). Leukopenia was most common with vinorelbine (46%) and trastuzumab/vinorelbine (38%). Neutropenia was most common with vinorelbine (30%) and trastuzumab/ vinorelbine (30%). The average monthly cost per patient for treating the most expensive chemotherapy-related complications included $3200 for anemia, $3820 for dehydration, $4217 for dyspnea, and $3453 for neutropenia. Similar costs Continued on page 15

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ESMO ANNUAL MEETING

New T-DM1 Reduces Disease Progression by 40% in Advanced Breast Cancer, with Low Toxicity By Caroline Helwick Stockholm, Sweden—Trastuzumab emtansine (T-DM1), a novel monoclonal antibody–guided therapy for HER2positive metastatic breast cancer, achieved almost a 40% reduction in the risk of disease progression compared with standard treatment with trastuzumab (Herceptin) and docetaxel (Taxotere), investigators reported at the 2011 European Multidisciplinary Cancer Congress. Excitement over T-DM1 has been steadily building since early results were presented several years ago. The results have been so encouraging that the manufacturer has a number of similar compounds in development, investigators said. T-DM1 is an antibody-drug conjugate that links a cytotoxic agent (maytansine) to a monoclonal antibody. It is only when the molecule binds to the HER2 receptor via the antibody and is absorbed into the tumor cell that the chemotherapy is released, producing a highly targeted blow and sparing normal tissues, thus avoiding adverse effects typically associated with chemotherapy, explained Sara Hurvitz, MD, University of California, Los Angeles, who presented the findings of the phase 2 trial. The study included 137 women with locally advanced or metastatic HER2-positive breast cancer and no prior treatment for advanced disease. They were randomized to 3.6 mg/kg

of T-DM1 or to the standard regimen of trastuzumab plus docetaxel. Progression-free survival (PFS) was 14.2 months with T-DM1 compared with 9.2 months with standard therapy—a 41% relative risk reduction (P = .035), Dr Hurvitz reported. Although response rates were similar, the median duration of response was markedly higher in the experimental arm. Patients receiving standard therapy were stable for 9.5 months, on average, but the median duration of response had not been reached in the T-DM1 arm at the time of analysis. This means the treatment “is probably very durable,” Dr Hurvitz said. Patients receiving T-DM1 also were able to remain on treatment much longer than those on standard therapy, primarily because of toxicities such as neuropathy, she pointed out. Overall toxicity was far lower with T-DM1, which is a key reason for its appeal, Dr Hurvitz suggested. Adverse events were reported by 46.4% of patients taking T-DM1 versus 89.4% of patients receiving standard treatment; discontinuation occurred in 7.2% versus 28.8%. Neutropenia, alopecia, diarrhea, and edema were also substantially less common with T-DM1. However, thrombocytopenia was observed more often with T-DM1 than with placebo (30.4% vs 6.1%, respectively), and liver enzymes were increased (39.1% vs 6.1%); thrombocy-

Overall toxicity was far lower with T-DM1, which is a key reason for its appeal. Adverse events were reported by 46.4% of patients taking T-DM1 versus 89.4% of patients receiving standard treatment. —Sara Hurvitz, MD topenia is likely tied to the drug’s effect on the bone marrow, Dr Hurvitz suggested. The results of 2 ongoing phase 3 trials—EMILIA/TDM4370g and MARIANNE—are expected in spring 2012. Martine Piccart-Gebhart, MD, PhD,

Therapy-Associated Complications... were incurred when these side effects occurred with anti-HER2 agents. The cost drivers associated with anemia and neutropenia were drug expenses, whereas dyspnea and dehydration costs were driven mostly by hospitalization expenses. The treatment-related costs in this study did not capture out-of-claims costs, such as alopecia and fatigue; therefore, the total cost of these complications is actually even higher, Dr Brammer noted. Skeletal-Related Events Linked to Heavy Resource Utilization Skeletal-related events (SREs) can lead to lengthy hospitalizations and many outpatient visits in patients with bone metastases, suggested Herbert Hoefeler, MD, of the For -

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schungszentrum Rhur in Witten, Germany. He presented results from a multicenter prospective observational study conducted in Europe, Canada, and the United States. The study estimated future resourcing needs and assessed the value of new treatments to prevent SREs. Although studies have shown that SREs increase health resource utilization and cost, “there is a lack of robust, prospective data” on which to base decisions, Dr Hoefeler said. “This is the first study to examine health resource utilization associated with different types of SREs prospectively in a large sample of patients in Europe.” The study included 478 European patients who had bone metastases secondary to breast cancer, prostate can-

of the Jules Bordet Institute, Brussels, Belgium, cautioned that these are early-phase results. Pending the results from the phase 3 trials, however, T-DM1 “hopefully will be available to patients in the not-too-distant future,” she predicted. ■

Continued from page 14

cer, lung cancer, or multiple myeloma, and who had at least 1 SRE within 90 days of study enrollment.

“Preventing SREs occurring in all individuals with cancer is important to substantially reduce patient burden and rate of hospitalization. This may reduce costly health resource utilization.” —Herbert Hoefeler, MD

Across all tumor types and countries, 21% to 48% of SREs required

inpatient stays, with an average duration of 13 to 27 days. Outpatient visits were required for 58% to 84% of SREs, with each SRE associated with a mean of 2.5 to 7.3 outpatient visits. Hospitalization rates were similar across tumor types, but a trend toward a higher percentage was seen for lung cancer—29% to 49% (according to country) versus 20% to 29% for other tumor types. Fewer outpatient visits were reported per SRE in the United Kingdom, which was primarily driven by greater use of single-fraction radiation. “Preventing SREs occurring in all individuals with cancer is important to substantially reduce patient burden and rate of hospitalization,” Dr Hoefeler said. “This may reduce costly health resource utilization.” ■

www.ValueBasedCancerCare.com

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VBCC PERSPECTIVE

The New Era of Personalized Medicine in Oncology: Novel Biomarkers Ushering in New Approaches to Cancer Therapy Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, AL

t is next to impossible for a day to go by without thinking about the contributions of personalized medicine to the care of patients living with cancer. Whether we are treating a newly diagnosed patient with HER2/neupositive breast cancer using trastuzumab, or using erlotinib in the management of a patient with non–small-cell lung cancer (NSCLC) whose tumor harbors specific mutations in the epidermal growth factor receptor genes, individualizing therapy based on molecular biology and genetic testing has become commonplace in contemporary oncology practice. Yet, as our knowledge of cancer biology continues to increase exponentially, we now find ourselves on the brink of where discovery and clinical practice collide, permanently changing the future of cancer medicine by altering the way we think not only about cancer therapy but also about cancer classification. In August 2011, the US Food and Drug Administration (FDA) approved 3 novel targeted therapies for patients with cancer. Although the availability of new drugs is often enough to generate attention among healthcare pro viders and patients with cancer alike, what is unique, in this case, is the simultaneous approval of 2 of these new drugs—crizotinib (Xalkori) and vemurafenib (Zelboraf)—with companion molecular assays, representing a potential paradigm shift in the FDA’s approach to new, niche, biomarkerguided therapies. The specificity of each of these drugs for discrete, and somewhat uncommon, molecular targets will undoubtedly change the way we approach the management of patients for which these new therapies may be indicated. Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor indicated for the management of locally advanced or metastatic NSCLC. Mutations or translocations within the ALK gene, which are found in only 3% to 5% of all NSCLCs, give rise to the overexpression of the fusion protein EML4-ALK, ultimately resulting in the constitutive activation of the Ras/MAP kinase pathway. When aberrantly activated, this signaling pathway is known to fuel canReprinted with permission from American Health & Drug Benefits. 2011;4:387-388.

cer growth by promoting cell proliferation and survival.1 Before prescrib ing crizotinib therapy to a patient, providers must first ensure that the patient is ALK-positive by using the concurrently approved molecular assay known as the Vysis ALK BreakApart FISH Probe Kit. This test uses fluorescence in situ hybridization technology to detect gene rearrangements within the 2p23 chromosome that indicate that a patient may derive benefit from treatment with crizotinib.

Much like the ALK mutations in NSCLC, these BRAF V600E mutations result in the activation of the MAP kinase pathway, thereby promoting tumor growth. However, it should be noted that vemurafenib has no activity in patients with wild-type BRAF, so patients must be screened by using the companion cobas 4800 BRAF V600 Mutation Test, which was concurrently approved by the FDA. The phase 3 BRAF Inhibitor in Melanoma (BRIM) 3 trial compared

The onslaught of new knowledge of cancer biology and the development of targeted therapies has begun a revolution in cancer medicine that will ultimately result in a totally new way of thinking about cancer and usher in a new era of personalized cancer medicine. For the small percentage of patients with NSCLC and the appropriate ALK mutations, the efficacy of crizotinib demonstrated in clinical trials suggests that this drug may be a valuable addition to our arsenal of available treatment options. The FDA granted crizotinib accelerated approval after the completion of 2 early-phase studies that enrolled a total of 255 patients (94% had received previous treatment).2 A phase 1 study demonstrated a 57% overall response rate (complete plus partial responses) and a 72% progression-free survival (PFS) at 6 months.3 Results from the phase 2 PROFILE 1005 trial confirmed similar findings, with an objective response rate of 61% and median response duration of 48 weeks.3 Furthermore, crizotinib appears to be well tolerated, with vision disorders (occurring in 62% of patients), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%) representing the most common adverse events.4 In view of the poor prognosis of patients with metastatic melanoma and the relative lack of therapies offering improved survival outcomes, the approval of vemurafenib represents a significant achievement for the role of personalized medicine in this deadly disease state. Mechanistically, vemurafenib is an inhibitor of the BRAF V600E mutation found in approximately 40% to 60% of all patients with cutaneous melanomas.

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October 2011

vemurafenib with dacarbazine, a standard of care for patients with meta static melanoma.5 With a primary end point of overall survival at 6 months, the BRIM 3 study demonstrated a significant improvement in favor of vemurafenib (84% vs 64% with dacarbazine). PFS was also more favorable with vemurafenib than with dacarbazine (5.3 months vs 1.6 months, respectively).5 Vemurafenib was well tolerated, with rash, arthralgia, and fatigue reported as the most common adverse events.5 Undoubtedly, the availability of vemurafenib and ipilimumab (a CTLA-4 targeted monoclonal antibody approved by the FDA in March 2011) represents a major stride in our understanding of the molecular basis of stage IV melanoma, for which the median survival has historically been only 8 to 18 months.6 Brentuximab vedotin (Adcetris)— the third new drug approved in August—not only offers new hope to patients with Hodgkin lymphoma who have previously failed autologous stem-cell transplant (ASCT) therapy or who are not candidates for ASCT after failing previous Hodgkin lymphoma therapy, but it may also help to reignite a debate regarding a new way of classifying malignant diseases based on underlying molecular abnormalities rather than the traditionally used organ-based system of origin. It has been well documented that

CD30 is expressed on a subset of ReedSternberg cells found in Hodgkin lymphoma and anaplastic large-cell lymphomas (which is also an FDAapproved indication for brentuximab), some T-cell lymphomas, and some Bcell non-Hodgkin lymphomas. Brentuximab vedotin combines a CD30-targeted monoclonal antibody with the antitubulin compound monomethyl auristatin E to form a potent novel drug capable of inducing apoptosis by inhibiting the cell cycle in the G2/M phase.7 In the Hodgkin lymphoma study, the overall response rate was 73%, with an astounding 32% of patients achieving a complete response. These results are especially significant in view of the historically poor prognosis observed in patients with Hodgkin lymphoma who failed ASCT.8 A new clinical trial will attempt to screen for CD30 positivity among patients with metastatic solid tumors who are running out of treatment options. Patients confirmed as CD30positive will be treated with brentuximab in the experimental setting to assess disease response.9 This idea of evaluating malignancies for commonly expressed molecular biomarkers and treating those patients with similar therapeutic approaches is not new. In a 1999 article published in Science, Golub and colleagues attempted to challenge our thinking of oncology practice by suggesting just such a molecular classification system.10 With 32 targeted therapies currently approved by the FDA for patients with cancer, and with, arguably, hundreds more in various stages of development, is it possible that we have entered the era of molecular classification of cancer? Is it possible that the historic nomenclature of breast cancer, lung cancer, pancreatic cancer, and so on, has become an outdated system of thinking that will be toppled by a new system in which malignancies will be thought about, classified, and treated according to their biomarkers (eg, CD30, ALK, mTOR, KRAS)? It is reasonable to believe that the onslaught of new knowledge of cancer biology and the development of targeted therapies has begun a revolution in cancer medicine that will ultimately result in a totally new way of thinking about cancer and usher in a new era of personalized cancer medicine. ■ References available at www.valuebased cancercare.com

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VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/17/11 3:37 PM Page 17

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NCCN HEMATOLOGY CONGRESS

Novel Agents Improve Outcomes as Maintenance... Columbus, during the recent National Comprehensive Cancer Network (NCCN) 6th Congress on Hematologic Malignancies. Dr Devine defined maintenance therapy as treatment designed to prevent relapse in patients who achieve complete response (CR) or partial response with induction therapy. Maintenance therapy for myeloma is usually of relatively low intensity and long duration, he said. Maintenance therapy for myeloma continues to evolve as new agents become available. Selection of the best drug for particular patient groups is the subject of ongoing trials. At present, NCCN guidelines recommend thalidomide, lenalidomide, and bortezomib for maintenance therapy. For maintenance, thalidomide has category 1 recommendation and bortezomib and lenalidomide have category 2A recommendation, but thalidomide carries a high risk for severe peripheral neuropathy. Lenalidomide is now included in the NCCN guidelines as an option for patients with active myeloma who respond to induction therapy; these patients can either continue induction chemotherapy to plateau or undergo

ASCT and then be treated with maintenance therapy. Lenalidomide as maintenance therapy is supported by two phase 3 trials (McCarthy PL, et al. Blood. 2010;116:abstr 37; Attal M, et al. Blood. 2010;116:abstr 310). Both studies showed that lenalidomide mainte-

that in contrast to thalidomide, lenalidomide maintenance therapy at doses of 5 to 15 mg/day is generally well tolerated. The intent should be to use it for at least 1 year,” said Kenneth C. Anderson, MD, Chief, Division of Hematologic Neoplasia, Director of

“In contrast to thalidomide, lenalidomide maintenance therapy at doses of 5 to 15 mg/day is generally well tolerated. The intent should be to use it for at least 1 year.” —Kenneth C. Anderson, MD

nance therapy doubled progressionfree survival (PFS) after ASCT from approximately 2 years to 4 years and numerically improved survival. Lenalidomide was generally well tolerated. Hematologic events were the most common side effects. A slight increase in secondary malignancies was reported in both studies, and patients are being monitored with this in mind. “Evidence from these trials suggests

the Jerome Lipper Multiple Myeloma Center, and Vice Chair of the Joint Program in Transfusion Medicine, at the Dana-Farber Cancer Institute. Bortezomib maintenance therapy has also been studied, but the data are less mature. The Haemato Oncology Foundation for Adults in the Netherlands (HOVON) trial (Sonneveld P, et al. Blood. 2010;116: abstr 40) showed that bortezomib maintenance improved CR, near-CR,

Continued from cover and partial response rates, as well as PFS and overall survival (OS) compared with thalidomide in newly diagnosed ASCT candidates. In contrast to lenalidomide, bortezomib appears to overcome poor-risk cytogenetic abnormalities, including 13q and 17p deletions. For elderly patients who are transplant-ineligible, melphalan (Alkeran)/ prednisone (Deltasone)/lenalidomide (MPR) followed by lenalidomide maintenance is a good option. A phase 3 study showed that MPR plus lenalidomide maintenance versus MPR alone or melphalan/prednisone (MP) improved PFS from 14 months and 13 months with MPR and MP alone, respectively, to 31 months. No OS advantage has been reported yet. A low rate of secondary malignancies was seen in this trial. Bortezomib-based induction therapy is another good option for elderly patients with newly diagnosed myeloma (Niesvizky R, et al. Blood. 2010; 116:abstr 619). In this study, 3 different bortezomib-based regimens were active, and bortezomib maintenance was well tolerated with increased rates of very good partial remission in all 3 arms. ■

Treatment Delay Feasible in Asymptomatic Follicular Lymphoma Has significant economic implications By Phoebe Starr New York, NY—Evidence suggests that maintenance therapy, as well as initiation of therapy for newly diagnosed follicular lymphoma, can be delayed in asymptomatic patients with low tumor burden, according to Andrew Zelenetz, MD, Chief of Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY. Speaking at the National Comprehensive Cancer Network 6th Congress on Hematologic Malignancies, which he chaired, Dr Zelenetz said, “The quality of life for follicular lymphoma patients who are asymptomatic and living with their disease is similar to that of patients in remission.” Although studies show that initial treatment and maintenance therapy improve progression-free survival (PFS) in patients with follicular lymphoma, no overall survival (OS) advantage has been reported. The ability to delay therapy in this patient population has economic implications, because treatment with single-agent rituximab (Rituxan) costs approximately $36,000 annually per patient. Dr Zelenetz estimated

that a treatment that costs this much but has no impact on OS would cost about “tens of millions of dollars” per quality-adjusted life-year, which is clearly unacceptable. “Currently we have the luxury of using therapy that doesn’t impact OS, but I can’t predict the future. It might be difficult to get paid for maintenance rituximab,” he said. Follicular lymphoma is an indolent B-cell lymphoma with a median survival of 12 to 16 years. Rituximab has dramatically improved PFS, but patients will eventually relapse. The decision to initiate therapy in an asymptomatic patient with follicular lymphoma rests on the patient’s preference. Dr Zelenetz said patients fall into 2 groups: those who want treatment for a disease they know they have, even if there are no symptoms, and those who are content to forego treatment while feeling well, preferring to receive treatment when they need it. He cautioned against routine treatment for every newly diagnosed follicular lymphoma. Patients who require

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October 2011

“The quality of life for follicular lymphoma patients who are asymptomatic and living with their disease is similar to that of patients in remission. Currently we have the luxury of using therapy that doesn’t impact OS, but I can’t predict the future. It might be difficult to get paid for maintenance rituximab.” —Andrew Zelenetz, MD immediate up-front treatment are symptomatic and have a tumor >3 cm, cytopenia, concurrent disease transformation, or compromised end-organ function. At least 4 different randomized clinical trials in patients with low tumor burden failed to show improvement in OS with any chemotherapy versus observation, suggesting that treatment

can be delayed in these patients. Studies by the European Organization for Research and Treatment of Cancer and by the Swiss Group for Clinical Cancer Research, along with the PRIMA, RESORT, and FIT studies, have shown that several maintenance regimens, including radioimmunotherapy or rituximab dramatically improve PFS in follicular lymphoma, but none of these regimens improved OS. Dr Zelenetz noted that PFS is not an ideal end point and an OS benefit would be more convincing. Researchers at Memorial SloanKettering Cancer Center are studying disease proliferation as a marker for the timing of initial treatment of follicular lymphoma. Based on image analysis of MIB-1/Li-67 staining, the researchers determined that the median time to need for treatment was 5 years in patients with disease proliferation <30% versus 18 months in those with disease proliferation >30%. They anticipate that markers such as disease proliferation will help ensure that available treatments are used more efficiently. ■

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FDA UPDATES Continued from page 7

Genetic Diagnostic for ALK-Positive Status The FDA also approved the Vysis ALK Break-Apart FISH Probe Kit (Abbott) as a companion diagnostic test for the diagnosis of the ALK gene in patients with NSCLC to identify appropriate candidates for crizotinib therapy. The test uses fluorescence in situ hybridization to detect those rearrangements on the 2p23 chromosome. (August 26, 2011)

the men receiving denosumab had new vertebral fractures versus 3.9% in the placebo group (P = .012). In the women’s study, at 12 months lumbar spine BMD increased by 4.8% with denosumab and decreased by 0.7% with placebo (P <.001).

In both studies, the most common adverse events with denosumab were arthralgia and back pain. Extremity and musculoskeletal pain were also observed. Hypocalcemia, associated only with denosumab, was reported in 2.4% of patients after 1 month of therapy.

Denosumab is already approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture and for the prevention of skeletal-related events in patients with bone metastases from solid tumors. (September 16, 2011) ■

ODAC Recommends Accelerated Approval for Iron Chelator Deferiprone The FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended accelerated approval of the iron chelator deferiprone (Ferriprox, ApoPharma) for patients with transfusional iron overload that is inadequately treated with deferoxamine (Desferal), the standard chelation therapy for patients with diseases such as thalassemia or sickle-cell disease, who must undergo multiple blood transfusions to survive. Approximately 25% of patients with thalassemia do not respond adequately to standard iron chelation treatment. Clinical data show that among transfusion-dependent pa tients who failed standard chelation therapy, 52% had successful treatment with deferiprone. ODAC also recommended further assessment of clinical efficacy and safety, especially in patients with sickle-cell disease. (September 14, 2011)

New Indications for Denosumab for Increasing Bone Density in Patients with Cancer The FDA approved 2 new indications for denosumab (Prolia, Amgen) for treating patients at high risk for therapy-induced bone fracture. The first indication is for increasing bone mineral density (BMD) in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer; the second is for increasing BMD in women receiving adjuvant aromatase inhibitor therapy for breast cancer. The approval was based on 2 in ternational randomized, placebo-controlled trials, one involving 1468 men with prostate cancer, the other including 252 women with breast cancer. At 24 months, BMD in the lumbar spine increased by 5.6% in men who received denosumab but decreased by 1% in those receiving placebo (P <.001). At 36 months, only 1.5% of

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NCCN HEMATOLOGY CONGRESS

Advances in the Management of Chronic Lymphocytic Leukemia By Phoebe Starr New York, NYâ&#x20AC;&#x201D;Several advances have been made in the diagnosis and treatment of chronic lymphocytic leukemia (CLL), according to Susan Oâ&#x20AC;&#x2122;Brien, MD, Chief, Acute Leukemia Section at M.D. Anderson Cancer Center, Houston. Treatment selection can now be guided by fluorescence in situ hybridization (FISH) testing for genetic abnormalities, and 2 new treatments in early-stage development hold promise for patients with a poor prognostic cytogenetic profile. FISH testing is used to identify 3 cytogenetic abnormalities of interest in CLL: 13q deletionsâ&#x20AC;&#x201D;a predictor of good prognosisâ&#x20AC;&#x201D;and deletions of 11q and 17p, predictors of poor prognosis. The presence of these markers can guide treatment selection. The National Comprehensive Cancer Network (NCCN) guidelines are clear for CLL patients with 13q deletions but not with 11q and 17p deletions. CLL with 11q deletions is associated with extensive lymphadenopathy, disease progression, and shorter median survival. Patients with CLL and these deletions, even if asymptomatic, will progress within 2 years. â&#x20AC;&#x153;Treatment [for 11q deletions] is needed, and the regimen should include an alkylating agent,â&#x20AC;? Dr Oâ&#x20AC;&#x2122;Brien said.

prognosis in CLL. FCR is probably not going to be effective in this group of patients. â&#x20AC;&#x153;The NCCN guidelines list many choices for therapy, and whenever there are so

Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1 t 5IF $FOUFST GPS .FEJDBSF .FEJDBJE 4FSWJDFT BTTJHOFE :&370: B QBTT UISPVHI TUBUVT JOEJDBUPS VOEFS UIF IPTQJUBM 0VUQBUJFOU 1SPTQFDUJWF 1BZNFOU 4ZTUFN 0114 FGGFDUJWF +VMZ

4QFDJm D QBZNFOU JOTUSVDUJPOT NBZ CF PCUBJOFE JO UIF +VMZ 0114 QSPHSBN JOTUSVDUJPOT BWBJMBCMF BU IUUQ XXX DNT HPW )PTQJUBM0VUQBUJFOU114 )01145SBOT MJTU BTQ 5PQ0G1BHF

t .JTDFMMBOFPVT DPEFT + OPU PUIFSXJTF DMBTTJm FE BOUJOFPQMBTUJD ESVHT + VODMBTTJm FE CJPMPHJDT BOE + VODMBTTJm FE ESVHT NBZ CF VTFE JO PUIFS TFUUJOHT VOUJM B QFSNBOFOU DPEF IBT CFFO BTTJHOFE The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Coding for YERVOY is dependent on the insurer and the care setting in which the drug will be administered. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements.

â&#x20AC;&#x201D;Susan Oâ&#x20AC;&#x2122;Brien, MD

Her preferred regimen is fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan) (FCR), which was developed at M.D. Anderson. â&#x20AC;&#x153;FCR is the only regimen shown to improve survival in CLL,â&#x20AC;? Dr Oâ&#x20AC;&#x2122;Brien said. A survival advantage for FCR over fludarabine and cyclophosphamide (FC), an older regimen, was demonstrated in the CLL8 trial: complete response rates were doubled with FCR versus FC, and 3-year survival was 87.2% with FCR versus 82.5% with FC. FCR is considered the standard of care for asymptomatic patients with CLL and 11q deletions, according to NCCN guidelines. Reduced-dose FCR is also an option for elderly patients with good performance status; palliative care is recommended for elderly patients who are compromised. The deletion of 17p predicts low response rates to treatment and poor

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CLL characterized by 17p deletions. â&#x20AC;&#x153;Alemtuzumab [Campath] is not effective in patients with bulky disease, but it may be a good option for patients with nonbulky disease,â&#x20AC;?

Announcing YERVOYâ&#x201E;˘ (ipilimumab) HCPCS Code C9284

â&#x20AC;&#x153;FCR is the only regimen shown to improve survival in CLL.â&#x20AC;?

many choices, it means that none of the therapies are particularly effective,â&#x20AC;? Dr Oâ&#x20AC;&#x2122;Brien said. Studies have failed to establish a good chemotherapy regimen for

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

REFERENCES 1. :&370: JQJMJNVNBC <QBDLBHF JOTFSU> 1SJODFUPO /+ #SJTUPM .ZFST 4RVJCC .BSDI 2. )$1$4 $ DPEFT &GGFDUJWF +VMZ $FOUFST GPS .FEJDBSF .FEJDBJE 4FSWJDFT 8FC TJUF IUUQ XXX DNT HPW )$1$43FMFBTF$PEF4FUT %PXOMPBET +VM @)$1$4@$ DPEFT [JQ "DDFTTFE +VOF 3. "MQIB OVNFSJD )$1$4 $FOUFST GPS .FEJDBSF .FEJDBJE 4FSWJDFT 8FC TJUF IUUQT XXX DNT HPW BQQT BNB MJDFOTF BTQ m MF )$1$43FMFBTF$PEF4FUT %PXOMPBET BOXFC [JQ "DDFTTFE .BSDI

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NCCN HEMATOLOGY CONGRESS she said. Bendamustine (Treanda) plus rituximab is also not recommended for CLL with 17p deletions. The best choice for patients with 17p deletions is a clinical trial. Those who achieve a partial or complete remission with frontline therapy should be considered for allogeneic stem-cell transplant.

New Drugs Dr O’Brien was enthusiastic about 2 new inhibitors of B-cell receptor signaling in early clinical trials that included patients with poor prognostic factors: PCI-32765 and CAL-101. “There is no question whether these 2 drugs will be approved. The question is when,” she said.

PCI-32765 is a small-molecule inhibitor of Bruton’s tyrosine kinase. Phase 1 trials showed promising results, especially in patients with a poor cytogenetic profile. The drug appears to be well tolerated and is associated with no cumulative toxicity. PCI-32765 is in phase 2 trials for CLL and nonHodgkin lymphoma.

CAL-101, an orally available smallmolecule inhibitor of phosphoinositide-3 kinase, achieved responses in the lymph nodes of CLL patients, including those with 17p deletions. The lymph nodes were reduced by 84% in volume, and hemoglobin and platelets were increased in studies of patients with refractory CLL. ■

Important Safety Information (cont) Recommended Dose Modifications 8JUIIPME EPTF GPS NPEFSBUF JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT VOUJM SFUVSO UP CBTFMJOF JNQSPWFNFOU UP NJME TFWFSJUZ PS DPNQMFUF SFTPMVUJPO BOE QBUJFOU JT SFDFJWJOH NH QSFEOJTPOF PS FRVJWBMFOU QFS EBZ 1FSNBOFOUMZ EJTDPOUJOVF :&370: JQJMJNVNBC GPS BOZ PG UIF GPMMPXJOH t 1FSTJTUFOU NPEFSBUF BEWFSTF SFBDUJPOT PS JOBCJMJUZ UP SFEVDF DPSUJDPTUFSPJE EPTF UP NH QSFEOJTPOF PS FRVJWBMFOU QFS EBZ t 'BJMVSF UP DPNQMFUF GVMM USFBUNFOU DPVSTF XJUIJO XFFLT GSPN BENJOJTUSBUJPO PG m STU EPTF t 4FWFSF PS MJGF UISFBUFOJOH BEWFSTF SFBDUJPOT Immune-mediated Enterocolitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF UISFBUFOJOH PS GBUBM EJBSSIFB PG ö TUPPMT BCPWF CBTFMJOF GFWFS JMFVT QFSJUPOFBM TJHOT (SBEF JNNVOF NFEJBUFE FOUFSPDPMJUJT PDDVSSFE JO BOE NPEFSBUF EJBSSIFB XJUI VQ UP TUPPMT BCPWF CBTFMJOF BCEPNJOBM QBJO NVDVT PS CMPPE JO TUPPM (SBEF FOUFSPDPMJUJT PDDVSSFE JO QBUJFOUT t "DSPTT BMM :&370: USFBUFE QBUJFOUT O EFWFMPQFE JOUFTUJOBM QFSGPSBUJPO EJFE BT B SFTVMU PG DPNQMJDBUJPOT BOE XFSF IPTQJUBMJ[FE GPS TFWFSF FOUFSPDPMJUJT t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG FOUFSPDPMJUJT TVDI BT EJBSSIFB BCEPNJOBM QBJO NVDVT PS CMPPE JO TUPPM XJUI PS XJUIPVU GFWFS BOE PG CPXFM QFSGPSBUJPO TVDI BT QFSJUPOFBM TJHOT BOE JMFVT o *O TZNQUPNBUJD QBUJFOUT SVMF PVU JOGFDUJPVT FUJPMPHJFT BOE DPOTJEFS FOEPTDPQJD FWBMVBUJPO GPS QFSTJTUFOU PS TFWFSF TZNQUPNT Immune-mediated Hepatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF UISFBUFOJOH PS GBUBM IFQBUPUPYJDJUZ "45 PS "-5 FMFWBUJPOT 9 UIF VQQFS MJNJU PG OPSNBM 6-/ PS UPUBM CJMJSVCJO FMFWBUJPOT 9 UIF 6-/ (SBEF PDDVSSFE JO XJUI GBUBM IFQBUJD GBJMVSF JO BOE IPTQJUBMJ[BUJPO JO t BEEJUJPOBM :&370: USFBUFE QBUJFOUT FYQFSJFODFE NPEFSBUF IFQBUPUPYJDJUZ NBOJGFTUFE CZ -'5 BCOPSNBMJUJFT "45 PS "-5 FMFWBUJPOT 9 CVU õ 9 UIF 6-/ PS UPUBM CJMJSVCJO FMFWBUJPO 9 CVU õ 9 UIF 6-/ (SBEF t .POJUPS -'5T IFQBUJD USBOTBNJOBTF BOE CJMJSVCJO MFWFMT BOE BTTFTT QBUJFOUT GPS TJHOT BOE TZNQUPNT PG IFQBUPUPYJDJUZ CFGPSF FBDI EPTF PG :&370: o *O QBUJFOUT XJUI IFQBUPUPYJDJUZ SVMF PVU JOGFDUJPVT PS NBMJHOBOU DBVTFT BOE JODSFBTF GSFRVFODZ PG -'5 NPOJUPSJOH VOUJM SFTPMVUJPO Immune-mediated Dermatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF UISFBUFOJOH PS GBUBM JNNVOF NFEJBUFE EFSNBUJUJT F H 4UFWFOT +PIOTPO TZOESPNF UPYJD FQJEFSNBM OFDSPMZTJT PS SBTI DPNQMJDBUFE CZ GVMM UIJDLOFTT EFSNBM VMDFSBUJPO PS OFDSPUJD CVMMPVT PS IFNPSSIBHJD NBOJGFTUBUJPOT (SBEF PDDVSSFE JO QBUJFOUT o QBUJFOU EJFE BT B SFTVMU PG UPYJD FQJEFSNBM OFDSPMZTJT o BEEJUJPOBM QBUJFOU SFRVJSFE IPTQJUBMJ[BUJPO GPS TFWFSF EFSNBUJUJT t 5IFSF XFSF :&370: USFBUFE QBUJFOUT XJUI NPEFSBUF (SBEF EFSNBUJUJT t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG EFSNBUJUJT TVDI BT SBTI BOE QSVSJUVT 6OMFTT BO BMUFSOBUF FUJPMPHZ IBT CFFO JEFOUJm FE TJHOT PS TZNQUPNT PG EFSNBUJUJT TIPVME CF DPOTJEFSFE JNNVOF NFEJBUFE Immune-mediated Neuropathies: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT DBTF PG GBUBM (VJMMBJO #BSSÏ TZOESPNF BOE DBTF PG TFWFSF (SBEF QFSJQIFSBM NPUPS OFVSPQBUIZ XFSF SFQPSUFE t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN PG :&370: NZBTUIFOJB HSBWJT BOE BEEJUJPOBM DBTFT PG (VJMMBJO #BSSÏ TZOESPNF IBWF CFFO SFQPSUFE t .POJUPS GPS TZNQUPNT PG NPUPS PS TFOTPSZ OFVSPQBUIZ TVDI BT VOJMBUFSBM PS CJMBUFSBM XFBLOFTT TFOTPSZ BMUFSBUJPOT PS QBSFTUIFTJB

Immune-mediated Endocrinopathies: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF UP MJGF UISFBUFOJOH JNNVOF NFEJBUFE FOEPDSJOPQBUIJFT SFRVJSJOH IPTQJUBMJ[BUJPO VSHFOU NFEJDBM JOUFSWFOUJPO PS JOUFSGFSJOH XJUI BDUJWJUJFT PG EBJMZ MJWJOH (SBEF PDDVSSFE JO o "MM QBUJFOUT IBE IZQPQJUVJUBSJTN BOE TPNF IBE BEEJUJPOBM DPODPNJUBOU FOEPDSJOPQBUIJFT TVDI BT BESFOBM JOTVGm DJFODZ IZQPHPOBEJTN BOE IZQPUIZSPJEJTN o PG UIF QBUJFOUT XFSF IPTQJUBMJ[FE GPS TFWFSF FOEPDSJOPQBUIJFT t .PEFSBUF FOEPDSJOPQBUIZ SFRVJSJOH IPSNPOF SFQMBDFNFOU PS NFEJDBM JOUFSWFOUJPO (SBEF PDDVSSFE JO :&370: USFBUFE QBUJFOUT BOE DPOTJTUFE PG IZQPUIZSPJEJTN BESFOBM JOTVGm DJFODZ IZQPQJUVJUBSJTN BOE DBTF FBDI PG IZQFSUIZSPJEJTN BOE $VTIJOH T TZOESPNF t .FEJBO UJNF UP POTFU PG NPEFSBUF UP TFWFSF JNNVOF NFEJBUFE FOEPDSJOPQBUIZ XBT XFFLT BOE SBOHFE VQ UP XFFLT BGUFS UIF JOJUJBUJPO PG :&370: t .POJUPS QBUJFOUT GPS DMJOJDBM TJHOT BOE TZNQUPNT PG IZQPQIZTJUJT BESFOBM JOTVGm DJFODZ JODMVEJOH BESFOBM DSJTJT BOE IZQFS PS IZQPUIZSPJEJTN o 1BUJFOUT NBZ QSFTFOU XJUI GBUJHVF IFBEBDIF NFOUBM TUBUVT DIBOHFT BCEPNJOBM QBJO VOVTVBM CPXFM IBCJUT BOE IZQPUFOTJPO PS OPOTQFDJm D TZNQUPNT XIJDI NBZ SFTFNCMF PUIFS DBVTFT TVDI BT CSBJO NFUBTUBTJT PS VOEFSMZJOH EJTFBTF o 6OMFTT BO BMUFSOBUF FUJPMPHZ IBT CFFO JEFOUJm FE TJHOT PS TZNQUPNT PG FOEPDSJOPQBUIJFT TIPVME CF DPOTJEFSFE JNNVOF NFEJBUFE o .POJUPS UIZSPJE GVODUJPO UFTUT BOE DMJOJDBM DIFNJTUSJFT BU UIF TUBSU PG USFBUNFOU CFGPSF FBDI EPTF BOE BT DMJOJDBMMZ JOEJDBUFE CBTFE PO TZNQUPNT o *O B MJNJUFE OVNCFS PG QBUJFOUT IZQPQIZTJUJT XBT EJBHOPTFE CZ JNBHJOH TUVEJFT UISPVHI FOMBSHFNFOU PG UIF QJUVJUBSZ HMBOE Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT DMJOJDBMMZ TJHOJm DBOU JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT TFFO JO XFSF OFQISJUJT QOFVNPOJUJT NFOJOHJUJT QFSJDBSEJUJT VWFJUJT JSJUJT BOE IFNPMZUJD BOFNJB t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN GPS :&370: JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT BMTP SFQPSUFE XJUI JODJEFODF XFSF NZPDBSEJUJT BOHJPQBUIZ UFNQPSBM BSUFSJUJT WBTDVMJUJT QPMZNZBMHJB SIFVNBUJDB DPOKVODUJWJUJT CMFQIBSJUJT FQJTDMFSJUJT TDMFSJUJT MFVLPDZUPDMBTUJD WBTDVMJUJT FSZUIFNB NVMUJGPSNF QTPSJBTJT QBODSFBUJUJT BSUISJUJT BOE BVUPJNNVOF UIZSPJEJUJT Pregnancy & Nursing: t :&370: JT DMBTTJm FE BT QSFHOBODZ DBUFHPSZ $ 5IFSF BSF OP BEFRVBUF BOE XFMM DPOUSPMMFE TUVEJFT PG :&370: JO QSFHOBOU XPNFO 6TF :&370: EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFm U KVTUJm FT UIF QPUFOUJBM SJTL UP UIF GFUVT t )VNBO *H( JT LOPXO UP DSPTT UIF QMBDFOUBM CBSSJFS BOE :&370: JT BO *H( UIFSFGPSF :&370: IBT UIF QPUFOUJBM UP CF USBOTNJUUFE GSPN UIF NPUIFS UP UIF EFWFMPQJOH GFUVT t *U JT OPU LOPXO XIFUIFS :&370: JT TFDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF TFDSFUFE JO IVNBO NJML BOE CFDBVTF PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF SFBDUJPOT JO OVSTJOH JOGBOUT GSPN :&370: B EFDJTJPO TIPVME CF NBEF XIFUIFS UP EJTDPOUJOVF OVSTJOH PS UP EJTDPOUJOVF :&370: Common Adverse Reactions: t 5IF NPTU DPNNPO BEWFSTF SFBDUJPOT ö JO QBUJFOUT XIP SFDFJWFE :&370: BU NH LH XFSF GBUJHVF EJBSSIFB QSVSJUVT SBTI BOE DPMJUJT

1MFBTF TFF CSJFG TVNNBSZ PG GVMM 1SFTDSJCJOH *OGPSNBUJPO JODMVEJOH Boxed WARNING regarding immune-mediated adverse reactions PO UIF GPMMPXJOH TQSFBE

ª #SJTUPM .ZFST 4RVJCC 64 "# 1SJOUFE JO 64" :&370: JT B USBEFNBSL PG #SJTUPM .ZFST 4RVJCC

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NCCN HEMATOLOGY CONGRESS

Progress in Molecular Markers that Predict Prognosis in AML By Phoebe Starr New York, NYâ&#x20AC;&#x201D;The era of personalized medicine is progressing. At the Fred Hutchinson Cancer Center, Seattle, WA, and at other centers, patients with intermediate-risk acute

myeloid leukemia (AML) are now being tested for 3 molecular markers that predict prognosis. The goal is to use these markers for treatment selection and for monitoring response.

As people age, they accumulate more cytogenetic markers of poor prognosis, said Jerald Radich, MD, Fred Hutchinson Cancer Center, who spoke at the National Comprehensive

YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3â&#x20AC;&#x201C;5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-BarrĂŠ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrĂŠ syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrĂŠ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3â&#x20AC;&#x201C;4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â&#x20AC;&#x201C;5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Immune-mediated Dermatitis

Cancer Network 6th Congress on Hematologic Malignancies. The 3 genetic mutations are FLT3ITD, NPM1, and CEPBA. The FLT3ITD mutation predicts poor prognosis,

VALUE-BASED CANCER CARE

October 2011

The following adverse reactions are discussed in greater detail in other sections of the labeling.

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

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NCCN HEMATOLOGY CONGRESS

whereas NPM1 and CEPBA mutations predict good prognosis. The presence of NPM1 trumps FLT3-I, meaning that NPM1 still predicts good prognosis despite the presence of FLT3-I. The presence of all 3 mutations also pre-

dicts improved outcomes. These markers are used in addition to conventional risk factors for AML, which include age, clinical status, and cytogenetics (recurrent abnormal chromosomal aberrations).

Based on cytogenetics, a patientâ&#x20AC;&#x2122;s prognosis is classified as favorable, intermediate, or poor. Approximately 40% of patients with AML have a normal cytogenetic profile and are considered to have

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â&#x20AC;&#x201C;5 events. Table 1:

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:

DRUG INTERACTIONS

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Percentage (%) of Patientsa

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE

PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

NO. 6

An important area of research is the use of cytogenetics and molecular testing for risk stratification, but funding for this research seems to be drying up.

There is no information on overdosage with YERVOY.

Including fatal outcome. Including intestinal perforation. c Underlying etiology not established.

VOL. 2

intermediate risk, but molecular markers (such as FLT3-ITD, NPM1, and CEPBA) identified by gene mutational studies can further refine risk stratification for disease progression within people with a normal cytogenetic profile. Approximately 84% of patients with intermediate risk and normal karyotypes will have mutations: of these, approximately 50% will have NPM1, 31% will have FLT3-ITD, and 14% will have CEPBA mutations, which can overlap in the same patient. Patients with NPM1 mutations have a better clinical course, and those with both NPM1 and FLT3-ITD mutations fare the best. â&#x20AC;&#x153;They are driven from intermediate risk to favorable risk,â&#x20AC;? Dr Radich commented.

Safety and effectiveness of YERVOY have not been established in pediatric patients.

â&#x20AC;&#x201D;Jerald Radich, MD

Pediatric Use

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

â&#x20AC;&#x153;The best technique for quantifying [minimum residual disease] is flow cytometry, because it is exquisitely sensitive to phenotype.â&#x20AC;?

1281558A2

IP-B0001A-03-11

Issued: March 2011

It is important to quantify the amount of FLT3-ITD that is present in a patient with AML: the greater the amount, the greater the risk for poor prognosis, Dr Radich said. Although a patient may have complete remission on induction/consolidation therapy, detecting the presence of minimal residual disease (MRD) predicts relapse. MRD is used before and after transplant to predict outcomes. Dr Radich cautioned that early identification of MRD does not improve outcomes. â&#x20AC;&#x153;The best technique for quantifying MRD is flow cytometry, because it is exquisitely sensitive to phenotype,â&#x20AC;? Dr Radich noted. An important area of research is the use of cytogenetics and molecular testing for risk stratification of enrollees in clinical trials, but funding for this research seems to be drying up, Dr Radich commented. â&#x2013;

www.ValueBasedCancerCare.com

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ONCOLOGY BEST PRACTICES

The First NCQA-Recognized Medical Home... Committee for Quality Assurance (NCQA) as a Level 3 PCMH. We obtained that recognition in April 2010 after several years of preparations. In 2005, we began to restructure our processes of care. The idea of applying for the NCQA-PCMH recognition evolved in late 2009, after realizing that our reengineered processes met the majority of the criteria for Level 3 recognition. The NCQA is now trying to determine the recognition process for other subspecialty practices, possibly developing criteria for medical home neighbor recognition. They will likely open up that process to other practices within the next 18 to 24 months. For a practice to be recognized as a medical home, it must currently meet 13 essential NCQA standards of patient-centric care, which our practice has surpassed. When we applied there were only 9 criteria, and the additional 4 are extensions of some of those 9. Although other cancer programs and practices are now using the term “medical home,” they have not yet attained an officially recognized medical home status. They are working toward that goal, in terms of disease management and utilization outcomes, to meet the criteria for an oncology PCMH designation.

Q: What was the impetus for launching your oncology medical home? Dr Sprandio: I founded our practice 23 years ago; we now have 9 physicians and more than 6000 active patients. We are in a very competitive environment in the Philadelphia suburbs. Our culture and belief have been, from the outset, to provide the best care and the highest level of service possible. To do that, we believe it is necessary to measure our performance on a consistent basis, to gain objective data, and to fix what needs fixing. This constant cycle of process improvement is also an NCQA requirement for a medical home. We developed this oncology medical home model because it was the right thing to do for patients: we also thought it would give us an advantage in a competitive marketplace. The article I published last Decem ber (Sprandio JD. Community Oncol. 2010;7:565-572) has helped to spread the word that this model may have real value. There is a growing understanding about the value of this model for oncology. Community oncology practice, as well as health systems that employ oncologists, are interested in differentiating themselves in their

market by potentially following our example and using our toolkit; they are engaging us to help them transform their practices to an oncology medical home. We have a Medicaid HMO contract that has been working

Continued from cover

visit or hospitalization. It also involves educating patients about selfmanagement of common symptoms, and helping them to coordinate care beyond the medical oncology office through patient navigators.

We have reduced emergency department utilization by 65% for patients receiving chemotherapy and hospitalizations by 43%. The annual cost-savings to our payers is between $6.5 million and $10 million from our practice alone, and in excess of $9500 to $12,000 per patient receiving chemotherapy. —John D. Sprandio, MD (jsprandio@cmoh.org) very well for about 1 year and are currently in negotiations with our larger payers.

Q: What are some of the characteristics of the medical home in oncology? Dr Sprandio: Studies have shown that the medical home is a wonderful model to enhance primary care delivery. It coordinates and reduces the fragmentation that plagues medical care today. And when this model is applied to an older, or more vulnerable, patient population with comorbidities, the potential benefits are multiplied. In cancer care, for example, because care is so expensive and the patient population is very vulnerable, better coordination in care delivery can lead to positive outcomes and fewer hospitalizations. The medical home was initially proposed by pediatricians in 1967 for children with severe, chronic medical conditions requiring ongoing, complicated care. Applying this model to cancer care is right in step with their original intentions. The oncology medical home model requires a standardized mechanism for providing enhanced patient communication and physician coordination of care; increasing patient access to care; monitoring preventive screening; having a standardized way of evaluating patients in the office; and a reproducible, reliable method of data collection and presentation to the physicians. It is all about increased care coordination, whole-person orientation, always measuring potentially avoidable complications, and addressing symptoms early—before they become major issues that can result in an emergency department

VALUE-BASED CANCER CARE

October 2011

Q: How do you address symptoms earlier than in other care models? Dr Sprandio: It begins at the time of the patient’s orientation to the practice. Our model truly engages our patients and their families. Patients are educated from the beginning about their responsibility to report symptoms. They are also given access to a telephone triage service that is very popular and well executed. We have about 30 different symptom algorithms that our nurses follow. When patients call into our office about a symptom, they are immediately connected to a nurse. She accesses all of their data and can quickly assess the situation and provide standardized recommendations. We track the result of every clinical call that comes to our practice. Last year we had 3900 symptom-related calls from patients. Of these calls, 76% of cases were managed over the phone, 4.2% were sent to the emergency department, about 5.5% were brought into the office that day, and another 4.5% were told to come in the next morning. We focus on early symptoms of potential complications, and our patients are indoctrinated to call early in the day. Our common phrase is, “If you wake up at 8 AM and you think you may have a problem, call us at 8:15 AM, not 4:15 PM.” Patients are also told that if they call and utilize our service, they will avoid wasting 8 hours in an emergency department and potentially having unnecessary testing or being admitted inappropriately.

Q: Do patients actually call the office with early symptoms? Dr Sprandio: The more we engage patients in this model, the more calls

we have received. For example, 5 years ago we only had 1200 or 1300 calls; last year we received 3900 calls. Our patients love it and never hesitate to call. They know they will have a live person on the phone who is a welltrained oncology nurse, with access to their complete data. Because their complete records are available in front of the nurse taking the call, patients know there will not be unnecessary questions. We engage them and give them access to prompt, accurate service that is painless and efficient.

Q: What role did electronic medical records play in your ability to establish the medical home? Dr Sprandio: An oncology-specific electronic medical record (EMR) system is essential for ordering of drugs and other tasks. Most of the EMR systems have not been developed to enhance information sharing. We installed our EMR system in 2004, and quickly learned that it had major deficiencies. We ended up developing a software overlay to add data from the oncology-specific EMR, and this has enabled us to standardize our communication processes. For example, 2 years ago the turnaround time for a document to be completed and sent

at a glance ➤ To be recognized as a medical home, a practice must meet 13 essential NCQA standards of patient-centric care ➤ Oncology medical home is all about increased care coordination, whole-person orientation, measuring avoidable complications, and addressing symptoms early. It also involves educating patients about selfmanagement of common symptoms and patient navigators ➤ Because cancer care is so expensive and the patient population is very vulnerable, better coordination in care delivery can lead to positive outcomes and fewer hospitalizations ➤ Our total annual office visits per chemotherapy patient has decreased by 12% in the past 2 years. Patients have fewer visits, less inconvenience, and fewer copayments

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ONCOLOGY BEST PRACTICES from our office after a visit was 28 days; the turnaround time now is <1 day. We can communicate within 1 day, or even within an afternoon, with other physicians who may be dealing with a very complicated patient. Our ability to communicate and coordinate care has increased exponentially, which is crucial when dealing with patients who are this ill. We have contacted many of the larger technology providers, but they are preoccupied with the HITECH Act’s meaningful use requirements and cannot address our needs right now. We did not create shortcuts for our physicians to complete their documentation; we created efficiencies: before we see a patient, all the data we could possibly need for that visit are available to us in a formatted way that we are used to, and that we utilize consistently. I saw 32 patients today: all my correspondence and documentation is not only done by now (4 PM), but it has already been sent to all the referring doctors for those 32 patients. In the past I would not be finished with that until late at night, the following day, or on the weekend. We have eliminated our transcription costs, streamlined the number of employees we have, and changed the job description for a lot of employees.

➤ We reduced unnecessary resource utilization by screening patients more carefully and by providing better care. Our survival rates are as good, or better than, those of a National Cancer Institute–designated Comprehensive Cancer Center ➤ The annual savings to our payers is between $6.5 million and $10 million from our practice alone, and in excess of $9500 to $12,000 per patient receiving chemotherapy ➤ Our chemotherapy-related emergency department utilization has been reduced by 65% and hospitalizations by 43%; however, this reduced utilization also means reduced revenue: this model has unique implications regarding reimbursement ➤ Our model should only be attempted by oncology practices that can find payers who will agree to develop a reimbursement contract that will pay them for managing patients more efficiently

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Q: How do you perceive the value of the medical home? Dr Sprandio: Value is in the eye of the beholder. Patients see very organized, comprehensive, and consistent care coming from our practice. They love to have access, the patient-centered service, and they love the information they receive. We also have a patient portal, where they can pull up their progress notes. Regarding the cost value of this model, if patients have fewer office visits, they also have fewer copayments. We have generated data that demonstrate that our total number of office visits per chemotherapy patient per year has decreased by 12% over the past 2 years. Patients have fewer visits, less inconvenience, and fewer copayments. Payers see value in that we have reduced emergency department utilization by 65% since 2005 for patients receiving chemotherapy, and reduced hospitalizations for chemotherapy by 43% since 2007. The conservative estimate for the collective annual cost-savings to our payers is between $6.5 million and $10 million from our practice alone, and in excess of $9500 to $12,000 per patient receiving chemotherapy.

ment. Our survival data are as good, or better, than those of a National Cancer Institute–designated Comprehensive Cancer Center.

Q: Are there reimbursement issues unique to the oncology medical home? Dr Sprandio: Yes, and this is rather interesting. After standardizing and streamlining many processes, we became very efficient and our full-time equivalent employee-to-physician ratio decreased from 8.4 to 5.5, which saved a fair amount of money. That was great until about 18 months ago, when we noticed significant reductions in revenue as a result of fewer hospitalizations and outpatient visits. We also realized reductions in chemotherapy revenue because of more consistent, open, and honest discussions regarding end-of-life care. So this model creates an interesting dilemma for oncologists. Our model should only be attempted by other oncology practices that can find payers who will be working with them to develop a reimbursement contract that will pay them for managing patients more efficiently. We have such a contract with a Phila-

Our employee-to-physician ratio decreased from 8.4 to 5.5, which saved a fair amount of money. But then we noticed significant reductions in revenue as a result of fewer hospitalizations and outpatient visits. We also realized reductions in chemotherapy revenue because of more honest discussions regarding end-of-life care. So this model creates an interesting dilemma for oncologists. There is no doubt that following chemotherapy pathways can save payers money. However, an international consulting firm interviewed us to assess the potential value of applying the medical home model to cancer care. They found that the savings from the pathways program is a finite number between 1% and 3% of the total cost of cancer care. They found that, by applying all of the medical home principles to cancer care, an additional 7% to 10% savings could be realized. This was using more conservative utilization targets than we had already achieved. We are not restricting care to save money; we are eliminating unnecessary resource utilization by screening patients more carefully and by providing better care. This saves money. Some people have asked about our clinical outcomes, because our patients spend less time in our offices, in the hospital, and in the emergency depart-

delphia-area Medicaid HMO, and we are now working with a large national payer on a broader contract platform. There is no incentive for a practice to do what we have done as long as they are paid on a fee-for-service basis. They will get penalized for doing things more efficiently. It has not been easy to convince payers about the value of this model in oncology, because they all have various issues regarding their information systems and their data analytics. This model raises unique reimbursement issues. Everyone is very focused on the cost of drugs. The cost of chemotherapy drugs is only 26% of the total cost of cancer care. We are willing to focus on that cost, but we are also focusing more intently on the other 74% of cancer care costs, by keeping people out of the hospital and the emergency department, by keeping them healthier. Gradually, payers are beginning to respond to us positively. The interest is

NCQA’s 9 Key Requirements for a Medical Home The following standards must be met to attain Level 3 medical home recognition: • Enhanced patient access to care and greater communication • A patient tracking and registry system with preventive screenings reminders • Patient management and adherence based on nationally accepted, evidence-based treatment standards • Strategies that ensure patient self-management and support for avoiding potential of treatment- and disease-related complications • E-prescribing and physicians’ ordering system • Tracking of referrals • Tracking of tests and patient compliance monitoring • Continually reporting and improving performance • An advanced electronic communications system that includes a portal for patients and referring physicians

clearly growing from different health plans and from Medicare. The Community Oncology Alliance’s Oncology Patient-Centered Medical Home (OPCMH) demonstration project proposal submitted to the Center for Medicare and Medicaid Innovation is based on our practice’s experience.

Q: Do you offer help to practices interested in your model? Dr Sprandio: We have developed a toolkit that is now available to other practices, and we have utilized this toolkit to successfully initiate this practice transformation in a similarsized oncology practice in downtown Philadelphia. We are showing that it is reproducible. In addition to the toolkit, we offer an OPCMH practice readiness assessment and gap analysis, and provide software and support tools to aid in the transformation. Through Oncology Management Services, we provide consulting services for health systems, payers, and practices working together, or payers alone. This is a step-by-step process that is like trying to feel your way through the dark. It will be a lot easier when this model is embraced by payers, and when we have a standardized contract with a national payer, which we expect to have in the next 6 months. ■

www.ValueBasedCancerCare.com

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HEALTH POLICY

US Preventive Services Task Force and the Future of Prostate Cancer Screening Ross D. Margulies, JD, MPH (Cand), and Jayson Slotnik, JD, MPH Mr Margulies is a Health Policy Specialist, Foley Hoag, LLP, Washington, DC; Mr Slotnik is a Partner at Health Policy Strategies, LLC, Washington, DC

he decision this month (October 2011) by the US Preventive Services Task Force (USPSTF) to recommend against a prostate-specific antigen (PSA)-based screening for prostate cancer in healthy men1 has caused quite a stir both in and outside of medical circles, reminding many people of the task force’s 2009 recommendation against routine breast cancer screenings for women under age 50 years. The task force’s “D” rating for the PSA test, which signifies that “there is moderate or high certainty that the service has no benefit or that the harms outweigh the benefits,”1 has no immediate effect on access to or coverage for the PSA screening test. Medicare, the single largest payer of healthcare costs in the country, for example, currently pays for 44% of preventive services receiving a D rating by the task force, including prostate cancer screenings for men aged ≥75 years.2 Moreover, in the Affordable Care Act, Congress overrode the task force’s under-age-50 mammography recommendation, in a legislation that was in a large part in response to the public backlash.3 Nevertheless, it would be shortsighted to assume that the task force’s recommendation carries no weight. What does the new rating ultimately mean for patient access? In this age of fiscal stress, will federal and private payers opt to cut a service that is esti-

With a D rating, plans may very well drop coverage for the screening procedure. Moreover, if Medicare does ultimately eliminate coverage for the PSA test, private payers will likely follow suit.

mated to cost $3 billion annually? Preventive services were excluded from Medicare coverage when it was created in 1965, and over the years, Congress has amended the Social Security Act to add individual preventive services. Private payers have historically followed Medicare’s lead in developing their coverage policies, and therefore, any major changes to Medicare coverage of products or services often has an industry-wide impact. In the Balanced Budget Act of 1997, for example, Congress mandated coverage for a number of preventive services, including “prostate screening

tests.”4 Private payers were quick to follow suit, if they were not already covering the service. With the passage of the Medicare Improvements for Patients and Providers Act in 2008, Congress empowered the Department of Health and Human Services to add preventive services to Medicare without congressional action.5 The law permits the Secretary of Health and Human Services to authorize Medicare coverage for services rated A or B by the USPSTF. In enacting the Affordable Care Act in 2010, Congress extended the reach of the task force to private health plans by requiring group health plans to cover items receiving an A or B rating from the task force. As noted, the task force’s recommendation has no immediate impact on coverage for and access to the PSA test. Ultimately, however, both federal and private payers may eliminate coverage for the test. For example, the Affordable Care Act requires that group health plans cover only services rated A and B by the task force. With a D rating, plans may very well drop coverage for the screening procedure. Moreover, if Medicare does ultimately eliminate coverage for the PSA test, private payers will likely follow suit. Critics of such a prediction argue that legislation requires Medicare to pay for the PSA test, and therefore, the

task force’s recommendation carries no weight in coverage for the test.6 Nevertheless, it is possible that Congress, facing increasing budgetary pressure, could amend the language to take into account the task force’s finding. Indeed, Congress predicted changes in coverage for prostate cancer screening tests in the statute, granting the Health and Human Services Secretary authority to cover other procedures taking into account “effectiveness” and “costs.”7 What will ultimately happen to the coverage of the PSA test remains to be seen. The draft Recommendation Statement is available for comment from October 11, 2011, until November 8, 2011, at www.uspreventiveservices taskforce.org/draftrec3.htm. ■ References

1. Chou R, Croswell JM, Dana T, et al. Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force. AHRQ Publication No. 12-05160-EF-3. www.uspreventiveservicestaskforce.org/uspstf12/prostate/pr ostateart.htm. Published October 2011. Accessed October 10, 2011. 2. Lesser LI, Krist AH, Kamerow DB, Bazemore AW. Comparison between US Preventive Services Task Force recommendations and Medicare coverage. Ann Fam Med. 2011;9: 44-49. 3. Patient Protection and Affordable Care Act §2713(a)(5), Pub L No. 111-148, 124 Stat 132 (2010). www.gpo.gov/fdsys/pkg/ PLAW-111publ148/pdf/PLAW-111publ148.pdf. Accessed Oct ober 10, 2011. 4. Balanced Budget Act of 1997 §4103, Pub L No. 105-33, 111 Stat 361 (1997). www.gpo.gov/fdsys/pkg/PLAW-105publ33/pdf/ PLAW-105publ33.pdf. Accessed October 10, 2011. 5. Medicare Improvements for Patients and Providers Act of 2008, Pub L No. 110-275 (2008). www.gpo.gov/fdsys/pkg/ PLAW-110publ275/pdf/PLAW-110 publ275.pdf. Accessed October 10, 2011. 6. Social Security Act §1861(s)(2)(P). www.ssa.gov/OP_Home/ ssact/title18/1861.htm. Accessed October 10, 2011. 7. Social Security Act §1861(oo). www.ssa.gov/OP_Home/ ssact/title18/1861.htm. Accessed October 10, 2011.

AACR Urges Congress to Increase Funding for the NIH and NCI

n September 2011, the American Association of Cancer Research (AACR) issued a new report, “AACR Cancer Progress Report 2011” (www.aacr.org/Uploads/Document Re pository/2011CPR/2011_AACR_CPR_ Text_web.pdf) on the current state of cancer research and the implications of recent cuts in funding for the National Institutes of Health (NIH) and the National Cancer Institute (NCI). These cuts in NIH and NCI funding are already adversely affecting the progress made in cancer research in the United States. The report highlights the many successes and advances made in cancer care since the National Cancer Act of

1971 was signed into law, but warns Congress that current trends in cutting funding for research could lead to serious consequences. “The declining NIH and NCI budgets are creating an environment where researchers face numerous disincentives to continue or even enter into re search careers in the first place,” say the authors of the report. “These disincentives are resulting in a loss of taxpayerfunded training and are adversely affecting the nation’s ability to maintain an optimal workforce for cancer research and to generate innovative scientific ideas for future implementation.” The report, which is signed by many cancer researchers and experts, states

VALUE-BASED CANCER CARE

October 2011

that since 2003, “appropriations for the NIH and NCI budget have remained essentially flat. Therefore, the NIH has lost about 13% of its purchasing power over the last 8 years due to inflation and the increasing costs of research and technology.” It is estimated that at least 50% of cancers in the United States are preventable, the report notes, which underscores the need for invigorated research to improve prevention strategies and mitigate many of the preventable causes of cancer, such as exposure to environmental carcinogens, radiation exposure, and infectious diseases. As a result of previous scientific research, “about 12 million cancer sur-

vivors are alive in the US today, and 15% of these cancer survivors were diagnosed more than 20 years ago.” To maintain that level of scientific successes in cancer, the AACR recommends that “Congress provide the NIH and NCI with annual budget increases of at least 5% above the biomedical inflation rate.” Indeed, such level “of sustained support will enable the future scientific advances needed to seize today’s scientific momentum…save countless lives, and spur innovation.” Some of the current 32 cancer drugs available in the United States have transformed cancer “from a death sentence into a chronic condition,” according to the report. ■

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Overall Survival Advantage Sustained at 3-Year Median Follow-up In Previously Untreated Multiple Myeloma (MM) VISTTA* OVER VISTA* OVERALL RALL SURVIV SURVIVAL VAL AL (OS) ANAL ANALYSIS: LY YSIS: VcMP† vs MP (36.7-month median follow-up)

MEDIAN OS NOT REACHED FOR VcMP

100 90

% PPatients atients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP ■ VE LCADE+MP (n=344) ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); PP=0.00084 =0.00084 =

0 0

Months Kaplan-Meier Kaplan-Meier estimate. estimate.

▼ ▼

▼

VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/18/11 12:23 PM Page 28

IN THE LITERATURE PARP Inhibitor Olaparib a Promising Treatment for Ovarian Cancer In phase 1 and 2 clinical trials, olaparib, a small-molecule poly(ADPribose) polymerase (PARP) inhibitor, has demonstrated objective responses in women with breast or ovarian can-

cer and BRCA1 and BRCA2 mutations. Results of a new study show that olaparib may be a promising therapy for women with aggressive ovarian cancer (Gelmon KA, et al. Lancet Oncol. 2011;12:852-861). In an open-label, nonrandomized phase 2 clinical study conducted in 6

centers in Canada, a total of 91 women (aged ≥18 years) with advanced highgrade serous and/or undifferentiated ovarian carcinoma (N = 65) or triplenegative breast cancer (N = 26) were enrolled and stratified according to BRCA mutation or lack of mutation; all of the patients received oral olaparib 400

Brief Summary INDICATIONS: 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. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. 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 www.VELCADE.com

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. V-11-0041 All rights reserved. Printed in USA

04/11

mg twice daily. The primary end point was the objective complete or partial response rate, based on the Response Evaluation Criteria in Solid Tumors. Objective responses were not reported for patients with breast cancer; of the 63 patients with ovarian cancer who were evaluable, objective responses were confirmed in 7 (41%) of the 17 women with BRCA mutations and in 11 (24%) of the 46 patients without a mutation. A total of 13 (20%) patients with ovarian cancer discontinued the study early for different reasons, including worsening disease, adverse events, and voluntary discontinuation. At study end, 13 patients with ovarian cancer and 26 of those with breast cancer were still receiving olaparib. The most common adverse events reported in both groups were fatigue, nausea, vomiting, and decreased appetite. Drug-related adverse events were reported in 88% of patients with ovarian cancer.

Nilotinib Sustains 24-Month Superiority to Imatinib in CML The BCR-ABL inhibitor nilotinib (Tasigna) was developed as a selective treatment for patients with chronic myeloid leukemia (CML) who are not responding appropriately to imatinib (Gleevec) therapy. Previous results from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study showed 12-month superior efficacy for nilotinib over imatinib in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) CML in the chronic phase. New results for additional 12-month follow-up show that patients treated with nilotinib sustained their molecular response for 24 months (Kantarijian HM, et al. Lancet Oncol. 2011;12:841-851). In this phase 3, multicenter, openlabel, randomized study, 847 adult patients with chronic-phase Ph+ CML were randomized to oral therapy with nilotinib 300 mg twice daily (N = 282), nilotinib 400 mg twice daily (N = 281), or imatinib 400 mg once daily (N = 283). The primary end point was major molecular response at 12 months. At 24 months, a major molecular response occurred in 71% of patients receiving nilotinib 300 mg twice daily, in 67% of patients receiving nilotinib 400 mg twice daily, and in only 44% of patients receiving imatinib 400 mg once daily (P <.001 for both comparisons vs imatinib). In addition, a complete molecular response occurred significantly more often in the 2 nilotinib groups (26% and 21%, respectively) Continued on page 32

VALUE-BASED CANCER CARE

October 2011

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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

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March 29-31, 2012 • JW Marriott • 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 • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • 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 Care™ 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 Credits™. 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.

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Registered Nurse Designation

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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_Oct_11_2_6_Follow ASCO Tabloid 10/18/11 12:25 PM Page 30

HEALTH POLICY

Recent Ruling on Genetic Patents Leaves Many Questions By Rosemary Frei, MSc

n July 29, 2011, a 3-judge panel from the US Court of Appeals for the Federal Circuit invalidated some patents held by Myriad Genetics and the University of Utah

Research Foundation for methods of analyzing individualsâ&#x20AC;&#x2122; gene sequences for the presence of BRCA1 and BRCA2 mutations, but upheld other related patents in a reversal of a lower court

ruling. The decision has left the door open to many questions. The court ruled that Myriadâ&#x20AC;&#x2122;s patents remain valid for the BRCA1 and BRCA2 sequences and for the

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companyâ&#x20AC;&#x2122;s methods of screening potential cancer therapies via changes in cell growth. However, experts suggest that this new ruling leaves the company open to new challenges, especially in light of the $3340 cost of the test that was developed more than a decade ago. Newer techniques for DNA sequencing are less costly and more efficient, but this decision gives the company time to upgrade its technology.

â&#x20AC;&#x153;There is clearly disagreement to be resolved about whether DNA sequences found in nature can be patented.â&#x20AC;? â&#x20AC;&#x201D;Robert Cook-Deegan, MD â&#x20AC;&#x153;Testing labs, or potential competitors, for deep-sequencing all 20-plus genes associated with breast or ovarian cancer, for example, might be able to do their analysis without much risk of infringement liability,â&#x20AC;? Robert CookDeegan, MD, Director of the Institute for Genome Sciences & Policyâ&#x20AC;&#x2122;s Center for Genome Ethics, Law & Policy, Duke University, Durham, NC, told ValueBased Cancer Care. Dr Cook-Deegan added that because 1 of the 3 judges sharply dissented from the other 2 on the patentability of DNA sequences, â&#x20AC;&#x153;that would leave Myriad only with claims on specific mutations and on PCR [polymerase chain reaction] primers. So, someone doing a PCR-based gene sequencing might infringe if reporting one of the patented mutations, but there may be some space for alternative methods.â&#x20AC;? The Controversy Continues Commenting on the decision, Peter Meldrum, President and Chief Executive Officer of Myriad Genetics, said, â&#x20AC;&#x153;We believe this decision is in the best interests of the agriculture, biotechnology, and pharmaceutical industries, as well as the hundreds of millions of people whose lives are bettered by the products these industries develop based on the promise of strong patent protection.â&#x20AC;? But groups that include the American Civil Liberties Union, the Public Patent Foundation, and other litigants are decrying the decision, which may well be appealed to the full Court of Appeals or to the US Supreme Court. â&#x20AC;&#x153;Such appeals are at the discretion of the courts, but this is a high-profile case, and there is clearly disagreement Continued on page 31

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HEALTH POLICY Continued from page 30

to be resolved about whether DNA sequences found in nature can be patented,â&#x20AC;? noted Dr Cook-Deegan. The dissenting judge said that patents on the BRCA1 and BRCA2 genes should be invalid. â&#x20AC;&#x153;Extracting a gene is akin to snapping a leaf from a tree,â&#x20AC;? Judge

William C. Bryson wrote. â&#x20AC;&#x153;Like a gene, a leaf has a natural starting and stopping point. It buds during spring from the same place that it breaks off and falls during autumn. Yet prematurely plucking the leaf would not turn it into a human-made invention.â&#x20AC;?

Daniel B. Ravicher, Executive Director of the Public Patents Foundation and counsel for plaintiffs in the lawsuit, said, â&#x20AC;&#x153;No one â&#x20AC;&#x2DC;inventsâ&#x20AC;&#x2122; genes. Inventions are things like new genetic tools or drugs, all of which can be patented because they are not genes themselves.â&#x20AC;?

The first 2 acts of this real-life oncology drama have taken place, the protagonists have made their positions clear, and now it remains to be seen whether the curtain will fall or the action will continue for the foreseeable future. â&#x2013;

Ask the HIT Expert

Noise-Canceling Information New discoveries in diagnosis, treatment, and prevention of cancer abound, but what is just â&#x20AC;&#x153;noiseâ&#x20AC;?? What is in oncology that is interesting, intriguing, inspiring, yet still just â&#x20AC;&#x153;noise,â&#x20AC;? because the path to action â&#x20AC;&#x153;here and nowâ&#x20AC;? is missing, or not obvious? If biology is a system of information,1 the practice of medicine is an evergrowing struggle of making sense of that information. With exponential growth in scope and diversity of raw information, processed knowledge, and predictive hypotheses, making the right decision and acting on it in oncology feels ever more elusive. And if leveraging information systems to provide the best-quality cancer care is not that easy,2 where does it leave us? Value-Based Cancer Care teamed up with Ron Ribitzky, MD, to facilitate a noise-canceling journey on this subject. The goal is to collaborate with you, the reader, to identify topics of interest and diversified points of view. This new column aims to respond to your queries in the pages of this journal and in an online forum. Submit your questions or suggestions for a topic of your interest at www. valuebasedcancercare.com/submit-noise.

ALOXI pr provides ovides powerful vention that prevention CINV pr evention canâ&#x20AC;&#x2122;tt be ignor ignored. canâ&#x20AC;&#x2122; ÂŽ

Help support your patientsâ&#x20AC;&#x2122; chemotherapy treatment goals s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 s Lasts long against nausea following moderately emetogenic chemotherapy s Powerful acute CINV prevention following highly emetogenic chemotherapy 4 s %ISAI OFFERS A VARIETY OF SUPPORT PROGRAMS AND RESOURCES

Indication ALOXIÂŽ (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

References

Important Safety Information

1. Maureen Cronin, PhD. Personalized Medicine World Conference. June 2010; Herzeliya, Isreal. 2. Cook G. Impact of EHRs on oncology practice: enhancing the value of cancer care. Value-Based Cancer Care. 2011;2(5):32-33.

!,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY ss ! ,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING ss OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Prescribing Please see the brief summary of the Full Pr escribing Information on the adjacent page. References: Gralla Van Vegt chemotherapy-induced moderately apy-induced nausea and vomiting following moder ately emetogenic an der V egt SS,, et al. PPalonosetron alonosetron improves prevention of chemother Refer ences: 1. Gr alla R, Lichinitser M, V chemotherapy: P, Figueroa-V Figueroa-Vadillo andomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, adillo JJ,, chemother apy: results of a double-blind rrandomized Zamoraa R, et al. Improved prevention of moder moderately chemotherapy-induced ately emetogenic chemother apy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results Zamor Cancer. 2003;98:2473-2482. 3. Data on file file.. Eisai Inc., W Woodcliff Lake, NJ.. 4. Aapro MS MS,, Grunberg SM, Manikhas GM, et al. A phase III, oodcliff Lak e, NJ of a phase III, single-dose trial versus dolasetron. Cancer chemotherapy-induced chemotherapy. apy-induced nausea and vomiting following highly emetogenic chemother apy. Ann Oncol. double-blind, randomized randomized trial of palonosetron compared with ondansetron in preventing chemother 2006;17:1441-1449.

Dr Ribitzky (www.linkedin.com/ in/ronribitzky) is a former clinician who converted to informatics, with more than 20 years of worldwide experience in the science and practice of information technology in healthcare and life-sciences informatics.

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STARTS STRONG. LASTS LONG.

ALOXIÂŽ IS A REGISTERED TRADEMARK OF (ELSINN (EALTHCARE 3! 3WITZERLAND USED UNDER LICENSE $ISTRIBUTED AND MARKETED BY %ISAI )NC ÂĽ %ISAI )NC !LL RIGHTS RESERVED 0RINTED IN 53! !,/ "

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IN THE LITERATURE Continued from page 28

than in the imatinib group (10%). Furthermore, BCR-ABL transcript levels were decreased below the threshold of 0.1% about 12 months earlier with nilotinib than with imatinib, and emerging BCR-ABL mutations in the nilotinib groups were 50% less

than in the imatinib group. Progression to accelerated or blastphase CML during treatment, including clonal evolution, occurred in 7 patients in the nilotinib groups and in 17 patients in the imatinib group. At 24 months, survival was comparable in all treatment groups, but CML-related death occurred less often with nilotinib (8 patients) than

with imatinib (10 patients). The only grade 3 or 4 adverse effects occurring more frequently with nilotinib were headache and rash. However, in the second 12-month follow-up study, 8 additional serious adverse events occurred—7 in the nilotinib group and 1 in the imatinib group. The investigators believe that as a

result of nilotinib’s faster, and more durable responses and significantly lower associated risk of progression, the drug should be considered a firstline therapy for CML in chronic phase.

Concurrent Chemotherapy and Radiation Therapy Extends Survival in NSCLC The concurrent use of chemotherapy and thoracic radiotherapy (TRT) confers a greater survival benefit in patients with stage III non–small-cell lung cancer (NSCLC) than a sequential use of these therapies, based on results from a phase 3 clinical study (Curran WJ, et al. J Natl Cancer Inst. 2011;103: 1452-1460). This study compared standard therapy (ie, chemotherapy followed by radiation) with 2 regimens of concurrent chemoradiation in 610 patients with inoperable stage II or III NSCLC enrolled from 153 centers in the United States and Canada. Patients were randomized to 1 of 3 treatment groups. Groups 1 (N = 203) and 2 (N = 204) received vincristine (Oncovin) administered once weekly for 5 weeks and cisplatin (Platinol) administered on days 1 and 29. Group 1 also received TRT once daily for 7 weeks, beginning on day 50, at the end of the vincristine/cisplatin regimen; group 2 received TRT once daily concurrently with the vincristine/cisplatin regimen for 7 weeks. Group 3 (N = 203) received 10 weeks of chemotherapy with cisplatin/etoposide (Toposar) concurrent with 6 weeks of TRT twice daily beginning on day 1. At a median follow-up of 11 years, the primary end point of 5-year overall survival was 16% in those receiving the concurrent regimen once daily (median survival, 17 months), 13% among those who received TRT twice daily concurrently (median survival, 15.6 months), and 10% among those who received TRT sequentially after chemotherapy (median survival, 14.6 months)—a significant difference favoring the oncedaily concurrent regimen. Patients receiving concurrent chemotherapy plus TRT once daily and twice daily had a higher rate of acute esophagitis (22% and 45%, respectively) than those receiving sequential therapy (4%), but the long-term rates (ranging from 1%-4%), along with the rates of other, late-occurring grade 3-5 toxic effects, did not differ significantly between any of the groups. The investigators acknowledge that unlike the patients included in their study, most patients with stage III NSCLC will have a poorer functional status and suffer from comorbid conditions that would limit their tolerability to adverse effects such as severe esophagitis. ■

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BREAST CANCER SYMPOSIUM

Novel HDAC Inhibitor Improves Outcomes in Patients with Estrogen-Sensitive Breast Cancer Entinostat plus exemestane combo doubles time to progression By Audrey Andrews San Francisco, CA—A novel histone deacetylase (HDAC) inhibitor, when added to the aromatase inhibitor exemestane (Aromasin), appears to restore sensitivity to the endocrine agent by significantly delaying recurrences and creating an increased survival trend. The findings come from the Enti nostat Combinations Overcoming Resistance (ENCORE 301) study presented at the 2011 Breast Cancer Symposium by Denise Yardley, MD, Sarah Cannon Research Institute and Tennessee Oncology, Nashville. “This combination may allow patients to remain on hormonal therapy longer, delaying the need for chemotherapy,” Dr Yardley suggested. ENCORE 301 was a phase 2 trial of exemestane with and without entinostat in postmenopausal women with estrogen receptor–positive advanced breast cancer that had progressed dur-

ing previous nonsteroidal aromatase inhibitor therapy. A total of 114 patients were randomized to exemestane plus placebo or weekly entinostat. The median progression-free survival (PFS) was 4.28 months with enti-

mestane alone—a 54% reduction in risk for mortality. “We saw a trend for an OS benefit. This is an exploratory end point with data that are still maturing,” Dr Yardley said. The regimen was well tolerated.

“This combination may allow patients to remain on hormonal therapy longer, delaying the need for chemotherapy. We saw a trend for an OS benefit. This is an exploratory end point with data that are still maturing.” —Denise Yardley, MD

nostat/exemestane versus 2.27 months with exemestane alone, a significant, 27% reduction in risk. At a median follow-up of 18 months, the median overall survival (OS) was 26.9 months with the combination versus 20.3 months with exe-

Pharmacodynamic Analysis Shows Strong Benefit in Subgroup In a biomarker analysis of a subgroup of 49 patients, those who demonstrated hyperacetylation (a chemical process) in blood samples derived the greatest benefit from the combination

therapy. The mechanism of action of HDAC inhibitors involves inducing hyperacetylation of lysines on histones and a number of other proteins. The risk of disease progression was reduced by 77% in this subgroup of patients: the median PFS was 8.54 months with the combination therapy versus 1.92 months with exemestane alone. “This suggests that entinostatinduced hyperacetylation tracked with improved outcomes and may be a potential marker of benefit,” Dr Yardley said. Joyce O’Shaughnessy, MD, Baylor Sammons Cancer Center, Dallas, TX, who moderated the symposium where these results were presented, called the use of entinostat in advanced hormonally sensitive breast cancer “very, very promising.” A phase 3 global study will begin enrolling patients in early 2012. ■

Breast Cancer Treatment Still Under Par for Patients Covered by Medicaid San Francisco, CA—Several studies presented at the 2011 Breast Cancer Symposium shed light on the quality of breast cancer care received by women who are uninsured or receiving Medicaid. In a study conducted at Rollins School of Public Health of Emory University, Atlanta, researchers investigated the quality of breast cancer treatment in patients enrolled under Medicaid and the Breast and Cervical Cancer Prevention and Treatment Act (BCCPTA) of 2000 in Georgia. The BCCPTA allows states to cover women diagnosed with breast or cervical cancer or those with precancerous cervical conditions under Med icaid at the time of diagnosis and while they receive treatment. Women must not be eligible for Medicaid under another mandatory covered group and must not have other health insurance. The study included 2048 Medicaid enrollees, of whom 1046 were covered under the BCCPTA, 674 were disabled, and 328 had “other” types of Medicaid eligibility. The researchers calculated the odds of receiving various types of treatment according to these various groups.

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After controlling for covariates, BCCPTA-covered women were more likely to receive any treatment (odds ratio [OR], 4.71), any drug regimen (OR, 3.58), any radiation therapy (OR, 1.61), or any definitive surgery (OR, 2.52) than other eligibility groups; disabled patients were more likely to receive recommended treatments than “other” patients.

and Management, Rollins School of Public Health. No significant differences were found in the use of a lumpectomy versus a mastectomy based on an eligibility group, but women covered under the BCCPTA were more likely to receive adjuvant treatment. “The BCCPTA program in Georgia appears to create a quicker pathway for

“The BCCPTA program in Georgia appears to create a quicker pathway for previously low-income uninsured women with breast cancer to access services and, in turn, receive more treatment than women enrolled in more traditional Medicaid eligibility groups.” —E. Kathleen Adams, PhD For example, treatment with “any drug” was given to 90% of patients covered under the BCCPTA and 83% of disabled patients versus 67% of “other” patients. Radiation therapy was administered to 61%, 50%, and 45% of patients, respectively, according to E. Kathleen Adams, PhD, Associate Professor of Health Policy

previously low-income uninsured women with breast cancer to access services and, in turn, receive more treatment than women enrolled in more traditional Medicaid eligibility groups,” Dr Adams said. “Yet the overall rate of adjuvant therapy, whether radiation or hormonal or chemotherapy, appears to fall short of national criteria.”

Worse Outcomes in Uninsured/ Medicaid Patients In a study from Michigan State University in Flint, 632 patients with breast cancer were analyzed according to race and insurance status. Patients with Medicaid or no insurance had a significantly lower overall survival rate at 5 years than patients with private insurance (P <.001) or who received Medicare disability benefits (P = .006). At 5 years, 76% of patients with private insurance and 75% of those with Medicare disability were alive compared with only 49% of those with Medicaid or no insurance, as reported by Mohammad Omaira, MD, a hematology/oncology fellow at Michigan State University, and colleagues. Although black patients were significantly more likely to present at an advanced stage of disease, this finding lost statistical significance after adjustment for insurance status. “Not all segments of the US population have experienced equal benefits from the major advances in early diagnosis and treatment of breast cancer,” the authors noted. —AA ■

www.ValueBasedCancerCare.com

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BREAST CANCER SYMPOSIUM

Targeted Radiation Therapy Gaining Momentum Decreased treatment time, lower dose to uninvolved tissue By Caroline Helwick San Francisco, CA—Accelerated partial breast irradiation using brachytherapy (APBIb) for breast cancer has been rapidly adopted in the United States, although its use varies by region, race, and ethnicity. Jona A. Hattangadi, MD, Harvard Radiation Oncology Program, Boston, reported the findings at the 2011 ASCO Breast Cancer Symposium, which was sponsored by 6 breast, oncology, and surgical societies. APBIb, a new alternative to whole breast irradiation (WBI), delivers radiation only to tissue within a few centimeters of the excision cavity (the area at highest risk for cancer recurrence). It has the advantage of decreased treatment time and lower radiation dose to uninvolved tissues. The concern is, however, that occult foci of cancer may exist elsewhere in the breast and are thus not well treated. The lack of long-term data and the possible expense of the approach are also of concern, Dr Hattangadi said. Dr Hattangadi and colleagues evaluated radiation therapy patterns in 138,815 patients with breast cancer using the Surveillance, Epidemiology and End Results (SEER) database. Patients received APBIb or WBI after lumpectomy from 2000 to 2007 and were classified as “suitable,” “cautionary,” or “unsuitable” for APBIb based on the 2009 guidelines of the

at a glance ➤ Accelerated partial breast irradiation using brachytherapy is gaining popularity as an alternative to whole breast irradiation ➤ This approach offers several advantages, including focused radiation to tissue within a few centimeters of the excision cavity only; decreased treatment time; and lower radiation dose to uninvolved tissues ➤ National guidelines indicate that patients with tumors >3 cm, extensive lymphovascular invasion, and no lymph node surgery are not suitable for this treatment, but data are lacking to show worse outcomes ➤ Although partial irradiation was initially more expensive than whole breast treatment, this trend has now reversed

American Society for Radiation Oncology. Unsuitable patients, according to these guidelines, are those with tumors >3 cm, extensive lymphovascular invasion, and no lymph node surgery. The current analysis showed a steadily rising trend for APBIb use; by 2007, 7% of the patients in the SEER database were treated with this approach overall. The use of APBIb rose steeply after 2002, when balloon brachytherapy received US Food and Drug Administration approval, and again in 2004, when Medicare began reimbursing for this treatment. The rise in use was seen across all 3 patient categories, with the steepest increase among suitable patients.

APBIb delivers radiation only to tissue within a few centimeters of the excision cavity and has the advantage of decreased treatment time and lower radiation dose to uninvolved tissues. Cost may become a concern. —Jona A. Hattangadi, MD

Disparities in APBIb Use Significant differences in the use of APBIb exist, the study shows. Non white patients are 20% to 50% less likely to receive APBIb than white patients, as are persons living outside of or adjacent to metropolitan areas versus those living in metropolitan areas. Patients aged ≥60 years are more likely to receive APBIb than younger patients. Geographical variation is common, with the highest rates of APBIb use in Atlanta, rural Georgia, Louisiana, Utah, and Kentucky. Patients in Atlanta were almost 13 times more likely to receive APBIb than patients in Hawaii and were 22 times more likely to receive APBIb if they fell into the unsuitable category. These same high-use regions had increased rates of APBIb use among unsuitable patients, Dr Hattangadi said, adding, “The odds ratio for use increased as the appropriateness of use decreased.” From 2006 to 2007, the use of APBIb increased 15-fold compared with the

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October 2011

Table

Cost of Whole Breast Irradiation versus Accelerated Partial Breast Irradiation Using Brachytherapy in a California Region

Health plan coverage

Cost of whole breast Cost of partial breast irradiation, 33 treatments brachytherapy, 10 in 33 days, $ treatments in 5 days, $

Medicare allowable, 2010

14,808

11,542

Medicare allowable, 2011

15,724

11,915

Blue Cross

11,436

9475

Source: Rakesh Patel, MD.

period between 2000 and 2002. Patients with larger tumor size and invasiveness, worse histologic grade, and positive lymph nodes were up to 50% less likely to receive APBIb. Oncologists’ Perspectives Robert Kuske, MD, Arizona Breast Cancer Specialists, Phoenix, AZ, who pioneered the brachytherapy approach years ago, commented on these findings to Value-Based Cancer Care, pointing out that the use of APBIb in unsuitable patients should not be considered out of line. “The APBIb movement started in Louisiana [where he practiced at the time] and is now being done all over the world. When I started it, and before guidelines were established, I wanted to be inclusive, not exclusive, in patient selection for my trials, to determine if APBIb was as good as,

“APBIb also has value when taking into account less time spent away from work and family, and the other parameters that go into complex decisionmaking.” —Rakesh Patel, MD

better than, or worse than WBI in aggressive cancers. Therefore, I included all different subtypes of the disease. I argued that dose-dense radiation, which you get with APBIb, might actually be more effective for the worst cancers. Some of my colleagues were skeptical and reserved it for the best of the best of cancers,” Dr Kuske said. “Since I am the only investigator who included the unfavorable subset,

and the guidelines were established based on the amount of evidence in patient groups, the unsuitable category is not based on negative data but on a paucity of data,” Dr Kuske said. Rakesh Patel, MD, Western Radiation Oncology, El Camino, CA, also commented on ths study. He agreed that the terms “suitable” and “unsuitable” are “difficult to interpret by patients and physicians,” adding that “it only takes 1 feature to ratchet patients” to a higher-risk category. “There are no data to suggest that cautionary or unsuitable patients do worse,” Dr Patel said. “We have to be careful when we look at the guidelines and interpret them as right or wrong. We have to look at the complexity of patients.” After a 6-year period of follow-up in the MammoSite registry trial, no differences in outcomes have emerged between the unsuitable and the suitable/cautionary guideline groups, said Dr Patel. “We should treat the patient, not the guidelines.” In doing so, it is possible to observe cost-savings. “This is not more expensive, although it used to be. Things have changed. In fact, it’s less expensive,” Dr Patel added, describing data from his practice area (Table). “APBIb also has value when taking into account less time spent away from work and family and the other parameters that go into complex decisionmaking,” he added. ■

Death rates for Hodgkin lymphoma, 1990-2006

Women:

Men:

0.5%

34.7%

▼

▼ 2011 estimates Incidence: 8830 Deaths: 1300

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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 ÂŠ2011 Genentech, Inc., So. San Francisco, CA HED0000596500 09/11

A Member of the Roche Group

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BREAST CANCER SYMPOSIUM

Occult Metastases Do Not Warrant Axillary Dissection in Breast Cancer Taken together, the 2 studies— NSABP B-32 and ACOSOG Z0011— suggest that aggressive approaches to surgically remove occult metastases are not necessary.

San Francisco, CA—The debate over the clinical significance of occult micrometastases in the lymph nodes of patients with breast cancer continues. NSABP B-32 Trial: No Effect on Overall Survival Investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial have reported very small but significant differences in outcomes for patients with occult metastases. However, in a follow-up analysis, they reported that survival is not improved if these patients undergo full lymph node dissection. Thomas B. Julian, MD, Allegheny General Hospital, Pittsburgh, PA, reported the study results at the 2011 Breast Cancer Symposium. Previous investigators found a 1.2% improvement in survival and a 2.8% improvement in disease-free survival (DFS) among patients lacking occult metastases; however, overall survival (OS) at 5 years was excellent in both groups: 94.6% with occult metastases and 95.8% without. “So our question was, if there is a difference according to the presence of occult metastases, did the addition of axillary dissection factor into this?” Dr Julian said. “We found no effect of treatment on OS and DFS.” In the subanalysis, nearly 16% of clinically node-negative patients were found to have occult metastases on

at a glance ➤ The clinical importance of occult metastases in breast cancer remains questionable ➤ Two new analyses found small but significant differences in outcomes, but these did not affect overall survival ➤ “The more you look, the more you find,” suggests one expert; occult metastases are not good predictors of outcome ➤ If additional treatment is given based exclusively on the presence of occult metastases, 90% of these patients would be overtreated, which would amount to $44.8 million ➤ Pathologists should continue to examine 2-mm sections, one from each block, without requiring levels or immunohistochemistry

more detailed assessment of the sentinel nodes. Among the 3986 patients with clinically and hematoxylin and eosin–negative sentinel nodes, occult metastases were identified in 616 patients: 316 in the axillary lymph node dissection (ALND) arm and 300 in the sentinel node dissection (SND) arm (for 51 per arm, occult metastases status remained unknown). The clinical outcomes of the patients were similar, whether they underwent SND or ALND, Dr Julian reported. “The clinical importance of immunohistochemistry-detected occult metastases is questionable,” he said. Among patients with occult nodal metastases, complete ALND did not significantly improve OS (hazard ratio [HR], 0.89; P = .62) or DFS (HR, 0.79; P = .16). The actual differences in outcomes were less than 3%. Similar Findings in ACOSOG Z0011 The results support previous findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study, which found no survival benefit from complete ALND compared with SND only. In Z0011, more extensive dissection revealed that 27% of patients had positive nodes beyond the sentinel nodes, said Armando E. Giuliano, MD, of Cedars-Sinai Medical

By Audrey Andrews

“About 27% of patients with SND-only had unresected cancer remaining in the axilla. We as surgeons affect survival by achieving local-regional control, and both approaches did that. There was no difference in survival.” —Armando E. Giuliano, MD

Center, Los Angeles, who was the principal investigator of Z0011. “About 27% of patients with SNDonly had unresected cancer remaining in the axilla,” he noted. “We as surgeons affect survival by achieving local-regional control, and both approaches did that. There was no difference in survival.”

Diminishing Returns, Increased Expense Donald L. Weaver, MD, University of Vermont College of Medicine, Burlington, who served as the NSABP B-32 protocol pathologist, agreed that the 2 studies have important implications; namely, they argue against intensively looking for small metastases that will not make a difference in outcome. “The more you look, the more you find,” Dr Weaver acknowledged, but this results in diminishing returns and additional work and is of questionable value to the patient, he suggested. “Occult metastases are not discriminatory predictors of outcome.” “If additional treatment was given based exclusively on the presence of occult metastases, 90% of these patients would be overtreated,” he said. Dr Weaver calculated that this amounts to $44.8 million in healthcare dollars spent annually to account for a 1.2% difference in outcome. His recommendation is that pathologists should continue to examine 2mm sections, one from each block, without requiring levels or immunohistochemistry. ■

Order of Initial Breast Cancer Treatment Does Not Affect Outcomes San Francisco, CA—Whether women receive chemotherapy or surgery first as their initial treatment for breast cancer does not affect long-term localregional recurrence, according to a large case series from the University of Texas M.D. Anderson Cancer Center, Houston, that was presented at the 2011 Breast Cancer Symposium.

“A woman can have chemotherapy or surgery first, and the choice will not affect her outcome.” —Elizabeth Ann Mittendorf, MD

“A woman can have chemotherapy or surgery first, and the choice will not affect her outcome,” said Elizabeth Ann Mittendorf, MD, a surgical oncologist at M.D. Anderson. “The

VALUE-BASED CANCER CARE

October 2011

molecular characteristics of the tumor and other factors have an impact on treatment success, but not the order in which chemotherapy and surgery is given.” Their retrospective evaluation included 2984 women treated between 1987 and 2005 with segmental mastectomy and whole breast irradiation, including 78% who underwent surgery before chemotherapy and 22% who had neoadjuvant chemotherapy then surgery. Dr Mittendorf reported that the rates of local-regional recurrence-free survival were excellent for both groups: at 5 years, 97% for the surgeryfirst group and 93% for the neoadjuvant chemotherapy group; at 10 years, 94% and 90%, respectively. Even in patients who had ≥1 adverse features, such as later disease stage and higher tumor grade or estrogen-receptor–negative status, no survival differences were observed.

Neoadjuvant chemotherapy resulted in downgrading of tumor stage in almost half the patients, and therefore made breast-conserving therapy (ie, lumpectomy) possible in these women. Lumpectomy was performed in 69% of patients with stage II breast cancer who underwent neoadjuvant chemotherapy compared with 19% who had surgery first, and in 24% and 1%, respectively, of stage III patients (P <.001). “Even women who present with clinical stage II or III disease may have good results with breast-conserving therapy after chemotherapy and not need a mastectomy,” Dr Mit tendorf said. Barbara Fowble, MD, of the University of California School of Medicine, San Francisco, the invited discussant of the abstract, said the study supports what has already been established by randomized controlled trials: the 2 approaches lead to comparable outcomes. —AA ■

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# $ '() $ $ ) + "* $ " $ " #& ) % %# '! ' ' ( ' $ %$ %"% . ( ' ) " $ %' ' )% ) + ". # $ $ & '(%$ " / ) )' )# $) % & ) $)( , ) $ ' " ( % $ *( )% " '$ #%' $ & ') & ) $ ) ( - ) $ ( *(( %$

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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. An international audience of approximately 250 oncologists/hematologists, pathologists, advanced practice nurses, research nurses, and clinical oncology pharmacists is expected.

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Who should attend All healthcare professionals who are involved in the management of patients with cancer are invited to join this exciting forum. Specifically, this conference is intended for: â&#x20AC;˘ Medical Oncologists and Hematologists â&#x20AC;˘ Pathologists â&#x20AC;˘ Geneticists â&#x20AC;˘ Advanced Practice Oncology Nurses â&#x20AC;˘ Research Nurses â&#x20AC;˘ Clinical Oncology Pharmacists â&#x20AC;˘ 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.

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VBCC_Oct_11_2_6_Follow ASCO Tabloid 10/18/11 12:35 PM Page 38

SURVIVORSHIP CARE

Survivorship Programs an Emerging Need, but Are They Cost-Effective? Patients feel abandoned at end of treatment By Caroline Helwick

he population of cancer survivors is rapidly growing. More than 12 million Americans are alive after a cancer diagnosis: most are living at least 5 years and 16% are alive 20 years after diagnosis. This growing population of cancer survivors is at risk for many comorbidities, especially as they age. A study of 10,397 childhood cancer survivors showed that group is 8 times more likely to have a severe or life-threatening condition than their siblings (Oeffinger K, et al. N Engl J Med. 2006; 355:1572-1582). Survivorship care, therefore, has become a topic of interest as oncologists aim to determine the best way to attend to patients’ long-term needs. One session at the recent annual meeting of the American Society of Clinical Oncology (ASCO) was devoted to survivorship care. “Patients report feeling abandoned at the end of their cancer treatment, and many complete treatment with persistent problems. Planning for recovery is important,” said Julia Rowland, PhD, of the National Cancer Institute. Personalized Care Dr Rowland cited several lessons learned recently about survivors and their need for personalized care: • The posttreatment survivorship phase brings its own set of unique needs and challenges—physical and medical, psychological, social, and existential/spiritual • Intervening early, when problems arise, leads to better outcomes • For many individuals, cancer provides “a teachable moment” • It’s not only healthcare providers who are concerned, but patients themselves are asking how they can reduce their risk of cancer recurrence and live healthier lives; it is important for healthcare providers to be prepared to answer their questions • The Institute of Medicine (IOM) has recommended that survivors receive a summary record that includes important disease characteristics and the treatments they received, and that they be provided with a follow-up care plan that incorporates evidence-based standards of care. ASCO has adopted this as a quality initiative, “but we have little information as to how this is being done and its impact in real practice,” Dr

Rowland said. What care should be provided and to whom? Who should provide this care, and where and when should it be given? What impact does this care-planning have on patient behavior, physician behavior, practice costs, payer investments, and patient health outcomes? All these questions remain to be answered, she noted.

“We have a long way to go before physicians are comfortable with the proposed shared-care model.” —Paul Han, MD Whose Job Is It? A much debated issue is determining which healthcare provider should be in charge of survivorship care: the oncologist or the patient’s primary care physician (PCP). Paul Han, MD, of Maine Medical Research Institute, in Scarborough, discussed the early findings of the Survey of Physician Attitudes Regarding the Care of Cancer Survivors (SPARCCS). One survey was administered to 1100 PCPs and a second one to 1100 oncologists, showing that the primary care model may not be preferred. “We wanted to examine the attitudes, knowledge, and practices of PCPs and oncologists regarding the care of cancer survivors,” Dr Han said. “We focused on breast and colon cancer survivors, and we looked at how physicians perceived their roles and responsibilities in the care of cancer survivors vis-à-vis one another.” PCPs rated their skills for caring for cancer survivors as low, and oncologists agreed. “These data could have implications, considering that many groups have argued that we should move toward a system of shared care between PCPs and oncologists, with PCPs demonstrating greater respon sibility for cancer survivor care,” Dr Han suggested. Neither PCPs nor oncologists selected a PCP-led model as the ideal model for survivorship care. In addition, although oncologists said they provide treatment summaries or care plans to PCPs most of the time, PCPs reported they rarely receive these. Oncologists also reported frequent communication with other physicians to clarify their respective roles in follow-up care, but

VALUE-BASED CANCER CARE

October 2011

PCPs reported that this communication occurred infrequently. Both specialties tended to overuse surveillance testing, especially PCPs. “We need to explore models where there is greater sharing of care with PCPs, yet these findings show that PCPs have very low confidence, and oncologists also rate PCPs’ skills and knowledge as very low. It suggests we have a long way to go before physicians are comfortable with the proposed shared-care model,” Dr Han said. Cost-Effectiveness Questioned Survivorship programs are wellmeaning, but do they really improve health outcomes and are they costeffective? A research team from Canada concluded that the survivorship care plan adopted by their center had no impact on patient outcomes or adherence to follow-up guidelines and was not a cost-effective use of “scarce health care resources.” In accordance with the IOM’s recommendation for providing cancer survivors with a formal survivorship care plan (SCP), the multicenter study assessed the effect of such a program and its cost-effectiveness.

“The SCP adopted was not cost-effective….Implementation of the SCP to all breast cancer patients would cost in excess of $1.3 million per year, with no evidence of improved health-related outcomes.” —Doug Coyle, PhD A randomized trial enrolled 408 patients with early-stage breast cancer who had completed treatment at a tertiary cancer center. In the intervention group, 200 patients received an SCP consisting of a treatment summary, a patient’s version of the follow-up guidelines, and brochures and information about local relevant supportive care resources. These were compiled into a binder and reviewed with the patient in a nurse-led 30-minute educational session. The family physicians received a copy of all documents plus the full guideline and a reminder table of recommended follow-up visits and tests.

The control group of 208 patients received a discharge visit and their physicians received a discharge letter, according to usual practice. The primary outcome was psychosocial adjustment 12 months after intervention. The secondary outcomes were continuity of care, health-related quality of life, patient satisfaction, and adherence to guidelines. A short-term study cannot adequately assess clinical outcomes, the investigators noted. Despite having received a formal SCP, the intervention group demonstrated no additional improvement in psychosocial adjustment or in any of the secondary outcomes studied, reported Eva Grunfeld, MD, of the University of Toronto. Costs included physician visits, diagnostic tests, patient travel costs, lost productivity, and cost of recurrence. In the SCP analysis, costs included the cost of developing and, where necessary, revising the plan, which included labor, administrative support, materials, and postage, totaling approximately $60 per patient. In the cost-effectiveness analysis, the base cost was $736.23 for the standard of care and $788.63 for the SCP. The analysis was performed from various perspectives, such as the healthcare system perspective, with inclusion and exclusion of lost productivity, and with exclusion and inclusion of recurrences. Standard care remained dominant over the SCP when costs and benefits were not discounted, when the analysis adopted the healthcare system perspective, when lost productivity was excluded, and when estimates of the costs were included, according to Doug Coyle, PhD, of the University of Ottawa, Canada. In the probabilistic analysis, the most likely finding was that standard care was more effective and less costly. For all threshold values of a qualityadjusted life-year <$100,000, the probability that the SCP was cost-effective was <30%. “The results of this study clearly suggest that the SCP adopted was not a cost-effective use of scarce healthcare resources,” Dr Coyle suggested. “Given the 22,500 new incident cases of breast cancer per year [in Canada], implementation of the SCP to all breast cancer patients would cost in excess of $1.3 million per year, with no evidence of improved health-related outcomes.” ■

VOL. 2

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

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